Clinical Trials Register

Summary
EudraCT Number:	2010-018523-26
Sponsor's Protocol Code Number:	AOBSMI2ENT001-010
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2010-03-03
Trial 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

Italy - Italian Medicines Agency

A.2

EudraCT number

2010-018523-26

A.3

Full title of the trial

Immediate versus delayed treatment with Entecavir in patients with active chronic hepatitis B (CHB): impact on liver fibrosis.

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

AOBSMI2ENT001-010

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

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	AZIENDA OSPEDALIERA SPEDALI CIVILI DI BRESCIA
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Non-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 Srl
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	ENTECAVIR
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	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.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

Patients with chronic HBV infection

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.1.3

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 which could be considered for NAs and for which NAs are not mandatory according to EASL guidelines ,with evolution of liver fibrosis after three years of follow up in a group of patients started on Entecavir versus a group of patients in which therapy is deferred.

E.2.2

Secondary objectives of the trial

To assess the impact of Entecavir treatment on biochemical and virological parameters and on the rate of adverse events. To identify the diagnostic and predictive value of liver stiffness estimated by transient elastometry (Fibroscan) and of non-invasive fibrosis serum markers ( Fibrotest, Forns, APRI, Fibroindex, FPI, FIB-4, Bonacini, SHASTA, Fibrometer, Hepascore) assessed at baseline and once a year after study entry on: - Definition of the stage of liver fibrosis (according to Metavir score) at baseline and at the end of the study; - Evaluation of the predictive value on the change of liver fibrosis stage (by METAVIR and Ishak s scores) at baseline and at the end of the study.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Signed written informed consent 1) Freely given informed consent must be obtained from subjects prior to clinical trial participation, including informed consent for any screening procedures conducted to establish subject eligibility for the study; 2) Patients with chronic HBV infection (detectable HBsAg at screening and for at least 24 weeks prior to screening, or detectable HBsAg for < 24 weeks and negative for IgM core antibody), HBeAg positive or negative; 3) ALT > ULN and ≤ 10 x ULN and HBVDNA >/= 2000 IU/ml at screening and at least once ≥ 12 weeks prior to screening; 4) Fibrosis stage at liver histology >/= 2 by METAVIR scoring in a biopsy performed no more than 6 months before study entry; 5) 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) 6) Nucleoside- and Nucleotide-naive subjects (previous recombinant interferon or pegylated interferon based therapy is admitted if it was withdrawn 6 months before study entry; 7) Males and females ≥ 18 years of age Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study (and for up to 6 weeks after the last dose of investigational product) in such a manner that the risk of pregnancy is minimized. WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal. WOCBP must have a negative serum or urine pregnancy test within 72 hours prior to the start of investigational product.

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 dose of investigational product; 2) WOCBP using a prohibited contraceptive method. At this time there are no known contraindicated contraceptives to entecavir; 3) Women who are pregnant or breastfeeding; 4) Women with a positive pregnancy test on enrollment or prior to investigational product administration; Target Disease Exceptions 5) Evidence of clinical condition correlated to liver disease for which, in the Investigator s opinion, NAs are mandatory; 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 (coinfection is defined as HCV Ab positive with detectable HCV RNA by PCR) or hepatitis D virus; Medical History and Concurrent Diseases 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); Physical and Laboratory Test Findings 11) Serum alpha fetoprotein (AFP) level > 100 ng/mL; If the AFP level is between 21 and 100 ng/mL, it must be repeated prior to randomization. If the repeat AFP level is between 21 and 100 ng/mL, and if ultrasonography or computerized tomography (CT) of the liver performed prior to the first dose of study medication does not demonstrate a focal lesion suggestive of carcinoma, the subject may be dosed in the study; Allergies and Adverse Drug Reactions 12) Known history of allergy to NAs;

E.5 End points

E.5.1

Primary end point(s)

Proportion of subjects (who were HBeAg-positive at baseline) with anti HBe seroconversion (HBeAg loss and presence of HBeAb); proportion of subjects with HBsAg loss and HBs serconversion; proportion of subjects with ALT normalization (≤ 1 x ULN) proportion of subjects who achieve and maintain undetectable HBV DNA until the end of the study rate of resistance mutations; frequency of adverse events (AEs), including modification of creatinine clearance, phosphatemia and phosphaturia values, serious adverse events (SAEs) and discontinuations from study due to adverse events or laboratory abnormalities; rate of adherence; rate of drops out; modification of liver stiffness assessed by Fibroscan and of the score obtained by the non-invasive serum markers (Fibrotest, Forns, APRI, Fibroindex, FPI, FIB-4, Bonacini, SHASTA, Fibrometer, Hepascore) in the two groups

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

E.6.5

Efficacy

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

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

inizio terapia verso non terapia

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

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

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

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	No
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	No
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	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Yes
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	Yes
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	202

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

2010-03-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2010-02-02

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2013-04-30

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