Clinical Trials Register

Summary
EudraCT Number:	2016-004374-18
Sponsor's Protocol Code Number:	GS-US-384-1943
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2017-05-10
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

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A. Protocol Information

A.1

Member State Concerned

Austria - BASG

A.2

EudraCT number

2016-004374-18

A.3

Full title of the trial

A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety and Efficacy of Selonsertib in Subjects with Nonalcoholic Steatohepatitis (NASH) and Bridging (F3) Fibrosis.

A.3.1

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

A Clinical trial to evaluate safety, and effectiveness of Selonsertib in Subjects with Nonalcoholic Steatohepatitis (NASH) and Bridging (F3) Fibrosis.

A.4.1

Sponsor's protocol code number

GS-US-384-1943

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03053050

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.3.1	Product name	Selonsertib
D.3.2	Product code	GS-4997
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	Selonsertib
D.3.9.1	CAS number	1448428-04-3
D.3.9.2	Current sponsor code	GS-4997
D.3.9.3	Other descriptive name	GS-4997, SEL
D.3.9.4	EV Substance Code	SUB167748
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	6
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	Selonsertib
D.3.2	Product code	GS-4997
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	Selonsertib
D.3.9.1	CAS number	1448428-04-3
D.3.9.2	Current sponsor code	GS-4997
D.3.9.3	Other descriptive name	GS-4997, SEL
D.3.9.4	EV Substance Code	SUB167748
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	18
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

E.1.1.2

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

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	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

The primary objective of this study is: To evaluate whether SEL can cause fibrosis regression and reduce progression to cirrhosis and associated complications in subjects with NASH and bridging (F3) fibrosis.

E.2.2

Secondary objectives of the trial

The secondary objective of this study is: To assess the safety and tolerability of SEL in subjects with NASH and bridging (F3) fibrosis.

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

Optional Pharmacokinetic (PK) Substudy
Subjects may choose to participate in an optional pharmacokinetic (PK) substudy with intensive PK sampling at any time between Week 4 and Week 48 (inclusive) in the Randomized Phase only.
Optional Genomic Testing
Optional blood samples will be collected at the Day 1 visit and at Weeks 48, 96, 144, 192 and 240 for genomic testing including DNA methylation.

E.3

Principal inclusion criteria

Subjects must meet all of the following inclusion criteria to be eligible for participation in this study.
1) Willing and able to give informed consent prior to any study specific procedures being performed.
2) Liver biopsy consistent with NASH (defined as the presence of at least grade 1 steatosis, hepatocellular ballooning, and lobular inflammation according to the NAFLD Activity Score [NAS]) and bridging (F3 fibrosis) according to the NASH CRN classification, in the opinion of the central reader.
3) Subject has laboratory parameters at the Screening visit, as determined by the central laboratory.
4) Body Mass Index (BMI) ≥ 18 kg/m2 at Screening.
5) Males and non-pregnant, non-lactating females between 18-70 years of age; inclusive based on the date of the Screening visit.
6) Females of childbearing potential must have a negative pregnancy test at Screening and Day 1.
7) Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception.

E.4

Principal exclusion criteria

Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Prior history of decompensated liver disease, including clinical ascites, HE, or variceal bleeding
2) CP score > 6, as determined at Screening, unless due to therapeutic anti-coagulation
3) MELD score > 12, as determined at Screening, unless due to therapeutic anti-coagulation
4) Chronic HBV infection (HBsAg positive).
5) Chronic HCV infection (HCV Ab and HCV RNA positive). Subjects cured of HCV infection less than 5 years prior to the Screening visit are not eligible.
6) Other causes of liver disease including, but not limited to, alcoholic liver disease, hepatitis-B,
hepatitis C, autoimmune disorders (e.g., primary biliary cholangitis, primary sclerosing cholangitis, and autoimmune hepatitis), drug-induced hepatotoxicity, Wilson disease, iron overload, and alpha-1-antitryspin deficiency, based on medical history and/or centralized review of liver histology.
7) History of liver transplantation.
8) Current or history of HCC.
9) Any weight reduction surgery in the 2 years prior to Screening or planned during the study (weight reduction surgery is disallowed during the study), and malabsorptive weight loss surgery (e.g., Roux-en-Y or distal gastric bypass) at any time prior to Screening.
10) Weight loss > 10% within 6 months of Screening.
11) HIV infection (HIV Ab and HIV ribonucleic acid [HIV RNA] positive).
12) Current alcohol consumption greater than 21 oz/week for males or 14 oz/week for females (1oz/30mL of alcohol is present in 1 12oz/360mL beer, 1 4oz/120mL glass of wine, and a 1 oz/30 mL measure of 40 proof alcohol).
13) Positive urine drug screen for amphetamines, cocaine or opiates (i.e. heroin, morphine) at
Screening. Subjects on stable methadone or buprenorphine maintenance treatment for at least
6 months prior to Screening may be included in the study. Subjects with a positive urine drug screen due to prescription opioid-based medication are eligible if the prescription and diagnosis are reviewed and approved by the investigator.
14) Unstable cardiovascular disease.
15) Use of any prohibited concomitant medication as described in Section 5.4. Subjects on Vitamin E must be on a stable dose for at least 6 months prior to the diagnostic liver biopsy and subjects on antidiabetic medications must be on a stable dose for at least 3 months prior to diagnostic liver biopsy.
16) History of a malignancy within 5 years of Screening.
17) Unable to safely undergo a liver biopsy.
18) Participation in another investigational study of a drug or device within 30 days or within 5 half-lives of the prior investigational agent (whichever is longer) prior to Screening.
19) Concurrent participation in another therapeutic clinical study.
20) Known hypersensitivity to SEL, the metabolites, or formulation excipient.
21) Any laboratory abnormality or condition that, in the investigator’s opinion, could adversely
affect the safety of the subject or impair the assessment of study results.
22) Presence of any condition that could, in the opinion of the investigator, compromise the
subject’s ability to participate in the study, including a history of substance abuse or a psychiatric condition requiring hospitalization or emergency room visit within 2 years of Screening.
23) Unavailable for follow-up assessment or concern for subject’s compliance with the protocol
procedures.

E.5 End points

E.5.1

Primary end point(s)

Primary Efficacy Endpoint
The primary efficacy endpoint at Week 48 includes the proportion of subjects who achieve a ≥ 1-stage improvement in fibrosis (according to the NASH CRN classification) without worsening of NASH (defined as a ≥ 1-point increase in hepatocellular ballooning or lobular inflammation).
Clinical Efficacy Endpoint
The clinical efficacy endpoint at Week 240 is EFS. EFS will be assessed by time to the first clinical event including progression to cirrhosis, liver decompensation events, liver transplantation, or all-cause mortality.

E.5.1.1

Timepoint(s) of evaluation of this end point

After the Screening period and a randomization visit at Day 1, study visits will occur on Weeks 1, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48 and every 12 weeks thereafter until Week 240 with a Follow Up visit and a Telephone Follow-Up visit. At minimum, review of AEs and concomitant medications and safety laboratory tests will be performed at every visit.

E.5.2

Secondary end point(s)

The secondary endpoints of this study are as follows:
Proportion of subjects who have progression to cirrhosis by Week 48.
a) Proportion of subjects who have a ≥ 1-stage improvement in fibrosis without worsening of
NASH at Week 240;
b) Proportion of subjects who have a ≥ 1-stage improvement in fibrosis at Week 48 and
Week 240;
c) Proportion of subjects who have NASH resolution without worsening of fibrosis at Week 48
and Week 240.

E.5.2.1

Timepoint(s) of evaluation of this end point

After the Screening period and a randomization visit at Day 1, study visits will occur on Weeks 1, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48 and every 12 weeks thereafter until Week 240 with a Follow-Up visit and a Telephone Follow-Up visit. At minimum, review of AEs and concomitant medications and safety laboratory tests will be performed at every 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

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)

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)

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

Argentina

Australia

Austria

Belgium

Brazil

Canada

France

Germany

Hong Kong

India

Israel

Italy

Japan

Korea, Republic of

Malaysia

Mexico

Netherlands

New Zealand

Poland

Portugal

Singapore

Spain

Switzerland

Taiwan

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's last observation (or visit).

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

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:

728

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

110

F.4.2.2

In the whole clinical trial

808

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

2017-05-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-08-31

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2019-06-12

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