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Tenofovir Alafenamide in HBV Related Decompensated Liver

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.

연구 개요

상태

모병

정황

연구 유형

중재적

등록 (예상)

100

단계

  • 4단계

연락처 및 위치

이 섹션에서는 연구를 수행하는 사람들의 연락처 정보와 이 연구가 수행되는 장소에 대한 정보를 제공합니다.

연구 연락처

  • 이름: Ming-Lung Yu, Professor
  • 전화번호: 7475 886-7-3121101
  • 이메일: fish6069@gmail.com

연구 장소

      • Kaohsiung, 대만, 807
        • 모병
        • Kaohsiung Medical University Hospital
        • 연락하다:

참여기준

연구원은 적격성 기준이라는 특정 설명에 맞는 사람을 찾습니다. 이러한 기준의 몇 가지 예는 개인의 일반적인 건강 상태 또는 이전 치료입니다.

자격 기준

공부할 수 있는 나이

20년 (성인, 고령자)

건강한 자원 봉사자를 받아들입니다

아니

연구 대상 성별

모두

설명

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.

공부 계획

이 섹션에서는 연구 설계 방법과 연구가 측정하는 내용을 포함하여 연구 계획에 대한 세부 정보를 제공합니다.

연구는 어떻게 설계됩니까?

디자인 세부사항

  • 주 목적: 치료
  • 할당: 무작위화되지 않음
  • 중재 모델: 병렬 할당
  • 마스킹: 없음(오픈 라벨)

무기와 개입

참가자 그룹 / 팔
개입 / 치료
실험적: 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.
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.
실험적: 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
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.

연구는 무엇을 측정합니까?

주요 결과 측정

결과 측정
측정값 설명
기간
Complete virological suppression
기간: 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

2차 결과 측정

결과 측정
측정값 설명
기간
Rate of adverse events
기간: week 48
Rate of adverse events including serious adverse events and discontinuation at Week 48
week 48
Rate of recovery from hepatic decompensation
기간: 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
기간: 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
기간: 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
기간: 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
기간: 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
기간: 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
기간: 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
기간: 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
기간: 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
기간: 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
기간: 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
기간: 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

공동 작업자 및 조사자

여기에서 이 연구와 관련된 사람과 조직을 찾을 수 있습니다.

수사관

  • 수석 연구원: Ming-Lung Yu, Professor, Hepatobiliary Division, Kaohsiung Medical University Hospital

간행물 및 유용한 링크

연구에 대한 정보 입력을 담당하는 사람이 자발적으로 이러한 간행물을 제공합니다. 이것은 연구와 관련된 모든 것에 관한 것일 수 있습니다.

일반 간행물

연구 기록 날짜

이 날짜는 ClinicalTrials.gov에 대한 연구 기록 및 요약 결과 제출의 진행 상황을 추적합니다. 연구 기록 및 보고된 결과는 공개 웹사이트에 게시되기 전에 특정 품질 관리 기준을 충족하는지 확인하기 위해 국립 의학 도서관(NLM)에서 검토합니다.

연구 주요 날짜

연구 시작 (실제)

2020년 9월 1일

기본 완료 (예상)

2021년 1월 31일

연구 완료 (예상)

2025년 4월 1일

연구 등록 날짜

최초 제출

2020년 11월 12일

QC 기준을 충족하는 최초 제출

2020년 12월 21일

처음 게시됨 (실제)

2020년 12월 24일

연구 기록 업데이트

마지막 업데이트 게시됨 (실제)

2020년 12월 24일

QC 기준을 충족하는 마지막 업데이트 제출

2020년 12월 21일

마지막으로 확인됨

2020년 11월 1일

추가 정보

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구독하다