Clinical Trials Register

Summary
EudraCT Number:	2006-000422-31
Sponsor's Protocol Code Number:	AI463-111
National Competent Authority:	Greece - EOF
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2008-04-30
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Greece - EOF

A.2

EudraCT number

2006-000422-31

A.3

Full title of the trial

A Comparative Study of Entecavir vs Adefovir Plus Lamivudine vs Combination
Entecavir plus Adefovir in Lamivudine-Resistant Chronic Hepatitis B Subjects: The
DEFINE Study

Revised Protocol 02, incorporating protocol amendment 02 (Version 2.0, date 23-Jan-2007), protocol amendment 03 (Version 4.0, date 07-Nov-2007) and Administrative Letter 01.

A.3.2

Name or abbreviated title of the trial where available

The DEFINE Study

A.4.1

Sponsor's protocol code number

AI463-111

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Bristol-Myers Squibb International Corporation
B.1.3.4	Country	Belgium
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Baraclude
D.2.1.1.2	Name of the Marketing Authorisation holder	Bristol-Myers Squibb Pharma EEIG
D.2.1.2	Country which granted the Marketing Authorisation	United States
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Entecavir
D.3.2	Product code	BMS-200475
D.3.4	Pharmaceutical form	Oral solution
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Entecavir
D.3.9.1	CAS number	209216-23-9
D.3.9.2	Current sponsor code	BMS-200475-01
D.3.9.3	Other descriptive name	ETV
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.05
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Information not present in EudraCT
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Information not present in EudraCT
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Baraclude
D.2.1.1.2	Name of the Marketing Authorisation holder	Bristol-Myers Squibb Pharma EEIG
D.2.1.2	Country which granted the Marketing Authorisation	United States
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Entecavir
D.3.2	Product code	BMS-200475
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Entecavir
D.3.9.1	CAS number	209216-23-9
D.3.9.2	Current sponsor code	BMS-200475-01
D.3.9.3	Other descriptive name	ETV
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Information not present in EudraCT
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Information not present in EudraCT
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Baraclude
D.2.1.1.2	Name of the Marketing Authorisation holder	Bristol-Myers Squibb Pharma EEIG
D.2.1.2	Country which granted the Marketing Authorisation	United States
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Entecavir
D.3.2	Product code	BMS-200475
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Entecavir
D.3.9.1	CAS number	209216-23-9
D.3.9.2	Current sponsor code	BMS-200475-01
D.3.9.3	Other descriptive name	ETV
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1.0
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Information not present in EudraCT
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Information not present in EudraCT
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 4
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Hepsera
D.2.1.1.2	Name of the Marketing Authorisation holder	Gilead Sciences International Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Adefovir dipivoxil
D.3.9.1	CAS number	142340-99-6
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Information not present in EudraCT
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Information not present in EudraCT
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 5
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Zeffix
D.2.1.1.2	Name of the Marketing Authorisation holder	Glaxo Group Ltd
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Lamivudine
D.3.9.1	CAS number	134678-17-4
D.3.9.3	Other descriptive name	LVD
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Information not present in EudraCT
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
D.3.11.5	Radiopharmaceutical medicinal product	Information not present in EudraCT
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Information not present in EudraCT
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 6
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Zeffix
D.2.1.1.2	Name of the Marketing Authorisation holder	Glaxo Group Ltd
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Oral solution
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Lamivudine
D.3.9.1	CAS number	134678-17-4
D.3.9.3	Other descriptive name	LVD
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Information not present in EudraCT
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
D.3.11.5	Radiopharmaceutical medicinal product	Information not present in EudraCT
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Information not present in EudraCT
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

CHRONIC HEPATITIS B VIRUS

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	9.1
E.1.2	Level	LLT
E.1.2	Classification code	10008910
E.1.2	Term	Chronic hepatitis B

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To compare the proportion of subjects in the ETV plus ADV combination therapy
group to the proportion of subjects in the ETV monotherapy treatment group and the ADV plus LVD treatment group who achieve HBV DNA < 50 IU/mL (approximately 300 copies/mL) by PCR at Week 48 of treatment using the Roche COBAS® TaqMan HBV Test for use with the High Pure System (HPS) assay.

E.2.2

Secondary objectives of the trial

Compare ETV monotherapy vs ADV+LVD combination vs ETV+ADV combination for:
* Proportion of subjects
- achieving HBV DNA < 50 IU/mL by PCR at Wk 96 using the Roche COBAS® TaqMan-HPS assay
- achieving HBV DNA < the lower limit of detection (LLD) for the Roche COBAS® TaqMan-HPS assay (Wk 48 & 96)
- with HBV DNA in relevant categories using the Roche COBAS® TaqMan-HPS assay (Wk 48 & 96)
- with ALT> 1 x ULN at screening who achieve ALT normalization (≤ 1 x ULN) at Wk 48 & 96
- with HBeAg loss (Wk 48 & 96)
- with HBe seroconversion (Wk 48 & 96)
- with HBsAg loss and HBs seroconversion (Wk 48 & 96)
* Mean log10 reduction from baseline in HBV DNA by PCR using the Roche COBAS® TaqMan-HPS assay (Wk 48 & 96)
* Frequency of AEs, SAEs, and study drug discontinuations due to AEs/laboratory abnormalities
* Evaluate ETV & ADV resistance profiles in each treatment arm

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Signed written informed consent;
2) Subjects must have a history of previous lamivudine treatment at screening, and must have LVD resistance substitutions at reverse transcriptase rtM204I/V;
3) Subjects must be nucleoside- and nucleotide-naïve, except for lamivudine, and
have chronic HBV infection (detectable HBsAg at screening and at least 24 weeks
prior to screening, or detectable HBsAg for < 24 weeks and negative for IgM core
antibody);
4) Subjects must have compensated liver function and must meet ALL of the
following criteria:
• International Normalization Ratio (INR) ≤ 1.5
• Serum albumin ≥ 3 g/dL (≥ 30 g/L)
• Serum total bilirubin ≤ 2.5 mg/dL (≤ 42.75 µmol/L)
5) HBV DNA ≥ 17,200 IU/mL (approximately 1,00,000 copies/mL) by PCR at
screening;
6) ALT ≤ 10 x ULN at screening;
7) Documentation of HBeAg-positive and HBeAb-negative status at screening and at
least once ≥ 4 weeks prior to screening;
8) Males and females ≥ 16 years of age (or minimum age of consent in a given
country).

E.4

Principal exclusion criteria

1) WOCBP who are unwilling or unable to use an acceptable method to avoid
pregnancy for the entire study period and for up to 6 weeks after the last does of
investigational product;
2) WOCBP using a prohibited contraceptive method. At this time there are no
known contraindicated contraceptives to entecavir or adefovir or lamivudine;
3) Women who are pregnant or breastfeeding;
4) Women with a positive pregnancy test on enrollment or prior to investigational
product administration;
5) Sexually active fertile men not using effective birth control if their partners are
WOCBP;
6) Evidence of decompensated cirrhosis including but not limited to: variceal
bleeding; hepatic encephalopathy; or ascites requiring management with diuretics
or paracentesis;
7) Coinfection with HIV, hepatitis C virus ([HCV]; coinfection is defined as HCV
Ab-positive with detectable HCV ribonucleic acid [RNA] by PCR), or hepatitis D
virus (HDV);
8) Recent history of pancreatitis (within 24 weeks prior to the first dose of study
medication);
9) Currently abusing illegal drugs or alcohol sufficient, in the Investigator’s opinion,
to prevent adequate compliance with study therapy or to increase the risk of
hepatotoxicity or pancreatitis;
10) Other serious medical conditions that might preclude completion of this study or
that require chronic administration of prohibited medications (see Exclusion
Criterion 19);
11) Serum creatinine > 1.5 mg/dL;
12) Hemoglobin < 10.0 g/dL;
13) Platelet count < 70,000/mm³;
14) Absolute neutrophil count < 1500 cells/mm³;
15) Serum alpha fetoprotein (AFP) level > 100 ng/mL;
16) Known history of allergy to nucleoside or nucleotide analogues;
17) Except lamivudine, any prior therapy with nucleoside or nucleotide analogue
antiviral agents with activity against hepatitis B (e.g., adefovir, entecavir,
famciclovir, tenofovir, telbivudine, clevudine, emtracitabine), or any other
experimental anti-HBV antiviral;
18) Therapy with interferon; thymosin alpha or other immuno-stimulators within
24 weeks of randomization into this study;
19) Required chronic administration of medications which cause immunosuppression
or which are associated with a high risk of nephrotoxicity or hepatotoxicity or
which affect renal excretion (See Protocol Section 5.5.1 for examples);
20) Prisoners or subjects who are compulsorily detained (involuntarily incarcerated)
for treatment of either a psychiatric or physical (e.g., infectious disease) illness
must not be enrolled into this study;
21) Unable to tolerate oral medication;
22) Poor peripheral venous access.

Subjects may be rescreened twice (for a total of three screens) if it can be reasonably expected that study criteria will be met. However, beyond this, subjects should be reevaluated only after consult with the clinical team.

E.5 End points

E.5.1

Primary end point(s)

* Primary Endpoint:

The proportion of subjects who achieve HBV DNA < 50 IU/mL (approximately 300 copies/mL) by PCR at Week 48 of treatment using the Roche COBAS® TaqMan HBV Test for use with the High Pure System (HPS) assay.

* Secondary Endpoints:

- Proportion of subjects who achieve HBV DNA < 50 IU/mL (approximately 300 copies/mL) by PCR at Week 96 of treatment using the Roche COBAS® TaqMan - HPS assay;
- Proportion of subjects who achieve HBV DNA < the lower limit of detection (LLD) for the Roche COBAS® TaqMan - HPS assay at Weeks 48 and 96 (LLD = 4.8 IU/ml [approximately 28 copies/mL] at the time of protocol development. Analyses will be done using the LLD as reported in the package insert at the time of analyses);
- Proportions of subjects with HBV DNA in relevant categories, e.g.: < LLD (4.8 IU/mL); LLD (4.8 IU/mL) to < 50; 50 to < 172; 172 to < 1,720; 1,720 to < 17,200; and ≥ 17,200 IU/mL (approximately < 28; 28 to < 300; 300 to < 10³; 10³ to < 10,000; 10,000 to < 100,000; and ≥ 100,000 copies/ml) at Weeks 48 and 96 using the Roche COBAS® TaqMan - HPS assay;
- Mean log10 reduction from baseline in HBV DNA by PCR at Weeks 48 and 96 using the Roche COBAS® TaqMan - HPS assay;
- Proportion of subjects with ALT > 1 x ULN at screening who achieve ALT normalization (≤ 1 x ULN) at Weeks 48 and 96;
- Proportion of subjects with loss of HBeAg at Weeks 48 and 96;
- Proportion of subjects with HBe seroconversion (HBeAg loss and presence of HBeAb) at Weeks 48 and 96;
- Proportion of subjects with HBsAg loss and HBs seroconversion at Weeks 48 and 96;
- Frequency of Adverse Events, Serious Adverse Events, and discontinuations from study drug due to adverse events or laboratory abnormalities.
- Rates of resistance in each treatment arm through Weeks 48 and 96.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

Information not present in EudraCT

E.7.1.2

Bioequivalence study

Information not present in EudraCT

E.7.1.3

Other

Information not present in EudraCT

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

ETV+ADV combination therapy vs ETV monotherapy vs ADV+LVD combination therapy

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LPLV

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.2

Adults (18-64 years)

Yes

F.1.3

Elderly (>=65 years)

Yes

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

102

F.4.2.2

In the whole clinical trial

462

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

At the end of study dosing, further treatment with commercially available therapies is at the discretion of the investigator. Decision should be based on laboratory results & on national/international treatment guidelines. Subjects who both discontinue study drug at/before Wk 100 & who don’t receive alternative anti-HBV therapy must be followed on-study for up to 24 wks of postdosing observation. Post-dosing observation ceases either after 24 wks or when alternative anti-HBV therapy is started.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2008-05-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2008-09-09

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2012-06-04

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