Chronic Hepatitis B Virus, Pediatric
Conditions
Brief summary
The purpose of this study was to evaluate the safety and efficacy of entecavir in pediatric patients with chronic hepatitis B virus infection
Interventions
DRUGEntecavir
Tablets/oral solution, 0.015 mg/kg up to 0.5 mg, administered orally, once daily, for 96 to144 weeks, depending on response
DRUGPlacebo
Tablets/oral solution, 0 mg, administered orally, once daily, for 48 to 96 weeks, depending on response
Sponsors
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
2 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria * Males and females, aged 2 to \<18 years * Hepatitis B surface antigen-positive * Detectable hepatitis B e (HBe) antigen, and no detectable anti-HBe antibodies * Alanine aminotransferase (ALT) 1.5 to \<10 times the upper limit of normal at screening and within 8 to 24 weeks prior to screening * Evidence of the presence of hepatitis B virus DNA at least 4 weeks before screening and \>100,000 copies/mL at screening Key
Exclusion criteria
* Any prior therapy with entecavir * At least 12 weeks of prior therapy with any nucleoside or nucleotide antiviral agent * Therapy with interferon alpha, thymosin alpha, or nucleototide antiviral agents within 24 weeks of screening * Coinfection with HIV, hepatitis C virus, or hepatitis D virus * Decompensated liver disease * Liver transplant recipients * Other forms of acute and chronic conditions which may cause increased ALT levels * Children who were breastfed while their mothers received lamivudine or whose mothers received lamivudine during pregnancy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieved a Combination of Hepatitis B Virus (HBV) DNA Suppression and Hepatitis B e Antigen (HBeAg) Seroconversion at Week 48 | At Week 48 | Suppression=HBV DNA\<50 IU/mL (approximately 300 copies/mL) using the Roche COBAS TaqMan HBV Test for use with the High Pure System assay; seroconversion=undetectable HBeAg and detectable anti-hepatitis B e antibodies. While the analysis of the primary endpoint was based on a randomized sample size of 123 participants (the Primary Cohort), the size of the overall study population was augmented to 180 randomized participants to meet global regulatory requirements. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Serum Alanine Aminotransferase ≤1*Upper Limit of Normal at Week 48 | At Week 48 | While the analysis of the primary endpoint was based on a randomized sample size of 123 participants (the Primary Cohort), the size of the overall study population was augmented to 180 randomized participants to meet global regulatory requirements. |
| Percentage of Participants With Hepatitis B Virus DNA <Limit of Quantitation (LOQ) at Week 48 | At Week 48 | LOQ=29 IU/mL. While the analysis of the primary endpoint was based on a randomized sample size of 123 participants (the Primary Cohort), the size of the overall study population was augmented to 180 randomized participants to meet global regulatory requirements. |
| Percentage of Participants With Hepatitis B e Antigen (HBeAg) Seroconversion at Week 48 (Undetectable HBeAg and Presence of Anti-HBeAb) | At Week 48 | Percentage of participants in the primary cohort with HBeAg seroconversion (undetectable HBeAg and presence of anti-HBe antibodies) at week 48 |
| Percentage of Participants Who Achieved Sustained HBeAg Seroconversion During Off-treatment Follow up Among Participants Who Achieved HBeAg Seroconversion at End of Dosing (EOD). | Week 48, EOD (2 years) | Participants who demonstrated HBeAg seroconversion at EOD were followed and assessed for presence of sustained HBeAg seroconversion during entire study. The study reached the end of dosing (EOD) on 22 Feb-2016. |
| Number of Participants With Adverse Events (Including Palatability Issues), SAEs, Discontinuous Due to Adverse Events, and HBV Disease Progression Through Week 48 | Day 1 through Week 48 on blinded therapy | AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Related=having certain, probable, possible, or unknown relationship to study drug. Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death. ALT=alanine aminotransferase. |
| Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) | Day 1 through Week 48 on blinded therapy | Toxicities graded per Division of AIDS criteria, Version 1.0, and modified World Health Organization criteria. INR=international normalization ratio of prothrombin time; ULN=upper limit of normal. Hemoglobin (g/dL): Grade 1=10-10.9; Grade 2=9-9.9; Grade 3=7-8.9; Grade 4= \<7. Platelets (/mm\^3): Grade 1=100,000-124,999; Grade 2=50,000-99,999; Grade 3=25,000-49,999; Grade 4= \<25,000. INR (\*ULN): Grade 1=1.1-1.5; Grade 2=1.6-2; Grade 3=2.1-3; Grade 4= \>3. WBC (/mm\^3): Grade 1=2000-2500; Grade 2=1500-1999; Grade 3=1000-1499; Grade 4= \<1000. Neutrophils (/mm\^3): Grade 1=1000-1300; Grade 2=750-999; Grade 3=500-749; Grade 4= \<500. |
| Percentage of Participants With Hepatitis B Virus (HBV) DNA <50 IU/mL at Week 48 | At Week 48 | While the analysis of the primary endpoint was based on a randomized sample size of 123 participants (the Primary Cohort), the size of the overall study population was augmented to 180 randomized participants to meet global regulatory requirements. |
| Percentage of Participants With HBeAg Seroconversion on ETV Over-time at Week 96 (All ETV Cohort) | At Week 96 | HBe seroconversion=undetectable HBe antigen and detectable anti-HBe antibodies. While the analysis of the primary endpoint was based on a randomized sample size of 123 participants (the Primary Cohort), the size of the overall study population was augmented to 180 randomized participants to meet global regulatory requirements. |
| Percentage of Participants Who Maintained HBeAg Seroconversion at Week 96 (End of Blinded Therapy) Among Participants With HBeAg Seroconversion at Week 48 | At Week 96 | Participants who achieved HBeAg seroconversion by Week 48 and maintained seroconversion to week 96 |
| Percentage of Participants With Death as Outcome, Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), Related AEs, Grade 2-4 Related AEs, Grade 3-4 AEs, Malignancies, ALT Flares, and Hepatic Disease Progression Through Week 96 | Day 1 through Week 96 | AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Related=having certain, probable, possible, or unknown relationship to study drug. Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death. ALT=alanine aminotransferase. |
| Percentage of Participants With HBeAg Seroconversion (Undetectable HBeAg and Presence of Anti-HBeAb) up to Week 96 | up to week 96 | On Treatment through week 96 - 2 year cohort NC = F: (The numerator was based on participants meeting the response criteria. The denominator was based on treated participants. Participants who had missing data at the analysis week were considered failures.) |
| Histological Analysis (Percentage) Among Participants With Available Liver Biopsy Data | Between weeks 48 and 96 | Liver function test elevations and abnormalities on blinded and open-label ETV (the All ETV Safety Cohort). Participants who experienced elevation of alanine aminotransferase (ALT) greater than three times ETV (entecavir) baseline measure (Participants who displayed liver biopsy with ALT value greater than three times baseline.) |
| Percentage of Participants With HbeAg Loss at Weeks 48 and 96 | At 48 and 96 weeks | HBeAg Loss (NC = F and NC = M) - On Treatment through Week 96 - Year 2 Efficacy Cohort Non-Completer - Failure (NC=F): The numerator was based on participants meeting the response criteria. The denominator was based on treated participants. Participants who had missing data at the analysis week were considered failures. Non-Completer - Missing (NC=M): The numerator was based on participants meeting the response criteria. The denominator was based on participants with data at the analysis week. Participants who had missing data at the analysis week were excluded. |
| Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) (Continued) | Day 1 through Week 48 on blinded therapy | Toxicities graded per Division of AIDS criteria, Version 1.0, and modified World Health Organization criteria. ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; ULN=upper limit of normal; LLN=lower limit of normal. ALT, AST (\*ULN): Grade 1=1.25-2; Grade 2=2.6-5; Grade 3=5.1-10; Grade 4 =\> 10. Bilirubin (\*ULN): Grade 1 = 1.1-1.5; Grade 2=1.6-2.5; Grade 3 = 2.6-5; Grade 4= \>5. Albumin (g/dL): Grade 1=3- \<LLN; Grade 2=2-2.9; Grade 3= \<2. Lipase (\*ULN): Grade 1=1.1-1.5; Grade 2=1.6-3; Grade 3=3.1-5; Grade 4= \>5. BUN/urea (\*ULN): Grade 1=1.25-\<2.6; Grade 2=2.6-\<5.1; Grade 3=5.1-10; Grade 4= \>10. Chloride, high (mEq/L): Grade 1=113-\<117; Grade 2=117-\<121; Grade 3=121-125; Grade 4= \>125. Potassium, low (mEq/L): Grade 1=3-3.4; Grade 2=2.5-\<3; Grade 3=2-\<2.5; Grade 4=\<2. Potassium, high (mEq/L): : Grade 1= 5.6-\<6.1; Grade 2=6.1-\<6.6; Grade 3=6.6-7; Grade 4= \>7. Sodium, high (mEq/L): Grade 1=146\<151; Grade 2=151-\<155; Grade 3=155-\<160; Grade 4= \>=160. |
Countries
Argentina, Belgium, Canada, Germany, Greece, India, Israel, Poland, Romania, Russia, South Korea, Taiwan, United Kingdom, United States
Participant flow
Pre-assignment details
Of 228 patients enrolled, 43 no longer met study criteria, 4 withdrew consent, and 1 withdrew for surgery. While the primary endpoint analysis was based on a randomized sample size of 123 participants, the overall study population was augmented to 180 to meet global regulatory requirements. All 180 randomized patients received study drug.
Participants by arm
| Arm | Count |
|---|---|
| Entecavir Participants received entecavir, 0.015 mg/kg up to 0.5 mg, once daily, for 96 to 144 weeks, depending on response. | 120 |
| Placebo Participants received placebo, 0 mg, once daily, for 48 to 96 weeks, depending on response | 60 |
| Total | 180 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Day 1 to Week 96 | Adverse Event | 0 | 3 |
| Day 1 to Week 96 | Lost to Follow-up | 1 | 0 |
| Day 1 to Week 96 | Poor compliance or noncompliance | 2 | 0 |
| Day 1 to Week 96 | Pregnancy | 0 | 1 |
| Day 1 to Week 96 | Removal by Medical Monitor | 0 | 1 |
| Day 1 to Week 96 | Subject request to stop study treatment | 1 | 0 |
| Day 1 to Week 96 | Withdrawal by Subject | 3 | 2 |
| Long-term Follow-up: Day 1-End of Study | Investigator Left Institution | 0 | 1 |
| Long-term Follow-up: Day 1-End of Study | Lost to Follow-up | 6 | 6 |
| Long-term Follow-up: Day 1-End of Study | Withdrawal by Subject | 13 | 8 |
Baseline characteristics
| Characteristic | Entecavir | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 10.5 Years STANDARD_DEVIATION 4.87 | 10.8 Years STANDARD_DEVIATION 4.82 | 10.6 Years STANDARD_DEVIATION 4.84 |
| Age, Customized >12 years to <18 years | 62 participants | 31 participants | 93 participants |
| Age, Customized >=2 years to <=6 years | 27 participants | 14 participants | 41 participants |
| Age, Customized >6 years to <=12 years | 31 participants | 15 participants | 46 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 48 Participants | 21 Participants | 69 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 70 Participants | 39 Participants | 109 Participants |
| Race/Ethnicity, Customized Asian | 57 participants | 30 participants | 87 participants |
| Race/Ethnicity, Customized Black/African American | 14 participants | 2 participants | 16 participants |
| Race/Ethnicity, Customized Native Hawaiian/Other Pacific Islander | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Other | 4 participants | 1 participants | 5 participants |
| Race/Ethnicity, Customized White | 44 participants | 27 participants | 71 participants |
| Sex: Female, Male Female | 42 Participants | 29 Participants | 71 Participants |
| Sex: Female, Male Male | 78 Participants | 31 Participants | 109 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 120 | 0 / 60 |
| other Total, other adverse events | 76 / 120 | 45 / 60 |
| serious Total, serious adverse events | 4 / 120 | 9 / 60 |
Outcome results
Primary
Percentage of Participants Who Achieved a Combination of Hepatitis B Virus (HBV) DNA Suppression and Hepatitis B e Antigen (HBeAg) Seroconversion at Week 48
Suppression=HBV DNA\<50 IU/mL (approximately 300 copies/mL) using the Roche COBAS TaqMan HBV Test for use with the High Pure System assay; seroconversion=undetectable HBeAg and detectable anti-hepatitis B e antibodies. While the analysis of the primary endpoint was based on a randomized sample size of 123 participants (the Primary Cohort), the size of the overall study population was augmented to 180 randomized participants to meet global regulatory requirements.
Time frame: At Week 48
Population: The first 123 participants who were randomized and received treatment (referred to as the Primary Cohort)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Entecavir | Percentage of Participants Who Achieved a Combination of Hepatitis B Virus (HBV) DNA Suppression and Hepatitis B e Antigen (HBeAg) Seroconversion at Week 48 | 24.4 Percentage of participants |
| Placebo | Percentage of Participants Who Achieved a Combination of Hepatitis B Virus (HBV) DNA Suppression and Hepatitis B e Antigen (HBeAg) Seroconversion at Week 48 | 2.4 Percentage of participants |
p-value: 0.004995% CI: [9.1, 31.4]Normal approximation
Secondary
Histological Analysis (Percentage) Among Participants With Available Liver Biopsy Data
Liver function test elevations and abnormalities on blinded and open-label ETV (the All ETV Safety Cohort). Participants who experienced elevation of alanine aminotransferase (ALT) greater than three times ETV (entecavir) baseline measure (Participants who displayed liver biopsy with ALT value greater than three times baseline.)
Time frame: Between weeks 48 and 96
Population: Randomized ETV subjects combined with PBO-randomized participants who received open-label ETV
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Entecavir | Histological Analysis (Percentage) Among Participants With Available Liver Biopsy Data | 5.9 Percentage of participants |
Secondary
Number of Participants With Adverse Events (Including Palatability Issues), SAEs, Discontinuous Due to Adverse Events, and HBV Disease Progression Through Week 48
AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Related=having certain, probable, possible, or unknown relationship to study drug. Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death. ALT=alanine aminotransferase.
Time frame: Day 1 through Week 48 on blinded therapy
Population: All treated participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Entecavir | Number of Participants With Adverse Events (Including Palatability Issues), SAEs, Discontinuous Due to Adverse Events, and HBV Disease Progression Through Week 48 | Deaths | 0 participants |
| Entecavir | Number of Participants With Adverse Events (Including Palatability Issues), SAEs, Discontinuous Due to Adverse Events, and HBV Disease Progression Through Week 48 | Serious Adverse Events | 4 participants |
| Entecavir | Number of Participants With Adverse Events (Including Palatability Issues), SAEs, Discontinuous Due to Adverse Events, and HBV Disease Progression Through Week 48 | Discontinuation due to Adverse Event | 0 participants |
| Entecavir | Number of Participants With Adverse Events (Including Palatability Issues), SAEs, Discontinuous Due to Adverse Events, and HBV Disease Progression Through Week 48 | any adverse event | 78 participants |
| Entecavir | Number of Participants With Adverse Events (Including Palatability Issues), SAEs, Discontinuous Due to Adverse Events, and HBV Disease Progression Through Week 48 | Related Adverse Events | 11 participants |
| Entecavir | Number of Participants With Adverse Events (Including Palatability Issues), SAEs, Discontinuous Due to Adverse Events, and HBV Disease Progression Through Week 48 | Related Grade 2 - 4 Adverse Events | 4 participants |
| Entecavir | Number of Participants With Adverse Events (Including Palatability Issues), SAEs, Discontinuous Due to Adverse Events, and HBV Disease Progression Through Week 48 | Grade 3 - 4 Adverse Events | 4 participants |
| Entecavir | Number of Participants With Adverse Events (Including Palatability Issues), SAEs, Discontinuous Due to Adverse Events, and HBV Disease Progression Through Week 48 | ALT Flares | 2 participants |
| Entecavir | Number of Participants With Adverse Events (Including Palatability Issues), SAEs, Discontinuous Due to Adverse Events, and HBV Disease Progression Through Week 48 | HBV disease progression | 0 participants |
| Entecavir | Number of Participants With Adverse Events (Including Palatability Issues), SAEs, Discontinuous Due to Adverse Events, and HBV Disease Progression Through Week 48 | Malignant neoplasms or pre-malignant lesions | 0 participants |
| Placebo | Number of Participants With Adverse Events (Including Palatability Issues), SAEs, Discontinuous Due to Adverse Events, and HBV Disease Progression Through Week 48 | ALT Flares | 5 participants |
| Placebo | Number of Participants With Adverse Events (Including Palatability Issues), SAEs, Discontinuous Due to Adverse Events, and HBV Disease Progression Through Week 48 | Deaths | 0 participants |
| Placebo | Number of Participants With Adverse Events (Including Palatability Issues), SAEs, Discontinuous Due to Adverse Events, and HBV Disease Progression Through Week 48 | Related Grade 2 - 4 Adverse Events | 2 participants |
| Placebo | Number of Participants With Adverse Events (Including Palatability Issues), SAEs, Discontinuous Due to Adverse Events, and HBV Disease Progression Through Week 48 | Serious Adverse Events | 7 participants |
| Placebo | Number of Participants With Adverse Events (Including Palatability Issues), SAEs, Discontinuous Due to Adverse Events, and HBV Disease Progression Through Week 48 | Malignant neoplasms or pre-malignant lesions | 0 participants |
| Placebo | Number of Participants With Adverse Events (Including Palatability Issues), SAEs, Discontinuous Due to Adverse Events, and HBV Disease Progression Through Week 48 | Discontinuation due to Adverse Event | 2 participants |
| Placebo | Number of Participants With Adverse Events (Including Palatability Issues), SAEs, Discontinuous Due to Adverse Events, and HBV Disease Progression Through Week 48 | Grade 3 - 4 Adverse Events | 3 participants |
| Placebo | Number of Participants With Adverse Events (Including Palatability Issues), SAEs, Discontinuous Due to Adverse Events, and HBV Disease Progression Through Week 48 | any adverse event | 46 participants |
| Placebo | Number of Participants With Adverse Events (Including Palatability Issues), SAEs, Discontinuous Due to Adverse Events, and HBV Disease Progression Through Week 48 | HBV disease progression | 0 participants |
| Placebo | Number of Participants With Adverse Events (Including Palatability Issues), SAEs, Discontinuous Due to Adverse Events, and HBV Disease Progression Through Week 48 | Related Adverse Events | 6 participants |
Secondary
Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4)
Toxicities graded per Division of AIDS criteria, Version 1.0, and modified World Health Organization criteria. INR=international normalization ratio of prothrombin time; ULN=upper limit of normal. Hemoglobin (g/dL): Grade 1=10-10.9; Grade 2=9-9.9; Grade 3=7-8.9; Grade 4= \<7. Platelets (/mm\^3): Grade 1=100,000-124,999; Grade 2=50,000-99,999; Grade 3=25,000-49,999; Grade 4= \<25,000. INR (\*ULN): Grade 1=1.1-1.5; Grade 2=1.6-2; Grade 3=2.1-3; Grade 4= \>3. WBC (/mm\^3): Grade 1=2000-2500; Grade 2=1500-1999; Grade 3=1000-1499; Grade 4= \<1000. Neutrophils (/mm\^3): Grade 1=1000-1300; Grade 2=750-999; Grade 3=500-749; Grade 4= \<500.
Time frame: Day 1 through Week 48 on blinded therapy
Population: All treated subjects
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Entecavir | Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) | Platelets | 3 Participants |
| Entecavir | Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) | White blood cells (WBC) | 2 Participants |
| Entecavir | Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) | INR | 2 Participants |
| Entecavir | Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) | Neutrophils + bands (absolute) | 14 Participants |
| Entecavir | Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) | Hemoglobin | 5 Participants |
| Placebo | Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) | Neutrophils + bands (absolute) | 2 Participants |
| Placebo | Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) | Hemoglobin | 4 Participants |
| Placebo | Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) | Platelets | 2 Participants |
| Placebo | Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) | INR | 6 Participants |
| Placebo | Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) | White blood cells (WBC) | 1 Participants |
Secondary
Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) (Continued)
Toxicities graded per Division of AIDS criteria, Version 1.0, and modified World Health Organization criteria. ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; ULN=upper limit of normal; LLN=lower limit of normal. ALT, AST (\*ULN): Grade 1=1.25-2; Grade 2=2.6-5; Grade 3=5.1-10; Grade 4 =\> 10. Bilirubin (\*ULN): Grade 1 = 1.1-1.5; Grade 2=1.6-2.5; Grade 3 = 2.6-5; Grade 4= \>5. Albumin (g/dL): Grade 1=3- \<LLN; Grade 2=2-2.9; Grade 3= \<2. Lipase (\*ULN): Grade 1=1.1-1.5; Grade 2=1.6-3; Grade 3=3.1-5; Grade 4= \>5. BUN/urea (\*ULN): Grade 1=1.25-\<2.6; Grade 2=2.6-\<5.1; Grade 3=5.1-10; Grade 4= \>10. Chloride, high (mEq/L): Grade 1=113-\<117; Grade 2=117-\<121; Grade 3=121-125; Grade 4= \>125. Potassium, low (mEq/L): Grade 1=3-3.4; Grade 2=2.5-\<3; Grade 3=2-\<2.5; Grade 4=\<2. Potassium, high (mEq/L): : Grade 1= 5.6-\<6.1; Grade 2=6.1-\<6.6; Grade 3=6.6-7; Grade 4= \>7. Sodium, high (mEq/L): Grade 1=146\<151; Grade 2=151-\<155; Grade 3=155-\<160; Grade 4= \>=160.
Time frame: Day 1 through Week 48 on blinded therapy
Population: All randomized participants who received at least 1 dose of study medication
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Entecavir | Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) (Continued) | ALT | 113 participants |
| Entecavir | Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) (Continued) | AST | 87 participants |
| Entecavir | Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) (Continued) | Total bilirubin | 5 participants |
| Entecavir | Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) (Continued) | Albumin | 0 participants |
| Entecavir | Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) (Continued) | Lipase | 38 participants |
| Entecavir | Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) (Continued) | BUN/Urea | 10 participants |
| Entecavir | Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) (Continued) | Chloride, high | 2 participants |
| Entecavir | Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) (Continued) | Potassium, low | 1 participants |
| Entecavir | Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) (Continued) | Potassium, high | 1 participants |
| Entecavir | Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) (Continued) | Sodium, high | 8 participants |
| Placebo | Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) (Continued) | Potassium, low | 1 participants |
| Placebo | Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) (Continued) | ALT | 59 participants |
| Placebo | Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) (Continued) | BUN/Urea | 2 participants |
| Placebo | Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) (Continued) | AST | 51 participants |
| Placebo | Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) (Continued) | Sodium, high | 4 participants |
| Placebo | Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) (Continued) | Total bilirubin | 6 participants |
| Placebo | Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) (Continued) | Chloride, high | 1 participants |
| Placebo | Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) (Continued) | Albumin | 1 participants |
| Placebo | Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) (Continued) | Potassium, high | 0 participants |
| Placebo | Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) (Continued) | Lipase | 20 participants |
Secondary
Percentage of Participants Who Achieved Sustained HBeAg Seroconversion During Off-treatment Follow up Among Participants Who Achieved HBeAg Seroconversion at End of Dosing (EOD).
Participants who demonstrated HBeAg seroconversion at EOD were followed and assessed for presence of sustained HBeAg seroconversion during entire study. The study reached the end of dosing (EOD) on 22 Feb-2016.
Time frame: Week 48, EOD (2 years)
Population: Participants who achieved HBeAg seroconversion at end of treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Entecavir | Percentage of Participants Who Achieved Sustained HBeAg Seroconversion During Off-treatment Follow up Among Participants Who Achieved HBeAg Seroconversion at End of Dosing (EOD). | EOD (end of dosing) | 100.0 Percentage of participants |
| Entecavir | Percentage of Participants Who Achieved Sustained HBeAg Seroconversion During Off-treatment Follow up Among Participants Who Achieved HBeAg Seroconversion at End of Dosing (EOD). | Week 48 | 74.4 Percentage of participants |
| Placebo | Percentage of Participants Who Achieved Sustained HBeAg Seroconversion During Off-treatment Follow up Among Participants Who Achieved HBeAg Seroconversion at End of Dosing (EOD). | EOD (end of dosing) | 100.0 Percentage of participants |
| Placebo | Percentage of Participants Who Achieved Sustained HBeAg Seroconversion During Off-treatment Follow up Among Participants Who Achieved HBeAg Seroconversion at End of Dosing (EOD). | Week 48 | 59.1 Percentage of participants |
Secondary
Percentage of Participants Who Maintained HBeAg Seroconversion at Week 96 (End of Blinded Therapy) Among Participants With HBeAg Seroconversion at Week 48
Participants who achieved HBeAg seroconversion by Week 48 and maintained seroconversion to week 96
Time frame: At Week 96
Population: participants with HBeAg seroconversion at Week 48
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Entecavir | Percentage of Participants Who Maintained HBeAg Seroconversion at Week 96 (End of Blinded Therapy) Among Participants With HBeAg Seroconversion at Week 48 | Week 48 | 24.2 Percentage of participants |
| Entecavir | Percentage of Participants Who Maintained HBeAg Seroconversion at Week 96 (End of Blinded Therapy) Among Participants With HBeAg Seroconversion at Week 48 | Week 96 | 36.7 Percentage of participants |
| Placebo | Percentage of Participants Who Maintained HBeAg Seroconversion at Week 96 (End of Blinded Therapy) Among Participants With HBeAg Seroconversion at Week 48 | Week 48 | 10.0 Percentage of participants |
| Placebo | Percentage of Participants Who Maintained HBeAg Seroconversion at Week 96 (End of Blinded Therapy) Among Participants With HBeAg Seroconversion at Week 48 | Week 96 | 20.0 Percentage of participants |
Secondary
Percentage of Participants With Death as Outcome, Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), Related AEs, Grade 2-4 Related AEs, Grade 3-4 AEs, Malignancies, ALT Flares, and Hepatic Disease Progression Through Week 96
AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Related=having certain, probable, possible, or unknown relationship to study drug. Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death. ALT=alanine aminotransferase.
Time frame: Day 1 through Week 96
Population: All treated participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Entecavir | Percentage of Participants With Death as Outcome, Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), Related AEs, Grade 2-4 Related AEs, Grade 3-4 AEs, Malignancies, ALT Flares, and Hepatic Disease Progression Through Week 96 | Deaths | 0 Percentage of participants |
| Entecavir | Percentage of Participants With Death as Outcome, Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), Related AEs, Grade 2-4 Related AEs, Grade 3-4 AEs, Malignancies, ALT Flares, and Hepatic Disease Progression Through Week 96 | SAEs | 4.7 Percentage of participants |
| Entecavir | Percentage of Participants With Death as Outcome, Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), Related AEs, Grade 2-4 Related AEs, Grade 3-4 AEs, Malignancies, ALT Flares, and Hepatic Disease Progression Through Week 96 | Discontinuations due to AEs | 0.6 Percentage of participants |
| Entecavir | Percentage of Participants With Death as Outcome, Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), Related AEs, Grade 2-4 Related AEs, Grade 3-4 AEs, Malignancies, ALT Flares, and Hepatic Disease Progression Through Week 96 | Related AEs | 8.2 Percentage of participants |
| Entecavir | Percentage of Participants With Death as Outcome, Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), Related AEs, Grade 2-4 Related AEs, Grade 3-4 AEs, Malignancies, ALT Flares, and Hepatic Disease Progression Through Week 96 | Grade 2-4 Related AEs | 2.3 Percentage of participants |
| Entecavir | Percentage of Participants With Death as Outcome, Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), Related AEs, Grade 2-4 Related AEs, Grade 3-4 AEs, Malignancies, ALT Flares, and Hepatic Disease Progression Through Week 96 | Grade 3-4 AEs | 4.1 Percentage of participants |
| Entecavir | Percentage of Participants With Death as Outcome, Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), Related AEs, Grade 2-4 Related AEs, Grade 3-4 AEs, Malignancies, ALT Flares, and Hepatic Disease Progression Through Week 96 | Malignancies | 0 Percentage of participants |
| Entecavir | Percentage of Participants With Death as Outcome, Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), Related AEs, Grade 2-4 Related AEs, Grade 3-4 AEs, Malignancies, ALT Flares, and Hepatic Disease Progression Through Week 96 | ALT flares | 1.8 Percentage of participants |
| Entecavir | Percentage of Participants With Death as Outcome, Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), Related AEs, Grade 2-4 Related AEs, Grade 3-4 AEs, Malignancies, ALT Flares, and Hepatic Disease Progression Through Week 96 | Hepatic disease progression | 0 Percentage of participants |
Secondary
Percentage of Participants With HbeAg Loss at Weeks 48 and 96
HBeAg Loss (NC = F and NC = M) - On Treatment through Week 96 - Year 2 Efficacy Cohort Non-Completer - Failure (NC=F): The numerator was based on participants meeting the response criteria. The denominator was based on treated participants. Participants who had missing data at the analysis week were considered failures. Non-Completer - Missing (NC=M): The numerator was based on participants meeting the response criteria. The denominator was based on participants with data at the analysis week. Participants who had missing data at the analysis week were excluded.
Time frame: At 48 and 96 weeks
Population: Participants with response rates at weeks 48 and 96 in Entecavir (ETV) and Placebo (PBO) randomized cohort
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Entecavir | Percentage of Participants With HbeAg Loss at Weeks 48 and 96 | 48 weeks | 25.0 Percentage of participants |
| Entecavir | Percentage of Participants With HbeAg Loss at Weeks 48 and 96 | 96 Weeks | 40.8 Percentage of participants |
| Placebo | Percentage of Participants With HbeAg Loss at Weeks 48 and 96 | 48 weeks | 10.0 Percentage of participants |
Secondary
Percentage of Participants With HBeAg Seroconversion on ETV Over-time at Week 96 (All ETV Cohort)
HBe seroconversion=undetectable HBe antigen and detectable anti-HBe antibodies. While the analysis of the primary endpoint was based on a randomized sample size of 123 participants (the Primary Cohort), the size of the overall study population was augmented to 180 randomized participants to meet global regulatory requirements.
Time frame: At Week 96
Population: Randomized ETV subjects combined with PBO-randomized participants who received open-label ETV
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Entecavir | Percentage of Participants With HBeAg Seroconversion on ETV Over-time at Week 96 (All ETV Cohort) | 38.6 Percentage of participants |
Secondary
Percentage of Participants With HBeAg Seroconversion (Undetectable HBeAg and Presence of Anti-HBeAb) up to Week 96
On Treatment through week 96 - 2 year cohort NC = F: (The numerator was based on participants meeting the response criteria. The denominator was based on treated participants. Participants who had missing data at the analysis week were considered failures.)
Time frame: up to week 96
Population: All randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Entecavir | Percentage of Participants With HBeAg Seroconversion (Undetectable HBeAg and Presence of Anti-HBeAb) up to Week 96 | 40.8 Percentage of participants |
Secondary
Percentage of Participants With Hepatitis B e Antigen (HBeAg) Seroconversion at Week 48 (Undetectable HBeAg and Presence of Anti-HBeAb)
Percentage of participants in the primary cohort with HBeAg seroconversion (undetectable HBeAg and presence of anti-HBe antibodies) at week 48
Time frame: At Week 48
Population: The first 123 participants who were randomized and received treatment (referred to as the Primary Cohort)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Entecavir | Percentage of Participants With Hepatitis B e Antigen (HBeAg) Seroconversion at Week 48 (Undetectable HBeAg and Presence of Anti-HBeAb) | 24.4 Percentage of participants |
| Placebo | Percentage of Participants With Hepatitis B e Antigen (HBeAg) Seroconversion at Week 48 (Undetectable HBeAg and Presence of Anti-HBeAb) | 12.2 Percentage of participants |
p-value: 0.1195% CI: [-1.5, 25.7]Normal approximation
Secondary
Percentage of Participants With Hepatitis B Virus DNA <Limit of Quantitation (LOQ) at Week 48
LOQ=29 IU/mL. While the analysis of the primary endpoint was based on a randomized sample size of 123 participants (the Primary Cohort), the size of the overall study population was augmented to 180 randomized participants to meet global regulatory requirements.
Time frame: At Week 48
Population: The first 123 participants who were randomized and received treatment (referred to as the Primary Cohort)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Entecavir | Percentage of Participants With Hepatitis B Virus DNA <Limit of Quantitation (LOQ) at Week 48 | 42.7 Percentage of participants |
| Placebo | Percentage of Participants With Hepatitis B Virus DNA <Limit of Quantitation (LOQ) at Week 48 | 2.4 Percentage of participants |
p-value: <0.000195% CI: [25.9, 50.5]Normal approximation
Secondary
Percentage of Participants With Hepatitis B Virus (HBV) DNA <50 IU/mL at Week 48
While the analysis of the primary endpoint was based on a randomized sample size of 123 participants (the Primary Cohort), the size of the overall study population was augmented to 180 randomized participants to meet global regulatory requirements.
Time frame: At Week 48
Population: The first 123 participants who were randomized and received treatment (referred to as the Primary Cohort)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Entecavir | Percentage of Participants With Hepatitis B Virus (HBV) DNA <50 IU/mL at Week 48 | 46.3 Percentage of participants |
| Placebo | Percentage of Participants With Hepatitis B Virus (HBV) DNA <50 IU/mL at Week 48 | 2.4 Percentage of participants |
p-value: <0.000195% CI: [29.4, 54.2]Normal approximation
Secondary
Percentage of Participants With Serum Alanine Aminotransferase ≤1*Upper Limit of Normal at Week 48
While the analysis of the primary endpoint was based on a randomized sample size of 123 participants (the Primary Cohort), the size of the overall study population was augmented to 180 randomized participants to meet global regulatory requirements.
Time frame: At Week 48
Population: The first 123 participants who were randomized and received treatment (referred to as the Primary Cohort)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Entecavir | Percentage of Participants With Serum Alanine Aminotransferase ≤1*Upper Limit of Normal at Week 48 | 67.1 Percentage of participants |
| Placebo | Percentage of Participants With Serum Alanine Aminotransferase ≤1*Upper Limit of Normal at Week 48 | 22.0 Percentage of participants |
p-value: <0.000195% CI: [29.2, 61.2]Normal approximation