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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT04683341




Registration number
NCT04683341
Ethics application status
Date submitted
12/11/2020
Date registered
24/12/2020
Date last updated
24/12/2020

Titles & IDs
Public title
Tenofovir Alafenamide in HBV Related Decompensated Liver
Scientific title
Safety and Efficacy of Tenofovir Alafenamide for Chronic Hepatitis B Patients With Decompensated Liver Disease
Secondary ID [1] 0 0
TAF-Deliver
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
HBV 0 0
Condition category
Condition code

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Tenofovir Alafenamide Tablets

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.

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


Treatment: Drugs: 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.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Complete virological suppression
Timepoint [1] 0 0
week 48
Secondary outcome [1] 0 0
Rate of adverse events
Timepoint [1] 0 0
week 48
Secondary outcome [2] 0 0
Rate of recovery from hepatic decompensation
Timepoint [2] 0 0
week 48, 96, and 144
Secondary outcome [3] 0 0
Liver transplant-free survival
Timepoint [3] 0 0
week 48, 96, and 144
Secondary outcome [4] 0 0
Rate of virological response
Timepoint [4] 0 0
week 96, and 144
Secondary outcome [5] 0 0
Rate of ALT normalization
Timepoint [5] 0 0
week 48, 96, and 144
Secondary outcome [6] 0 0
Rate of HBeAg loss/seroconversion, HBsAg loss/seroconversion
Timepoint [6] 0 0
week 48, 96, and 144
Secondary outcome [7] 0 0
Changes of serum creatinine
Timepoint [7] 0 0
week 48, 96, and 144
Secondary outcome [8] 0 0
Changes of calculated creatinine clearance
Timepoint [8] 0 0
week 48, 96, and 144
Secondary outcome [9] 0 0
Changes in bone mineral density
Timepoint [9] 0 0
week 144
Secondary outcome [10] 0 0
Changes in value of transient elastography
Timepoint [10] 0 0
week 144
Secondary outcome [11] 0 0
Changes in body mass index
Timepoint [11] 0 0
week 48, 96, and 144
Secondary outcome [12] 0 0
Changes in blood lipid profile
Timepoint [12] 0 0
week 48, 96, and 144
Secondary outcome [13] 0 0
Changes in blood glucose
Timepoint [13] 0 0
week 48, 96, and 144

Eligibility
Key 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
Minimum age
20 Years
Maximum age
100 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
1/09/2020
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/04/2025
Actual
Sample size
Target
100
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 0 0
Taiwan
State/province [1] 0 0
Kaohsiung

Funding & Sponsors
Primary sponsor type
Other
Name
Kaohsiung Medical University Chung-Ho Memorial Hospital
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/ct2/show/NCT04683341
Trial related presentations / publications
Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat. 2004 Mar;11(2):97-107. doi: 10.1046/j.1365-2893.2003.00487.x.
Liaw YF, Chu CM. Hepatitis B virus infection. Lancet. 2009 Feb 14;373(9663):582-92. doi: 10.1016/S0140-6736(09)60207-5.
Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HL, Chen CJ, Chen DS, Chen HL, Chen PJ, Chien RN, Dokmeci AK, Gane E, Hou JL, Jafri W, Jia J, Kim JH, Lai CL, Lee HC, Lim SG, Liu CJ, Locarnini S, Al Mahtab M, Mohamed R, Omata M, Park J, Piratvisuth T, Sharma BC, Sollano J, Wang FS, Wei L, Yuen MF, Zheng SS, Kao JH. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int. 2016 Jan;10(1):1-98. doi: 10.1007/s12072-015-9675-4. Epub 2015 Nov 13.
European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu; 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.
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.
Yao FY, Bass NM. Lamivudine treatment in patients with severely decompensated cirrhosis due to replicating hepatitis B infection. J Hepatol. 2000 Aug;33(2):301-7. doi: 10.1016/s0168-8278(00)80371-2.
Fontana RJ, Hann HW, Perrillo RP, Vierling JM, Wright T, Rakela J, Anschuetz G, Davis R, Gardner SD, Brown NA. Determinants of early mortality in patients with decompensated chronic hepatitis B treated with antiviral therapy. Gastroenterology. 2002 Sep;123(3):719-27. doi: 10.1053/gast.2002.35352.
Schiff E, Lai CL, Hadziyannis S, Neuhaus P, Terrault N, Colombo M, Tillmann H, Samuel D, Zeuzem S, Villeneuve JP, Arterburn S, Borroto-Esoda K, Brosgart C, Chuck S; Adefovir Dipivoxil Study 45 Intrnational Investigators Group. Adefovir dipivoxil for wait-listed and post-liver transplantation patients with lamivudine-resistant hepatitis B: final long-term results. Liver Transpl. 2007 Mar;13(3):349-60. doi: 10.1002/lt.20981.
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.
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.
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. Erratum In: Lancet Gastroenterol Hepatol. 2016 Nov;1(3):e2.
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. Erratum In: Lancet Gastroenterol Hepatol. 2016 Nov;1(3):e2.
Dai CY, Chuang WL, Hou NJ, Lee LP, Hsieh MY, Lin ZY, Chen SC, Huang JF, Hsieh MY, Wang LY, Tsai JF, Wen-Yu, Yu ML. Early mortality in Taiwanese lamivudine-treated patients with chronic hepatitis B-related decompensation: evaluation of the model for end-stage liver disease and index scoring systems as prognostic predictors. Clin Ther. 2006 Dec;28(12):2081-92. doi: 10.1016/j.clinthera.2006.12.016.
Public notes
This record is viewable in the ANZCTR as it had previously listed Australia and/or New Zealand as a recruitment site, however these sites have since been removed

Contacts
Principal investigator
Name 0 0
Ming-Lung Yu, Professor
Address 0 0
Hepatobiliary Division, Kaohsiung Medical University Hospital
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Ming-Lung Yu, Professor
Address 0 0
Country 0 0
Phone 0 0
886-7-3121101
Fax 0 0
Email 0 0
fish6069@gmail.com
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT04683341