Clinical Trials Register

Summary
EudraCT Number:	2004-005119-27
Sponsor's Protocol Code Number:	GS-US-174-0102
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2007-08-08
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2004-005119-27

A.3

Full title of the trial

A randomized, double blind, controlled evaluation of Tenofovir DF versus Adefovir Dipivoxil for the treatment of presumed pre-core mutant chronic hepatitis B.

Studio randomizzato, in doppio cieco, controllato per la valutazione di Tenofovir DF 300 mg QD verso Adefovir Dipivoxil nel trattamento dell'epatite B cronica da virus presunto pre-core mutante.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A study in people with long-lasting hepatitis B to assess the effectiveness and safety of the two drugs Viread and Hepsera.

Sudio su persone affette da epatite B da lungo tmepo per valutare l`efficacia e la sicurezza dei due farmaci Viread e Hepsera.

A.4.1

Sponsor's protocol code number

GS-US-174-0102

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Gilead Sciences Inc.
B.1.3.4	Country	United States
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	Gilead Sciences Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Gilead Sciences International Ltd.
B.5.2	Functional name of contact point	Medical Monitor
B.5.3	Address:
B.5.3.1	Street Address	Flowers Building, Granta Park
B.5.3.2	Town/ city	Great Abington, Cambridge
B.5.3.3	Post code	CB216GT
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+44 01223 897 496
B.5.5	Fax number	+44 01223 897 284
B.5.6	E-mail	clinical.trials@gilead.com

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	VIREAD*30CPR 245MG
D.2.1.1.2	Name of the Marketing Authorisation holder	GILEAD SCIENCES INT.LTD
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	No
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	TENOFOVIR DISOPROXIL FUMARATE
D.3.9.1	CAS number	202138-50-9
D.3.9.4	EV Substance Code	SUB12607MIG
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	300
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)	No
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	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
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	No
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	Yes
D.3.11.13.1	Other medicinal product type	Non Applicabile
D.IMP: 2
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	HEPSERA*1FL 30CPR 10MG
D.2.1.1.2	Name of the Marketing Authorisation holder	GILEAD SCIENCES 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	Tablet
D.3.4.1	Specific paediatric formulation	No
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.3.9.4	EV Substance Code	SUB12454MIG
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)	No
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	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
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	No
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Treatment of chronic hepatitis B

Trattamento dell'epatite B cronica

E.1.1.1

Medical condition in easily understood language

Long-term infection with the hepatitis B virus

Infezione a lungo termine da virus dell`epatite B

E.1.1.2

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	PT
E.1.2	Classification code	10019731
E.1.2	Term	Hepatitis B
E.1.2	System Organ Class	10021881 - Infections and infestations

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 efficacy of tenofovir DF 300 mg QD versus adefovir dipivoxil 10 mg QD for the treatment of presumed pre-core mutant chronic hepatitis B. •To compare the safety and tolerability of tenofovir DF 300 mg QD versus adefovir dipivoxil 10 mg QD for the treatment of presumed pre-core mutant chronic hepatitis B

.Confrontare l`efficacia di Tenofovir Disoproxil Fumarato 300 mg verso Adefovir dipivoxil 10 mg nel trattamento dell`epatite B cronica da virus presunto pre-core mutante . Confrontare la sicurezza e la tollerabilita` di Tenofovir Disoproxil Fumarato 300 mg verso Adefovir dipivoxil 10 mg nel trattamento dell`epatite B cronica da virus presunto pre-core mutanteutante

E.2.2

Secondary objectives of the trial

-To compare the incidence of drug resistant mutations between treatment arms at Week 48 and every 48 weeks thereafter. -To compare the virological, biochemical, serological and histological response to tenofovir DF 300 mg QD versus adefovir dipivoxil 10 mg QD for the treatment of presumed pre-core mutant chronic hepatitis B at Week 48. -To evaluate persistent virological response (i.e.,serum HBV DNA < 400 copies/mL) between randomized treatment arms post Week 48. -To compare the virological, biochemical, serological and histological response of continuous treatment of tenofovir DF (early) versus sequential treatment of tenofovir DF (deferred; 48 weeks of adefovir dipivoxil followed by tenofovir DF treatment). Antiviral response (virological, biochemical and serological) will be evaluated annually at Weeks 96, 144, 192, 240, 288, 336 and 384. Annual resistance surveillance will be conduc

-Confrontare l`incidenza delle mutazioni farmaco-resistenti e la risposta virologica, biochimica sierologica ed istologica tra i due bracci di trattamento

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

PHARMACOGENOMIC:
Vers:Amend. 4
Date:2011/09/09
Title:Pharmacogenomic substudy
Objectives:An optional blood sample may be obtained for exploratory biomarker and pharmacogenomic discovery research. This sample may be collected at any time during the study or a separate post study visit, if necessary. Subjects who agree to have drawn for these porposes will sign a separate informed consent form.

FARMACOGENOMICA:
Vers:Amend. 4
Data:2011/09/09
Titolo:Sottostudio di farmacogenomica
Obiettivi:Saranno prelevati campioni di sangue aggiuntivi per la determinazione di biomarker ed elementi di farmacogenomica. Questi campioni saranno raccolti ad ogni visita durante lo studio o durante le visite post studio, se necessario. I soggetti che aderiranno al sottostudio dovranno firmare un consenso informato specifico.

E.3

Principal inclusion criteria

-Chronic HBV infection, defined as positive serum HBsAg for at least 6 months; -18 through 69 years of age, inclusive; -Active HBeAg negative chronic HBV infection, with all of the following: -HBeAg negative and HBeAb positive at screening; -ALT level >ULN and ≤10xULN; -Serum HBV DNA >100000 copies/ml at screening; _creatinine clearance ≥70 ml/min; -hemoglobin ≥8 g/dl; -neutrophilis ≥1000 /mm3; -Nucleotide naive, i.e., no prior nucleotide (tenofovir DF or adefovir dipivoxil) therapy for greater than 12 weeks; -NUcleoside naive, i.e., no prior nucleoside (any nucleoside) therapy for greater than 12 weeks. However, up to 120 patinets with greater than 12 weeks prior lamivudine or emtricitabine experienced prior to eligible.

-inf

E.4

Principal exclusion criteria

-Males and females of reproductive potential who are unwilling to use an `effective` method of contraception during the study; -Decompensated liver disease defined as conjugated bilirubin > 1.5xULN, PT >1.5ULN, platelets < 75.000/mm3, serum albumin <3.0 g/dl, or prior history of clinical hepatic decompensation (e.g., ascites, jaundice, encephalophaty, variceal hemorrhage); -Received any nucleoside, nucleotide (tenofovir DF or adefovir dipivoxil) or interferon (pegylated or not) therapy within 6 months prior of the pre-treatment biopsy; -Evidence of hepatocellular carcinoma (HCC); -Co-infection with HCV, HIV or HDV; -Significant renal, cardiovascular, pulmonary, or neurological disease; -Is currently receiving therapy with immunomodulators (e.g., corticosteroids, ect.), investigationals agents, nephrotoxic agents, or agents susceptible of modifying renal excretion.

-Uomini e donne in età fertile che non utilizzano un efficace metodo contraccetivo nel periodo di studio. -Patologia epatica scompensata definita dai valori di bilirubina > 1.5xULN, PT >1.5xULN, piastine < 75.000/mm3, albumina sierica <3.0g/dl, o precedente storia di patologia epatica scompensata (ascite, ittero, encefalopatia,varici emorragiche); -Trattamento precedente con antivirali nucleosidici, nucleotidici (tenofovir DF o adefovir dipivoxil) o interferone (pegylato o non) nei sei mesi antecedenti allo studio ed alla biopsia; -Diagnosi di carcinoma epatocellulare (HCC); -Coinfezione da virus HCV, HIV O HDV; -Rilevanti patologie renali, cardiovascolari, polmonari o neurologiche; -Trattamento concomitante con farmaci immunomodulatori (corticosteroidi), farmaci sperimentali, nefrotossici o potenzialmente escreti dall`apparato renale.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy parameter is the proportion of patients with complete response, i.e., serum HBV DNA levels below 400 copies/mL and histologic improvement defined as at least a 2 point reduction in the Knodell necroinflammatory score without worsening in Knodell fibrosis score.

La percentuale di pazienti che presentano a 48 settimane livelli sierici di HBV-DNA inferiori a 400 copie/ml ed un miglioramento istologico definito come riduzione pari ad almeno 2 punti dell'indice necroinfiammatorio di Knodell in assenza di peggioramento dell'indice di fibrosi di Knodell.

E.5.1.1

Timepoint(s) of evaluation of this end point

48 weeks

48 settimane

E.5.2

Secondary end point(s)

Secondary endpoints are change from baseline in log10 serum HBV DNA and ALT levels, proportion of patients with serum HBV DNA below 400 copies/mL, percentage of patients with normal ALT, incidence of drug resistant mutations, percentage of patients with HBsAg loss and seroconversion, percentage of patients with histological improvement, change from baseline in histological scores (to include Ishak).

L`endpoint secondario è la valutazione in scala log10 dal basale dei livelli sierici di HBV DNA e ALT, la percentuale di pazienti con livelli inferiori a 400 copie/ml di HVB DNA, la percentuale delle mutazioni che causano farmaco resistenza, la percentuale di pazienti con diminuzione di HBsAg e seroconversione, la percentuale di pazienti che ottengono un miglioramento istologico, la variazione dal basale dello score istologico (incluso Ishak).

E.5.2.1

Timepoint(s) of evaluation of this end point

48 weeks

48 settimane

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

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

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)

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

double-dummy

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

E.8.2.4

Number of treatment arms in the trial

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

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

Australia

Canada

New Zealand

Turkey

United States

E.8.7

Trial has a data monitoring committee

Yes

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

LVLS

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

100

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

F.1.1

Number of subjects for this age range:

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)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

285

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

Yes

F.3.3.2

Women of child-bearing potential using contraception

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

157

F.4.2.2

In the whole clinical trial

300

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)

Viread is available in EU for the treatment of CHB

Viread è disponibile in UE per il trattamento dell`epatite B cronica

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

2005-10-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2005-11-07

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-01-19

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