Clinical trial NCT04683341: Tenofovir Alafenamide in HBV Related Decompensated Liver
Official title: Safety and Efficacy of Tenofovir Alafenamide for Chronic Hepatitis B Patients With Decompensated Liver Disease
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: HBV
Lead sponsor: Kaohsiung Medical University Chung-Ho Memorial Hospital
Sponsor class: OTHER
First posted: 2020-12-24
Enrollment: 100
Sex: ALL
Minimum age (years): 20
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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.
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Complete virological suppression
timeFrame: week 48
Secondary outcomes:
measure: Rate of adverse events
timeFrame: week 48
measure: Rate of recovery from hepatic decompensation
timeFrame: week 48, 96, and 144
measure: Liver transplant-free survival
timeFrame: week 48, 96, and 144
measure: Rate of virological response
timeFrame: week 96, and 144
measure: Rate of ALT normalization
timeFrame: week 48, 96, and 144
measure: Rate of HBeAg loss/seroconversion, HBsAg loss/seroconversion
timeFrame: week 48, 96, and 144
measure: Changes of serum creatinine
timeFrame: week 48, 96, and 144
measure: Changes of calculated creatinine clearance
timeFrame: week 48, 96, and 144
measure: Changes in bone mineral density
timeFrame: week 144
measure: Changes in value of transient elastography
timeFrame: week 144
measure: Changes in body mass index
timeFrame: week 48, 96, and 144
measure: Changes in blood lipid profile
timeFrame: week 48, 96, and 144
measure: Changes in blood glucose
timeFrame: week 48, 96, and 144
Other outcomes:
Locations:
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University Hospital
Study officials:
affiliation: Hepatobiliary Division, Kaohsiung Medical University Hospital
name: Ming-Lung Yu, Professor
role: PRINCIPAL_INVESTIGATOR
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