Clinical Trials Register

Summary
EudraCT Number:	2014-003413-28
Sponsor's Protocol Code Number:	TMC435HPC2019
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-11-25
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

Spain - AEMPS

A.2

EudraCT number

2014-003413-28

A.3

Full title of the trial

A Phase 2, Open-label Study to Investigate the Efficacy and Safety of the Combination of Simeprevir and Daclatasvir in Chronic Hepatitis C Genotype 1b-Infected Subjects With Advanced Liver Disease

Estudio Fase 2, abierto, para investigar la eficacia y seguridad de la combinación de simeprevir y daclatasvir en pacientes con infección crónica por el virus de la hepatitis C de genotipo 1b con enfermedad hepática avanzada.

A.3.1

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

A Study to Assess the Efficacy and Safety of the Combination of Simeprevir and Daclatasvir in Chronic Hepatitis C Genotype 1b-Infected Participants With Advanced Liver Disease

El objetivo principal es determinar la eficacia de un régimen de tratamiento de 12 semanas de simeprevir en combinación con daclatasvir, medida por la RVS12 (respuesta virológica sostenida a las 12 semanas después del final del tratamiento [FT] real), en pacientes con infección crónica por el VHC de genotipo 1b no pretratados que presenten fibrosis avanzada o cirrosis compensada

A.3.2

Name or abbreviated title of the trial where available

COMMIT

A.4.1

Sponsor's protocol code number

TMC435HPC2019

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	Janssen-Cilag International NV
B.1.3.4	Country	Belgium
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	Janssen R&D 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	Janssen-Cilag, S.A.
B.5.2	Functional name of contact point	Global Clinical Operations Spain
B.5.3	Address:
B.5.3.1	Street Address	Pº de las Doce Estrellas, 5-7
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	28042
B.5.3.4	Country	Spain
B.5.4	Telephone number	+3491722 81 00
B.5.5	Fax number	+3491722 86 28
B.5.6	E-mail	agonza45@its.jnj.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	OLYSIO
D.2.1.1.2	Name of the Marketing Authorisation holder	Janssen-Cilag International NV
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	JNJ-38733214-AAA - capsule, hard (G019) - 150mg
D.3.2	Product code	TMC435 (or R494617)
D.3.4	Pharmaceutical form	Capsule, hard
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	Simeprevir
D.3.9.2	Current sponsor code	TMC435
D.3.9.3	Other descriptive name	JNJ-38733214-AAA
D.3.9.4	EV Substance Code	SUB26723
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	150
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	Yes
D.2.1.1.1	Trade name	OLYSIO
D.2.1.1.2	Name of the Marketing Authorisation holder	Janssen-Cilag International NV
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.3.1	Product name	JNJ-38733214-AAA - capsule, hard (G028) - 150mg
D.3.2	Product code	TMC435 (or R494617)
D.3.4	Pharmaceutical form	Capsule, hard
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	Simeprevir
D.3.9.2	Current sponsor code	TMC435
D.3.9.3	Other descriptive name	JNJ-38733214-AAA
D.3.9.4	EV Substance Code	SUB26723
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	150
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.2.1.1.1	Trade name	Daklinza
D.2.1.1.2	Name of the Marketing Authorisation holder	Bristol-Myers Squibb Pharma EEIG
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Daclatasvir
D.3.2	Product code	BMS-790052 / DCV
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	daclatasvir
D.3.9.2	Current sponsor code	BMS-790052
D.3.9.3	Other descriptive name	DACLATASVIR
D.3.9.4	EV Substance Code	SUB34092
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	60
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

Hepatitis C Virus (HCV) genotype-1b Infection

Virus de la hepatitis C (VHC) de genotipo 1b

E.1.1.1

Medical condition in easily understood language

Hepatitis C Virus (HCV) genotype-1 Infection

Virus de la hepatitis C (VHC) de genotipo 1

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	17.1
E.1.2	Level	PT
E.1.2	Classification code	10019744
E.1.2	Term	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

To determine the efficacy of a 12-week treatment regimen of simeprevir in combination with daclatasvir, as measured by SVR12, in treatment-naïve, chronic HCV genotype 1b-infected subjects who have advanced fibrosis or compensated cirrhosis

El objetivo principal es determinar la eficacia de un régimen de tratamiento de 12 semanas de simeprevir en combinación con daclatasvir, medida por la RVS12 (respuesta virológica sostenida tras 12 semanas del final del tratamiento [FT]), en pacientes con infección crónica por el VHC de genotipo 1b que no hayan recibido tratamiento previo, que presenten fibrosis avanzada o cirrosis compensada.

E.2.2

Secondary objectives of the trial

- To evaluate the efficacy of a 12-week treatment regimen containing simeprevir and daclatasvir with respect to the percentage of subjects achieving SVR4 and SVR24
- To evaluate the incidence of on-treatment failure.
- To evaluate the incidence of viral relapse.
- To determine/characterize emerging NS3/4A and NS5A mutations in subjects not achieving SVR.
- To evaluate safety and tolerability of a 12-week treatment regimen containing simeprevir and daclatasvir.

- Evaluar la eficacia de un régimen de tratamiento de 12 semanas basado en simeprevir y daclatasvir con respecto al porcentaje de pacientes que logran RVS4 y RVS24.
- Evaluar la incidencia del fracaso durante el tratamiento.
- Evaluar la incidencia de recidiva viral.
- Determinar/caracterizar las mutaciones de NS3/4A y NS5A que aparezcan en los pacientes que no alcancen RVS.
- Evaluar la seguridad y la tolerabilidad de un régimen de tratamiento de 12 semanas basada en simeprevir y daclatasvir.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Participant must have chronic Hepatitis C virus (HCV) genotype 1b infection confirmed at Screening
- Participant must have HCV ribonucleic acid (RNA) greater than (>) 10,000 international unit per milliliter (IU/mL) at Screening - Participant must have documented advanced fibrosis or compensated liver cirrhosis at Screening (METAVIR F3 or F4)
- Participants who have cirrhosis must have an hepatic imaging procedure (ultrasound, computed tomography [CT] scan or magnetic resonance imaging [MRI]) within 6 months prior to the Screening visit (or between Screening and Day 1) with no findings suspicious for hepatocellular carcinoma
- Participant must have a body mass index (BMI) greater than or equal to (>=) 18 Kilogram per meter^2 (kg/m^2)
- Participant must be treatment naive (that is, have not received prior treatment for HCV with any approved or investigational drug)

Se reclutarán varones o mujeres de 18 o más años de edad con infección crónica por el VHC de genotipo 1b confirmada en la selección, un valor de ARN del VHC en la selección >10.000 UI/ml, fibrosis avanzada o cirrosis hepática compensada comprobadas mediante elastografía de ondas de cizalladura (Fibroscan) con un resultado > 9,6 kPa (cirrosis ? 14,6 kPa) en los ? 6 meses previos a de la selección o durante la selección con resultados disponibles antes del día 1 o mediante una biopsia que demuestre una puntuación METAVIR F3 (en las 24 semanas previas a la selección) o F4 (en cualquier momento previo) y no tratados previamente (es decir, que no hayan recibido tratamiento previo del VHC con ningún fármaco aprobado o en investigación). En los pacientes con cirrosis deberá descartarse el carcinoma hepatocelular

E.4

Principal exclusion criteria

- Participant has co-infection with HCV of a genotype other than genotype 1b
- Participant has the presence of genetic variants coding for the NS5A-Y93H and/or L31M/V amino acid substitutions at Screening
- Participant has evidence of current or previous episodes of hepatic decompensation (including controlled or uncontrolled ascites, bleeding varices or hepatic encephalopathy)
- Participant has chronic liver disease of a non-HCV etiology (including but not limited to hemochromatosis, Wilson?s disease, alfa 1-antitrypsin deficiency, cholangitis, drug- or alcohol-related liver disease, primary biliary cirrhosis)
- Participant has any other uncontrolled clinically significant disease or clinically significant findings during Screening that in the opinion of the investigator could compromise the Participants' safety or could interfere with the Participant participating in and completing the study
- Participant has co-infection with human immunodeficiency virus (HIV) type 1 or 2 (positive HIV-1 or HIV-2 antibody test at Screening)
- Participant has received a solid organ transplant

Se excluirá a los posibles pacientes si tienen infección concurrente con VHC de un genotipo distinto del genotipo 1b, variantes genéticas que codifican las sustituciones de aminoácidos NS5A-Y93H o L31M/V, pruebas de episodios actuales o previos de descompensación hepática, enfermedad hepática crónica de etiología distinta del VHC o infección concurrente con los virus de la hepatitis B o de la inmunodeficiencia humana de tipo 1 ó 2

E.5 End points

E.5.1

Primary end point(s)

Percentage of Participants With Sustained Virologic Response 12 Weeks After end of Study Drug Treatment (SVR12)

El criterio de valoración principal es la RVS12, definida como el porcentaje de pacientes con ARN-VHC <LIC 12 semanas después del FT

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 24

Semana 24

E.5.2

Secondary end point(s)

1- Percentage of Participants with SVR 4 Weeks After end of Study Drug Treatment (SVR4) and SVR 24 Weeks After end of Study Drug Treatment (SVR24)
2- Percentage of Participants with On-treatment Failure
3- Percentage of Participants with viral breakthrough
4- Percentage of Participants With Viral Relapse

El porcentaje de pacientes con:
1-RVS4
2-RVS24
3-Fracaso durante el tratamiento, incluido rebote viral
4-Recidiva viral
Se utilizarán las definiciones de RVS, fracaso durante el tratamiento, rebote viral y recidiva viral facilitadas en Definiciones de términos para caracterizar la respuesta al tratamiento basándose en los resultados del ARN del VHC

E.5.2.1

Timepoint(s) of evaluation of this end point

1- Week 16 and Week 36
2- Week 12
3- Week 12
4- Week 12

1-Semana 16 y semana 36
2-Semana 12
3-Semana 12
4-Semana 12

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

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

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

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

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

Last patient last visit

Ultima visita del último paciente

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

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:

100

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

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

110

F.4.2.2

In the whole clinical trial

110

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)

Expected normal treatment of that condition

Tratamiento normal esperado de esa condición.

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

2015-01-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-01-13

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-04-11

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