Clinical Trials Register

Summary
EudraCT Number:	2008-000733-21
Sponsor's Protocol Code Number:	ANRS HB 05
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2008-06-19
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

France - ANSM

A.2

EudraCT number

2008-000733-21

A.3

Full title of the trial

A randomized, double blind, multicenter study evaluating efficacy and safety of Clevudine monotherapy versus Tenofovir monotherapy versus combination therapy of Clevudine and Tenofovir for 96 weeks in HBeAg negative patients with chronic hepatitis B, naïve to anti-VHB therapy

A.4.1

Sponsor's protocol code number

ANRS HB 05

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	ANRS
B.1.3.4	Country	France
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	No
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	Clevudine
D.3.2	Product code	PSI-5268
D.3.4	Pharmaceutical form	Capsule*
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	Clevudine
D.3.9.1	CAS number	163252-36-6
D.3.9.2	Current sponsor code	PSI-5268
D.3.9.3	Other descriptive name	L-FMAU, LFMAU 1-(2'-Deoxy-2'-fluoro-bêta-L-arabinofuranosyl)-5-methyluracil
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
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	Information not present in EudraCT
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	Viread
D.2.1.1.2	Name of the Marketing Authorisation holder	Gilead Sciences
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	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	Ténofovir disoproxil
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)	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	Information not present in EudraCT

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	Capsule*
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	Coated 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

For chronic HBV infection, an optimal pharmacological agent to promote recovery from chronic HBV infection would be one that inhibits HBV DNA polymerase, combined with the clearance from the liver of cccDNA to block HBV reactivation after the circulating viral burden has been eliminated by therapy
The activity of clevudine on cccDNA in combination with its potent antiviral activity on HBV polymerase makes it the optimal agent in combination with tenofovir for this protocol.

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

Information not present in EudraCT

E.2 Objective of the trial

E.2.1

Main objective of the trial

Primary Objective

To compare the long term efficacy of new anti-HBV strategies of CLV monotherapy versus TDF monotherapy versus the combination of CLV + TDF for 96 weeks in HBeAg negative patients with CHB, naïve to anti-HBV-therapy, at 24 weeks post-treatment.

E.2.2

Secondary objectives of the trial

Secondary Objectives

To compare the safety profile of CLV + TDF compared to that of CLV and TDF in HBeAg negative patients with CHB, naïve to anti-HBV-therapy.

To compare perceived toxicity as expressed by the nature and the number of self-reported side effects and perception of fatigue impact on physical, cognitive and psychosocial functioning.

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

"Evaluation of anti-HBV immune response" cf: protocol page 36

The aim of this sub-study is to evaluate, humoral, cellular and intrahepatic response.

E.3

Principal inclusion criteria

Inclusion Criteria

1. Male and female patients  18 years of age
2. Chronic hepatitis B, HBs Ag-positive for  6 months, anti HBs negative
3. Patients with HBeAg- negative chronic hepatitis B (CHB) and anti HBe positive at screen
4. Patients naïve to anti-HBV nucleoside or nucleotide therapy and any other experimental nucleoside/nucleotide analog for HBV
5. Serum HBV-DNA quantifiable at  2000 IU/mL at screening
6. ALT ≥ 1.25 ULN and ≤ 10 ULN
7. Liver biopsy (baseline or within prior 6 months) with evidence of chronic hepatic inflammatory injury (Metavir Activity score ≥ 1, Knodell necroinflammatory score ≥ 3, Ishak score ≥ 1)

E.4

Principal exclusion criteria

1. Cirrhosis or bridging fibrosis on liver fibrosis
2. Subjects who have received any form of alpha interferon in the past 6 months prior to the first administration of randomized treatment
3. Any systemic anti-viral, anti-neoplastic or immuno-modulatory treatment (including supraphysiologic doses of steroids and radiation)  6 months prior to the first dose of randomized treatment and during the study (except for  10 days of acyclovir for herpetic lesions, or prednisone ≤ 10 mg/days for ≤ 10 days more than 1 month)
4. Women with ongoing pregnancy or breast feeding
5. Positive test at screening for anti-HAV IgM Ab, anti-HIV Ab, anti-HCV Ab, HCV RNA, anti-HDV Ab
6. History or other evidence of a medical condition associated with chronic liver disease other than HBV (e.g., hemochromatosis, autoimmune hepatitis, metabolic liver disease including Wilson’s disease and alpha1-antitrypsin deficiency, alcoholic liver disease, toxin exposures, toxic thalassemia, NASH)
7. History or other evidence of bleeding from oesophageal varices or other clinical conditions consistent with decompensated liver disease (defined by one of the following criteria being met : serum albumin < 3.5 g/L, prothrombin time > 4 seconds prolonged, serum bilirubin > 34 µmol/L, history of encephalopathy, history of ascites)
8. Neutrophil count < 1200 cells/mm3 or platelet count < 90,000 cells/mm3 at screening
9. Serum creatinine level > 130µmol/l or calculated creatinine clearance < 70 ml/min (Cockcroft-Gault)
10. Evidence or history of tubular nephropathy , Fanconi syndrom or hypophosphoremia
11. Evidence of drug abuse (including excessive alcohol consumption) within one year of study entry
12. History of a severe seizure disorder or current anticonvulsant use
13. History of immunologically mediated disease (e.g., inflammatory bowel disease, idiopathic thrombocytopenic purpura, lupus erythematosus, autoimmune hemolytic anemia, scleroderma, severe psoriasis, rheumatoid arthritis etc.)
14. History of major organ transplantation with an existing functional graft
15. History or other evidence of severe illness or any other conditions which would make the patient, in the opinion of the investigator, unsuitable for the study
16. Evidence of an active or suspected cancer or a history of malignancy where the risk of recurrence is  20 % within 2 years.
17. Patients with a value of alpha-fetoprotein > 100 ng/mL are excluded, unless stability (less than 10 % increase) has been documented over at least the previous 3 months
18. Patients included in another trial within 8 weeks prior to screening
19. Inability or unwillingness to provide informed consent or abide by the requirements of the study

E.5 End points

E.5.1

Primary end point(s)

Primary Endpoints
Proportion of patients with HBV DNA <50 IU/mL using the Roche TaqMan® Assay at 24 weeks following cessation of 96 Weeks of study treatment.

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

Yes

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

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Information not present in EudraCT

E.8.2.2

Placebo

Yes

E.8.2.3

Other

Information not present in EudraCT

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

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

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

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

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	100
F.4.2	For a multinational trial
F.4.2.1	In the EEA	50
F.4.2.2	In the whole clinical trial	150

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

2008-07-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2008-10-10

P. End of Trial
P.	End of Trial Status	Ongoing

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