Tenofovir Alafenamide in HBV Related Decompensated Liver

NCT04683341 | Unknown Phase 4 DMC FDA Drug

• 1 other identifier: TAF-Deliver
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

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.

Conditions

HBV

Outcome Measures

Primary Outcomes (1)

• Complete virological suppression

  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.

  week 48

Secondary Outcomes (13)

• Rate of adverse events

  week 48

• Rate of recovery from hepatic decompensation

  week 48, 96, and 144

• Liver transplant-free survival

  week 48, 96, and 144

• Rate of virological response

  week 96, and 144

• Rate of ALT normalization

  week 48, 96, and 144

Study Arms (2)

Arm A - initial TAF treatment group

EXPERIMENTAL

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

Arm B - switch to TAF treatment group

EXPERIMENTAL

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

Interventions

Tenofovir Alafenamide Tablets DRUG

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.

Arm A - initial TAF treatment group; Arm B - switch to TAF treatment group

Eligibility Criteria

• Age: 20 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Kaohsiung Medical University Chung-Ho Memorial Hospital: lead

Study Sites (1)

Kaohsiung Medical University Hospital

Kaohsiung City, 807, Taiwan

RECRUITING

Related Publications (13)

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• Liaw YF, Chu CM. Hepatitis B virus infection. Lancet. 2009 Feb 14;373(9663):582-92. doi: 10.1016/S0140-6736(09)60207-5.

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• European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol. 2017 Aug;67(2):370-398. doi: 10.1016/j.jhep.2017.03.021. Epub 2017 Apr 18.

  PMID: 28427875 BACKGROUND

• Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, Brown RS Jr, Bzowej NH, Wong JB. Update on Prevention, Diagnosis, and Treatment of Chronic Hepatitis B: AASLD 2018 Hepatitis B Guidance. Clin Liver Dis (Hoboken). 2018 Aug 22;12(1):33-34. doi: 10.1002/cld.728. eCollection 2018 Jul. No abstract available.

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• Shim JH, Lee HC, Kim KM, Lim YS, Chung YH, Lee YS, Suh DJ. Efficacy of entecavir in treatment-naive patients with hepatitis B virus-related decompensated cirrhosis. J Hepatol. 2010 Feb;52(2):176-82. doi: 10.1016/j.jhep.2009.11.007. Epub 2009 Dec 16.

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• Liaw YF, Sheen IS, Lee CM, Akarca US, Papatheodoridis GV, Suet-Hing Wong F, Chang TT, Horban A, Wang C, Kwan P, Buti M, Prieto M, Berg T, Kitrinos K, Peschell K, Mondou E, Frederick D, Rousseau F, Schiff ER. Tenofovir disoproxil fumarate (TDF), emtricitabine/TDF, and entecavir in patients with decompensated chronic hepatitis B liver disease. Hepatology. 2011 Jan;53(1):62-72. doi: 10.1002/hep.23952. Epub 2010 Oct 27.

  PMID: 21254162 BACKGROUND

• Chan HL, Fung S, Seto WK, Chuang WL, Chen CY, Kim HJ, Hui AJ, Janssen HL, Chowdhury A, Tsang TY, Mehta R, Gane E, Flaherty JF, Massetto B, Gaggar A, Kitrinos KM, Lin L, Subramanian GM, McHutchison JG, Lim YS, Acharya SK, Agarwal K; GS-US-320-0110 Investigators. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of HBeAg-positive chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol. 2016 Nov;1(3):185-195. doi: 10.1016/S2468-1253(16)30024-3. Epub 2016 Sep 22.

  PMID: 28404091 BACKGROUND

• Buti M, Gane E, Seto WK, Chan HL, Chuang WL, Stepanova T, Hui AJ, Lim YS, Mehta R, Janssen HL, Acharya SK, Flaherty JF, Massetto B, Cathcart AL, Kim K, Gaggar A, Subramanian GM, McHutchison JG, Pan CQ, Brunetto M, Izumi N, Marcellin P; GS-US-320-0108 Investigators. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol. 2016 Nov;1(3):196-206. doi: 10.1016/S2468-1253(16)30107-8. Epub 2016 Sep 22.

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  PMID: 17296464 BACKGROUND

MeSH Terms

Interventions

tenofovir alafenamide

Study Officials

• Ming-Lung Yu, Professor

  Hepatobiliary Division, Kaohsiung Medical University Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Ming-Lung Yu, Professor

CONTACT

886-7-3121101; fish6069@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: November 12, 2020
• First Posted: December 24, 2020
• Study Start: September 1, 2020
• Primary Completion: January 31, 2021
• Study Completion: April 1, 2025
• Last Updated: December 24, 2020

Record last verified: 2020-11

Data Sharing

• IPD Sharing: Will not share

Locations

TW (1)