Tenofovir Alafenamide in HBV Related Decompensated Liver
21. desember 2020 oppdatert av: Kaohsiung Medical University Chung-Ho Memorial Hospital
Safety and Efficacy of Tenofovir Alafenamide for Chronic Hepatitis B Patients With Decompensated Liver Disease
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.
Studieoversikt
Studietype
Intervensjonell
Registrering (Forventet)
100
Fase
- Fase 4
Kontakter og plasseringer
Denne delen inneholder kontaktinformasjon for de som utfører studien, og informasjon om hvor denne studien blir utført.
Studiekontakt
- Navn: Ming-Lung Yu, Professor
- Telefonnummer: 7475 886-7-3121101
- E-post: fish6069@gmail.com
Studiesteder
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Kaohsiung, Taiwan, 807
- Rekruttering
- Kaohsiung Medical University Hospital
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Ta kontakt med:
- Ming-Lung Yu
- Telefonnummer: 7475 +886-7-312-1101
- E-post: fish6069@gmail.com
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Deltakelseskriterier
Forskere ser etter personer som passer til en bestemt beskrivelse, kalt kvalifikasjonskriterier. Noen eksempler på disse kriteriene er en persons generelle helsetilstand eller tidligere behandlinger.
Kvalifikasjonskriterier
Alder som er kvalifisert for studier
20 år til 100 år (Voksen, Eldre voksen)
Tar imot friske frivillige
Nei
Kjønn som er kvalifisert for studier
Alle
Beskrivelse
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.
Studieplan
Denne delen gir detaljer om studieplanen, inkludert hvordan studien er utformet og hva studien måler.
Hvordan er studiet utformet?
Designdetaljer
- Primært formål: Behandling
- Tildeling: Ikke-randomisert
- Intervensjonsmodell: Parallell tildeling
- Masking: Ingen (Open Label)
Våpen og intervensjoner
Deltakergruppe / Arm |
Intervensjon / Behandling |
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Eksperimentell: 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.
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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.
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Eksperimentell: 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
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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.
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Hva måler studien?
Primære resultatmål
Resultatmål |
Tiltaksbeskrivelse |
Tidsramme |
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Complete virological suppression
Tidsramme: week 48
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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.
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week 48
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Sekundære resultatmål
Resultatmål |
Tiltaksbeskrivelse |
Tidsramme |
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Rate of adverse events
Tidsramme: week 48
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Rate of adverse events including serious adverse events and discontinuation at Week 48
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week 48
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Rate of recovery from hepatic decompensation
Tidsramme: week 48, 96, and 144
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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.
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week 48, 96, and 144
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Liver transplant-free survival
Tidsramme: week 48, 96, and 144
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Liver transplant-free survival at week 48, 96, and 144 of TAF therapy in FAS, mFAS and PP populations.
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week 48, 96, and 144
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Rate of virological response
Tidsramme: week 96, and 144
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Rate of virological response (HBV DNA < 20 IU/ml) at week 96, and 144 of TAF therapy
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week 96, and 144
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Rate of ALT normalization
Tidsramme: week 48, 96, and 144
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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.
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week 48, 96, and 144
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Rate of HBeAg loss/seroconversion, HBsAg loss/seroconversion
Tidsramme: week 48, 96, and 144
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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.
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week 48, 96, and 144
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Changes of serum creatinine
Tidsramme: week 48, 96, and 144
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Changes of serum creatinine from baseline to week 48, 96, and 144 of TAF in mFAS and PP populations.
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week 48, 96, and 144
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Changes of calculated creatinine clearance
Tidsramme: week 48, 96, and 144
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Changes of calculated creatinine clearance (Cockcroft-Gault) from baseline to week 48, 96, and 144 of TAF in mFAS and PP populations.
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week 48, 96, and 144
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Changes in bone mineral density
Tidsramme: week 144
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Changes in bone mineral density from baseline to week 144 of TAF in mFAS and PP populations.
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week 144
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Changes in value of transient elastography
Tidsramme: week 144
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Changes in value of transient elastography (Fibroscan, kPa) from baseline to week 144 in mFAS and PP populations.
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week 144
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Changes in body mass index
Tidsramme: week 48, 96, and 144
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Changes in body mass index (BMI) from baseline to week 48, 96, and 144 of TAF in mFAS and PP populations.
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week 48, 96, and 144
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Changes in blood lipid profile
Tidsramme: week 48, 96, and 144
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Changes in fasting blood lipid profiles from baseline to week 48, 96, and 144 of TAF in mFAS and PP populations.
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week 48, 96, and 144
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Changes in blood glucose
Tidsramme: week 48, 96, and 144
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Changes in fasting blood glucose from baseline to week 48, 96, and 144 of TAF in mFAS and PP populations.
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week 48, 96, and 144
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Samarbeidspartnere og etterforskere
Det er her du vil finne personer og organisasjoner som er involvert i denne studien.
Etterforskere
- Hovedetterforsker: Ming-Lung Yu, Professor, Hepatobiliary Division, Kaohsiung Medical University Hospital
Publikasjoner og nyttige lenker
Den som er ansvarlig for å legge inn informasjon om studien leverer frivillig disse publikasjonene. Disse kan handle om alt relatert til studiet.
Generelle publikasjoner
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
Studierekorddatoer
Disse datoene sporer fremdriften for innsending av studieposter og sammendragsresultater til ClinicalTrials.gov. Studieposter og rapporterte resultater gjennomgås av National Library of Medicine (NLM) for å sikre at de oppfyller spesifikke kvalitetskontrollstandarder før de legges ut på det offentlige nettstedet.
Studer hoveddatoer
Studiestart (Faktiske)
1. september 2020
Primær fullføring (Forventet)
31. januar 2021
Studiet fullført (Forventet)
1. april 2025
Datoer for studieregistrering
Først innsendt
12. november 2020
Først innsendt som oppfylte QC-kriteriene
21. desember 2020
Først lagt ut (Faktiske)
24. desember 2020
Oppdateringer av studieposter
Sist oppdatering lagt ut (Faktiske)
24. desember 2020
Siste oppdatering sendt inn som oppfylte QC-kriteriene
21. desember 2020
Sist bekreftet
1. november 2020
Mer informasjon
Begreper knyttet til denne studien
Ytterligere relevante MeSH-vilkår
Andre studie-ID-numre
- TAF-Deliver
Plan for individuelle deltakerdata (IPD)
Planlegger du å dele individuelle deltakerdata (IPD)?
NEI
Legemiddel- og utstyrsinformasjon, studiedokumenter
Studerer et amerikansk FDA-regulert medikamentprodukt
Ja
Studerer et amerikansk FDA-regulert enhetsprodukt
Nei
produkt produsert i og eksportert fra USA
Ja
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