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Tenofovir Alafenamide in HBV Related Decompensated Liver

21. december 2020 opdateret af: 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.

Studieoversigt

Status

Rekruttering

Betingelser

Intervention / Behandling

Undersøgelsestype

Interventionel

Tilmelding (Forventet)

100

Fase

  • Fase 4

Kontakter og lokationer

Dette afsnit indeholder kontaktoplysninger for dem, der udfører undersøgelsen, og oplysninger om, hvor denne undersøgelse udføres.

Studiekontakt

  • Navn: Ming-Lung Yu, Professor
  • Telefonnummer: 7475 886-7-3121101
  • E-mail: fish6069@gmail.com

Studiesteder

  • Taiwan
      • Kaohsiung, Taiwan, 807
        • Rekruttering
        • Kaohsiung Medical University Hospital
        • Kontakt:

Deltagelseskriterier

Forskere leder efter personer, der passer til en bestemt beskrivelse, kaldet berettigelseskriterier. Nogle eksempler på disse kriterier er en persons generelle helbredstilstand eller tidligere behandlinger.

Berettigelseskriterier

Aldre berettiget til at studere

20 år til 100 år (Voksen, Ældre voksen)

Tager imod sunde frivillige

Ingen

Køn, der er berettiget til at studere

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

Dette afsnit indeholder detaljer om studieplanen, herunder hvordan undersøgelsen er designet, og hvad undersøgelsen måler.

Hvordan er undersøgelsen tilrettelagt?

Design detaljer

  • Primært formål: Behandling
  • Tildeling: Ikke-randomiseret
  • Interventionel model: Parallel tildeling
  • Maskning: Ingen (Åben etiket)

Våben og indgreb

Deltagergruppe / Arm
Intervention / Behandling
Eksperimentel: 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.
Medicin: 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.
Eksperimentel: 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
Medicin: 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.

Hvad måler undersøgelsen?

Primære resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
Complete virological suppression
Tidsramme: 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.
week 48

Sekundære resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
Rate of adverse events
Tidsramme: week 48
Rate of adverse events including serious adverse events and discontinuation at Week 48
week 48
Rate of recovery from hepatic decompensation
Tidsramme: 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.
week 48, 96, and 144
Liver transplant-free survival
Tidsramme: week 48, 96, and 144
Liver transplant-free survival at week 48, 96, and 144 of TAF therapy in FAS, mFAS and PP populations.
week 48, 96, and 144
Rate of virological response
Tidsramme: week 96, and 144
Rate of virological response (HBV DNA < 20 IU/ml) at week 96, and 144 of TAF therapy
week 96, and 144
Rate of ALT normalization
Tidsramme: 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.
week 48, 96, and 144
Rate of HBeAg loss/seroconversion, HBsAg loss/seroconversion
Tidsramme: 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.
week 48, 96, and 144
Changes of serum creatinine
Tidsramme: week 48, 96, and 144
Changes of serum creatinine from baseline to week 48, 96, and 144 of TAF in mFAS and PP populations.
week 48, 96, and 144
Changes of calculated creatinine clearance
Tidsramme: 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.
week 48, 96, and 144
Changes in bone mineral density
Tidsramme: week 144
Changes in bone mineral density from baseline to week 144 of TAF in mFAS and PP populations.
week 144
Changes in value of transient elastography
Tidsramme: week 144
Changes in value of transient elastography (Fibroscan, kPa) from baseline to week 144 in mFAS and PP populations.
week 144
Changes in body mass index
Tidsramme: 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.
week 48, 96, and 144
Changes in blood lipid profile
Tidsramme: 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.
week 48, 96, and 144
Changes in blood glucose
Tidsramme: 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.
week 48, 96, and 144

Samarbejdspartnere og efterforskere

Det er her, du vil finde personer og organisationer, der er involveret i denne undersøgelse.

Sponsor

Kaohsiung Medical University Chung-Ho Memorial Hospital

Efterforskere

  • Ledende efterforsker: Ming-Lung Yu, Professor, Hepatobiliary Division, Kaohsiung Medical University Hospital

Publikationer og nyttige links

Den person, der er ansvarlig for at indtaste oplysninger om undersøgelsen, leverer frivilligt disse publikationer. Disse kan handle om alt relateret til undersøgelsen.

Generelle publikationer

Datoer for undersøgelser

Disse datoer sporer fremskridtene for indsendelser af undersøgelsesrekord og resumeresultater til ClinicalTrials.gov. Studieregistreringer og rapporterede resultater gennemgås af National Library of Medicine (NLM) for at sikre, at de opfylder specifikke kvalitetskontrolstandarder, før de offentliggøres på den offentlige hjemmeside.

Studer store datoer

Studiestart (Faktiske)

1. september 2020

Primær færdiggørelse (Forventet)

31. januar 2021

Studieafslutning (Forventet)

1. april 2025

Datoer for studieregistrering

Først indsendt

12. november 2020

Først indsendt, der opfyldte QC-kriterier

21. december 2020

Først opslået (Faktiske)

24. december 2020

Opdateringer af undersøgelsesjournaler

Sidste opdatering sendt (Faktiske)

24. december 2020

Sidste opdatering indsendt, der opfyldte kvalitetskontrolkriterier

21. december 2020

Sidst verificeret

1. november 2020

Mere information

Begreber relateret til denne undersøgelse

Yderligere relevante MeSH-vilkår

Andre undersøgelses-id-numre

  • TAF-Deliver

Plan for individuelle deltagerdata (IPD)

Planlægger du at dele individuelle deltagerdata (IPD)?

INGEN

Lægemiddel- og udstyrsoplysninger, undersøgelsesdokumenter

Studerer et amerikansk FDA-reguleret lægemiddelprodukt

Ja

Studerer et amerikansk FDA-reguleret enhedsprodukt

Ingen

produkt fremstillet i og eksporteret fra U.S.A.

Ja

Disse oplysninger blev hentet direkte fra webstedet clinicaltrials.gov uden ændringer. Hvis du har nogen anmodninger om at ændre, fjerne eller opdatere dine undersøgelsesoplysninger, bedes du kontakte register@clinicaltrials.gov. Så snart en ændring er implementeret på clinicaltrials.gov, vil denne også blive opdateret automatisk på vores hjemmeside .

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