Trial Outcomes & Findings for A Phase III Study of the Safety and Efficacy of Entecavir in Pediatric Patients With Chronic Hepatitis B Virus Infection (NCT NCT01079806)

NCT ID: NCT01079806

Last Updated: 2019-05-09

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 180 participants
• Primary outcome timeframe: At Week 48
• Results posted on: 2019-05-09

Participant Flow

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.

Participant milestones

Measure	Entecavir Participants received entecavir, 0.015 mg/kg up to 0.5 mg, once daily, for 96 to 144 weeks, depending on response.	Placebo Participants received placebo, 0 mg, once daily, for 48 to 96 weeks, depending on response
Day 1 to Week 96 STARTED	120	60
Day 1 to Week 96 Received Treatment	120	60
Day 1 to Week 96 Primary Endpoint Cohort	82	41
Day 1 to Week 96 COMPLETED	113	53
Day 1 to Week 96 NOT COMPLETED	7	7
Long-term Follow-up: Day 1-End of Study STARTED	111	58
Long-term Follow-up: Day 1-End of Study COMPLETED	92	43
Long-term Follow-up: Day 1-End of Study NOT COMPLETED	19	15

Reasons for withdrawal

Measure	Entecavir Participants received entecavir, 0.015 mg/kg up to 0.5 mg, once daily, for 96 to 144 weeks, depending on response.	Placebo Participants received placebo, 0 mg, once daily, for 48 to 96 weeks, depending on response
Day 1 to Week 96 Adverse Event	0	3
Day 1 to Week 96 Withdrawal by Subject	3	2
Day 1 to Week 96 Pregnancy	0	1
Day 1 to Week 96 Poor compliance or noncompliance	2	0
Day 1 to Week 96 Lost to Follow-up	1	0
Day 1 to Week 96 Subject request to stop study treatment	1	0
Day 1 to Week 96 Removal by Medical Monitor	0	1
Long-term Follow-up: Day 1-End of Study Withdrawal by Subject	13	8
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

Baseline Characteristics

A Phase III Study of the Safety and Efficacy of Entecavir in Pediatric Patients With Chronic Hepatitis B Virus Infection

Baseline characteristics by cohort

Measure	Entecavir n=120 Participants Participants received entecavir, 0.015 mg/kg up to 0.5 mg, once daily, for 96 to 144 weeks, depending on response.	Placebo n=60 Participants Participants received placebo, 0 mg, once daily, for 48 to 96 weeks, depending on response	Total n=180 Participants Total of all reporting groups
Age, Continuous	10.5 Years STANDARD_DEVIATION 4.87 • n=5 Participants	10.8 Years STANDARD_DEVIATION 4.82 • n=7 Participants	10.6 Years STANDARD_DEVIATION 4.84 • n=5 Participants
Age, Customized >=2 years to <=6 years	27 participants n=5 Participants	14 participants n=7 Participants	41 participants n=5 Participants
Age, Customized >6 years to <=12 years	31 participants n=5 Participants	15 participants n=7 Participants	46 participants n=5 Participants
Age, Customized >12 years to <18 years	62 participants n=5 Participants	31 participants n=7 Participants	93 participants n=5 Participants
Sex: Female, Male Female	42 Participants n=5 Participants	29 Participants n=7 Participants	71 Participants n=5 Participants
Sex: Female, Male Male	78 Participants n=5 Participants	31 Participants n=7 Participants	109 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	48 Participants n=5 Participants	21 Participants n=7 Participants	69 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	70 Participants n=5 Participants	39 Participants n=7 Participants	109 Participants n=5 Participants
Race/Ethnicity, Customized Asian	57 participants n=5 Participants	30 participants n=7 Participants	87 participants n=5 Participants
Race/Ethnicity, Customized Black/African American	14 participants n=5 Participants	2 participants n=7 Participants	16 participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian/Other Pacific Islander	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants
Race/Ethnicity, Customized White	44 participants n=5 Participants	27 participants n=7 Participants	71 participants n=5 Participants
Race/Ethnicity, Customized Other	4 participants n=5 Participants	1 participants n=7 Participants	5 participants n=5 Participants

PRIMARY outcome

Timeframe: At Week 48

Population: The first 123 participants who were randomized and received treatment (referred to as the Primary Cohort)

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.

Outcome measures

Measure	Entecavir n=82 Participants Participants received entecavir, 0.015 mg/kg up to 0.5 mg, once daily, for 96 to 144 weeks, depending on response.	Placebo n=41 Participants Participants received placebo, 0 mg, once daily, for 48 to 96 weeks, depending on response
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	2.4 Percentage of participants

SECONDARY outcome

Timeframe: At Week 48

Population: The first 123 participants who were randomized and received treatment (referred to as the Primary Cohort)

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.

Outcome measures

Measure	Entecavir n=82 Participants Participants received entecavir, 0.015 mg/kg up to 0.5 mg, once daily, for 96 to 144 weeks, depending on response.	Placebo n=41 Participants Participants received placebo, 0 mg, once daily, for 48 to 96 weeks, depending on response
Percentage of Participants With Hepatitis B Virus (HBV) DNA <50 IU/mL at Week 48	46.3 Percentage of participants	2.4 Percentage of participants

SECONDARY outcome

Timeframe: At Week 48

Population: The first 123 participants who were randomized and received treatment (referred to as the Primary Cohort)

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.

Outcome measures

Measure	Entecavir n=82 Participants Participants received entecavir, 0.015 mg/kg up to 0.5 mg, once daily, for 96 to 144 weeks, depending on response.	Placebo n=41 Participants Participants received placebo, 0 mg, once daily, for 48 to 96 weeks, depending on response
Percentage of Participants With Serum Alanine Aminotransferase ≤1*Upper Limit of Normal at Week 48	67.1 Percentage of participants	22.0 Percentage of participants

SECONDARY outcome

Timeframe: At Week 48

Population: The first 123 participants who were randomized and received treatment (referred to as the Primary Cohort)

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.

Outcome measures

Measure	Entecavir n=82 Participants Participants received entecavir, 0.015 mg/kg up to 0.5 mg, once daily, for 96 to 144 weeks, depending on response.	Placebo n=41 Participants Participants received placebo, 0 mg, once daily, for 48 to 96 weeks, depending on response
Percentage of Participants With Hepatitis B Virus DNA <Limit of Quantitation (LOQ) at Week 48	42.7 Percentage of participants	2.4 Percentage of participants

SECONDARY outcome

Timeframe: At Week 48

Population: The first 123 participants who were randomized and received treatment (referred to as the Primary Cohort)

Percentage of participants in the primary cohort with HBeAg seroconversion (undetectable HBeAg and presence of anti-HBe antibodies) at week 48

Outcome measures

Measure	Entecavir n=82 Participants Participants received entecavir, 0.015 mg/kg up to 0.5 mg, once daily, for 96 to 144 weeks, depending on response.	Placebo n=41 Participants Participants received placebo, 0 mg, once daily, for 48 to 96 weeks, depending on response
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	12.2 Percentage of participants

SECONDARY outcome

Timeframe: Week 48, EOD (2 years)

Population: Participants who achieved HBeAg seroconversion at end of treatment.

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.

Outcome measures

Measure	Entecavir n=39 Participants Participants received entecavir, 0.015 mg/kg up to 0.5 mg, once daily, for 96 to 144 weeks, depending on response.	Placebo n=22 Participants Participants received placebo, 0 mg, once daily, for 48 to 96 weeks, depending on response
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	100.0 Percentage of participants
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	59.1 Percentage of participants

SECONDARY outcome

Timeframe: Day 1 through Week 48 on blinded therapy

Population: All treated participants

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.

Outcome measures

Measure	Entecavir n=120 Participants Participants received entecavir, 0.015 mg/kg up to 0.5 mg, once daily, for 96 to 144 weeks, depending on response.	Placebo n=60 Participants Participants received placebo, 0 mg, once daily, for 48 to 96 weeks, depending on response
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	0 participants
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	7 participants
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	2 participants
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	46 participants
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	6 participants
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	2 participants
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	3 participants
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	5 participants
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	0 participants
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	0 participants

SECONDARY outcome

Timeframe: Day 1 through Week 48 on blinded therapy

Population: All treated subjects

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.

Outcome measures

Measure	Entecavir n=120 Participants Participants received entecavir, 0.015 mg/kg up to 0.5 mg, once daily, for 96 to 144 weeks, depending on response.	Placebo n=60 Participants Participants received placebo, 0 mg, once daily, for 48 to 96 weeks, depending on response
Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) Hemoglobin	5 Participants	4 Participants
Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) Platelets	3 Participants	2 Participants
Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) INR	2 Participants	6 Participants
Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) White blood cells (WBC)	2 Participants	1 Participants
Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) Neutrophils + bands (absolute)	14 Participants	2 Participants

SECONDARY outcome

Timeframe: Day 1 through Week 48 on blinded therapy

Population: All randomized participants who received at least 1 dose of study medication

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.

Outcome measures

Measure	Entecavir n=120 Participants Participants received entecavir, 0.015 mg/kg up to 0.5 mg, once daily, for 96 to 144 weeks, depending on response.	Placebo n=60 Participants Participants received placebo, 0 mg, once daily, for 48 to 96 weeks, depending on response
Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) (Continued) ALT	113 participants	59 participants
Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) (Continued) AST	87 participants	51 participants
Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) (Continued) Total bilirubin	5 participants	6 participants
Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) (Continued) Albumin	0 participants	1 participants
Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) (Continued) Lipase	38 participants	20 participants
Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) (Continued) BUN/Urea	10 participants	2 participants
Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) (Continued) Chloride, high	2 participants	1 participants
Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) (Continued) Potassium, low	1 participants	1 participants
Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) (Continued) Potassium, high	1 participants	0 participants
Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) (Continued) Sodium, high	8 participants	4 participants

SECONDARY outcome

Timeframe: At Week 96

Population: Randomized ETV subjects combined with PBO-randomized participants who received open-label ETV

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.

Outcome measures

Measure	Entecavir n=171 Participants Participants received entecavir, 0.015 mg/kg up to 0.5 mg, once daily, for 96 to 144 weeks, depending on response.	Placebo Participants received placebo, 0 mg, once daily, for 48 to 96 weeks, depending on response
Percentage of Participants With HBeAg Seroconversion on ETV Over-time at Week 96 (All ETV Cohort)	38.6 Percentage of participants	—

SECONDARY outcome

Timeframe: At Week 96

Population: participants with HBeAg seroconversion at Week 48

Participants who achieved HBeAg seroconversion by Week 48 and maintained seroconversion to week 96

Outcome measures

Measure	Entecavir n=120 Participants Participants received entecavir, 0.015 mg/kg up to 0.5 mg, once daily, for 96 to 144 weeks, depending on response.	Placebo n=60 Participants Participants received placebo, 0 mg, once daily, for 48 to 96 weeks, depending on response
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	20.0 Percentage of participants
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	10.0 Percentage of participants

SECONDARY outcome

Timeframe: Day 1 through Week 96

Population: All treated participants

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.

Outcome measures

Measure	Entecavir n=171 Participants Participants received entecavir, 0.015 mg/kg up to 0.5 mg, once daily, for 96 to 144 weeks, depending on response.	Placebo Participants received placebo, 0 mg, once daily, for 48 to 96 weeks, depending on response
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	—
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	—
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	—
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	—
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	—
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	—
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	—
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	—
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 outcome

Timeframe: up to week 96

Population: All randomized participants who received at least 1 dose of study drug.

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.)

Outcome measures

Measure	Entecavir n=120 Participants Participants received entecavir, 0.015 mg/kg up to 0.5 mg, once daily, for 96 to 144 weeks, depending on response.	Placebo Participants received placebo, 0 mg, once daily, for 48 to 96 weeks, depending on response
Percentage of Participants With HBeAg Seroconversion (Undetectable HBeAg and Presence of Anti-HBeAb) up to Week 96	40.8 Percentage of participants	—

SECONDARY outcome

Timeframe: Between weeks 48 and 96

Population: Randomized ETV subjects combined with PBO-randomized participants who received open-label ETV

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.)

Outcome measures

Measure	Entecavir n=171 Participants Participants received entecavir, 0.015 mg/kg up to 0.5 mg, once daily, for 96 to 144 weeks, depending on response.	Placebo Participants received placebo, 0 mg, once daily, for 48 to 96 weeks, depending on response
Histological Analysis (Percentage) Among Participants With Available Liver Biopsy Data	5.9 Percentage of participants	—

SECONDARY outcome

Timeframe: At 48 and 96 weeks

Population: Participants with response rates at weeks 48 and 96 in Entecavir (ETV) and Placebo (PBO) randomized cohort

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.

Outcome measures

Measure	Entecavir n=120 Participants Participants received entecavir, 0.015 mg/kg up to 0.5 mg, once daily, for 96 to 144 weeks, depending on response.	Placebo n=60 Participants Participants received placebo, 0 mg, once daily, for 48 to 96 weeks, depending on response
Percentage of Participants With HbeAg Loss at Weeks 48 and 96 48 weeks	25.0 Percentage of participants	10.0 Percentage of participants
Percentage of Participants With HbeAg Loss at Weeks 48 and 96 96 Weeks	40.8 Percentage of participants	—

Adverse Events

ETV (Entecavir)

Serious events: 4 serious events

Other events: 76 other events

Deaths: 0 deaths

PLACEBO

Serious events: 9 serious events

Other events: 45 other events

Deaths: 0 deaths

Serious adverse events

Measure	ETV (Entecavir) n=120 participants at risk Subjects received 0.015 milligram per kilogram per day (mg/kg/day) (up to a maximum dose of 0.5 mg/day) ETV as oral solution or tablets, once daily (QD).	PLACEBO n=60 participants at risk Subjects received ETV matched placebo as oral solution or tablets, QD.
Congenital, familial and genetic disorders Hydrocele	0.83% 1/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	0.00% 0/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
Gastrointestinal disorders Gastritis	0.00% 0/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	1.7% 1/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
Gastrointestinal disorders Inflammatory bowel disease	0.00% 0/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	1.7% 1/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
Hepatobiliary disorders Hepatic function abnormal	0.00% 0/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	3.3% 2/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
Infections and infestations Bronchitis	0.83% 1/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	0.00% 0/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
Infections and infestations Cellulitis	0.00% 0/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	1.7% 1/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
Infections and infestations Chronic hepatitis b	0.00% 0/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	1.7% 1/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
Infections and infestations Ear infection	0.83% 1/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	0.00% 0/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
Infections and infestations Infectious colitis	0.00% 0/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	1.7% 1/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
Infections and infestations Mastoiditis	0.00% 0/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	1.7% 1/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
Infections and infestations Pharyngitis	0.00% 0/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	1.7% 1/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
Metabolism and nutrition disorders Diabetic ketoacidosis	0.00% 0/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	1.7% 1/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	1.7% 1/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
Musculoskeletal and connective tissue disorders Juvenile idiopathic arthritis	0.00% 0/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	1.7% 1/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
Psychiatric disorders Schizophrenia	0.00% 0/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	1.7% 1/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
Respiratory, thoracic and mediastinal disorders Asthma	0.83% 1/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	0.00% 0/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
Respiratory, thoracic and mediastinal disorders Tonsillar hypertrophy	0.83% 1/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	0.00% 0/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).

Other adverse events

Measure	ETV (Entecavir) n=120 participants at risk Subjects received 0.015 milligram per kilogram per day (mg/kg/day) (up to a maximum dose of 0.5 mg/day) ETV as oral solution or tablets, once daily (QD).	PLACEBO n=60 participants at risk Subjects received ETV matched placebo as oral solution or tablets, QD.
Gastrointestinal disorders Abdominal discomfort	4.2% 5/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	5.0% 3/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
Gastrointestinal disorders Abdominal pain	7.5% 9/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	15.0% 9/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
Gastrointestinal disorders Diarrhoea	5.8% 7/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	11.7% 7/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
Gastrointestinal disorders Dyspepsia	0.00% 0/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	6.7% 4/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
Gastrointestinal disorders Nausea	5.0% 6/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	8.3% 5/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
Gastrointestinal disorders Vomiting	11.7% 14/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	16.7% 10/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
General disorders Fatigue	2.5% 3/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	8.3% 5/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
General disorders Pyrexia	15.0% 18/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	16.7% 10/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
Infections and infestations Bronchitis	6.7% 8/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	10.0% 6/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
Infections and infestations Ear infection	5.8% 7/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	1.7% 1/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
Infections and infestations Gastroenteritis	5.0% 6/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	6.7% 4/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
Infections and infestations Influenza	5.0% 6/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	6.7% 4/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
Infections and infestations Nasopharyngitis	15.0% 18/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	23.3% 14/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
Infections and infestations Pharyngitis	4.2% 5/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	18.3% 11/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
Infections and infestations Pharyngitis streptococcal	3.3% 4/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	6.7% 4/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
Infections and infestations Pneumonia	5.0% 6/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	0.00% 0/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
Infections and infestations Tonsillitis	5.0% 6/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	1.7% 1/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
Infections and infestations Upper respiratory tract infection	15.8% 19/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	20.0% 12/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
Nervous system disorders Headache	15.0% 18/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	15.0% 9/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
Respiratory, thoracic and mediastinal disorders Cough	12.5% 15/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	20.0% 12/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
Respiratory, thoracic and mediastinal disorders Epistaxis	6.7% 8/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	5.0% 3/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	5.8% 7/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	8.3% 5/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
Respiratory, thoracic and mediastinal disorders Rhinitis allergic	4.2% 5/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	5.0% 3/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
Skin and subcutaneous tissue disorders Acne	2.5% 3/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	5.0% 3/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
Skin and subcutaneous tissue disorders Alopecia	0.83% 1/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	8.3% 5/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
Skin and subcutaneous tissue disorders Rash	5.8% 7/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	3.3% 2/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).
Skin and subcutaneous tissue disorders Urticaria	1.7% 2/120 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).	5.0% 3/60 • All non-serious adverse events were collected from start of study treatment through Week 48, while all serious adverse events were evaluated through out the study (5 years).

Additional Information

Bristol-Myers Squibb Study Director

Bristol-Myers Squibb

Phone: please email

Email: Clinical.Trials@bms.com

Results disclosure agreements

• Principal investigator is a sponsor employee Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.
• Publication restrictions are in place

Restriction type: OTHER