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Tenofovir Alafenamide in HBV Related Decompensated Liver

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ClinicalTrials.gov Identifier: NCT04683341
Recruitment Status : Recruiting
First Posted : December 24, 2020
Last Update Posted : December 24, 2020
Sponsor:
Information provided by (Responsible Party):
Kaohsiung Medical University Chung-Ho Memorial Hospital

Brief Summary:
TAF is a new prodrug of tenofovir, specifically designed to achieve higher intracellular active drug concentration allowing for dosing of only 25 mg once daily and thus can potentially lower the already relatively low risk of renal toxicity and bone loss with TDF. However, such renal and bone complications with TDF may become more pronounced in decompensated CHB patients10. In the phase 3 trials11, 12, TAF had demonstrated a compatible antiviral effect (noninferior efficacy), and a higher rate of alanine aminotransferase (ALT) normalization to TDF. TAF also demonstrated an improved renal function and less bone loss compared to TDF. Therefore, TAF was approved as the first line therapy for CHB patients with compensated liver function. The lack of data regarding TAF therapy in decompensated CHB patients raised the concern of safety and efficacy of TAF in this group of patients. A small, single arm Phase 2 switch study (GS-US-320-4035; Study 4035; NCT03180619) which has enrolled 31 subjects with CPT scores ≥7, either at time of screening or by history, who were virally suppressed on TDF and/or other oral antiviral agents is currently underway with favorable safety and efficacy results through 48 weeks.[Lim YS, Lin CY, Heo J, et al. EASL 2020, poster SAT442.] While Gilead Study 4035 will continue through 96 weeks of treatment, additional data in this population are thus needed, particularly in CHB patients who have decompensated liver disease and are not being treated and are viremic. Herein, we conduct the present study and aim to investigate the safety and efficacy of TAF in CHB patients with hepatic decompensation.

Condition or disease Intervention/treatment Phase
HBV Drug: Tenofovir Alafenamide Tablets Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Approximately 100 adults, cirrhotic or non-cirrhotic (capped at 50), CHB patients with hepatic decompensation, will receive initial treatment (Arm A) with or switch (Arm B) to TAF 25 mg/day for 144 weeks. For Initiation Arm, CHB patients with hepatic decompensation, who are currently not under HBV antiviral treatment will be enrolled. For Switch Arm, CHB patients who are currently with hepatic decompensation and virally suppressed under HBV NUC treatment (HBV DNA < 20 IU/mL) will be enrolled.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Safety and Efficacy of Tenofovir Alafenamide for Chronic Hepatitis B Patients With Decompensated Liver Disease
Actual Study Start Date : September 1, 2020
Estimated Primary Completion Date : January 31, 2021
Estimated Study Completion Date : April 1, 2025

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm A - initial TAF treatment group
cirrhotic or non-cirrhotic CHB patients with hepatic decompensation and HBV NUC treatment naïve or experienced (except prior TAF) will receive initial treatment (Arm A) with TAF 25 mg/day.
Drug: Tenofovir Alafenamide Tablets
Approximately 100 adults, cirrhotic or non-cirrhotic (capped at 50), CHB patients with hepatic decompensation, will receive initial treatment (Arm A) with or switch (Arm B) to TAF 25 mg/day for 144 weeks. For Initiation Arm (Arm A), CHB patients with hepatic decompensation, who are currently not under HBV antiviral treatment will be enrolled. For Switch Arm (Arm B), CHB patients who are currently with hepatic decompensation and virally suppressed under HBV NUC treatment (HBV DNA < 20 IU/mL) will be enrolled.

Experimental: Arm B - switch to TAF treatment group
cirrhotic or non-cirrhotic CHB patients with hepatic decompensation and currently under HBV NUC treatment (except TAF) with HBV DNA < 20 IU/mL within 6 months prior screening will switch (Arm B) to TAF 25 mg/day
Drug: Tenofovir Alafenamide Tablets
Approximately 100 adults, cirrhotic or non-cirrhotic (capped at 50), CHB patients with hepatic decompensation, will receive initial treatment (Arm A) with or switch (Arm B) to TAF 25 mg/day for 144 weeks. For Initiation Arm (Arm A), CHB patients with hepatic decompensation, who are currently not under HBV antiviral treatment will be enrolled. For Switch Arm (Arm B), CHB patients who are currently with hepatic decompensation and virally suppressed under HBV NUC treatment (HBV DNA < 20 IU/mL) will be enrolled.




Primary Outcome Measures :
  1. Complete virological suppression [ Time Frame: week 48 ]
    Proportion of patients treated with TAF who achieve complete virological suppression (HBV DNA < 20 IU/ml) at week 48 of TAF therapy in per-protocol (PP) population.


Secondary Outcome Measures :
  1. Rate of adverse events [ Time Frame: week 48 ]
    Rate of adverse events including serious adverse events and discontinuation at Week 48

  2. Rate of recovery from hepatic decompensation [ Time Frame: week 48, 96, and 144 ]
    Rate of recovery from hepatic decompensation (improvement of CTP score ≥1) at week 48, 96, and 144 of TAF therapy in FAS, modified FAS (mFAS) and PP populations.

  3. Liver transplant-free survival [ Time Frame: week 48, 96, and 144 ]
    Liver transplant-free survival at week 48, 96, and 144 of TAF therapy in FAS, mFAS and PP populations.

  4. Rate of virological response [ Time Frame: week 96, and 144 ]
    Rate of virological response (HBV DNA < 20 IU/ml) at week 96, and 144 of TAF therapy

  5. Rate of ALT normalization [ Time Frame: week 48, 96, and 144 ]
    Rate of ALT normalization by local (<40 U/L), and AASLD (male ≤35, female ≤25 U/L) criteria at week 48, 96, and 144 of TAF therapy in FAS, mFAS and PP populations.

  6. Rate of HBeAg loss/seroconversion, HBsAg loss/seroconversion [ Time Frame: week 48, 96, and 144 ]
    Rate of HBeAg loss/seroconversion in baseline HBeAg-seropositive patients, HBsAg loss/seroconversion, and change in HBsAg titer at week 48, 96, and 144 of TAF therapy.

  7. Changes of serum creatinine [ Time Frame: week 48, 96, and 144 ]
    Changes of serum creatinine from baseline to week 48, 96, and 144 of TAF in mFAS and PP populations.

  8. Changes of calculated creatinine clearance [ Time Frame: week 48, 96, and 144 ]
    Changes of calculated creatinine clearance (Cockcroft-Gault) from baseline to week 48, 96, and 144 of TAF in mFAS and PP populations.

  9. Changes in bone mineral density [ Time Frame: week 144 ]
    Changes in bone mineral density from baseline to week 144 of TAF in mFAS and PP populations.

  10. Changes in value of transient elastography [ Time Frame: week 144 ]
    Changes in value of transient elastography (Fibroscan, kPa) from baseline to week 144 in mFAS and PP populations.

  11. Changes in body mass index [ Time Frame: week 48, 96, and 144 ]
    Changes in body mass index (BMI) from baseline to week 48, 96, and 144 of TAF in mFAS and PP populations.

  12. Changes in blood lipid profile [ Time Frame: week 48, 96, and 144 ]
    Changes in fasting blood lipid profiles from baseline to week 48, 96, and 144 of TAF in mFAS and PP populations.

  13. Changes in blood glucose [ Time Frame: week 48, 96, and 144 ]
    Changes in fasting blood glucose from baseline to week 48, 96, and 144 of TAF in mFAS and PP populations.



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Ages Eligible for Study:   20 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male or non-pregnant female, age ≥20 years
  • Chronic HBV infection with positive hepatitis B surface antigen (HBsAg) for at least 6 months at screening.
  • Hepatic decompensation, defined as Child-Turcotte-Pugh (CTP) score ≥7, or the presence of portal hypertension related complications including ascites, hepatic encephalopathy (<grade 2) at screening.
  • HBV NUC treatment naïve or experienced (except prior TAF) for Arm A or currently under HBV NUC treatment (except TAF) with HBV DNA < 20 IU/mL within 6 months prior screening for Arm B.
  • Patients with either liver cirrhosis or non-cirrhosis (defined by histology, non-invasive assessments, or imaging/clinical based diagnosis).
  • Estimated creatinine clearance ≥30 ml/min (using the Cockcroft-Gault method) at screening. (Note: multiply estimated rate by 0.85 for women).
  • Willing and able to provide informed consent
  • Able to comply with dosing instructions for study drug administration and able to complete the study schedule of assessments

Exclusion Criteria:

  • Pregnant women, women who are breast feeding or who believe they may wish to become pregnant during the course of the study.
  • Previous recipient of a solid organ (including liver), or bone marrow transplant.
  • Severe or uncontrolled comorbidities determined by the Investigator.
  • Currently ≥grade 2 hepatic encephalopathy, currently or history (within 60 days) of variceal bleeding, hepatorenal syndrome, refractory ascites or spontaneous bacterial peritonitis; cytopenia of absolute neutrophil count < 750/mm3, or hemoglobin < 8 g/dL, or platelet <30000/mm3; or MELD score ≥30 at screening.
  • Malignancy history including hepatocellular carcinoma, except basal cell skin cancer without recurrence for more than 5 years.
  • Acute exacerbation of HBV, defined as an elevation of alanine aminotransferase (ALT) activity to more than 10 times the upper limit of normal and more than twice the baseline value.
  • On any of the disallowed concomitant medications listed in the prior and concomitant medications list (pg. 16). Subjects on prohibited medications who are otherwise eligible will need a wash out period of at least 30 days prior to the Screening.
  • Males and females of reproductive potential who are unwilling to use "effective" protocol-specified method(s) of contraception during the study.

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): NCT04683341


Contacts
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Contact: Ming-Lung Yu, Professor 886-7-3121101 ext 7475 fish6069@gmail.com

Locations
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Taiwan
Kaohsiung Medical University Hospital Recruiting
Kaohsiung, Taiwan, 807
Contact: Ming-Lung Yu    +886-7-312-1101 ext 7475    fish6069@gmail.com   
Sponsors and Collaborators
Kaohsiung Medical University Chung-Ho Memorial Hospital
Investigators
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Principal Investigator: Ming-Lung Yu, Professor Hepatobiliary Division, Kaohsiung Medical University Hospital
Publications:

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Responsible Party: Kaohsiung Medical University Chung-Ho Memorial Hospital
ClinicalTrials.gov Identifier: NCT04683341    
Other Study ID Numbers: TAF-Deliver
First Posted: December 24, 2020    Key Record Dates
Last Update Posted: December 24, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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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