Clinical Trials Register

Summary
EudraCT Number:	2014-001022-14
Sponsor's Protocol Code Number:	M14-423
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:	2014-10-20
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

2014-001022-14

A.3

Full title of the trial

An Open-Label, Multicenter Study to Evaluate Long-Term Outcomes with ABT-450/Ritonavir/ABT-267 (ABT-450/r/ABT-267) and ABT-333 With or Without Ribavirin (RBV) in Adults With Genotype 1 Chronic Hepatitis C Virus (HCV) Infection

Studio multicentrico in aperto finalizzato alla valutazione degli esiti a lungo termine della terapia con ABT-450/ritonavir/ABT-267 (ABT-450/r/ABT-267) e ABT-333 con o senza ribavirina (RBV) negli adulti con infezione cronica da virus dell’epatite C (HCV) di genotipo 1 (TOPAZ-I)

A.3.1

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

A.4.1

Sponsor's protocol code number

M14-423

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	AbbVie Deutschland GmbH & Co. KG
B.1.3.4	Country	Germany
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	AbbVie 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	AbbVie Ltd.
B.5.2	Functional name of contact point	EU Clinical Trials Helpdesk
B.5.3	Address:
B.5.3.1	Street Address	Abbott House, Vanwall Business Park, Vanwall Road,
B.5.3.2	Town/ city	Maidenhead, Berkshire
B.5.3.3	Post code	SL6 4XE
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+441628773355
B.5.5	Fax number	+441628672566
B.5.6	E-mail	eu-clinical-trials@abbvie.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	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	ABT-450/r/ABT-267
D.3.2	Product code	ABT-450/r/ABT-267
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	ABT-450
D.3.9.2	Current sponsor code	ABT-450
D.3.9.3	Other descriptive name	A-1043422.0
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	75
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	RITONAVIR
D.3.9.2	Current sponsor code	RITONAVIR
D.3.9.4	EV Substance Code	SUB10342MIG
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	50
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ABT-267
D.3.9.2	Current sponsor code	ABT-267
D.3.9.3	Other descriptive name	A-1233617.0, Ombitasvir
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	12.5
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)	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.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	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	ABT-333
D.3.2	Product code	ABT-333
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	ABT-333
D.3.9.2	Current sponsor code	ABT-333
D.3.9.3	Other descriptive name	A-998821.5, Dasabuvir
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	250
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.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.2.5	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	Ribavirin
D.3.2	Product code	Ribavirin
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	RIBAVIRIN
D.3.9.2	Current sponsor code	RIBAVIRIN
D.3.9.3	Other descriptive name	RIBAVIRIN
D.3.9.4	EV Substance Code	SUB10297MIG
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	200
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Chronic Hepatitis C Infection

Infezione cronica da Epatite C

E.1.1.1

Medical condition in easily understood language

Chronic Hepatitis C Infection

Infezione cronica da Epatite C

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	17.0
E.1.2	Level	PT
E.1.2	Classification code	10008912
E.1.2	Term	Chronic hepatitis C
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

The primary objective of this study is to evaluate the effect of response to treatment (assessed by SVR12 status) on the long-term progression of liver disease in adults with chronic HCV GT1 infection who received treatment with ABT-450/r/ABT-267 and ABT-333 with or without ribavirin, as measured by all-cause death, liver-related death, liver decompensation, liver transplantation, and hepatocellular carcinoma.

L’obiettivo primario di questo studio è valutare gli effetti della risposta al trattamento (definita in base alla risposta virologica sostenuta [sustained virological response, SVR12]) sulla progressione a lungo termine dell’epatopatia negli adulti con infezione cronica da HCV GT1 già sottoposti a trattamento con ABT-450/r/ABT-267 e ABT-333 con o senza ribavirina, in base all’incidenza di decessi per tutte le cause o correlati al fegato, decompensazione epatica, trapianti di fegato e carcinomi epatocellulari.

E.2.2

Secondary objectives of the trial

To evaluate the long-term progression of fibrosis by baseline fibrosis stage and sustained virologic response, as measured by change from baseline in liver stiffness measured by transient elastography (FibroScan®) when available, in adults with genotype 1 (GT1) chronic HCV infection who received treatment with ABT-450/r/ABT-267 and ABT-333 with or without ribavirin.

To evaluate the percentage of subjects achieving SVR12 with ABT-450/r/ABT-267 and
ABT-333 with or without ribavirin in adults with GT1 chronic HCV infection

Valutare la progressione a lungo termine della fibrosi in base allo stadio della patologia al basale e alla risposta virologica sostenuta, alla luce delle variazioni rispetto al basale del grado di rigidità del fegato, misurate tramite elastografia a impulsi (FibroScan®) laddove disponibile, negli adulti con infezione cronica da HCV di genotipo 1 (GT1) precedentemente trattati con ABT-450/r/ABT-267 e ABT-333 con o senza ribavirina. Valutare la percentuale di soggetti che raggiungono la SVR12 in seguito al trattamento con ABT-450/r/ABT-267 e ABT-333 con o senza ribavirina negli adulti con infezione cronica da HCV GT1.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Males and females at least 18 years old at screening
2. Females must be post-menopausal for more than 2 years or surgically sterile or practicing acceptable forms of birth control
3. Males must be surgically sterile or agree to practice acceptable forms of birth control
4. Chronic HCV infection prior to study enrollment.
5. Screening laboratory result indicating HCV genotype 1 infection.

1. Pazienti di ambo i sessi di età uguale o superiore ai 18 anni al momento dello screening; 2. I soggetti di sesso femminile devono essere in fase post-menopausale da almeno 2 anni, chirurgicamente sterili oppure devono utilizzare metodi di contraccezione accettabili; 3. I soggetti di sesso maschile devono essere chirurgicamente sterili oppure devono accettare di utilizzare metodi di contraccezione accettabili; 4. Infezione cronica da HCV precedente l’arruolamento nello studio; 5. Risultati di laboratorio allo screening indicanti infezione da HCV di genotipo 1.

E.4

Principal exclusion criteria

1. Use of contraindicated medication within 2 weeks of dosing
2. Abnormal laboratory tests
3. Current or past clinical evidence of Child-Pugh B or C classification or history of liver decompensation
4. Confirmed presence of hepatocellular carcinoma
5. History of solid organ transplant

1. Uso di farmaci controindicati nelle 2 settimane precedenti alla somministrazione; 2. Valori anomali alle analisi di laboratorio; 3. Attuale o pregressa evidenza di classificazione B o C di Child-Pugh o storia di decompensazione epatica; 4. Presenza confermata di carcinoma epatocellulare; 5. Storia di trapianto di organo solido

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is the incidence of all-cause death, liver-related death, liver decompensation, liver transplantation, hepatocellular carcinoma, and the composite of any of the above outcomes observed during the post-treatment period.

L’endpoint primario è l’incidenza di decessi per tutte le cause o correlati al fegato, decompensazione epatica, trapianti di fegato, carcinomi epatocellulari e la combinazione di qualsiasi degli esiti sopra indicati osservata durante il periodo di post-trattamento.

E.5.1.1

Timepoint(s) of evaluation of this end point

12 weeks after last dose of study drugs

12 settimane dopo l’ultima dose dei farmaci in studio

E.5.2

Secondary end point(s)

1. The effect of sustained virologic response and baseline fibrosis stage on longitudinal change from baseline in Fibroscan score (assessed at the end of treatment and/or post-treatment visits) will be evaluated by comparing mean change between subjects who achieve SVR12 and those who do not. Point estimates and 95% confidence intervals will be provided.
2. The percentage of subjects achieving SVR12 (HCV RNA < LLOQ 12 weeks after the last actual dose of study drug). The simple percentage of subjects achieving SVR12 will be calculated and a two-sided 95% confidence interval of the percentage will be computed based on Wilson's score method.

1. Saranno valutati l’effetto della risposta virologica sostenuta e lo stadio della fibrosi al basale con variazione longitudinale con il punteggio Fibroscan (valutazione alle visite di fine trattamento e/o post-trattamento) facendo un confronto tra i soggetti che ottengono SVR12 e quelli che non raggiungono questo obiettivo. Saranno forniti gli intervalli di confidenza (IC) al 95% e le stime dei punti. 2. La percentuale dei soggetti che ottengono SVR12 (HCV RNA < LLOQ 12 settimane dopo l’ultima effettiva dose del farmaco in studio). Sarà calcolata la semplice percentuale di soggetti che ottengono SVR12 e l’intervallo di confidenza bilaterale al 95% della percentuale sarà determinato sulla base del punteggio di Wilson.

E.5.2.1

Timepoint(s) of evaluation of this end point

1) 12 weeks after the last dose of study drug.
2) 260 weeks after the last dose of study drug.

1) 12 settimane dopo l’ultima dose del farmaco in studio. 2) 260 settimane dopo l’ultima dose del farmaco in studio.

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

Yes

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)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

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

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

120

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

Algeria

Australia

Austria

Belgium

Bulgaria

Canada

Denmark

European Union

Finland

France

Germany

Greece

Israel

Mexico

Netherlands

Norway

Poland

Portugal

Qatar

Romania

Russian Federation

Saudi Arabia

Spain

Sweden

Switzerland

Turkey

United Arab Emirates

United Kingdom

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

260 weeks following the last dose

260 settimane dopo l’ultima dose.

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

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:

1470

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

180

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

168

F.4.2

For a multinational trial

F.4.2.1

In the EEA

1065

F.4.2.2

In the whole clinical trial

1650

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)

Following discontinuation of study drug, the subject will be treated in accordance with the treating physician's best clinical judgment.

In seguito all’interruzione del farmaco in studio, il soggetto sarà trattato in base al giudizio clinico del medico curante.

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

2014-12-09

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-11-11

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

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