Trial Outcomes & Findings for Comparative Trial of Entecavir Versus Adefovir in the Treatment of Chronic Hepatitis B Infection (NCT NCT00096785)

NCT ID: NCT00096785

Last Updated: 2010-08-10

Results Overview

Antiviral efficacy, as measured by the mean reduction in serum HBV DNA levels by PCR (log10 copies/mL) at Week 12, adjusted for baseline (Week 12 - baseline). A negative value = improvement.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 69 participants
• Primary outcome timeframe: Baseline, Week 12
• Results posted on: 2010-08-10

Participant Flow

132 enrolled; 63 not randomized (59 did not meet study criteria, 3 withdrew consent, 1 lost to follow-up). 1 randomized to adefovir (ADV) received entecavir (ETV) throughout treatment, & is counted in the ADV group for primary efficacy analysis, not included in the secondary efficacy analyses, & counted in the ETV group in safety analyses.

Participant milestones

Measure	Entecavir ETV 0.5 mg once daily (QD)	Adefovir ADV 10 mg QD
Overall Study STARTED	35	34
Overall Study As-Randomized Population	35	34
Overall Study As-Treated Population	36	33
Overall Study COMPLETED	33	33
Overall Study NOT COMPLETED	2	1

Reasons for withdrawal

Measure	Entecavir ETV 0.5 mg once daily (QD)	Adefovir ADV 10 mg QD
Overall Study Lost to Follow-up	1	0
Overall Study Withdrawal by Subject	0	1
Overall Study Relocated	1	0

Baseline Characteristics

Comparative Trial of Entecavir Versus Adefovir in the Treatment of Chronic Hepatitis B Infection

Baseline characteristics by cohort

Measure	Entecavir n=35 Participants ETV 0.5 mg once daily (QD)	Adefovir n=34 Participants ADV 10 mg QD	Total n=69 Participants Total of all reporting groups
Age Continuous	38 participants n=93 Participants	28 participants n=4 Participants	31 participants n=27 Participants
Sex: Female, Male Female	13 Participants n=93 Participants	11 Participants n=4 Participants	24 Participants n=27 Participants
Sex: Female, Male Male	22 Participants n=93 Participants	23 Participants n=4 Participants	45 Participants n=27 Participants
Race/Ethnicity, Customized Asian	31 Participants n=93 Participants	30 Participants n=4 Participants	61 Participants n=27 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants	1 Participants n=4 Participants	1 Participants n=27 Participants
Race/Ethnicity, Customized Black or African American	3 Participants n=93 Participants	2 Participants n=4 Participants	5 Participants n=27 Participants
Race/Ethnicity, Customized White	1 Participants n=93 Participants	1 Participants n=4 Participants	2 Participants n=27 Participants
Region of Enrollment North America	9 participants n=93 Participants	13 participants n=4 Participants	22 participants n=27 Participants
Region of Enrollment East Asia	26 participants n=93 Participants	21 participants n=4 Participants	47 participants n=27 Participants
Prior interferon (IFN) Prior IFN	1 Participants n=93 Participants	1 Participants n=4 Participants	2 Participants n=27 Participants
Prior interferon (IFN) No prior IFN	34 Participants n=93 Participants	33 Participants n=4 Participants	67 Participants n=27 Participants
Alanine Aminotransferease (ALT)	109.4 U/L STANDARD_DEVIATION 81.76 • n=93 Participants	176.4 U/L STANDARD_DEVIATION 207.22 • n=4 Participants	142.4 U/L STANDARD_DEVIATION 159.12 • n=27 Participants
Hepatitis B virus DNA (HBV DNA) by Polymerase Chain Reaction (PCR)	10.45 log10 copies/mL STANDARD_DEVIATION 2.125 • n=93 Participants	9.89 log10 copies/mL STANDARD_DEVIATION 1.201 • n=4 Participants	10.18 log10 copies/mL STANDARD_DEVIATION 1.742 • n=27 Participants

PRIMARY outcome

Timeframe: Baseline, Week 12

Population: As-randomized participants who completed 12 weeks of treatment

Antiviral efficacy, as measured by the mean reduction in serum HBV DNA levels by PCR (log10 copies/mL) at Week 12, adjusted for baseline (Week 12 - baseline). A negative value = improvement.

Outcome measures

Measure	Entecavir n=33 Participants ETV 0.5 mg once daily (QD)	Adefovir n=33 Participants ADV 10 mg QD
Change From Baseline in Hepatitis B Virus DNA (HBV DNA) by Polymerase Chain Reaction (PCR) Assay at Week 12	-6.23 log10 copies/mL Standard Error 0.247	-4.52 log10 copies/mL Standard Error 0.357

SECONDARY outcome

Timeframe: Baseline, Week 48

Population: Treated subjects who had both baseline and Week 12 HBV DNA measurements and who received the randomized treatment. 1 participant randomized to ADV actually received ETV and is not counted in secondary efficacy analyses.

Antiviral efficacy, as measured by the mean reduction in serum HBV DNA levels by PCR (log10 copies/mL) at Week 48, adjusted for baseline (Week 48 - Baseline). A negative value = improvement.

Outcome measures

Measure	Entecavir n=33 Participants ETV 0.5 mg once daily (QD)	Adefovir n=32 Participants ADV 10 mg QD
Change From Baseline in HBV DNA by PCR Assay at Week 48	-7.28 log10 c/mL Standard Error 0.327	-5.08 log10 c/mL Standard Error 0.455

SECONDARY outcome

Timeframe: Week 48

Population: Treated participants who had both baseline and Week 12 HBV DNA measurements and who received the randomized treatment. 1 participant randomized to ADV actually received ETV and is not counted in secondary efficacy analyses.

Number of Subjects with HBV DNA <300 copies/mL by Roche COBAS® Amplicor (limit of quantitation 300 copies/mL)

Outcome measures

Measure	Entecavir n=33 Participants ETV 0.5 mg once daily (QD)	Adefovir n=32 Participants ADV 10 mg QD
Viral Load Undetectable (HBV DNA <300 Copies/mL)	19 Participants	6 Participants

SECONDARY outcome

Timeframe: Week 48

Population: treated subjects who had both baseline and Week 12 HBV DNA measurements and who received the randomized treatment. 1 participant randomized to ADV actually received ETV and is not counted in secondary efficacy analyses.

Number of participants with ALT ≤ 1 x upper limit of normal (ULN)

Outcome measures

Measure	Entecavir n=33 Participants ETV 0.5 mg once daily (QD)	Adefovir n=32 Participants ADV 10 mg QD
Alanine Aminotransferase (ALT) Normalization	25 participants	20 participants

SECONDARY outcome

Timeframe: Week 12

Population: Treated subjects who had both baseline and Week 12 HBV DNA measurements and who received the randomized treatment. 1 participant randomized to ADV actually received ETV and is not counted in secondary efficacy analyses.

The biphasic decline of HBV DNA is characterized via a 4-parameter exponential decay model previously published for HBV compounds. The model parameters of interest are the effectiveness of the drug in blocking virus production from infected cells (efficacy, ε) and effectiveness of the study treatment in blocking de novo infection of susceptible cells (η). The model parameters reflect the biphasic pattern that is typically observed after initiation of antiviral therapy. Parameters were estimated for each subject separately and then averaged within each treatment group.

Outcome measures

Measure	Entecavir n=33 Participants ETV 0.5 mg once daily (QD)	Adefovir n=32 Participants ADV 10 mg QD
HBV DNA Viral Kinetics Estimates of Exponential Decay Model - Efficacy in Blocking Virus Production and de Novo Infections Efficacy in blocking virus production - ε	99.87 percent effective	99.46 percent effective
HBV DNA Viral Kinetics Estimates of Exponential Decay Model - Efficacy in Blocking Virus Production and de Novo Infections Effectiveness in blocking de novo infections - η	6.07 percent effective	5.87 percent effective

SECONDARY outcome

Timeframe: Week 12

Population: Treated subjects who had both baseline and Week 12 HBV DNA measurements and who received the randomized treatment. 1 participant randomized to ADV actually received ETV and is not counted in secondary efficacy analyses.

The biphasic decline of HBV DNA is characterized via a 4-parameter exponential decay model previously published for HBV compounds. The model parameters of interest are the clearance rate of the free virus (c), the death rate of productively infected cells (δ), The model parameters reflect the biphasic pattern that is typically observed after initiation of antiviral therapy. Parameters were estimated for each subject separately and then averaged within each treatment group.

Outcome measures

Measure	Entecavir n=33 Participants ETV 0.5 mg once daily (QD)	Adefovir n=32 Participants ADV 10 mg QD
HBV DNA Viral Kinetics Estimates of Exponential Decay Model - Viral Clearance Rate and Infected Cell Death Rate Viral Clearance - c	1.70 per day	0.91 per day
HBV DNA Viral Kinetics Estimates of Exponential Decay Model - Viral Clearance Rate and Infected Cell Death Rate Infected cell death - δ	0.08 per day	0.04 per day

SECONDARY outcome

Timeframe: Week 12

Population: Treated subjects who had both baseline and Week 12 HBV DNA measurements and who received the randomized treatment. 1 participant randomized to ADV actually received ETV and is not counted in secondary efficacy analyses.

The biphasic decline of HBV DNA is characterized via a 4-parameter exponential decay model previously published for HBV compounds. An important derived parameter is the half-life of free virus (ie, the average amount of time for HBV particles in plasma to be reduced to half the initial level), calculated as 24*ln(2)/c. The model parameters reflect the biphasic pattern that is typically observed after initiation of antiviral therapy. Parameters were estimated for each subject separately and then averaged within each treatment group.

Outcome measures

Measure	Entecavir n=33 Participants ETV 0.5 mg once daily (QD)	Adefovir n=32 Participants ADV 10 mg QD
HBV DNA Viral Kinetics Estimates of Exponential Decay Model - Half-Life of Free Virus	14.52 hours	32.46 hours

SECONDARY outcome

Timeframe: Week 12

Population: Treated subjects who had both baseline and Week 12 HBV DNA measurements and who received the randomized treatment. 1 participant randomized to ADV actually received ETV and is not counted in secondary efficacy analyses.

This analysis uses a 3-parameter piece-wise linear model and describes the biphasic decline in HBV DNA (measured by PCR assay) through Week 12. The 3 parameters are the values for the 2 slopes, describing the first and second phase declines, respectively, and the estimated HBV DNA at the knot (at day 10; the time point where the 2 phases join). The biphasic viral decay kinetics for each treatment were obtained using a spline fitting procedure to estimate the 3 parameters for each subject; these estimates were then averaged within each treatment group.

Outcome measures

Measure	Entecavir n=33 Participants ETV 0.5 mg once daily (QD)	Adefovir n=32 Participants ADV 10 mg QD
HBV DNA Viral Kinetics - Spline Model First slope (first phase of viral decay)	-0.391 log10 copies/mL	-0.329 log10 copies/mL
HBV DNA Viral Kinetics - Spline Model Second slope (second phase of viral decay)	-0.034 log10 copies/mL	-0.024 log10 copies/mL

SECONDARY outcome

Timeframe: cumulative through the end of on-treatment observation as available at the time of the Week 48 dataset

Population: As-treated population. 1 participant was randomized to ADV, but treated with ETV was counted in the ETV group.

AE=new untoward medical occurrence or worsening of pre-existing medical condition regardless of causal relationship to treatment. SAE=untoward medical occurrence that is life-threatening, a congenital anomaly/birth defect, or an important medical event, or results in death, inpatient hospitalization/prolongation of hospitalization, or persistent/significant disability. AE grades: mild (1), moderate (2), severe (3), life-threatening (4), death (5). ALT flare= >2x baseline & >10x ULN up to end of therapy + 5 days. Hepatic SAE=SAEs consistent with worsening of hepatitis or hepatic decompensation.

Outcome measures

Measure	Entecavir n=36 Participants ETV 0.5 mg once daily (QD)	Adefovir n=33 Participants ADV 10 mg QD
Summary of Safety - Most Frequent (> 10%) Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs, and Deaths Death	0 Participants	0 Participants
Summary of Safety - Most Frequent (> 10%) Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs, and Deaths Serious AE	1 Participants	3 Participants
Summary of Safety - Most Frequent (> 10%) Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs, and Deaths Discontinuation due to AE	0 Participants	1 Participants
Summary of Safety - Most Frequent (> 10%) Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs, and Deaths Malignant neoplasm	0 Participants	0 Participants
Summary of Safety - Most Frequent (> 10%) Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs, and Deaths On Treatment: Any AE	28 Participants	27 Participants
Summary of Safety - Most Frequent (> 10%) Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs, and Deaths On Treatment: Headache	9 Participants	6 Participants
Summary of Safety - Most Frequent (> 10%) Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs, and Deaths On Treatment: Upper Respiratory Infection	8 Participants	8 Participants
Summary of Safety - Most Frequent (> 10%) Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs, and Deaths On Treatment: Influenza	6 Participants	4 Participants
Summary of Safety - Most Frequent (> 10%) Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs, and Deaths On Treatment: Nasopharyngitis	4 Participants	6 Participants
Summary of Safety - Most Frequent (> 10%) Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs, and Deaths On Treatment: Pyrexia	4 Participants	6 Participants
Summary of Safety - Most Frequent (> 10%) Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs, and Deaths On Treatment: Back Pain	0 Participants	5 Participants
Summary of Safety - Most Frequent (> 10%) Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs, and Deaths On Treatment: Grade 3-4 AEs	2 Participants	5 Participants
Summary of Safety - Most Frequent (> 10%) Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs, and Deaths ALT Flare	0 Participants	1 Participants
Summary of Safety - Most Frequent (> 10%) Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs, and Deaths Hepatic SAE	1 Participants	2 Participants

SECONDARY outcome

Timeframe: Week 48

Population: As-treated population. 1 participant who was randomized to ADV, but treated with ETV was counted in the ETV group.

Laboratory abnormalities reported as clinical AEs

Outcome measures

Measure	Entecavir n=36 Participants ETV 0.5 mg once daily (QD)	Adefovir n=33 Participants ADV 10 mg QD
Summary of Safety - Laboratory Abnormalities Reported as Clinical AEs ALT increased	1 Participants	2 Participants
Summary of Safety - Laboratory Abnormalities Reported as Clinical AEs Lipase increased	1 Participants	2 Participants
Summary of Safety - Laboratory Abnormalities Reported as Clinical AEs Blood phosphorus decreased	0 Participants	1 Participants
Summary of Safety - Laboratory Abnormalities Reported as Clinical AEs Liver function test abnormal	0 Participants	1 Participants
Summary of Safety - Laboratory Abnormalities Reported as Clinical AEs Platelet count decreased	0 Participants	1 Participants
Summary of Safety - Laboratory Abnormalities Reported as Clinical AEs Protein urine present	0 Participants	1 Participants

Adverse Events

ADV 10 mg

Serious events: 2 serious events

Other events: 16 other events

Deaths: 0 deaths

ETV 0.5 mg

Serious events: 1 serious events

Other events: 17 other events

Deaths: 0 deaths

Serious adverse events

Measure	ADV 10 mg n=33 participants at risk	ETV 0.5 mg n=36 participants at risk
Investigations ALANINE AMINOTRANSFERASE INCREASED	3.0% 1/33	2.8% 1/36
Injury, poisoning and procedural complications RIB FRACTURE	3.0% 1/33	0.00% 0/36

Other adverse events

Measure	ADV 10 mg n=33 participants at risk	ETV 0.5 mg n=36 participants at risk
Investigations LIPASE INCREASED	6.1% 2/33	0.00% 0/36
Nervous system disorders HEADACHE	15.2% 5/33	22.2% 8/36
Nervous system disorders DIZZINESS	6.1% 2/33	0.00% 0/36
Gastrointestinal disorders ABDOMINAL PAIN	3.0% 1/33	5.6% 2/36
Infections and infestations INFLUENZA	6.1% 2/33	11.1% 4/36
Infections and infestations NASOPHARYNGITIS	6.1% 2/33	5.6% 2/36
Infections and infestations UPPER RESPIRATORY TRACT INFECTION	6.1% 2/33	11.1% 4/36
Musculoskeletal and connective tissue disorders BACK PAIN	6.1% 2/33	0.00% 0/36
Respiratory, thoracic and mediastinal disorders COUGH	12.1% 4/33	5.6% 2/36
Respiratory, thoracic and mediastinal disorders RHINORRHOEA	6.1% 2/33	0.00% 0/36
General disorders MALAISE	6.1% 2/33	0.00% 0/36

Additional Information

BMS Study Director

Bristol-Myers Squibb

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