Clinical Trials Register

Summary
EudraCT Number:	2014-003578-17
Sponsor's Protocol Code Number:	GS-US-337-1116
Clinical Trial Type:	Outside EU/EEA
Date on which this record was first entered in the EudraCT database:	2015-01-28
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
H.4 THIRD COUNTRY IN WHICH THE TRIAL WAS FIRST AUTHORISED

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A. Protocol Information

A.2

EudraCT number

2014-003578-17

A.3

Full title of the trial

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

A.3.1

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

A study with Ledipasvir/Sofosbuvir for adolecents and children with chronic Hepatitis C infection.

A.4.1

Sponsor's protocol code number

GS-US-337-1116

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/003/2015

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 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.5.5	Fax number	+4401223897284
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	Harvoni 90 mg/400 mg film-coated tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	Gilead Sciences International Ltd.
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	Harvoni
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.3.9.3	Other descriptive name	SOFOSBUVIR
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	Ledipasvir
D.3.9.2	Current sponsor code	GS-5885
D.3.9.3	Other descriptive name	GS-5885
D.3.9.4	EV Substance Code	SUB32080
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	90
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	LDV/SOF FDC
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	Yes
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	Ledipasvir
D.3.9.3	Other descriptive name	GS-5885
D.3.9.4	EV Substance Code	SUB32080
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	22.5
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.3.9.3	Other descriptive name	SOFOSBUVIR
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	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	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 C virus infection

E.1.1.1

Medical condition in easily understood language

Hepatitis 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	17.1
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	17.1
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.1.3

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 the PK Lead-in Phase of this study is:
- To evaluate the steady state pharmacokinetics (PK) and confirm the dose of LDV/SOF FDC in chronic HCV-infected pediatric subjects
The primary objective of the Treatment Phase of this study is:
- To evaluate the safety and tolerability of LDV/SOF FDC for 12 or 24 weeks in chronic HCV-infected pediatric subjects

E.2.2

Secondary objectives of the trial

The secondary objective of the PK Lead-in Phase of this study:
-Evaluate the safety, tolerability, and antiviral activity of 10 days of dosing of LDV/SOF FDC in chronic HCV-infected pediatric subjects
The secondary objectives of the Treatment Phase of this study:
- Determine the antiviral efficacy of 12 or 24 weeks of LDV/SOF FDC treatment in chronic HCV-infected subjects (including the impact of HCV genotype, IL28 genotype, and prior treatment experience)
- Determine the antiviral efficacy of 12 oe 24 weeks of LDV/SOF FDC treatment in chronic HCV-infected subjects
- Evaluate the kinetics of circulating HCV RNA during treatment and after completion of treatment
- Evaluate the emergence of viral resistance to LDV and SOF during treatment and after completion of treatment
- Evaluate the effect of growth and development on pediatric subjects during and after treatment

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

All subjects will be eligible to participate in the Pharmacogenomic (PG) Substudy. For subjects who provide written consent for the PG Substudy, a blood sample will be drawn at the Day 1 visit. If not obtained at Day 1, the sample may be drawn at any time during the study.

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.
2. 3 years to < 18 years of age as determined at Day 1 (consent of parent or legal guardian required)
3. PK Lead-in only: subjects in Cohort 1 (age 12 to <18 years of age) must weigh ≥ 45 kg
4. PK Lead-in only: all subjects must be treatment naïve: no prior exposure to any IFN, RBV, or other approved or experimental HCV-specific DAA agent
5. Treatment experienced subjects: prior treatment failure to a regimen including interferon either with or without RBV that was completed at least 8 weeks prior to Day 1.
i. Interferon intolerant: Subject who discontinued therapy (≤ 12 weeks total) due to ≥ 1 adverse event
ii. Interferon non-responder: Subject who did not achieve undetectable HCV RNA levels while on treatment
iii. Relapse/breakthrough: Subject who achieved undetectable HCV RNA during treatment or within 4 weeks of the end of treatment but did not achieve a sustained virologic response (SVR)
6. Chronic HCV-infection documented by either:
a) a positive anti-HCV antibody test or positive HCV RNA or positive HCV genotyping test
at least 6 months prior to the Day 1 visit, or
b) a liver biopsy performed prior to the Day 1 visit with evidence of chronic HCV-infection
7. Infection with HCV as determined at Screening.
8. HCV RNA ≥ 1000 IU/mL at Screening
9. Adequate hematologic function (absolute neutrophil count ≥ 1,500/mm3; hemoglobin ≥ 11 g/dL or ≥ 12 g/dL for GT-3 only ).
10. Negative serum beta-HCG pregnancy test
11. Subject able to provide written assent, if they have the ability to read and write, as determined by IRB/IEC/local requirements and Investigator’s discretion

E.4

Principal exclusion criteria

1. Pregnant or lactating subjects
2. Sexually-active males or females of childbearing potential who are not willing to use an effective method of contraception during the study
3. Decompensated liver disease
4. Chronic liver disease of a non-HCV etiology (eg, hemochromatosis, Wilson’s disease, alpha-1 antitrypsin deficiency)
5. alpha-fetoprotein > 50 ng/mL
6. Serum creatinine > 1.5 mg/dL
7. Estimated glomerular filtration rate < 90 mL/min/1.73m2, as calculated by the Schwartz Formula
8. Evidence of hepatocellular carcinoma (HCC)
9. Co-infection with HIV, acute HAV, or HBV
10. Significant cardiovascular, pulmonary, or neurological disease
11. Evidence of a gastrointestinal malabsorption syndrome that may interfere with absorption of orally administered medications
12. History of solid organ or bone marrow transplantation
13. Chronic daily non-steroidal anti-inflammatory drug therapy
14. Systemic corticosteroid use for > 2 weeks (pulmonary/nasal administration is permitted)
15. Investigational agents taken within the past 28 days (except with the expressed approval of the Sponsor)
16. Clinically-relevant alcohol or drug abuse within 12 months of screening.
17. Known hypersensitivity to the study drugs, the metabolites, or formulation excipients
18. Any other condition (including alcohol or substance abuse) or prior therapy that, in the opinion of the Investigator, would make the subject unsuitable for the study or unable to comply with dosing requirements
19. Use of any prohibited concomitant medications
20. PK Lead-in only: subjects with history of cirrhosis

E.5 End points

E.5.1

Primary end point(s)

- For the PK Lead-in Phase, the appropriateness of the LDV/SOF FDC dose will be assessed by evaluating the steady-state PK of the LDV/SOF FDC. The primary endpoint for determining steady state PK is AUCtau of GS-331007, SOF, and LDV. Additional steady-state PK parameters of GS-331007, SOF, and LDV (e.g., AUClast, Cmax, Tmax, Clast, Tlast, Ctau, λz, CL/F, Vz/F and t½) will be estimated and summarized..

- For the Treatment Phase, the primary safety endpoint is any AE leading to permanent discontinuation of study drug (s).

E.5.1.1

Timepoint(s) of evaluation of this end point

- In the PK lead in phase 12 weeks data will be collected at screening Day1, Day 3 and Day 10 following Day 10 visits will be as per the treatment phase.

- treatment phase - Screening, Day 1, Week 1, 2, 4, 8 and 12 (and Weeks 16, 20, and 24 for subjects requiring 24 weeks of treatment). AEs will be collected throughout the treatment phase

E.5.2

Secondary end point(s)

- For the PK Lead-in Phase, the secondary endpoint will include antiviral activity measurements including assessment of HCV RNA. AEs leading to permanent discontinuation of study drug will be evaluated as a secondary safety endpoint.

- For the Treatment Phase, the key efficacy endpoint is SVR12 and secondary efficacy endpoints include SVR4, SVR24, breakthrough and relapse. Additional efficacy evaluations may include HCV RNA change from Day 1; ALT normalization; and viral kinetic parameters. Secondary safety endpoints of growth and development measurements will be assessed (e.g. height, weight, and Tanner Stage Assessment).

E.5.2.1

Timepoint(s) of evaluation of this end point

Efficacy endpoints at 4 and 24 weeks after treatment end
PK and safety endpoints are accessed during the course of treatment

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

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

Will this trial be conducted at a single site globally?

E.8.4

Will this trial be conducted at multiple sites globally?

Yes

E.8.6 Trial involving sites outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

Specify the countries outside of the EEA in which trial sites are planned

Australia

New Zealand

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

Last subject last visit

E.8.9 Initial estimate of the duration of the trial

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:

200

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

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

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

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.2

For a multinational trial

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 experimental or approved anti-HCV therapy will be followed every 6 months for assessments of growth, quality of life, and long-term viral suppression (if applicable) in a separate protocol (GS-US-334-1113). This follow-up will continue for 5 years.

G. Investigator Networks to be involved in the Trial

H.4 Third Country in which the Trial was first authorised
H.4.1	Third Country in which the trial was first authorised:	United States

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