Clinical Trials Register

Summary
EudraCT Number:	2016-002446-23
Sponsor's Protocol Code Number:	GS-US-342-1143
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:	2019-05-30
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

2016-002446-23

A.3

Full title of the trial

A Phase 2, Open-Label, Multicenter, Multi-cohort Study to Investigate the Safety and Efficacy of Sofosbuvir/Velpatasvir in Adolescents and Children
with Chronic HCV Infection

Studio di Fase 2, in aperto, multicentrico, multi-coorte, per esaminare la sicurezza e l’efficacia di sofosbuvir/velpatasvir in adolescenti e bambini con infezione cronica da virus dell’epatite C (Hepatitis C virus, HCV)

A.3.1

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

A trial investigating the safety and efficacy of a drug combination Sofosbuvir/Velpatasvir for Adolescents and Children with hepatitis C

Studio per esaminare la sicurezza e l’efficacia di sofosbuvir/velpatasvir in adolescenti e bambini con epatite C

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

GS-US-342-1143

A.5.4

Other Identifiers

Name:

Number:

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/99/2015

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	GILEAD SCIENCES INCORPORATED
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 Ltd.
B.5.2	Functional name of contact point	Clinical Trials Mailbox
B.5.3	Address:
B.5.3.1	Street Address	Granta Park
B.5.3.2	Town/ city	Cambridge
B.5.3.3	Post code	CB21 6GT
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+44 1223 897 284
B.5.5	Fax number	+44 1223 897 284
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	Yes
D.2.1.1.1	Trade name	Epclusa
D.2.1.1.2	Name of the Marketing Authorisation holder	Gilead Sciences International
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.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
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.3.9.4	EV Substance Code	SUB121170
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Velpatasvir
D.3.9.2	Current sponsor code	GS-5816
D.3.9.4	EV Substance Code	SUB180213
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	100
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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

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 virus infection

Infezione cronica da virus dell’epatite C

E.1.1.1

Medical condition in easily understood language

Hepatitis C

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	20.1
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.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
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

PK Lead-in phase is: To evaluate the steady state pharmacokinetics (PK) and confirm the dose of sofosbuvir/velpatasvir (SOF/VEL) in pediatric
subjects with chronic hepatitis C virus (HCV) infection

Treatment Phase is: To evaluate the safety and tolerability of SOF/VEL for 12 weeks in paediatric subjects with chronic HCV

L’obiettivo primario della fase di lead-in (iniziale) di farmacocinetica (pharmacokinetics, PK) è:
- Valutare la farmacocinetica (PK) allo stato costante e confermare la dose di sofosbuvir/velpatasvir (SOF/VEL) nei soggetti pediatrici con infezione cronica da virus dell’epatite C (HCV)

L’obiettivo primario della fase di trattamento del presente studio è:
- Valutare la sicurezza e la tollerabilità di SOF/VEL per 12 settimane nei soggetti pediatrici con HCV cronica

E.2.2

Secondary objectives of the trial

PK Lead-in Phase is: To evaluate the safety, tolerability, and antiviral activity of 7 days of dosing of SOF/VEL in paediatric subjects with chronic HCV

Treatment Phase is: Determine the efficacy of SOF/VEL for 12 weeks in paediatric subjects with chronic HCV infection, as assessed by the
proportion of subjects with SVR 12 weeks after cessation of treatment; Determine the proportion of subjects with SVR 4 and 24 weeks; Evaluate
the proportion of subjects with virologic failure; Evaluate the kinetics of circulating HCV RNA during treatment and after cessation of treatment;
Evaluate the emergence of viral resistance to SOF and VEL during treatment and after cessation of treatment; Evaluate the effect of treatment with SOF/VEL on QoL; Evaluate the effect of SOF/VEL on
growth and development of paediatric subjects during and after treatment; Evaluate the acceptability, including palatability, of formulations used

Gli obiettivi secondari della fase di trattamento dello studio sono:
- Determinare l’efficacia di SOF/VEL per 12 settimane nei soggetti pediatrici con infezione cronica da HCV, valutata in base alla percentuale di soggetti con risposta virologica sostenuta (sustained virological response, SVR) 12 settimane dopo la cessazione del trattamento (SVR12)
- Determinare la percentuale di soggetti con SVR a 4 e a 24 settimane dopo la cessazione del trattamento (SVR4 e SVR24)
- Valutare la percentuale di soggetti con fallimento virologico, tra cui episodi virali/mancata risposta e recidiva
- Valutare la cinetica dell’RNA HCV circolante durante il trattamento e dopo la cessazione del trattamento
- Valutare l’insorgenza della resistenza virale a SOF e VEL durante il trattamento e dopo la cessazione del trattamento
- Valutare l’effetto del trattamento con SOF/VEL sulla qualità della vita misurata mediante il questionario pediatrico sulla qualità della vita PedsQL™
- Valutare l’effetto di SOF/VEL s

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

Amend#1-Tue Sep 20 00:00:00 CEST 2016-Pharmacogenomics substudy-To identify or validate genetic markers that may be predictive of the natural history of disease, response to therapy, and/or tolerability of medical therapies through genetic discovery research in subjects who provide their separate and specific consent for the Pharmacogenomics substudy

Amend#1-Tue Sep 20 00:00:00 CEST 2016-Sottostudio di farmacogenomica-Identificare o convalidare i marcatori genetici che potrebbero essere predittivi della storia naturale della malattia, della risposta alla terapia e/o della tollerabilità delle terapie mediche tramite un’indagine di ricerca genetica nei soggetti che forniscono il proprio consenso specifico e separato per il sottostudio farmacogenomico

E.3

Principal inclusion criteria

1) Parent or legal guardian able to provide written informed consent prior to any screening evaluations and willing to comply with study requirements. Subjects will provide assent if possible, in accordance with IRB/IEC/local requirements and the Investigator's discretion.
2) 3 years to < 18 years of age as determined at Day 1
3) Chronic HCV-infection (≥ 6 months) as documented by prior medical history or liver biopsy
4) HCV RNA ≥ 1000 IU/mL at Screening
5) Subjects must have a determination of prior treatment status:
a) Treatment-naïve is defined as having never been exposed to an
approved or experimental HCV-specific direct acting antiviral agents or
prior treatment of HCV with interferon or ribavirin.
b) Treatment-experienced is defined as prior treatment failure or intolerance to a regimen containing interferon with or without RBV and
with or without a protease inhibitor that was completed at least 8 weeks prior to Day 1.
c) Interferon intolerant: Subject who discontinued therapy (≤ 12 weeks total) due to ≥ 1 adverse event
6) A negative serum pregnancy test is required at screening and a negative urine test is required at Day 1 for female subjects of child
bearing potential.
7) Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified
method(s) of contraception.
8) Lactating females must agree to discontinue nursing before the IMP is administered.
9) Subject must be able to comply with the dosing instructions for study drug administration and be able to complete the study schedule of
assessments.

Si veda sezione 4.2 del Protocollo

E.4

Principal exclusion criteria

1) Prior use of an HCV NS5A inhibitor
2) Current or prior history of clinical hepatic decompensation (eg, ascites, jaundice, encephalopathy, variceal hemorrhage)
3) Any of the following laboratory parameters at screening: a) INR > 1.2 x ULN b) Platelets < 50,000/mm3 c) albumin < 3.5 g/dL d) ALT > 10 x
the upper limit of normal (ULN) e) AST > 10 x ULN f) Direct bilirubin > 1.5 x ULN g) Estimated glomerular filtration rate < 90 mL/min/1.73m2, as calculated by the Schwartz Formula
4) Chronic liver disease of a non-HCV etiology (eg, hemochromatosis, Wilson's disease, alpha-1 antitrypsin deficiency)
5) Evidence of hepatocellular carcinoma (HCC) or other malignancy (with the exception of certain resolved skin cancers)
6) Co-infection with HIV, acute HAV, or HBV
7) Current or prior history of any of the following:
a) Significant cardiovascular, pulmonary, or neurological disease
b) Evidence of a gastrointestinal malabsorption syndrome that may interfere with absorption of orally administered medications
c) History of solid organ or bone marrow transplantation
d) Psychiatric hospitalization, suicide attempt, and/or a period of disability as a result of their psychiatric illness within the last 5 years.
8) Clinically-relevant alcohol or drug abuse within 12 months of screening.
9) Sexually-active males or females of childbearing potential who are

Si veda sezione 4.3 del Protocollo

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint of the PK Lead-in Phase is to determine steadystate PK, is AUCtau of VEL, SOF, and its major metabolite (GS-331007).
The primary endpoint of the Treatment Phase is assessment of any AEs with a focus on AEs that lead to discontinuation of study drug.

Per la fase di lead-in di PK, i parametri di PK plasmatici principali sono AUCtau per SOF, GS-331007, e VEL.

Per la fase di trattamento, l’endpoint di sicurezza primario è l’analisi di tutti gli EA, in particolare sugli eventi che determinano l'interruzione del tratameno

E.5.1.1

Timepoint(s) of evaluation of this end point

PK lead in phase - Day 7
Treatment phase - SVR 12 weeks

Fase di lead-in di PK - Giorno 7
Fase di trattamento - SVR 12 settimane

E.5.2

Secondary end point(s)

The secondary endpoints of the PK Lead-in Phase are:
- Antiviral activity measurements, including assessment of HCV RNA from baseline through Day 7.
- Any AE leading to permanent discontinuation of study drug.

The secondary endpoints of the Treatment Phase are:
- The proportion of subjects with sustained virological response (SVR) 12 weeks after cessation of treatment (SVR12). SVR12 is the key efficacy endpoint.
- The proportion of subjects with HCV RNA < LLOQ at 4 or 24 weeks after cessation of treatment (SVR4 and SVR24).
- The proportion of subjects with virologic failure, including breakthrough/nonresponse and relapse
- The proportion of subjects with HCV RNA < LLOQ on treatment
- Emergence of viral resistance to SOF and /or VEL during treatment and treatment is discontinued
- HCV RNA change from Baseline/Day 1
- Quality of life endpoints and neuropsychiatric assessments as measured by PedsQL™ Pediatric Quality of Life survey
- Growth and development measurements including height and weight percentiles, Tanner Stage, parental height, and bone age
- Acceptability assessed by swallowability and palatability

Gli endpoint secondari della fase di lead-in PK sono:
- Misurazioni di attività antivirale, compresa la valutazione di HCV RNA dal basale a 7 giorni.
- Qualsiasi AE che ha portato alla sospensione permanente del farmaco in studio.

Gli endpoint secondari della fase di trattamento sono:
- La percentuale di soggetti con risposta virologica sostenuta (SVR) 12 settimane dopo la fine del trattamento (SVR12). SVR12 è l'endpoint chiave di efficacia.
- La percentuale di soggetti con HCV RNA <LLOQ a 4 o 24 settimane dopo l'interruzione del trattamento (SVR4 e SVR24).
- La percentuale di soggetti con fallimento virologico, compresi breakthrough / mancata risposta e ricaduta
- La percentuale di soggetti con HCV RNA <LLOQ sul trattamento
- Insorgenza di resistenza virale per SOF e / o VEL durante il trattamento e il trattamento viene interrotto
- Cambiamento di HCV RNA dal basale / Giorno 1
- Endpoint sulla qualità della vita e valutazioni neuropsichiatriche come misurato da PedsQL™ Pediatric Quality of Life survey
- le misure di crescita e di sviluppo, tra cui altezza e peso percentili, stadio di Tanner, l'altezza dei genitori, e l'età ossea
- Accettabilità valutata da deglutibilità e appetibilità

E.5.2.1

Timepoint(s) of evaluation of this end point

SVR 4, 12 and 24 weeks

SVR 4, 12 e 24 Settimane

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

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

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

Information not present in EudraCT

E.8.1.6

Cross over

Information not present in EudraCT

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

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

Belgium

Italy

United Kingdom

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

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

Yes

F.1.1

Number of subjects for this age range:

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)

Yes

F.1.1.5.1

Number of subjects for this age range:

100

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

100

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

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

Yes

F.3.3.2

Women of child-bearing potential using contraception

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

200

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)

All subjects (those who attain SVR24 or those who do not attain SVR24) who do not initiate other experimental or approved anti-HCV
therapy will be eligible to participate in the Pediatric registry Study.
The pediatric registry study is described in a separate protocol (GS-US- 334-1113). This follow-up study will continue for 5 years.

Tutti i soggetti (quelli che raggiungono la SVR24 o quelli che non raggiungono la SVR24) che non parteciperano ad altre sperimentazioni su terapie anti-HCV avranno diritto a partecipare allo studio di registro pediatrico.
Lo studio di registro pediatrico è descritto in un protocollo separato (GS-US- 334-1113). Questo studio di follow-up continuerà per 5 anni.

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

2016-12-20

Ethics Committee Opinion of the trial application

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

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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