NCT01079806

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

Completed Phase 3 Results posted Last updated 9 May 2019

What this trial tests

Phase 3 trial testing Entecavir in Chronic Hepatitis B Virus, Pediatric in 180 participants. Completed in 31 March 2018.

Timeline

30 June 2010

Primary endpoint
31 March 2013

31 March 2018

Quick facts

Lead sponsor	Bristol-Myers Squibb
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	treatment
Enrollment	180
Start date	30 June 2010
Primary completion	31 March 2013
Estimated completion	31 March 2018
Sites	44 locations across Russia, Greece, Belgium, Taiwan, United Kingdom, Germany, Israel, Poland

Drugs / interventions tested

• Entecavir (ENTECAVIR) — full drug profile →
• Placebo

Conditions studied

• Chronic Hepatitis B Virus, Pediatric — all drugs for Chronic Hepatitis B Virus, Pediatric →

Sponsor

Bristol-Myers Squibb — full company profile →

Who can join

Adults 2 to 17, any sex, with Chronic Hepatitis B Virus, Pediatric. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Percentage of Participants Who Achieved a Combination of Hepatitis B Virus (HBV) DNA Suppression and Hepatitis B e Antigen (HBeAg) Seroconversion at Week 48 Primary · 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.

Group	Value	95% CI
Entecavir	24.4
Placebo	2.4

Percentage of Participants With Hepatitis B Virus (HBV) DNA <50 IU/mL at Week 48 Secondary · 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.

Group	Value	95% CI
Entecavir	46.3
Placebo	2.4

Percentage of Participants With Serum Alanine Aminotransferase ≤1*Upper Limit of Normal at Week 48 Secondary · 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.

Group	Value	95% CI
Entecavir	67.1
Placebo	22.0

Percentage of Participants With Hepatitis B Virus DNA <Limit of Quantitation (LOQ) at Week 48 Secondary · 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.

Group	Value	95% CI
Entecavir	42.7
Placebo	2.4

Percentage of Participants With Hepatitis B e Antigen (HBeAg) Seroconversion at Week 48 (Undetectable HBeAg and Presence of Anti-HBeAb) Secondary · At Week 48

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

Group	Value	95% CI
Entecavir	24.4
Placebo	12.2

Percentage of Participants Who Achieved Sustained HBeAg Seroconversion During Off-treatment Follow up Among Participants Who Achieved HBeAg Seroconversion at End of Dosing (EOD). Secondary · 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.

EOD (end of dosing)

Group	Value	95% CI
Entecavir	100.0
Placebo	100.0

Week 48

Group	Value	95% CI
Entecavir	74.4
Placebo	59.1

Number of Participants With Adverse Events (Including Palatability Issues), SAEs, Discontinuous Due to Adverse Events, and HBV Disease Progression Through Week 48 Secondary · 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

Deaths

Group	Value	95% CI
Entecavir	0
Placebo	0

Serious Adverse Events

Group	Value	95% CI
Entecavir	4
Placebo	7

Discontinuation due to Adverse Event

Group	Value	95% CI
Entecavir	0
Placebo	2

any adverse event

Group	Value	95% CI
Entecavir	78
Placebo	46

Related Adverse Events

Group	Value	95% CI
Entecavir	11
Placebo	6

Related Grade 2 - 4 Adverse Events

Group	Value	95% CI
Entecavir	4
Placebo	2

Grade 3 - 4 Adverse Events

Group	Value	95% CI
Entecavir	4
Placebo	3

ALT Flares

Group	Value	95% CI
Entecavir	2
Placebo	5

Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) Secondary · 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=75

Hemoglobin

Group	Value	95% CI
Entecavir	5
Placebo	4

Platelets

Group	Value	95% CI
Entecavir	3
Placebo	2

INR

Group	Value	95% CI
Entecavir	2
Placebo	6

White blood cells (WBC)

Group	Value	95% CI
Entecavir	2
Placebo	1

Neutrophils + bands (absolute)

Group	Value	95% CI
Entecavir	14
Placebo	2

Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) (Continued) Secondary · 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; Gra

ALT

Group	Value	95% CI
Entecavir	113
Placebo	59

AST

Group	Value	95% CI
Entecavir	87
Placebo	51

Total bilirubin

Group	Value	95% CI
Entecavir	5
Placebo	6

Albumin

Group	Value	95% CI
Entecavir	0
Placebo	1

Lipase

Group	Value	95% CI
Entecavir	38
Placebo	20

BUN/Urea

Group	Value	95% CI
Entecavir	10
Placebo	2

Chloride, high

Group	Value	95% CI
Entecavir	2
Placebo	1

Potassium, low

Group	Value	95% CI
Entecavir	1
Placebo	1

Percentage of Participants With HBeAg Seroconversion on ETV Over-time at Week 96 (All ETV Cohort) Secondary · 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.

Group	Value	95% CI
Blinded and Open-Label (All ETV)	38.6

Percentage of Participants Who Maintained HBeAg Seroconversion at Week 96 (End of Blinded Therapy) Among Participants With HBeAg Seroconversion at Week 48 Secondary · At Week 96

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

Week 48

Group	Value	95% CI
Entecavir	24.2
Placebo	10.0

Week 96

Group	Value	95% CI
Entecavir	36.7
Placebo	20.0

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 Secondary · 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

Deaths

Group	Value	95% CI
Blinded and Open-Label (All ETV)	0

SAEs

Group	Value	95% CI
Blinded and Open-Label (All ETV)	4.7

Discontinuations due to AEs

Group	Value	95% CI
Blinded and Open-Label (All ETV)	0.6

Related AEs

Group	Value	95% CI
Blinded and Open-Label (All ETV)	8.2

Grade 2-4 Related AEs

Group	Value	95% CI
Blinded and Open-Label (All ETV)	2.3

Grade 3-4 AEs

Group	Value	95% CI
Blinded and Open-Label (All ETV)	4.1

Malignancies

Group	Value	95% CI
Blinded and Open-Label (All ETV)	0

ALT flares

Group	Value	95% CI
Blinded and Open-Label (All ETV)	1.8

Adverse events — posted to ClinicalTrials.gov

Time frame: 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).. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

ETV (Entecavir)

Serious: 4/120 (3%)

Deaths: 0/120

PLACEBO

Serious: 9/60 (15%)

Deaths: 0/60

Serious adverse events (17 terms)

Reaction	System	ETV (Entecavir)	PLACEBO
Hepatic function abnormal	Hepatobiliary disorders	—	—
Hydrocele	Congenital, familial and genetic disorders	—	—
Gastritis	Gastrointestinal disorders	—	—
Inflammatory bowel disease	Gastrointestinal disorders	—	—
Bronchitis	Infections and infestations	—	—
Cellulitis	Infections and infestations	—	—
Chronic hepatitis b	Infections and infestations	—	—
Ear infection	Infections and infestations	—	—
Infectious colitis	Infections and infestations	—	—
Mastoiditis	Infections and infestations	—	—
Pharyngitis	Infections and infestations	—	—
Diabetic ketoacidosis	Metabolism and nutrition disorders	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—
Juvenile idiopathic arthritis	Musculoskeletal and connective tissue disorders	—	—
Schizophrenia	Psychiatric disorders	—	—
Asthma	Respiratory, thoracic and mediastinal disorders	—	—
Tonsillar hypertrophy	Respiratory, thoracic and mediastinal disorders	—	—

Other adverse events (27 terms — click to expand)

Reaction	System	ETV (Entecavir)	PLACEBO
Upper respiratory tract infection	Infections and infestations	—	—
Pyrexia	General disorders	—	—
Nasopharyngitis	Infections and infestations	—	—
Headache	Nervous system disorders	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—
Vomiting	Gastrointestinal disorders	—	—
Pharyngitis	Infections and infestations	—	—
Abdominal pain	Gastrointestinal disorders	—	—
Bronchitis	Infections and infestations	—	—
Epistaxis	Respiratory, thoracic and mediastinal disorders	—	—
Diarrhoea	Gastrointestinal disorders	—	—
Ear infection	Infections and infestations	—	—
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	—	—
Rash	Skin and subcutaneous tissue disorders	—	—
Nausea	Gastrointestinal disorders	—	—
Gastroenteritis	Infections and infestations	—	—
Influenza	Infections and infestations	—	—
Pneumonia	Infections and infestations	—	—
Tonsillitis	Infections and infestations	—	—
Abdominal discomfort	Gastrointestinal disorders	—	—
Fatigue	General disorders	—	—
Rhinitis allergic	Respiratory, thoracic and mediastinal disorders	—	—
Alopecia	Skin and subcutaneous tissue disorders	—	—
Dyspepsia	Gastrointestinal disorders	—	—
Pharyngitis streptococcal	Infections and infestations	—	—
Acne	Skin and subcutaneous tissue disorders	—	—
Urticaria	Skin and subcutaneous tissue disorders	—	—

Most-reported serious reactions: Hepatic function abnormal, Hydrocele, Gastritis, Inflammatory bowel disease, Bronchitis, Cellulitis, Chronic hepatitis b, Ear infection.

Data from ClinicalTrials.gov NCT01079806 adverse events section.

Sponsor's own description

The purpose of this study was to evaluate the safety and efficacy of entecavir in pediatric patients with chronic hepatitis B virus infection

Publications & conference data

1 peer-reviewed publication reference this trial (live from Europe PMC):

1. Hepatitis B and C.
   Karnsakul W, Schwarz KB. · · 2017 · cited 18× · PMID 28502443 · DOI 10.1016/j.pcl.2017.01.007