Clinical Trials Register

Summary
EudraCT Number:	2016-002496-10
Sponsor's Protocol Code Number:	GS-US-402-1852
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-12-21
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

UK - MHRA

A.2

EudraCT number

2016-002496-10

A.3

Full title of the trial

A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety, Tolerability, and Efficacy of GS-9674 in Subjects with Nonalcoholic Steatohepatitis (NASH)

A.3.1

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

An investigational study to assess the safety and efficacy of a new investigational drug in subjects with Non-Alcoholic Steatohepatitis (NASH)

A.4.1

Sponsor's protocol code number

GS-US-402-1852

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02854605

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 Ltd.
B.5.2	Functional name of contact point	Clinical Trials Mailbox
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.5.5	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.3.2	Product code	GS-9674
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	Not available
D.3.9.1	CAS number	1418274-28-8
D.3.9.2	Current sponsor code	GS-9674
D.3.9.4	EV Substance Code	SUB183672
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	30
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.3.2	Product code	GS-9674
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	Not available
D.3.9.1	CAS number	1418274-28-8
D.3.9.2	Current sponsor code	GS-9674
D.3.9.3	Other descriptive name	GS-9674
D.3.9.4	EV Substance Code	SUB183672
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

Nonalcoholic steatohepatitis (NASH)

E.1.1.1

Medical condition in easily understood language

Inflammation of the liver due to accumulation of fat, not related to alcohol consumption

E.1.1.2

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

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	10053219
E.1.2	Term	Non-alcoholic steatohepatitis
E.1.2	System Organ Class	10019805 - Hepatobiliary disorders

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 evaluate the safety and tolerability of GS-9674 in subjects with NASH.

E.2.2

Secondary objectives of the trial

The exploratory objectives of this study are as follows:
-To evaluate changes in steatosis as measured by Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF) including the proportion of subjects with >30% reduction;
-To evaluate changes in liver stiffness as measured by both Magnetic Resonance Elastography (MRE) and FibroScan®;
-To assess changes in markers of liver injury and function: ALT, AST, bilirubin, GGT and ALP;
-To assess changes in non-invasive markers of fibrosis including ELFTM test score and FibroSURE/FibroTest®;
-To assess changes in apoptosis as measured by serum CK-18 levels;
-To determine the effect of GS-9674 on metabolism and cardiovascular risk factors (insulin resistance, hyperlipidemia, obesity and blood pressure);
-To evaluate the pharmacokinetics (PK) of GS-9674;
-To evaluate the pharmacodynamics (PD) of GS-9674 as evidenced by changes in FGF19, C4, and bile acids;
-To assess changes in QoL assessments.

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

PK and PD Substudy
For subjects who provide consent, plasma and serum samples will be collected relative to dosing of GS-9674 to measure concentrations of GS-9674 (and its metabolites, as applicable) and the PD biomarkers FGF19 and C4 for GS-9674.

E.3

Principal inclusion criteria

-Meets all of the following conditions:
a. A clinical diagnosis of nonalcoholic fatty liver disease (NAFLD) and
b. Screening magnetic resonance imaging-proton density fat fraction (MRI-PDFF) with ≥8% steatosis and
c. Screening magnetic resonance elastography (MRE) with liver stiffness ≥ 2.5 kPa
Note: criterion a. must be met before evaluating criteria b. and c.
OR
d. A historical liver biopsy within 12 months of Screening consistent with NASH (defined as the presence of steatosis, lobular inflammation, and hepatocellular ballooning) with fibrosis, but not cirrhosis, and
e. No documented weight loss > 5% between the date of the liver biopsy and Screening.
Note: Screening MRI-PDFF and MRE will be performed prior to the baseline visit for all subjects including those with historical liver biopsies meeting criteria 3d.
-Platelet count ≥ 150,000/mm^3;
-Albumin ≥ 3.3 g/dL;
-Serum Creatinine ≤ ULN

E.4

Principal exclusion criteria

-Pregnant or lactating females;
-ALT > 5X ULN;
-Other causes of liver disease including autoimmune, viral, and alcoholic liver disease;
-Cirrhosis of the liver
-Body mass index (BMI) < 18 kg/m^2;
-Uncontrolled diabetes mellitus (hemoglobin A1c > 9% at screening);
-International normalized ratio (INR) > 1.2 unless on anticoagulant therapy;
-Total bilirubin > 1x ULN, except with diagnosis of Gilbert’s syndrome.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is the safety of GS-9674 in subjects with NASH. Safety endpoints include adverse events and laboratory evaluations.

E.5.1.1

Timepoint(s) of evaluation of this end point

Safety will be assessed during the study through the reporting of AEs, and by clinical laboratory tests and vital sign assessments at various time points during the study (Baseline/Day1, week 1, 4, 8, 12, 16, 20, 24 and follow-up visit)

E.5.2

Secondary end point(s)

The exploratory efficacy endpoints are:
-Change from baseline in steatosis as measured by MRI-PDFF including the proportion of subjects with ≥ 30% reduction;
-Change from baseline in liver stiffness as measured by both MRE and FibroScan®;
-Change from baseline in markers of liver injury and function: ALT, AST, bilirubin, GGT and ALP;
-Change from baseline in non-invasive markers of fibrosis including the ELF™ test score and FibroSURE/FibroTest®;
-Change from baseline in apoptosis as measured by serum CK-18 levels;
-Change from baseline in homeostatic assessment of insulin resistance (HOMA-IR), serum lipid profiles, and HbA1c levels;
-Change from baseline in health related QoL;
-Change from baseline in body weight;
-Change from baseline in Pooled Cohort Risk Score.

E.5.2.1

Timepoint(s) of evaluation of this end point

Exploratory efficacy endpoints will be assessed at various time points during the study (Baseline/Day1, week 1, 4, 8, 12, 16, 20, 24 and follow-up visit)

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

Yes

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)

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

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)

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

Austria

Canada

France

Hong Kong

New Zealand

Switzerland

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

End of study is defined as when the last patient last visit (LPLV) for the Follow-Up visit (four weeks after their last dose of study drug) occurs, or the ET visit, whichever occurs later.

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:

100

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

F.4.2.2

In the whole clinical trial

140

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)

None

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

2017-01-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-02-24

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-01-09

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