Clinical trial NCT04201808: Efficacy and Safety of TAF in Patients With Suboptimal Response to Other Nucleos(t)Ides
Official title: Efficacy and Safety of Tenofovir Alafenamide in Chronic Hepatitis B Patients With Suboptimal Response Following Nucleos(t)Ide Therapy
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Hepatitis B, Chronic
Lead sponsor: New Discovery LLC
Sponsor class: INDUSTRY
Collaborators: name: Beijing Ditan Hospital
First posted: 2019-12-17
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: 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.
Primary purpose: TREATMENT

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.

Detailed description: This is a prospective, single-arm, multicenter cohort study evaluating the efficacy, safety, and tolerability of TAF monotherapy in in Asian CHB adults with SOR to the nucleos(t)ide therapy by assessing the HBV DNA suppression in 48 weeks. Approximately one hundred adults who received the aforementioned nucleos(t)ide therapy will be prospectively enrolled during the period from December 2019 to June 2021. Subjects will be enrolled by medical clinic in about 10 university centers in different regions in China. Approximately 10-15 consecutive eligible patients will be enrolled from each participating sites. This study will be conducted in accordance with the guidelines of Good Clinical Practices (GCPs) including Institutional Review Board (IRB) approval and consent will be applied. Patient identification (ID) will be de-identified for submitting to the central database for analyses from all study sites. Free TAF treatment will be provided to all enrolled patients for 48 weeks. Patients will be under the local standard of care upon the completion of the current study.

Patients aged 18-80 with CHB infection who had received nucleos(t)ide therapy over 24 weeks of LAM/LdT/ADV or 48 weeks of ETV with medication adherence, but failure to achieve the levels of HBV-DNA below 300 IU/mL will be eligible. Subjects will be excluded if they meet the following criteria: co-infected with HIV or other viral hepatitis; the serum levels of HBV DNA are too low (i.e. about 300 IU/mL) to be analyzed for the genotypic mutation(s); nucleos(t)ide resistant mutants have been detected at screening visit, 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.

Eligibility criteria: Inclusion Criteria:

* 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.

Exclusion Criteria:

* 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
* History of solid organ or bone marrow transplantation
* Ongoing therapy with any of the following: Nephrotoxic agents

  * Parenteral aminoglycoside antibiotics (e.g., gentamicin, tobramycin, amikacin)
  * Cidofovir
  * Cisplatin
  * Foscarnet
  * IV amphotericin B
  * IV pentamidine
  * Oral or IV ganciclovir
  * Cyclosporine
  * Tacrolimus
  * IV vancomycin
  * Chronic daily non-steroidal anti-inflammatory drug therapy
  * Competitors of renal excretion (e.g., probenecid) Systemic chemotherapeutic agents
  * Systemic corticosteroids
  * Interleukin-2 (IL-2) and other immunomodulating agents
* Investigational agents (except with the expressed approval of the lead investigators)

Note: administration of any of the above medications must be discontinued at least 30 days prior to the Baseline Visit and for the duration of the study period.

* Known hypersensitivity to the study drugs, the metabolites or formulation excipients
* Any other condition (including alcohol or substance abuse) or prior therapy that, in the opinion of the Investigators, would make the subject unsuitable for the study or unable to comply with dosing requirements

Primary outcomes:
measure: 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.
timeFrame: 48 weeks
Secondary outcomes:
measure: Incidence of Treatment-Emergent Adverse Events in Patients as stratified by the CTCAE v 5.0
timeFrame: At 12, 24, 36, and 48 weeks
measure: Percentage of Patients Who Discontinue the Therapy Due to Issues with Tolerability
timeFrame: At 12, 24, 36, and 48 weeks
measure: Percentage of patients with Alanine transferase (ALT) levels within the normal limit
timeFrame: 48 weeks
measure: Percentage of patients with Aspartamine transferase (AST) levels within the normal limit
timeFrame: 48 weeks
measure: Percentage of patients who experience loss/seroconversion of HBsAg and/or HBeAg during the study.
timeFrame: 48 weeks
measure: Percentage of patients with detectable drug resistance mutations
timeFrame: 48 weeks
measure: Percentage of patients who have skipped TAF treatment during the study
timeFrame: 48 weeks.
Other outcomes:
Locations:
city: Bengbu
country: China
facility: The First Affiliated Hospital of Bengbu Medical College
state: Anhui
city: Beijing
country: China
facility: Beijing Ditan Hospital, Capital Medical University
state: Beijing
city: Chongqing
country: China
facility: Southwest Hospital
state: Chongqing
city: Fuzhou
country: China
facility: Liver Research Center, The First Affiliated Hospital of Fujian Medical University
state: Fujian
city: Guangzhou
country: China
facility: Third Affiliated Hospital of Sun Yat-sen University
state: Guangdong
city: Wuhan
country: China
facility: Wuhan Union Hospital, Tongji Medical College (TJMC), Huazhong University of Science and Technology (HUST)
state: Hubei
city: Shengyang
country: China
facility: Shengjing Hospital of China Medical University
state: Liaoning
city: Xi'an
country: China
facility: Department of Infectious Diseases, Xi'an Jiaotong University Second Affiliated Hospital
state: Shaanxi
city: Jing'an
country: China
facility: Huashan Hospital Fudan University
state: Shanghai
city: Hebei
country: China
facility: The Third Hospital of Hebei Medical University
state: Shijiazhuang
Study officials:
affiliation: NYU Langone Health
name: Calvin Q Pan, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Capital Medical University
name: Wen Xie, MD
role: STUDY_DIRECTOR
References:
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citation: 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.
citation: 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.
citation: 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.