Clinical Trials Register

Summary
EudraCT Number:	2017-003956-22
Sponsor's Protocol Code Number:	GS-US-337-2091
Clinical Trial Type:	Outside EU/EEA
Date on which this record was first entered in the EudraCT database:	2017-09-29
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

2017-003956-22

A.3

Full title of the trial

A Phase 1 Relative Bioavailability and Food Effect Study of a Pediatric Oral Granule Formulation of Ledipasvir/Sofosbuvir in Healthy Adult Subjects

A.3.1

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

A clinical study in healthy adults to compare the bioavailability of Harvoni tablets to that of pediatric granules.

A.4.1

Sponsor's protocol code number

GS-US-337-2091

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/063/2017

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	Benedetta Massetto
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	+1650522-5057
B.5.6	E-mail	Benedetta.Massetto@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
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	Ledipasvir
D.3.9.1	CAS number	1256388-51-8
D.3.9.3	Other descriptive name	LEDIPASVIR
D.3.9.4	EV Substance Code	SUB120165
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.3.8 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	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	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 capsules
D.3.4	Pharmaceutical form	Granules
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.3.9.1	CAS number	1256388-51-8
D.3.9.3	Other descriptive name	LEDIPASVIR
D.3.9.4	EV Substance Code	SUB120165
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.3.8 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	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.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

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	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.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
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 objectives of this study are as follows:
 To evaluate the relative bioavailability of a pediatric granules formulation of LDV/SOF relative to tablet formulation in healthy subjects.
 To evaluate the effect of concomitant food intake on the pharmacokinetics of a pediatric granules formulation LDV/SOF.

E.2.2

Secondary objectives of the trial

The secondary objective of this study is as follows:
 To evaluate the safety and tolerability of a pediatric granules formulation of LDV/SOF following single-dose administration in healthy subjects.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subjects must meet all of the following inclusion criteria to be eligible for participation in this study.
1. Have the ability to understand and sign a written informed consent form (ICF),
2. Be between 18 and 45 years of age, inclusive
3. Must have a calculated BMI between ≥19.0 to ≤30.0 kg/m2 at Screening
4. Creatinine clearance (CLCr) must be ≥90 mL/min
5. Females of childbearing potential (as defined in Appendix 3) must have a negative serum pregnancy test at Screening and Day -1
6. Females of childbearing potential must agree to utilize protocol recommended highly effective contraception methods (as defined in Appendix 3) from 3 weeks prior to clinic admission until 30 days following the last dose of study drug
7. Male subjects must agree to utilize a highly effective method of contraception (as defined in Appendix 3) during heterosexual intercourse from clinic admission until 90 days following the last dose of study drug.
8. Male subjects must agree to refrain from sperm donation from Day -1 until at least 90 days after the study drug dose
9. Subjects must have refrained from blood donation within 56 days or plasma donation within 7 days of study dosing and from clinic admission until 30 days following the last dose of study drug
10. In the opinion of the investigator, subjects must be in good health based upon medical history and physical examination (including vital signs)
11. Screening laboratory evaluations without clinically significant abnormalities as assessed by the investigator
12. Be willing and able to comply with all study requirements

E.4

Principal exclusion criteria

Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1. Alcohol or substance abuse as assessed by the investigator
2. A positive screening test result for human immunodeficiency virus type 1 (HIV-1) antibody, Hepatitis B surface antigen (HBsAg), or Hepatitis C virus (HCV) antibody
3. Nursing female
4. Have previously been participated in an investigational trial involving administration of any investigational compound (last dose) within 30 days prior to the study dosing (Day 1)
5. Have poor venous access limiting phlebotomy
6. Have been vaccinated within 90 days, or for the influenza vaccine, within 14 days prior to study dosing
7. Have taken any prescription medications or over-the-counter medications including herbal products within 28 days of commencing study drug dosing with the exception of vitamins and/or acetaminophen and/or ibuprofen and/or hormonal contraceptive medications
8. Have taken systemic steroids, immunosuppressant therapies or chemotherapeutic agents within 3 months of study screening or expected to receive these agents during the study
9. Have a history of any of the following:
a. Significant drug sensitivity or drug allergy (such as anaphylaxis or hepatoxicity)
b. Significant serious skin disease, such as but not limited to, rash or eruptions, food allergy, eczema, psoriasis, or urticaria
c. Known hypersensitivity to the study drugs, the metabolites or to formulation excipients (see Section 5.2.1)
d. Syncope, palpitations, or unexplained dizziness
e. Liver disease or liver function tests such as alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT), aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT), serum total bilirubin, or alkaline phosphatase above the upper limit of normal at Screening
f. Severe peptic ulcer disease, gastroesophageal reflux disease, or other gastric acid hypersecretory conditions requiring prolonged (> 6 months) medical treatment
g. Medical or surgical treatment that permanently alters gastric absorption (eg, gastric or intestinal surgery)
h. Significant cardiac disease (including history of myocardial infarction based on electrocardiogram [ECG] and/or clinical history, any history of ventricular tachycardia, congestive heart failure, or dilated cardiomyopathy with left ventricular ejection fraction < 40%) or a family history of Long QT Syndrome
10. The following ECG abnormalities at Screening: QRS > 120 msec; heart rate < 45 beats per minute; second or third degree heart block, QTcF interval > 450 msec for males or > 470 msec for females; PR interval > 200 msec and any other clinically relevant abnormality
11. Believed, by the study investigator, to be inappropriate for study participation for any reasond. Syncope, palpitations, or unexplained dizziness
e. Liver disease or liver function tests such as alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT), aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT), serum total bilirubin, or alkaline phosphatase above the upper limit of normal at Screening
f. Severe peptic ulcer disease, gastroesophageal reflux disease, or other gastric acid hypersecretory conditions requiring prolonged (> 6 months) medical treatment
g. Medical or surgical treatment that permanently alters gastric absorption (eg, gastric or intestinal surgery)
h. Significant cardiac disease (including history of myocardial infarction based on electrocardiogram [ECG] and/or clinical history, any history of ventricular tachycardia, congestive heart failure, or dilated cardiomyopathy with left ventricular ejection fraction < 40%) or a family history of Long QT Syndrome
10. The following ECG abnormalities at Screening: QRS > 120 msec; heart rate < 45 beats per minute; second or third degree heart block, QTcF interval > 450 msec for males or > 470 msec for females; PR interval > 200 msec and any other clinically relevant abnormality
11. Believed, by the study investigator, to be inappropriate for study participation for any reason

E.5 End points

E.5.1

Primary end point(s)

The primary endpoints are PK parameters Cmax, AUClast, and AUCinf, for SOF, GS-566500, GS-331007, and LDV.

E.5.1.1

Timepoint(s) of evaluation of this end point

Scheduled assessment points throughout the treatment period

E.5.2

Secondary end point(s)

The secondary endpoints are the incidences of AEs, laboratory abnormalities and vital signs.
The secondary PK endpoints are % AUCexp, Tmax, Clast, Tlast, λz, CL/F, and t1/2 as appropriate.

E.5.2.1

Timepoint(s) of evaluation of this end point

Scheduled assessment points throughout the treatment period

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

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

Yes

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)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

Yes

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)

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

E.8.1.6

Cross over

Yes

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

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?

Yes

E.8.4

Will this trial be conducted at multiple sites globally?

E.8.6 Trial involving sites outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

Yes

E.8.6.3

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

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

LPLV

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

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.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

Yes

F.3.2

Patients

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.4.2

For a multinational trial

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)

Not applicable

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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