Efficacy and Safety of TAF in Patients With Suboptimal Response to Other Nucleos(t)Ides

NCT04201808 | Unknown Phase 4 DMC

• 1 other identifier: IN-CN-320-5556
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 10

Brief Summary

Both tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are potent antiviral agents for hepatitis B virus (HBV) and recommended by the American Association for the Study of Liver Disease (AASLD) as well as the European Association for the Study of Liver (EASL) guidelines for the treatment of nucleos(t)ide therapy induced HBV resistance. However, it is not clear if chronic hepatitis B (CHB) patients with nucleos(t)ide treatment experience without genotypic mutations would be benefit from TAF therapy. Previous studies have observed that suboptimal response (SOR) following antiviral therapy with nucleos(t)ide treatment is associated with an increased risk of subsequent treatment failure and viral resistance. It remains unclear whether switching to TAF is a reasonable approach in patients with SOR to second-line antivirals Lamivudine (LAM)/ Telbivudine (LdT)/ Adefovir Dipivoxil (ADV) and its combinations with other second-line antivirals for 24 weeks, or SOR to the first-line antiviral Entecavir (ETV) or any antiviral combinations containing ETV for 48 weeks. This study is aimed to determine how the aforementioned patients with SOR to nucleos(t)ide treatment respond to TAF monotherapy. The investigator's study will provide evidence base for therapy selection in SOR patients, especially in China where the majority of patients with CHB are treated with nucleos(t)ide therapy.

Conditions

Hepatitis B, Chronic

Outcome Measures

Primary Outcomes (1)

• this study seeks to evaluate the efficacy of TAF in Asian CHB adults with a proven SOR to previous nucleo(t)side therapy by assessing the percentage of patients who achieve HBV DNA viral suppression over a time span of 48 weeks.

  In this study, HBV DNA viral suppression is defined as a HBV DNA level \<20 IU/mL, and previous nucleo(t)side therapy is defined as treatments including LAM, LdT, ADV, and ETV before switching to TAF. The parameters for SOR will be set as patients who exhibit a 1 log10 IU/mL decrease in HBV DNA with medication adherence, but still present with an HBV DNA level of \>300 IU/mL and has no detectable genotype mutation(s) when treated with the second-line antivirals LAM/LdT/ADV and its combinations with other second-line antivirals for 24 weeks, or treated with the first-line antiviral ETV or any antiviral combinations containing ETV for 48 weeks.

  48 weeks

Secondary Outcomes (7)

• Incidence of Treatment-Emergent Adverse Events in Patients as stratified by the CTCAE v 5.0

  At 12, 24, 36, and 48 weeks

• Percentage of Patients Who Discontinue the Therapy Due to Issues with Tolerability

  At 12, 24, 36, and 48 weeks

• Percentage of patients with Alanine transferase (ALT) levels within the normal limit

  48 weeks

• Percentage of patients with Aspartamine transferase (AST) levels within the normal limit

  48 weeks

• Percentage of patients who experience loss/seroconversion of HBsAg and/or HBeAg during the study.

  48 weeks

Study Arms (1)

Single Arm Intervention Group

EXPERIMENTAL

All approximately 100 patients experienced previous suboptimal response to other direct acting antivirals. Patients must have received nucleos(t)ide therapy consisting of LAM/LdT/ADV and its combinations with other second-line antivirals for 24 weeks, or with the first-line antiviral ETV or any antiviral combinations containing ETV for 48 weeks with medication adherence. All patients in this study are in the same arm.

Drug: Tenofovir Alafenamide 25 MG

Interventions

Tenofovir Alafenamide 25 MG DRUG

All patients will receive Tenofovir Alafenamide, 25mg PO, to treat chronic hepatitis B and their previous suboptimal response over the study duration of 48 weeks. Patients will be followed every 12 weeks for medication adherence, medication refill, and follow up as per standard of care.

Also known as: Vemlidy

Single Arm Intervention Group

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must be 18-80 years of age.
• Patients must have documented compensated and stable chronic hepatitis B defined by all of the following:
• HBsAg persistently positive \> 6 months.
• Clinical history, physical findings, and test results are compatible with compensated chronic hepatitis B
• Patients must have received nucleos(t)ide therapy consisting of LAM/LdT/ADV and its combinations with other second-line antivirals for 24 weeks, or with the first-line antiviral ETV or any antiviral combinations containing ETV for 48 weeks with medication adherence.
• Although having undergone therapy, patients have had failure to achieve the levels of HBV-DNA below 300 IU/mL.
• Patient is willing and able to comply with the study drug regimen and all other study requirements.
• Patient must understand the risk, and be willing and able to provide written informed consent to participate in the study.

You may not qualify if:

• Pregnant women, and women who are breastfeeding or who believe they may wish to become pregnant during the course of the study.
• Males and females of reproductive potential who are not willing to use an effective method of contraception during the study. For males, condoms should be used and for females, a barrier contraception method should be used in combination with one other form of contraception.
• Unwilling and/or unable to provide written informed consent
• Patients with CHB but are also co-infected with HIV or other viral hepatitis
• Patients whose serum levels of HBV DNA are too low (i.e. about 300 IU/mL) to be analyzed for the genotypic mutation(s) at the onset of this trial, i.e. baseline
• At the screening visit, nucleos(t)ide resistant mutants have been detected in the strain of HBV of the patient
• The patient is under a clinical research protocol of phase I-III development; unable to consent or unlikely to complete one year follow up after the enrollment; and other medical condition may affect the ability to participate the study.
• Decompensated liver disease defined as direct (conjugated) bilirubin ≥ 1.2 Upper Limit of Normal (ULN); Prothrombin Time (PT) ≥ 1.2 ULN, platelets ≤ 150,000/mm3, or serum albumin ≤ 3.5 g/dL
• Prior history of clinical hepatic decompensation (e.g., ascites, jaundice, encephalopathy) or variceal hemorrhage
• Serum α-fetoprotein ≥ 50 ng/mL
• Evidence of hepatocellular carcinoma (HCC)
• History of significant renal disease (e.g., nephrotic syndrome, renal dysgenesis, polycystic kidney disease, congenital nephrosis, acute tubular necrosis, other renal disease)
• History of significant bone disease (e.g., osteomalacia, chronic osteomyelitis, osteogenesis imperfecta, osteochondrosis, multiple bone fractures)
• Significant cardiovascular, pulmonary or neurological disease
• Evidence of a gastrointestinal malabsorption syndrome that may interfere with absorption of orally administered medications

Sponsors & Collaborators

• New Discovery LLC: lead
• Beijing Ditan Hospital: collaborator

Study Sites (10)

The First Affiliated Hospital of Bengbu Medical College

Bengbu, Anhui, 233000, China

RECRUITING

Beijing Ditan Hospital, Capital Medical University

Beijing, Beijing Municipality, 100015, China

RECRUITING

Southwest Hospital

Chongqing, Chongqing Municipality, 400038, China

RECRUITING

Liver Research Center, The First Affiliated Hospital of Fujian Medical University

Fuzhou, Fujian, China

RECRUITING

Third Affiliated Hospital of Sun Yat-sen University

Guangzhou, Guangdong, 510630, China

RECRUITING

Wuhan Union Hospital, Tongji Medical College (TJMC), Huazhong University of Science and Technology (HUST)

Wuhan, Hubei, 430022, China

RECRUITING

Shengjing Hospital of China Medical University

Shengyang, Liaoning, 110004, China

RECRUITING

Department of Infectious Diseases, Xi'an Jiaotong University Second Affiliated Hospital

Xi'an, Shaanxi, 710004, China

RECRUITING

Huashan Hospital Fudan University

Jing’an, Shanghai Municipality, 200040, China

RECRUITING

The Third Hospital of Hebei Medical University

Hebei, Shijiazhuang, 050035, China

RECRUITING

Related Publications (8)

• Agarwal K, Brunetto M, Seto WK, Lim YS, Fung S, Marcellin P, Ahn SH, Izumi N, Chuang WL, Bae H, Sharma M, Janssen HLA, Pan CQ, Celen MK, Furusyo N, Shalimar D, Yoon KT, Trinh H, Flaherty JF, Gaggar A, Lau AH, Cathcart AL, Lin L, Bhardwaj N, Suri V, Mani Subramanian G, Gane EJ, Buti M, Chan HLY; GS-US-320-0110; GS-US-320-0108 Investigators. 96 weeks treatment of tenofovir alafenamide vs. tenofovir disoproxil fumarate for hepatitis B virus infection. J Hepatol. 2018 Apr;68(4):672-681. doi: 10.1016/j.jhep.2017.11.039. Epub 2018 Jan 17.

  PMID: 29756595 BACKGROUND

• 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.

  PMID: 28404092 BACKGROUND

• 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.

  PMID: 28427875 BACKGROUND

• Lu L, Yip B, Trinh H, Pan CQ, Han SH, Wong CC, Li J, Chan S, Krishnan G, Wong CC, Nguyen MH. Tenofovir-based alternate therapies for chronic hepatitis B patients with partial virological response to entecavir. J Viral Hepat. 2015 Aug;22(8):675-81. doi: 10.1111/jvh.12368. Epub 2014 Nov 24.

  PMID: 25417914 BACKGROUND

• Pan CQ, Chan S, Trinh H, Yao A, Bae H, Lou L. Similar efficacy and safety of tenofovir in Asians and non-Asians with chronic hepatitis B. World J Gastroenterol. 2015 May 14;21(18):5524-31. doi: 10.3748/wjg.v21.i18.5524.

  PMID: 25987775 BACKGROUND

• Pan CQ, Hu KQ, Yu AS, Chen W, Bunchorntavakul C, Reddy KR. Response to tenofovir monotherapy in chronic hepatitis B patients with prior suboptimal response to entecavir. J Viral Hepat. 2012 Mar;19(3):213-9. doi: 10.1111/j.1365-2893.2011.01533.x. Epub 2011 Oct 17.

  PMID: 22329376 BACKGROUND

• 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. Hepatology. 2018 Apr;67(4):1560-1599. doi: 10.1002/hep.29800. No abstract available.

  PMID: 29405329 BACKGROUND

• Tong MJ, Pan CQ, Han SB, Lu DS, Raman S, Hu KQ, Lim JK, Hann HW, Min AD. An expert consensus for the management of chronic hepatitis B in Asian Americans. Aliment Pharmacol Ther. 2018 Apr;47(8):1181-1200. doi: 10.1111/apt.14577. Epub 2018 Feb 26.

  PMID: 29479728 BACKGROUND

MeSH Terms

Conditions

Hepatitis B, Chronic

Interventions

tenofovir alafenamide

Condition Hierarchy (Ancestors)

Hepatitis B; Blood-Borne Infections; Communicable Diseases; Infections; Hepadnaviridae Infections; DNA Virus Infections; Virus Diseases; Hepatitis, Viral, Human; Hepatitis, Chronic; Hepatitis; Liver Diseases; Digestive System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Calvin Q Pan, MD

  NYU Langone Health

  PRINCIPAL INVESTIGATOR

• Wen Xie, MD

  Capital Medical University

  STUDY DIRECTOR

Central Study Contacts

Wen Xie, MD

CONTACT

(+86) 13651113763; Xiewen6218@163.com

Calvin Q Pan, MD

CONTACT

(+001) 7188887728; Panc01@nyu.edu

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: This is single-arm, multicenter cohort study evaluating the efficacy, safety, and tolerability of TAF monotherapy in Asian CHB adults with SOR to the nucleos(t)ide therapy by assessing the HBV DNA suppression over a duration of 48 weeks.

Study Record Dates

• First Submitted: December 6, 2019
• First Posted: December 17, 2019
• Study Start: May 1, 2021
• Primary Completion: September 30, 2023
• Study Completion: September 30, 2023
• Last Updated: November 17, 2020

Record last verified: 2019-12

Locations

CN (10)