BRISTOL-MYERS SQUIBB COMPANY

BRISTOL-MYERS SQUIBB COMPANY
ENTECAVIR
Final Clinical Study Report for Study AI463050
ABBREVIATED REPORT
A STUDY OF THE SAFETY AND ANTI-VIRAL ACTIVITY OF
OPEN-LABEL ENTECAVIR IN ADULTS WITH CHRONIC
HEPATITIS B INFECTION WHO HAVE COMPLETED DOSING IN
A PREVIOUS PHASE II/III STUDY IN CHINA
Indication:
Phase:
Study Initiation Date:
Study Completion Date:
Report Date:
Chronic HBV in Adults
3b
17-May-2004
28-Aug-2007
08-Apr-2008
Document Control Number: 930027096
Previous Version(s) of this
Report:
None
THIS STUDY WAS CONDUCTED IN ACCORDANCE WITH GOOD CLINICAL PRACTICE
Sponsor’s Responsible Medical Officer:
Cyril C Llamoso, MD
Bristol-Myers Squibb Research and Development
5 Research Parkway, Wallingford, CT 06492
This document is a confidential communication of Bristol-Myers Squibb Company. Acceptance of this
document constitutes an agreement by the recipient that no unpublished information contained herein will
be published or disclosed without Bristol-Myers Squibb Company's prior written approval.
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Name of Sponsor/Company:
Bristol-Myers Squibb
Name of Finished Product:
Baraclude ®
Name of Active Ingredient:
entecavir
Individual Study Table Referring
to the Dossier
AI463050
Final Clinical Study Report
(For National Authority Use
Only)
SYNOPSIS
Final Clinical Study Report for Study AI463050
ABBREVIATED REPORT
TITLE OF STUDY: A Study of the Safety and Anti-Viral Activity of Open-Label Entecavir in Adults
with Chronic Hepatitis B Infection Who Have Completed Dosing in a Previous Phase II/III Study in China
INVESTIGATORS/STUDY CENTERS: 26 sites in China
PUBLICATIONS: None
STUDY PERIOD: Study Initiation Date: 17-May-2004
CLINICAL PHASE: 3b
Study Completion Date: 28-Aug-2007
INTRODUCTION: Study AI463050 was a rollover study designed to provide open-label entecavir (ETV)
to subjects who had completed the required dosing period in previous ETV Phase 2 or 3 studies in China
and were assessed by the investigators as likely to benefit from additional therapy for treatment of their
hepatitis B virus (HBV) infection. The interim clinical study report (CSR), completed in May 2007,
presents safety and efficacy results that occurred during the on-treatment period. This final CSR presents
the key observations in the analyses related to the safety and antiviral activity of ETV in adults with
chronic HBV infection that occurred during the off-treatment phase of the study.
OBJECTIVES: The primary objective was to assess the safety of oral ETV (0.5 or 1.0 mg once daily
[QD]) as measured by the number and percentage of subjects with adverse events (AEs) and laboratory
abnormalities.
METHODOLOGY: This was a Phase 3b rollover study designed to provide open-label ETV to subjects
who had received study therapy in previous ETV Phase 2 or 3 studies in China:
• Study AI463012 was a study in nucleoside-naive subjects comparing the safety and anti-viral activity
of 2 doses of ETV (0.1 and 0.5 mg QD) to placebo given for 28 days during the blinded dosing phase.
After a 56 day post-dosing period, all eligible subjects received open-label ETV 0.5 mg QD for up to
48 weeks
• Study AI463056 was a study in subjects who had failed previous lamivudine (LVD) treatment that
evaluated the safety and anti-viral activity of ETV 1 mg QD administered for 12 weeks compared to
placebo. After completing the blinded dosing phase, all eligible subjects were to receive open-label
ETV 1.0 mg QD for 36 weeks
• Study AI463023 was a study in nucleoside-naive subjects comparing the safety and anti-viral activity
of ETV 0.5 mg QD to LVD 100 mg QD for up to 96 weeks.
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In Study AI463050, a complete response was defined as HBV deoxyribonucleic acid (DNA) by polymerase
chain reaction (PCR) assay < 10 4 copies/mL plus seroconversion on 2 sequential measurements drawn at
least 24 weeks apart for subjects hepatitis B e antigen (HBeAg) positive at baseline and as HBV DNA by
PCR assay < 10 4 copies/mL and normal alanine aminotransferase (ALT) (< 1.25 times upper limit of
normal [ULN]) on 2 sequential measurements drawn at least 24 weeks apart for subjects HBeAg negative
at baseline. Subjects who achieved a complete response were to discontinue study drug and be followed off
anti-HBV therapy for 24 weeks post-dosing. Subjects who relapsed during the 24-week post-dosing phase
could resume dosing of ETV or begin alternative anti-HBV therapy as recommended by their physician.
Relapse (defined as HBV DNA by PCR assay ≥ 10 4 copies/mL and/or HBeAg positive for subjects HBeAg
positive at baseline and as HBV DNA by PCR assay ≥ 10 4 copies/mL and/or ALT ≥ 1.5 times ULN for
subjects HBeAg negative at baseline) must have been confirmed on 2 successive determinations at least 2
weeks apart.
NUMBER OF SUBJECTS (Planned and Analyzed): Overall, 139 of 575 subjects (24%) entered the
post-dosing follow-up phase of Study AI463050 (8, 31, 59, and 41 in the ETV 012, ETV 023, LVD 023,
and ETV 056 cohorts, respectively). During the post-dosing phase, 27 subjects who relapsed were
re-treated.
DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION: Subjects who had completed the required
dosing period in a previous ETV Phase 2 or 3 study in China (Studies AI463012, AI463023, or AI463056),
met the criteria for enrollment in Study AI463050, and had been assessed by the investigators as likely to
benefit from additional therapy for treatment of their HBV infection.
TEST PRODUCT, DOSE AND MODE OF ADMINISTRATION, DURATION OF TREATMENT,
BATCH NUMBERS: One 0.5-mg ETV tablet QD (for subjects enrolling from Study AI463012) or 2
0.5-mg ETV tablets for a total of 1.0 mg QD (for subjects enrolling from Studies AI463056 and
AI463023). Batch nos. were 3C73622 and 3M56459.
REFERENCE THERAPY, DOSE AND MODE OF ADMINISTRATION, DURATION OF
TREATMENT, BATCH NUMBERS: Not applicable
CRITERIA FOR EVALUATION:
Efficacy: The sustained response at 24 weeks off-treatment was assessed for subjects who had achieved a
complete response at end of dosing (EOD). The following endpoints were included: (1) HBV DNA < 300
copies/mL; (2) HBV DNA < 10,000 copies/mL; (3) ALT ≤ 1 x ULN; (4) loss of HBeAg; and (5) HBeAg
seroconversion.
Safety: All subjects who received at least 1 dose of ETV during the treatment phase and entered the
off-treatment phase were to be evaluated for safety, including the evaluation of AEs and laboratory test
results (hematology, biochemistry, and urinalysis).
STATISTICAL CONSIDERATIONS: The sustained response at 24 weeks off-treatment follow-up was
assessed for subjects who achieved a complete response at EOD. For each of the selected endpoints, the
analysis was based on complete responders who had reached the endpoint at EOD. Subjects were classified
as failures if they (1) lost the endpoint; (2) did not complete the 24-week follow-up; or (3) did not have a
measurement in the analysis window. Safety analyses tabulate the proportion of subjects with events during
off-treatment follow-up.
SUMMARY OF RESULTS:
Disposition, Demographics, and Other Pertinent Baseline Characteristics: Demographics and other
background characteristics are summarized in the Study AI463050 interim CSR. No additional analyses
were conducted for the subjects with off-treatment follow-up data or re-treatment data.
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Efficacy Results: Week 24 sustained response for HBV DNA < 300 copies and ALT ≤ 1 ULN was higher
among HBeAg-positive subjects (24% and 51%, respectively) vs. HBeAg-negative subjects (15% and 41%,
respectively) (Table 1).
Table 1:
Sustained Response at Week 24 Off Treatment
Responders/Evaluable (%)
LVD 023 +
Sustained Response at Week 24 Off Treatment
Baseline HBeAg Status in Parent Study
ETV 023
N = 29
ETV 056
N=82
Total
N=118
HBV DNA < 300 copies/mL
HBeAg + 2/21 (10) 14/49 (29) 18/76 (24)
HBeAg - 1/5 (20) 4/28 (14) 5/34 (15)
HBV DNA < 10000 copies/mL
HBeAg + 7/24 (29) 28/53 (53) 38/83 (46)
HBeAg - 2/5 (40) 8/29 (28) 10/35 (29)
Loss of HBeAg
HBeAg + 10/24 (42) 32/53 (60) 46/83 (55)
HBeAg seroconversion
HBeAg + 10/20 (50) 26/42 (62) 40/68 (59)
ALT ≤ 1 x ULN
HBeAg + 9/24 (38) 29/51 (57) 41/80 (51)
HBeAg - 2/4 (50) 11/29 (38) 13/34 (38)
Safety Results: No deaths or malignancies were reported during the post-dosing or re-treatment periods.
None of the 27 subjects who were re-treated discontinued study medication due to AEs. Nine of 137
subjects (7%) experienced serious adverse events (SAEs) (ALT increased [6%], aspartate aminotransferase
[AST] increased [3%], and abortion threatened [< 1%]). Five subjects (4%) experienced ALT flares, and all
events occurred without selected clinical or laboratory events. Four subjects (3%) experienced hepatic
SAEs with ALT flares and 2 subjects (1%) experienced hepatic SAEs without ALT flares.
Off treatment, 29 of 137 subjects (21%) experienced AEs. AEs reported in > 1% of subjects included ALT
increased and nasopharyngitis (9 subjects [7%] each) and AST increased and upper respiratory tract
infection (4 subjects [3%] each).
Nine of 27 re-treated subjects experienced AEs. AEs included ALT increased (5 subjects [19%]) and AST
increased, decreased appetite, fatigue, hepatic pain (2 subjects [7%] each), and diarrhea, nasopharyngitis,
rash, and vertigo (1 subject [4%] each).
With the exception of increased serum ALT, most laboratory values were normal during the off-treatment
phase, and few Grade 3-4 laboratory abnormalities were reported.
CONCLUSIONS:
• The overall safety profile of long-term treatment (up to 3 years) with ETV in this study was consistent
with the safety profile established in both China and global Phase 2 or 3 studies
• Over the course of the study, no deaths were reported. Two malignancies were reported, both during
the treatment period
• ALT flares observed during the off-treatment period were low
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• Durability of response up to 24 weeks was observed in a minority of both HBeAg-positive and
HBeAg-negative subjects.
DATE OF REPORT: 08-Apr-2008
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