Tenofovir Alafenamide in HBV Related Decompensated Liver

Study Overview
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Brief Summary
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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.

Official Title
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Safety and Efficacy of Tenofovir Alafenamide for Chronic Hepatitis B Patients With Decompensated Liver Disease

Conditions
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HBV

Intervention / Treatment
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* Drug: Tenofovir Alafenamide Tablets


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A - initial TAF treatment group<br>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. | Drug: Tenofovir Alafenamide Tablets<br>* 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.<br>|
| Experimental: Arm B - switch to TAF treatment group<br>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 | Drug: Tenofovir Alafenamide Tablets<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete virological suppression | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of adverse events | Rate of adverse events including serious adverse events and discontinuation at Week 48 | week 48 | 
| Rate of recovery from hepatic decompensation | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 |