Clinical trial NCT03258710: A Study of Switching From Entecavir to Tenofovir Disoproxil Fumarate in Subjects With Chronic Hepatitis B
Official title: A Multi-centre, One-arm Prospective Study to Evaluate Efficacy and Safety of Switching From Entecavir (ETV) to Tenofovir Disoproxil Fumarate (TDF) in Japanese Chronic Hepatitis B HBeAg-positive and HBV-DNA Undetectable Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Hepatitis B, Chronic
Keywords: Tenofovir Disoproxil Fumarate
safety
chronic hepatitis B
virological effect
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2017-08-23
Enrollment: 75
Sex: ALL
Minimum age (years): 20
Maximum age (years): 69
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: This is a single arm study where on-going ETV treatment is switched to TDF treatment. There is no randomization in this study.
Primary purpose: TREATMENT

Brief summary: Tenofovir Disoproxil Fumarate is a nucleos(t)ide analogue that inhibits Hepatitis B Virus (HBV) growth, and is marketed in Japan with an indication for inhibition of HBV growth in subjects with chronic hepatitis B associated with HBV growth and abnormal liver function. This study has been planned to evaluate the virological effects and safety of switching from ETV to TDF in chronic hepatitis B (hepatitis B e-antigen \[HBeAg\])-positive and HBV- deoxyribonucleic acid (DNA) undetectable subjects. This study is designed as a multi-center, one-arm, post-marketing clinical study to investigate the HBsAg reduction in subjects who have not achieved the long-term goal, the loss of hepatitis B surface antigen (HBsAg). The study will be conducted in HBeAg-positive and HBV-DNA undetectable subjects treated with ETV. After switching ETV to TDF, TDF will be administered for 96 weeks. Approximately 80 subjects will be screened to achieve 65 evaluable subjects.


Eligibility criteria: Inclusion Criteria:

* Subjects must be 20 to 69 years of age inclusive, at the time of signing the informed consent
* Male and female subjects. A female subject is eligible to participate if she is not pregnant and not breastfeeding, and at least one of the following conditions applies:

  * Not a woman of childbearing potential (WOCBP), OR
  * A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 4 days after the last dose of study treatment
* Capable of giving signed informed consent form (ICF)
* Subjects with chronic hepatitis B (CHB) (excluding hospitalized subjects)
* Subjects treated with ETV for at least 2 years prior to initiation of study treatment.
* The serum HBV-DNA level at screening is below the limit of quantitation (\< 2.1 Log10 copies/milliliter \[mL\] or \< 20 international unit \[IU\]/mL).
* Subjects with serum HBeAg positive at screening
* Meet either of the following serum HBsAg levels at screening:

  * Serum HBsAg 80 \< to \< 800 IU/mL and fluctuation range is equal or more than -0.1 Log10 IU/mL per year
  * Serum HBsAg \>=800 IU/mL
* Meet all of the following criteria at screening:

  * Creatinine clearance (CLcr) \>=70 mL/minute. CLcr is calculated using the following Cockcroft-Gault formula.

Male: CLcr = (body weight in kilogram \[kg\] multiplied by \[140 minus age in years\]) divided by (72 multiplied by serum creatinine \[milligram {mg}/deciliter {dL}\]) Female: CLcr = CLcr (male) multiplied by 0.85

* Hemoglobin \>= 8 gram/dL
* WBC \>=1000 per cubic millimeter (mm\^3)

Exclusion Criteria:

* QTc \> 450 millisecond (msec) or \> 480 msec for subjects with bundle branch block
* Received any interferon or Hepatitis B vaccine therapy within 24 weeks prior to initiation of the study treatment.
* Received overdose of nonsteroidal anti-inflammatory drugs (NSAIDs) (excluding temporary or topical use) within 7 days prior to initiation of the study treatment.
* Received any of the following drugs within 8 weeks prior to initiation of the study treatment (excluding topical products such as ointment and/or cream etc).

  * Drugs causing renal impairment (examples: aminoglycosides, amphotericin B, vancomycin, foscarnet, cisplatin, pentamidine, tacrolimus, cyclosporine, some contrast mediums \[ionic high-osmolar contrast media, ionic low-osmolar contrast media\]
  * Competitors of renal excretion (except temporary use, example: probenecid)
  * Immunosuppressants (examples: azathioprine, cycolphosphamide) or chemotherapeutics (example: etoposide)
  * Glucocorticoid preparation
* Received TDF, Adefovir pivoxil (ADV) or Tenofovir Alafenamide Fumarate (TAF) within 2 years prior to initiation of the study treatment
* Participation in another clinical study within 6 months prior to screening, or planned participation in another clinical study simultaneously with this study.
* Co-infection with human immunodeficiency virus (HIV) or hepatitis C virus (HCV)
* Subjects with serious complication other than compensated CHB (cancer, significant renal, cardiovascular, pulmonary, or neurological disease, uncontrollable diabetes, etc.)
* Received or have a plan for solid organ or bone marrow transplantation
* Has proximal tubulopathy.
* Subjects with decompensated CHB who meet the following: direct bilirubin \> 1.5 times upper limit of normal (ULN), Prothrombin Time (PT) \< 60%, platelets \< 75,000/mm3 and serum albumin \< 3.0 g/dL
* Autoimmune hepatitis (Antinuclear titer \> 1:160), excluding CHB
* Subjects with or suspected of having hepatocellular carcinoma (HCC) (including both primary and metastatic) from diagnostic imaging at screening, or with serum alpha-fetoprotein (AFP) \> 50 nanogram (ng)/mL at screening
* History of HCC (except subjects who underwent resection or received curative treatment by radiofrequency, and with AFP \<=10 ng/mL at screening)
* Woman who is pregnant, possibly pregnant, lactating or planning a pregnancy during the study period.
* Psychiatry disorder or cognitive disorder that may affect the subject's ability to give informed consent or to follow specified study procedures.
* Subjects with a history of alcohol or drug abuse
* Subjects whom the investigator (or sub-investigator) considers ineligible for the study.
* Subjects with hypersensitivity to study treatments or their components, nucleoside and/or nucleotide analogues. Subjects with drug allergy that, in the investigator's (sub-investigator's) \[or medical monitor's\] opinion, labeled contraindication for participation in the study, or other allergy.

Primary outcomes:
measure: Percentage of Participants Who Achieved 0.25 Logarithm to the Base 10 (Log10) Hepatitis B Surface Antigen (HBsAg) Reduction From the Baseline at Week 48
timeFrame: Baseline (Day 1, Pre-dose) and at Week 48
Secondary outcomes:
measure: Percentage of Participants Who Achieved 0.25 Log10 HBsAg Reduction From the Baseline at Weeks 24 and 96
timeFrame: Baseline (Day 1, Pre-dose) and at Weeks 24 and 96
measure: Percentage of Participants Who Achieved HBsAg Loss at Weeks 24, 48 and 96
timeFrame: At Weeks 24, 48 and 96
measure: Percentage of Participants Who Achieved HBsAg/Ab Seroconversion at Weeks 24, 48 and 96
timeFrame: At Weeks 24, 48 and 96
measure: Percentage of Participants Who Achieved HBeAg Loss at Weeks 24, 48 and 96
timeFrame: At Weeks 24, 48 and 96
measure: Percentage of Participants Who Achieved HBeAg/Ab Seroconversion at Weeks 24, 48 and 96
timeFrame: At Weeks 24, 48 and 96
measure: Change From Baseline Log Values for HBsAg Titer at Weeks 24, 48 and 96
timeFrame: Baseline (Day 1, Pre-dose) and at Weeks 24, 48 and 96
measure: Change From Baseline Log Values for HBcrAg Titer at Weeks 24, 48 and 96
timeFrame: Baseline (Day 1, Pre-dose) and at Weeks 24, 48 and 96
measure: Number of Participants Who Reported Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs)
timeFrame: Up to Week 96
measure: Absolute Values for Clinical Chemistry Parameter: Alpha-fetoprotein (AFP)
timeFrame: Baseline (Day 1, Pre-dose) and at Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96
measure: Absolute Values for Clinical Chemistry Parameters: Albumin and Total Protein
timeFrame: Baseline (Day 1, Pre-dose) and at Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96
measure: Absolute Values for Clinical Chemistry Parameters: Alkaline Phosphate (ALP), Alanine Amino Transferase (ALT), Aspartate Amino Transferase (AST), Creatinine Kinase (CPK), Gamma Glutamyl Transferase (GGT) and Lactate Dehydrogenase (LDH)
timeFrame: Baseline (Day 1, Pre-dose) and at Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96
measure: Absolute Values for Clinical Chemistry Parameters: Amylase and Lipase
timeFrame: Baseline (Day 1, Pre-dose) and at Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96
measure: Absolute Values for Clinical Chemistry Parameters: Direct Bilirubin, Total Bilirubin, Creatinine and Uric Acid
timeFrame: Baseline (Day 1, Pre-dose) and at Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96
measure: Absolute Values for Clinical Chemistry Parameters: Calcium, Chloride, Glucose, Potassium, Lactic Acid, Sodium, Phosphorus and Blood Urea Nitrogen (BUN)
timeFrame: Baseline (Day 1, Pre-dose) and at Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96
measure: Absolute Values for Clinical Chemistry Parameter: Creatinine Clearance
timeFrame: Baseline (Day 1, Pre-dose) and at Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96
measure: Absolute Values for Clinical Chemistry Parameter: Glomerular Filtration Rate (GFR)
timeFrame: Baseline (Day 1, Pre-dose) and at Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96
measure: Percentage of Basophils at Indicated Time Points
timeFrame: At Weeks 36, 48, 60, 72, 84 and 96
measure: Percentage of Eosinophils at Indicated Time Points
timeFrame: At Weeks 36 , 48, 60, 72, 84 and 96
measure: Percentage of Lymphocytes at Indicated Time Points
timeFrame: At Weeks 36, 48, 60, 72, 84 and 96
measure: Percentage of Monocytes at Indicated Time Points
timeFrame: At Weeks 36, 48, 60, 72, 84 and 96
measure: Percentage of Total Neutrophils at Indicated Time Points
timeFrame: At Weeks 36, 48, 60, 72, 84 and 96
measure: Absolute Values for Hematology Parameter: Hemoglobin
timeFrame: Baseline (Day 1, Pre-dose) and at Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96
measure: Absolute Values for Hematology Parameter: Hematocrit
timeFrame: Baseline (Day 1, Pre-dose) and at Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96
measure: Absolute Values for Hematology Parameters: Platelet Count and White Blood Cell (WBC) Count
timeFrame: Baseline (Day 1, Pre-dose) and at Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96
measure: Absolute Values for Hematology Parameter: Prothrombin Time
timeFrame: Baseline (Day 1, Pre-dose) and at Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96
measure: Absolute Values for Hematology Parameter: Red Blood Cell (RBC) Count
timeFrame: Baseline (Day 1, Pre-dose) and at Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96
measure: Number of Participants With Abnormal Urinalysis Values at Weeks 4, 12, 24, 36 and 48
timeFrame: Weeks 4, 12, 24, 36 and 48
measure: Number of Participants With Abnormal Urinalysis Values at Weeks 60, 72, 84 and 96
timeFrame: Weeks 60, 72, 84 and 96
measure: Change From Baseline Values for Beta-2-microglobulin
timeFrame: Baseline (Day 1, Pre-dose) and at Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96
measure: Change From Baseline Values for Urine Creatinine Concentration and Urine Phosphate
timeFrame: Baseline (Day 1, Pre-dose) and at Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96
measure: Absolute Values for Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: Baseline (Day 1, Pre-dose) and at Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96
measure: Absolute Values for Heart Rate
timeFrame: Baseline (Day 1, Pre-dose) and at Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96
measure: Absolute Values for Temperature
timeFrame: Baseline (Day 1, Pre-dose) and at Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96
measure: Number of Participants With Worst Case Post-Baseline Electrocardiogram (ECG) Values
timeFrame: Up to Week 96
measure: Change From Baseline Values for Bone Density
timeFrame: Baseline (Day -1) and at Weeks 24, 48, 72 and 96
Other outcomes:
Locations:
city: Aichi
country: Japan
facility: GSK Investigational Site
city: Chiba
country: Japan
facility: GSK Investigational Site
city: Ehime
country: Japan
facility: GSK Investigational Site
city: Ehime
country: Japan
facility: GSK Investigational Site
city: Fukuoka
country: Japan
facility: GSK Investigational Site
city: Fukuoka
country: Japan
facility: GSK Investigational Site
city: Fukuoka
country: Japan
facility: GSK Investigational Site
city: Hiroshima
country: Japan
facility: GSK Investigational Site
city: Hokkaido
country: Japan
facility: GSK Investigational Site
city: Hokkaido
country: Japan
facility: GSK Investigational Site
city: Kanagawa
country: Japan
facility: GSK Investigational Site
city: Kanagawa
country: Japan
facility: GSK Investigational Site
city: Kumamoto
country: Japan
facility: GSK Investigational Site
city: Nagasaki
country: Japan
facility: GSK Investigational Site
city: Osaka
country: Japan
facility: GSK Investigational Site
city: Tokyo
country: Japan
facility: GSK Investigational Site
city: Tokyo
country: Japan
facility: GSK Investigational Site
city: Tottori
country: Japan
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Suzuki F, Suzuki Y, Karino Y, Tanaka Y, Kurosaki M, Yatsuhashi H, Atarashi T, Atsukawa M, Watanabe T, Enomoto M, Kudo M, Maeda N, Kohno H, Joko K, Michitaka K, Miki K, Takahashi K, Ide T, Fujiyama S, Kohno T, Itoh H, Tsukamoto S, Suzuki Y, Kawano Y, Sugiura W, Kumada H. Switching from entecavir to tenofovir disoproxil fumarate for HBeAg-positive chronic hepatitis B patients: a phase 4, prospective study. BMC Gastroenterol. 2021 Dec 20;21(1):489. doi: 10.1186/s12876-021-02008-9.