Clinical Trials Register

Summary
EudraCT Number:	2012-002457-29
Sponsor's Protocol Code Number:	GS-US-334-0125
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:	2012-10-31
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

2012-002457-29

A.3

Full title of the trial

A Phase 2, Multicenter, Open-Label, Randomized Study to Investigate the Safety and Efficacy of GS-7977 and Ribavirin Administered for 24 weeks in Patients Infected with Chronic HCV with Cirrhosis and Portal Hypertension with or without Liver Decompensation.

Estudio de fase 2, multicéntrico, abierto y aleatorizado para evaluar la seguridad y la eficacia de GS-7977 y ribavirina durante 24 semanas en pacientes con VHC crónico con cirrosis e hipertensión portal con o sin descompensación hepática.

A.3.1

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

A study with GS-7977 and Ribavirin in Hepatitis C patients with cirrhosis and portal hypertension

Estudio con GS-7977 y ribavirina en pacientes con Hepatitis C con cirrosis e hipertensión portal.

A.4.1

Sponsor's protocol code number

GS-US-334-0125

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 Inc
B.5.2	Functional name of contact point	Medical Monitor
B.5.3	Address:
B.5.3.1	Street Address	333 Lakeside Drive
B.5.3.2	Town/ city	Foster City
B.5.3.3	Post code	CA 94404
B.5.3.4	Country	United States
B.5.4	Telephone number	+1650574 3000
B.5.5	Fax number	+1650578 9264
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	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	Sofosbuvir
D.3.2	Product code	GS-7977
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	Sofosbuvir
D.3.9.1	CAS number	1190307-88-0
D.3.9.2	Current sponsor code	GS-7977
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	400
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	Ribasphere
D.2.1.1.2	Name of the Marketing Authorisation holder	Three Rivers Pharmaceuticals LLC
D.2.1.2	Country which granted the Marketing Authorisation	United States
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.3.4	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.3.9.1	CAS number	36791-04-5
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

Subjects infected with chronic HCV with cirrhosis and portal hypertension with or without liver decompensation

Pacientes con VHC crónico con cirrosis e hipertensión portal con o sin descompensación hepática

E.1.1.1

Medical condition in easily understood language

Patients with Hepatitis C and liver cirrhosis

Pacientes con Hepatitis C y cirrosis hepática

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	10019744
E.1.2	Term	Hepatitis C
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
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

To determine the antiviral efficacy of combination therapy with GS-7977 + Ribavirin (RBV) for 24 weeks in compensated and decompensated chronic HCV subjects as measured by sustained virologic response 12 weeks after discontinuation of therapy (SVR12 defined as HCV RNA < lower limit of Quantification [LLoQ] 12 weeks post-treatment).

Determinar la eficacia antivírica de la terapia combinada con GS-7977 + ribavirina (RBV) durante 24 semanas en sujetos con infección por VHC crónica compensada y descompensada medida según la respuesta virológica sostenida 12 semanas después de la interrupción del tratamiento (RVS12 definida como ARN del VHC < límite inferior de cuantificación[LIC] 12 semanas después del tratamiento).

E.2.2

Secondary objectives of the trial

? To determine the effect of 24 weeks of dosing with GS-7977 + RBV on portal pressure as measured by HVPG measurements
? To evaluate the safety and tolerability of the regimen in this patient population
? To determine the proportion of subjects who attain sustained virologic response at 4, 24 and 48 weeks after discontinuation of therapy (SVR4, SVR24 and SVR48)
? To determine therapeutic efficacy as measured by the change of CPT score, MELD score, serum biochemical test results and time to transplant or death.
? To evaluate the emergence of viral resistance to GS-7977 during and after treatment discontinuation.
? To evaluate the kinetics of plasma HCV RNA during and after treatment

? Determinar el efecto de 24 semanas de dosificación con GS-7977 + RBV sobre la presión portal medida según el Gradiente de Presión Venosa Hepática (GPVH)
? Evaluar la seguridad y la tolerabilidad de la pauta posológica en esta población de pacientes
? Determinar la proporción de sujetos que alcanzan una respuesta virológica sostenida a las 4, 24 y 48 semanas después de interrumpir la terapia (RVS4, RVS24 y RVS48)
? Determinar la eficacia terapéutica medida según el cambio de la puntuación de Child-Pugh-Turcotte (CPT), la puntuación del Modelo de insuficiencia renal terminal (MELD), los resultados de los análisis bioquímicos en suero y tiempo para el transplante o muerte
? Evaluar la aparición de resistencia vírica a GS-7977 durante el tratamiento y tras la interrupción del mismo
? Evaluar la cinética del ARN del VHC en plasma durante el tratamiento y después del mismo

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

Pharmacokinetics (PK) Substudy:
An intensive pharmacokinetic substudy will be performed on subjects who provide separate consent to assess the PK of GS-7977 metabolites.

Pharmacogenomic Substudy:
All subjects will be eligible to participate in the Pharmacogenomic Substudy if locally approved and if separate consent is obtained. The objective of this substudy is to identify or validate genetic markers that may be predictive of the natural history of disease, virologic response to therapy and/or the tolerability of medical therapies through genetic discovery research.

Subestudio de farmacocinética (FC):
Se llevará a cabo un subestudio de farmacocinética intensivo en sujetos que otorguen un consentimiento aparte para evaluar la FC de GS-7977 y los metabolitos.

Subestudio de farmacogenómica:
Todos los sujetos serán aptos para participar en el subestudio de farmacogenómica siempre que se obtenga un consentimeinto aparte aprobado localmente. El objetivo de este subestudio es identificar o validar marcadores genéticos
que pueden ser predictivos de la historia natural de la enfermedad, la respuesta virológica a la terapia y/o la tolerabilidad a las terapias médicas a través de la investigación genética.

E.3

Principal inclusion criteria

1. Willing and able to provide written informed consent
2. Age ?18 years
3. Subjects with compensated cirrhosis (CPT Score 5-6) or decompensated cirrhosis (CPT Score 7-10) with the presence of esophageal or gastric varices on endoscopy
4. Hepatic Venous Pressure Gradient (HVPG) > 6 mmHg
5. HCV RNA > 103 IU/mL at Screening
6. Body mass index (BMI) ?18 kg/m2
7. Naïve to all nucleotides/nucleoside treatments for chronic HCV infection
8. Non-pregnant, non-nursing female

1. Capaces y dispuestos a proporcionar consentimiento informado por escrito.
2. Edad ? 18 años
3. Sujetos con cirrosis compensada (puntuación CPT de 5-6) o descompensada (puntuación CPT de 7-10) con presencia de varices esofágicas o gástricas en la endoscopia.
4. Gradiente de presión venosa hepática (GPVH) > 6 mmHg.
5. ARN del VHC > 103 UI/ml en la Selección.
6. Índice de masa corporal (IMC) ? 18 kg/m2
7. Sin tratamiento previo con ningún nucleótido/nucleósido para la infección crónica por VHC.
8. Mujer que no esté embarazada ni amamantando.

E.4

Principal exclusion criteria

1. Any serious or active medical or psychiatric illness
2. HIV or chronic hepatitis B virus (HBV) infection (HBsAg positive)
3. AFP > 50 unless negative imaging for hepatic masses
4. Malignancy within the 5 years prior to screening
5. Refractory ascites as defined by requiring paracentesis > twice
6. Prior placement of a portosystemic shunt (such as TIPS)
7. Imaging evidence or history of portal vein thrombosis
8. Active variceal bleeding within 6 months of screening
9. Expected survival of < 1 year
11. Chronic use of systemic immunosuppressive agents
17. Evidence of renal impairment (CrCl < 50 mL/min) using the Cockcroft-Gault equation

1. Padecer alguna enfermedad médica o psiquiátrica grave o activa.
2. Infección por VIH o virus de la hepatitis B (VHB) crónica (HBsAg positivo).
3. Alfa-fetoproteína (AFP) > 50 salvo que se obtengan imágenes negativas para masas hepáticas.
4. Tumor maligno durante los 5 años previos a la selección.
5. Ascitis resistente al tratamiento definida como aquella que haya requerido paracentesis > dos veces.
6. Colocación previa de una derivación portosistémica (por ejemplo, TIPS)
7. Antecedentes o imágenes que muestren trombosis venosa portal
8. Varices hemorrágicas activas en los 6 meses previos a la selección
9. Esperanza de vida < 1 año
11. Uso crónico de inmunosupresores sistémicos.
17. Evidencia de insuficiencia renal (CrCl < 50 ml/min) según la ecuación de Cockcroft-Gault

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint is SVR12 (HCV RNA < lower limit of Quantification [LLoQ] 12 weeks after last dose of study drug). SVR12 during the observational period for subjects in Arm 2 will be defined as HCV RNA < lower limit of Quantification [LLoQ] for 12 consecutive weeks, any time during the observational period.

El criterio de valoración de la eficacia primario para este estudio será la proporción de sujetos con RVS12, definida como ARN VHC < LLoQ 12 semanas después de dejar el fármaco del estudio. RVS12 durante el período observacional para los sujetos del Grupo 2 se define como ARN VHC < LLoQ durante 12 semanas consecutivas, en cualquier momento durante el período observacional.

E.5.1.1

Timepoint(s) of evaluation of this end point

12 weeks after last dose of study drug

12 semanas después de la última dosis del fármaco del estudio

E.5.2

Secondary end point(s)

Secondary efficacy endpoints include HVPG measurements, CPT and MELD scores, SVR4,
SVR24, SVR48, viral breakthrough and relapse.

Los criterios de valoración de eficacia secundarios incluyen medidas del Gradiente de Presión Venosa Hepática (GPVH), puntuaciones de Child-Pugh-Turcotte (CPT) y del Modelo de insuficiencia renal terminal (MELD), RVS4, RVS24, RVS48, progreso viral y recaída.

E.5.2.1

Timepoint(s) of evaluation of this end point

4, 24 and 48 weeks after last dose of study drug

4, 24 y 48 semanas después de la última dosis del fármaco del estudio

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)

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Untreated observation parallel to the treatment arm for 24 weeks (later followed by treatment)

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

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

France

New Zealand

Spain

United States

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

LVLS at 48 weeks after the last dose of study drug

Última visita del último paciente a las 48 semanas después de la última dosis del fármaco en estudio

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:

F.1.3

Elderly (>=65 years)

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

F.4.2.2

In the whole clinical trial

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)

Subjects who do not achieve SVR will be eligible for enrollment in a Sequence Registry Study (GS-US-248-0123) to monitor variants in the viral population for up to 3 years.
Subjects who achieve SVR will be eligible for enrollment in the SVR Registry Study (GS-US-248-0122) to evaluate the durability of SVR for up to 3 years post-treatment.

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

2013-01-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-12-13

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

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IMP with orphan designation in the indication
Orphan Designation Number:
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