Clinical Trials Register

Summary
EudraCT Number:	2013-000636-10
Sponsor's Protocol Code Number:	GS-US-320-0110
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:	2014-01-10
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Spain - AEMPS

A.2

EudraCT number

2013-000636-10

A.3

Full title of the trial

A Phase 3, Randomized, Double-Blind Study to Evaluate the Safety and Efficacy of Tenofovir Alafenamide (TAF) 25 mg QD versus Tenofovir Disoproxil Fumarate (TDF) 300 mg QD for the Treatment of HBeAg Positive, Chronic Hepatitis B

Estudio de fase 3, aleatorizado, doble ciego, para evaluar la seguridad y eficacia de tenofovir alafenamida 25 mg una vez al día frente a fumarato de tenofovir disoproxil 300 mg una vez al día para el tratamiento de la hepatitis B crónica HBeAg-positivo.

A.3.1

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

A study to understand the safety and effectiveness of a new drug called TAF compared to an existing treatment called Viread for the treatment of long term hepatitis B infection.

Estudio para comprender la seguridad y eficacia de un nuevo medicamento denominado TAF comparado con un tratamiendo existente denominado Viread para el tratamiento de la infección de Hepatitis B crónica.

A.4.1

Sponsor's protocol code number

GS-US-320-0110

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 International Limited
B.5.2	Functional name of contact point	Legal Representative of Sponsor
B.5.3	Address:
B.5.3.1	Street Address	Flowers Building, Granta Park
B.5.3.2	Town/ city	Abington, Cambridge
B.5.3.3	Post code	CB21 6GT
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+441223897300
B.5.5	Fax number	+441223897284
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	Tenofovir alafenamide (as hemi-fumarate)
D.3.2	Product code	GS-7340
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	Tenofovir alafenamide (as hemi-fumarate)
D.3.9.2	Current sponsor code	GS-7340
D.3.9.4	EV Substance Code	SUB87688
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	25
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	Comparator
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 International Limited
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	Viread
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	Tenofovir disoproxil (as fumarate)
D.3.9.1	CAS number	202138-50-9
D.3.9.4	EV Substance Code	SUB12607MIG
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	245
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
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	Film-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

Chronic Hepatitis B

Hepatitis B Crónica

E.1.1.1

Medical condition in easily understood language

Long term infection with hepatitis B virus

Infección a largo plazo con virus de hepatitis B

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	16.1
E.1.2	Level	PT
E.1.2	Classification code	10008910
E.1.2	Term	Chronic 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

The primary objectives of this study are as follows:

To compare the efficacy of tenofovir alafenamide (TAF) 25 mg QD versus tenofovir disoproxil fumarate (TDF) 300 mg QD for the treatment of HBeAg-positive, chronic hepatitis B at Week 48 in treatment naïve and treatment experienced subjects. The primary efficacy parameter is the proportion of
subjects with plasma HBV DNA levels below 29 IU/mL.

To compare the safety and tolerability of TAF 25 mg QD versus TDF 300 mg QD for the treatment of HBeAg-positive, chronic hepatitis B at Week 48 in treatment naïve and treatment experienced subjects.

Los objetivos principales de este estudio son los siguientes:

Comparar la eficacia de tenofovir alafenamida (TAF) 25 mg
una vez al día frente a fumarato de tenofovir disoproxil (TDF)
300 mg una vez al día, en la semana 48, para el tratamiento de
la hepatitis B crónica HBeAg-positivo en pacientes con y sin
tratamiento previo. El parámetro principal de la eficacia es la
proporción de pacientes con una concentración plasmática de
ADN del VHB inferior a 29 UI/ml.

Comparar la seguridad y tolerabilidad de TAF 25 mg una vez
al día frente a TDF 300 mg una vez al día, en la semana 48,
para el tratamiento de la hepatitis B crónica HBeAg-positivo en
pacientes con y sin tratamiento previo.

E.2.2

Secondary objectives of the trial

Key secondary objectives:

To compare the safety of TAF 25 mg QD versus TDF 300 mg QD as determined by the percent change from baseline in hip and spine BMD at Week 48.

To compare the safety of TAF 25 mg QD versus TDF 300 mg QD as determined by the change from baseline in serum creatinine at Week 48.

To compare the serological response (loss of HBeAg with seroconversion to anti-HBe) of TAF 25 mg QD versus TDF 300 mg QD for the treatment of HBeAg-positive, chronic hepatitis B at Week 48.

Principales objetivos secundarios:

Comparar la seguridad de TAF 25 mg una vez al día frente a
TDF 300 mg una vez al día, determinada mediante el cambio
porcentual desde el inicio hasta la semana 48 en la densidad
mineral ósea (DMO) de la cadera y la columna.

Comparar la seguridad de TAF 25 mg una vez al día frente a
TDF 300 mg una vez al día, determinada mediante el cambio
desde el inicio hasta la semana 48 en la creatinina sérica.

Comparar la respuesta serológica (pérdida de HBeAg con
seroconversión a anti-HBe) a TAF 25 mg una vez al día frente
a TDF 300 mg una vez al día para el tratamiento de la hepatitis
B crónica HBeAg-positivo, en la semana 48.

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

Intensive PK Substudy (Optional)
For subjects who provide a separate informed consent (n=16 and upto n=32), an intensive pharmacokinetic substudy will be performed once, at either of the Weeks 4, 8 or 12 visits at select study sites to assess intensive PK profiling in plasma.
Subjects participating in the PK substudy (at sites which can process PBMCs) will also be asked to provide a PBMC (pre-dose) sample at the intensive PK substudy visit. This will be used to evaluate PBMC concentrations of tenofovir diphosphate (TFV-DP), the active form of tenofovir (TFV).

Ophthalmologic Substudy (Optional)
For subjects who provide a separate informed consent (n = 30), a substudy will be conducted to assess ophthalmologic findings, including fundoscopic examination with retinal photographs (both eyes), anytime during the screening period, but must be completed prior to the first dose of study drug, and at Weeks 24, 48, 72, 96 and 144/ED visits at select sites.
An examination of the full retinal field should be conducted noting changes or abnormalities. Photographs of the retina must be taken at each exam and filed in the subject?s source medical records. A central vendor will be used to assess the retinal photographs.

Subestudio FC intensivo (opcional)
En el caso de los pacientes que otorguen un consentimiento informado aparte (n = 16 y hasta n = 32), se realizará un subestudio farmacocinético intensivo una vez en la visita de la
semana 4, la semana 8 o la semana 12 en centros seleccionados, para evaluar en profundidad el perfil FC en plasma.
Se pedirá a los pacientes que participen en el subestudio FC (en centros que puedan procesar CMSP) que proporcionen una muestra para CMSP (antes de la dosis) en el momento de la
visita del subestudio FC intensivo. Esta muestra se utilizará para evaluar la concentración de difosfato de tenofovir (TFV-DP), el metabolito activo de tenofovir (TFV), en CMSP.

Subestudio oftalmológico (opcional)
En el caso de los pacientes que otorguen un consentimiento informado aparte (n = 30), se llevará a cabo un subestudio para evaluar los resultados oftalmológicos de la oftalmoscopia
con fotografías de la retina (ambos ojos), en cualquier momento durante el periodo de selección, pero antes de la primera dosis del fármaco del estudio, y en las semanas 24, 48, 72,
96 y la visita de la semana 144/IA, en centros seleccionados.
Se debe realizar una exploración del campo retiniano completo para detectar todo cambio o anomalía. Se deben tomar fotografías de la retina en cada exploración y archivarlas en los
informes médicos originales del paciente. Se contará con un proveedor central para evaluar las fotografías de la retina.

E.3

Principal inclusion criteria

1) Must have the ability to understand and sign a written informed consent form.

2) Adult male and non-pregnant, non-lactating female subjects, 18 years of age and older. A negative serum pregnancy test at Screening is required for female subjects of childbearing potential (unless surgically sterile or greater than two years post-menopausal).

3) Documented evidence of chronic HBV infection.

4) HBeAg positive, chronic hepatitis B.

5) Treatment naïve subjects or treatment experienced subjects will be eligible for enrollment. Treatment experienced subjects receiving oral antiviral treatment at Screening must continue their treatment regimen until the time of randomization, when it will be discontinued.

6) Any previous treatment with interferon (pegylated or non-pegylated) must have ended at least 6 months prior to the baseline visit.

7) Estimated creatinine clearance (CLCr) > or = 60 mL/min (using the Cockcroft-Gault method) based on serum creatinine and actual body weight as measured at the Screening evaluation.

8) Normal ECG.

9) Willing and able to comply with all study requirements.

1. Tener la capacidad de entender y firmar un formulario de consentimiento informado por escrito, que se debe obtener antes de iniciar los procedimientos del estudio.

2. Pacientes adultos, hombres y mujeres no embarazadas ni en periodo de lactancia, de 18 años en adelante en la fecha de la visita de selección. Prueba de embarazo en suero
negativa en la selección, en el caso de mujeres con capacidad para concebir (a menos que sean quirúrgicamente estériles o posmenopáusicas desde hace más de dos años).

3. Pruebas documentadas de infección crónica por el VHB.

4. Hepatitis B crónica, HBeAg-positivo.

5. Los pacientes sin tratamiento previo O los pacientes tratados
previamente serán aptos para la inscripción. Los pacientes tratados previamente que, en el momento de la selección, estén recibiendo antivíricos orales deben continuar su pauta terapéutica hasta la aleatorización, momento en que dejarán de recibirlos.

6. Todo tratamiento previo con interferón (pegilado o no pegilado) debe haber finalizado al menos 6 meses antes de la visita inicial.

7. Aclaramiento de creatinina estimado (ACr) > o = 60 ml/min (usando el método de Cockcroft-Gault), según la creatinina sérica y el peso corporal real determinados en la evaluación de
selección.

8. ECG normal.

9. Voluntad y capacidad de cumplir todos los requisitos del estudio.

E.4

Principal exclusion criteria

1) Pregnant women, women who are breastfeeding or who believe they may wish to become pregnant during the course of the study.

2) Males and females of reproductive potential who are unwilling to use an "effective", protocol specified method(s) of contraception during the study.

3) Co-infection with HCV, HIV or HDV.

4) Evidence of hepatocellular carcinoma.

5) Any history of, or current evidence of, clinical hepatic decompensation.

6) Abnormal hematological and biochemical parameters.

7) Received solid organ or bone marrow transplant.

8) Significant renal, cardiovascular, pulmonary, or neurological disease in the opinion of the investigator.

9) Significant bone disease (eg, osteomalacia, chronic osteomyelitis, osteogenesis
imperfecta, osteochrondroses), or multiple bone fractures.

1. Mujeres embarazadas, en periodo de lactancia, o que crean que quizá deseen quedarse embarazadas durante el transcurso del estudio.

2. Hombres y mujeres con capacidad reproductiva que no deseen utilizar durante el estudio un método anticonceptivo ?eficaz? especificado en el protocolo.

3. Coinfección con el VHC, VIH o VHD.

4. Signos de carcinoma hepatocelular.

5. Antecedentes o signos en curso de descompensación hepática clínica

6. Parámetros bioquímicos y hematológicos anormales.

7. Recepción de un trasplante de víscera maciza o médula ósea.

8. Enfermedad renal, cardiovascular, pulmonar o neurológica, que sea significativa en opinión del investigador.

9. Osteopatía significativa (p. ej., osteomalacia, osteomielitis crónica, osteogénesis imperfecta u osteocondrosis) o fracturas óseas múltiples.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint is the proportion of subjects with plasma HBV DNA < 29 IU/mL at Week 48.

El criterio principal de valoración de la eficacia es la proporción de pacientes con ADN del VHB < 29 UI/ml en la semana 48.

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 48

Semana 48

E.5.2

Secondary end point(s)

The secondary endpoints are:
- The percent change from baseline at Week 48 in spine and hip BMD
- The change from baseline at Week 48 in creatinine clearance (measured by Cockcroft-Gault method)
- The proportion of subjects with HBeAg loss with seroconversion to anti-HBe at Week 48

Los principales criterios secundarios de valoración son:
- El cambio porcentual desde el inicio hasta la semana 48 en la DMO de la cadera y la columna.
- El cambio desde el inicio hasta la semana 48 en el aclaramiento de creatinina (medida por el método Cockcroft-Gault).
- La proporción de pacientes con pérdida de HBeAg con seroconversión a anti-HBe en la semana 48.

E.5.2.1

Timepoint(s) of evaluation of this end point

Week 48

Semana 48

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

Yes

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)

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

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)

Yes

E.8.2.2

Placebo

Yes

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

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

Bulgaria

Canada

China

France

Italy

Japan

New Zealand

Romania

Australia

Germany

Hong Kong

India

Korea, Republic of

Spain

Poland

Russian Federation

Singapore

Taiwan

Turkey

United Kingdom

United States

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

LPLV

Última 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

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:

834

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

200

F.4.2.2

In the whole clinical trial

864

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)

Standard of care.

Tratamiento habitual.

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

2013-12-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-10-28

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2022-10-13

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