Clinical Trials Register

Summary
EudraCT Number:	2005-000336-25
Sponsor's Protocol Code Number:	ML18675
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:	2005-07-06
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

2005-000336-25

A.3

Full title of the trial

Longitudinal analysis of HBV-specific T cell responses in patients with HBeAg-negative chronic hepatitis B (CHB) treated with pegylated interferon alfa-2a (40 KD) (PEGASYS, Ro 25-8310). Immunology sub-study for a selected subgroup of patients participating in study ML 18253

Analisi longitudinale delle risposte T linfocitarie HBV-specifiche in pazienti con epatite cronica B HBeAg negativa trattati con Peginterferon alfa-2a 40KD (PEGASYS, Ro 25-8310). Sotto-studio immunologico in un sottogruppo di pazienti selezionati che partecipano allo studio ML 18253

A.4.1

Sponsor's protocol code number

ML18675

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	ROCHE
B.1.3.4	Country	Italy
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	Pegasys
D.2.1.1.2	Name of the Marketing Authorisation holder	ROCHE SpA *
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Peginterferon alfa-2a
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.3	Concentration number	180
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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.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, HBeAg-negative

epatite cronica B, HBeAg negativa

E.1.1.2

Therapeutic area

Diseases [C] - Virus Diseases [C02]

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

This is an exploratory immunological investigation which has the objective to understand the extent and nature of the antigen-specific and non-specific immune defects in patients with HBeAg-negative CHB and their modulation by therapy with PEGASYS during the first 6 months of treatment

Studio immunologico esplorativo, che ha lo scopo di definire l'entita' e la natura dei difetti immunitari antigene-specifici e non-specifici in pazienti con epatite cronica B HBeAg negativa e la loro modulazione da parte di PEGASYS durante i primi sei mesi di trattamento.

E.2.2

Secondary objectives of the trial

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Male and female patients >18 and <55 years of age • Chronic hepatitis B: HBsAg-positive for >6 months, anti-HBs negative, HBeAg-negative, anti-HBe positive • ALT >ULN but <10x ULN and HBV-DNA between 105 and 107 copies/mL or ALT >2.5x ULN but <10x ULN and HBV-DNA >105 copies /mL • Liver biopsy carried out within the preceding 18 months demonstrating liver disease consistent with chronic hepatitis with Ishak Fibrosis Score >2 • Patients with a histological diagnosis of cirrhosis (Ishak Fibrosis Score 6) and compensated liver disease (Child A, score 5) can be included. • Negative urine or blood pregnancy test (for women of childbearing potential) documented within the 24-hour period prior to the first dose of study drug.

• Pazienti di entrambi i sessi di eta` >18 and <55 • Epatite cronica B: HBsAg positiva da almeno 6 mesi, anti-HBs negativa, HBeAg negativa e anti-HBe positiva • ALT >ULN ma <10x ULN e HBV-DNA tra 105 e 107 copie/mL o ALT >2.5x ULN ma <10x ULN e HBV-DNA >105 copie/mL • Patienti con diagnosi istologica di cirrosi con un punteggio di fibrosi ≥ 2 secondo Ishak, effettuata nei 18 mesi precedenti allo screening • Pazienti con diagnosi istologica di cirrosi (score di fibrosi secondo Ishak pari a 6) e con malattia epatica compensata (Child A, score 5) • Test di gravidanza negativo, su urine o sangue (per donne in eta` fertile) documentato entro le 24 ore precedenti alla prima somministrazione dei farmaci in studio.

E.4

Principal exclusion criteria

• Interferon-based therapy or any systemic anti-HBV <12 months prior to the first dose of randomized treatment.• Antiviral, anti-neoplastic or immuno-modulatory treatment (including supraphysiologic doses of steroids and radiation) <12 months prior to the first dose of randomized treatment (except for <7 days of acyclovir for herpetic lesions more than 1 month prior to first administration of randomized treatment).Patients who are expected to need systemic antiviral therapy other than that provided by the study at any time during their participation are also excluded.• Patients who were non responders (with evidence by ALT >1.5x ULN and HBV DNA >100,000 copies/mL on treatment) to a previous IFN therapy will be excluded.Patients who developed clinical resistance to lamivudine (re-emergence of HBV DNA >100,000 copies/mL after an initial drop at the beginning of therapy) will be excluded.• Compensated liver disease Child A score 6 or decompensated liver disease (Child B or C) or history or other evidence of GI bleeding or endoscopic evidence of GI varices >grade 2.• Positive test at screening for anti-HAV IgM, anti-HIV, anti-HCV, anti-HDV IgG • 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, thalassemia) • Women with ongoing pregnancy or breast feeding • Neutrophil count <1500 cells/mm3 or platelet count <90,000 cells/mm3 at screening • Hemoglobin <11.5 g/dL for females and <12.5 g/dL for men at screening • Serum creatinine level >1.5 times the upper limit of normal at screening or evidence of severe renal disease • History of severe psychiatric disease, especially depression.Severe psychiatric disease is defined as treatment with an antidepressant medication or a major tranquilizer at therapeutic doses for major depression or psychosis, respectively, for at least 3 months at any previous time or any history of the following: a suicidal attempt, hospitalization for psychiatric disease, or a period of disability due to a psychiatric disease.• Evidence of drug abuse or treatment with methadone within one year of study entry • Patients consuming alcohol in excess of 20g/day for women and 30g/day for men in the 6 months preceding enrollment • History of a severe seizure disorder or current anticonvulsant use • History of immunologically mediated disease (e.g., inflammatory bowel disease, idiopathic thrombocytopenic purpura, lupus erythematosus, autoimmune hemolytic anemia, scleroderma, psoriasis, rheumatoid arthritis etc.) • History or other evidence of chronic pulmonary disease associated with functional limitation • History of severe cardiac disease (e.g., NYHA Functional Class III or IV, myocardial infarction within 6 months, ventricular tachyarrhythmias requiring ongoing treatment, unstable angina or other significant cardiovascular diseases) • History of major organ transplantation with an existing functional graft • 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 • Evidence of an active or suspected cancer or a history of malignancy where the risk of recurrence is 20% within 2 years.Patients with a lesion suspicious for hepatic malignancy on a screening imaging study will be excluded.• Patients with a value of alpha-fetoprotein >100 ng/mL are excluded.Patients with values >20 ng/mL but <100 ng/mL may be enrolled, if hepatic neoplasia has been excluded by liver imaging.• Thyroid function not adequately controlled.• History or evidence of severe retinopathy or clinically relevant ophthalmologic disorder (e.g.due to hypertension or diabetes mellitus) et al....

• Pazienti che abbiano ricevuto trattamenti con interferone o con qualsiasi farmaco anti-HBV nei 12 mesi precedenti all'arruolamento • Pazienti che abbiano ricevuto trattamenti con farmaci antivirali, anti-neoplastici ed immuno-modulanti nei 12 mesi precedenti all'arruolamento (ad eccezione della terapia con acyclovir < 7 giorni per lesioni erpetiche, piu` di 1 mese prima dell'arruolamento).Saranno inoltre esclusi I pazienti che potrebbero avere necessita` di una terapia antivirale diversa da quelle fornite dallo studio in qualsiasi momento durante la partecipazione alla sperimentazione. • Pazienti che non abbiano risposto ad una precedente terapia con IFN (con evidenza di ALT >1.5x ULN e HBV DNA >100.000 copie/mL), o che abbiano sviluppato resistenza clinica alla lamivudina (ricomparsa di HBV DNA >100.000 copie/mL dopo una caduta della viremia a inizio terapia). • Pazienti che siano affetti da malattia epatica compensata Child A score 6 o scompensata (Child-Pugh B o C) o con storia o altra evidenza di sanguinamento GI o evidenza endoscopica di varici GI ≥ grado 2, • Pazienti positivi allo screening per anti-HAV IgM, anti-HCV, anti-HDV IgG, anti-HIV.• Storia o altra evidenza di condizione clinica associata a malattia epatica cronica diversa da HBV (ad es.emocromatosi, epatite autoimmune, malattia epatica metabolica come la malattia di Wilson e deficit di alfa1-antitripsina, malattia epatica alcolica, esposizione a tossine, talassemia) • Donne in stato di gravidanza o in allattamento • Neutrofili <1500 cell/mm3 e/o piastrine <90,000 cell/mm3 allo screening • Emoglobina <11.5 g/dL per le donne e <12.5 g/dL per gli uomini allo screening • Creatinina >1.5x ULN allo screening o evidenza di grave nefropatia • Storia di malattia psichiatrica severa, specialmente depressione.La malattia psichiatrica severa e` definita come trattamento con farmaci antidepressivi o con tranquillanti a dosi terapeutiche, rispettivamente per depressione o psicosi, per almeno 3 mesi in qualsiasi momento precedente o storia di uno dei seguenti: tentativo di suicidio, ospedalizzazione per malattia psichiatrica o periodo di inabilita` dovuto a malattia psichiatrica • Evidenza di abuso di droghe o trattamento con metadone entro 1 anno dall'arruolamento nello studio • Consumo di alcol oltre i 20 g/die per le donne e i 30 g/die per gli uomini nei 6 mesi precedenti l'arruolamento • Storia di epilessia severa o terapia in corso con anticovulsivanti • Storia di patologia immuno-mediata (ad es.malattia infiammatoria intestinale, porpora trombocitopenica idiopatica, lupus erythematosus, anemia emolitica autoimmune, sclerodermia, psoriasi, artrite reumatoide, ecc.) • Storia o altra evidenza di pneumopatia cronica associata a limitazione funzionale • Storia di cardiopatia severa (ad es.cardiopatia di classe III o IV NYHA, infarto miocardio nei 6 mesi precedenti, tachiaritmia ventricolare che necessiti terapia, angina instabile o altre patologie cardiovascolari importanti) • Storia di trapianto d'organo con rigetto funzionale • Storia o altra evidenza di malattia severa o altra condizione che potrebbe rendere il paziente non idoneo allo studio, a giudizio dello sperimentatore • Evidenza o sospetto di cancro o storia di malignita` dove il rischio di ricaduta sia >20% entro 2 anni.Saranno esclusi i pazienti con lesione sospetta per malignita` epatica alla diagnostica per immagini dello screening • Valori di alfa-fetoproteina >100 ng/mL.Pazienti con valori >20 ng/mL ma 100 ng/mL potranno essere inclusi previa esclusione di neoplasia epatica tramite diagnostica per immagini epatica • Funzionalita` tiroidea non adeguatamente controllata • Storia o evidenza di retinopatia severa o disordini oftalmologici rilevanti (ad es.dovuti ad ipertensione o diabete mellito) et al...

E.5 End points

E.5.1

Primary end point(s)

This is an exploratory immunological study.

Lo studio proposto e` di tipo immunologico esplorativo.

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

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

studio di fase IIIb

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

E.8.1.2

Open

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

Yes

E.8.1.7.1

Other trial design description

studio immunologico esplorativo

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

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

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

E.8.7

Trial has a data monitoring committee

Information not present in EudraCT

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

F. Population of Trial Subjects
F.1 Age Range
F.1.1	Trial has subjects under 18	No
F.1.1	Number of subjects for this age range:	0
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)	No
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	Yes
F.3.3.2	Women of child-bearing potential using contraception	No
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	15

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

2005-04-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2005-02-28

P. End of Trial
P.	End of Trial Status	Completed

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