Clinical Trials Register

Summary
EudraCT Number:	2019-000204-14
Sponsor's Protocol Code Number:	GS-US-428-4194
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2019-06-27
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

2019-000204-14

A.3

Full title of the trial

A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety, Tolerability, and Efficacy of Cilofexor in Non-Cirrhotic Subjects with Primary Sclerosing Cholangitis

A.3.1

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

A study to assess the safety and efficacy of a new investigational drug in subjects with Primary Sclerosing Cholangitis Without Cirrhosis

A.4.1

Sponsor's protocol code number

GS-US-428-4194

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03890120

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.5.4	Telephone number	+441223897300
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	Yes
D.2.5.1	Orphan drug designation number	EMA/OD/0000002498
D.3 Description of the IMP
D.3.1	Product name	Cilofexor
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	Cilofexor
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.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	Yes
D.2.5.1	Orphan drug designation number	EMA/OD/0000002498
D.3 Description of the IMP
D.3.1	Product name	Cilofexor
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	Cilofexor
D.3.9.1	CAS number	1418274-28-8
D.3.9.2	Current sponsor code	GS-6974
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	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.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

Primary Sclerosing Cholangitis

E.1.1.1

Medical condition in easily understood language

Primary sclerosing cholangitis is a chronic disease which causes scarring of the bile ducts. This can block the flow of bile which can cause damage to the liver over time.

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	LLT
E.1.2	Classification code	10036732
E.1.2	Term	Primary sclerosing cholangitis
E.1.2	System Organ Class	100000004871

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate whether cilofexor (CILO, previously known as GS-9674) reduces the risk of fibrosis progression among non-cirrhotic subjects with primary sclerosing cholangitis (PSC)

E.2.2

Secondary objectives of the trial

-To assess the safety and tolerability of CILO
-To evaluate changes in serum concentrations of alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), and bile acids
-To evaluate whether CILO increases the proportion of subjects with ≥ 25% relative reduction in serum ALP concentration from baseline (biochemical response) and no worsening of fibrosis according to the Ludwig classification (histologic response)
-To evaluate changes in liver fibrosis including hepatic collagen content, fibrosis stage improvement, progression to cirrhosis, and changes in noninvasive markers of fibrosis, including liver stiffness by FibroScan® and enhanced liver fibrosis test (ELF™ test) score
-To evaluate changes in health-related quality of life (QoL) based on the disease-specific PSC patient-reported outcome (PSC-PRO)

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 Intensive PK and PD Substudy
All subjects will have the option to participate in the intensive PK and PD substudy. For subjects who agree to participate and provide their consent, the intensive PK and PD sampling will be performed once any time between Week 4 to Week 84 (inclusive).

E.3

Principal inclusion criteria

1) Diagnosis of large duct PSC based on cholangiogram (magnetic resonance cholangiopancreatography [MRCP], endoscopic retrograde cholangiopancreatography [ERCP], or percutaneous transhepatic cholangiogram [PTC])
2) Liver biopsy at screening that is deemed acceptable for interpretation and demonstrates stage F0 – F3 fibrosis (according to the Ludwig classification) in the opinion of the central reader
a. A historical liver biopsy within 6 months of the screening visit may be accepted as the screening biopsy if the sample is deemed acceptable for interpretation by the central reader.
3) Subject has the following laboratory parameters at the screening visit, as determined by the central laboratory:
a. Platelet count ≥ 150,000/mm3
b. Estimated glomerular filtration rate (eGFR) ≥ 30 milliliter/minute (mL/min), as calculated by the Cockcroft-Gault equation
c. ALT ≤ 8 x upper limit of normal (ULN)
d. Total bilirubin < 2 mg/dL, unless the subject is known to have Gilbert’s syndrome or hemolytic anemia
e. International normalized ratio (INR) ≤ 1.4, unless due to therapeutic anticoagulation
f. Negative anti-mitochondrial antibody
4) For subjects on ursodeoxycholic acid (UDCA), the dose of UDCA must have been stable in the opinion of the investigator for at least 6 months before screening. For subjects not on UDCA, no UDCA use for at least 6 months prior to screening.

E.4

Principal exclusion criteria

1) Current or prior history of any of the following:
a. Cirrhosis as defined by any of the following:
i. Liver biopsy demonstrating stage F4 fibrosis according to the Ludwig classification (or equivalent)
ii. Decompensated liver disease, including ascites, hepatic encephalopathy (HE), or variceal hemorrhage
iii. Liver stiffness > 20.0 kPa by FibroScan®
b. Liver transplantation
c. Cholangiocarcinoma or hepatocellular carcinoma (HCC). If a dominant stricture has been identified, cholangiocarcinoma must be adequately excluded in the opinion of the investigator prior
to Day 1.
d. Ascending cholangitis within 30 days of screening
2) Presence of a percutaneous drain or biliary stent
3) Other causes of liver disease including immunoglobulin (IgG4)-related sclerosing
cholangitis, autoimmune hepatitis/PSC overlap syndrome, secondary sclerosing cholangitis, small duct PSC (histologic evidence of PSC with normal bile ducts on cholangiography), and viral, metabolic, alcoholic, and other autoimmune conditions. Subjects with hepatic steatosis may be included if there is no evidence of nonalcoholic steatohepatitis (NASH) on liver biopsy in the opinion of the central reader
4) Current or prior history of any of the following:
a. Malignancy within 5 years of screening with the following exceptions:
i. Adequately treated carcinoma in situ of the cervix
ii. Adequately treated basal or squamous cell cancer or other localized non-melanoma skin cancer.
Subjects under evaluation for possible malignancy are not eligible.
b. Unstable cardiovascular disease as defined by any of the following:
i. Unstable angina, myocardial infarction, coronary artery bypass graft surgery or coronary angioplasty within 6 months prior to screening
ii. Transient ischemic attack or cerebrovascular accident within 6 months prior to screening
iii. Symptomatic obstructive valvular heart disease or hypertrophic cardiomyopathy
iv. Symptomatic congestive heart failure
v. Uncontrolled or recurrent ventricular tachycardia or other arrhythmia requiring an automatic implantable cardioverter defibrillator (AICD). Stable, controlled atrial fibrillation is allowed.
c. Hypercoagulable condition or venous or arterial thromboembolic disease
d. Intestinal resection or malabsorptive condition that may limit the absorption of CILO. Prior cholecystectomy and appendectomy are permitted.
5) Child-Pugh (CP) score > 6 at Screening, unless due to an alternative etiology such as Gilbert’s syndrome or therapeutic anticoagulation
6) Model for End-stage Liver Disease (MELD) score > 12 at Screening, unless due to an alternate etiology such as therapeutic anticoagulation
7) HIV infection (HIV antibody [Ab] and HIV RNA positive)
8) Chronic HBV infection (hepatitis B surface antigen [HBsAg] positive)
9) Chronic HCV infection (HCV Ab and HCV RNA positive). Subjects cured of HCV infection ≥ 2 years prior to screening are eligible.
10) Current moderate to severe inflammatory bowel disease (IBD) (including ulcerative colitis, Crohn’s disease, and indeterminate colitis) defined as a screening visit Partial Mayo score of > 4 and/or a score in the screening visit Rectal Bleeding domain > 1, unless bleeding is due to perianal disease
Note: Subjects with IBD who currently have an external ostomy bag are not subject to this exclusion criterion and need not undergo Partial Mayo evaluation at screening
11) Habitual alcohol consumption greater than 21 oz/week for males or 14 oz/week for females (1 oz/30 mL of alcohol is present in one 12 oz/360 mL beer, one 4 oz/120 mL glass of wine, and a 1 oz/30 mL measure of 40% proof alcohol)
12) Use of antibiotics (eg, vancomycin, metronidazole, minocycline, etc.) for the treatment of PSC within 60 days of Screening. Antibiotic prophylaxis for ascending cholangitis is permitted if stable in the opinion of the investigator for at least 6 months prior to Screening
13) Use of any prohibited concomitant medications

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is the proportion of subjects with progression of liver fibrosis, as defined by a ≥ 1-stage increase in fibrosis according to the Ludwig classification at Week 96

E.5.1.1

Timepoint(s) of evaluation of this end point

Baseline/Day 1 and at Week 96

E.5.2

Secondary end point(s)

The secondary endpoints of this study are as follows:
-Changes from baseline in serum concentrations of ALP, GGT, ALT, and bile acids at Week 96
-The proportion of subjects with ≥ 25% relative reduction in serum ALP concentration from baseline (biochemical response) and no worsening of fibrosis according to the Ludwig classification (histologic response)
-Changes from baseline in liver fibrosis, including hepatic collagen content, fibrosis improvement, and progression to cirrhosis (according to the Ludwig classification), and noninvasive markers of fibrosis, including liver stiffness by FibroScan® and ELF™ test score, at Week 96
-Changes from baseline in health-related QoL based on the disease specific PSC-PRO at Week 96

E.5.2.1

Timepoint(s) of evaluation of this end point

Baseline/Day 1 and at Week 96

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

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

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

Australia

Austria

Belgium

Canada

Denmark

France

Germany

Israel

Italy

Japan

Netherlands

New Zealand

Spain

Sweden

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

Last patient last visit (LPLV)

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:

360

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

160

F.4.2.2

In the whole clinical trial

400

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

2019-07-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-07-15

P. End of Trial
P.	End of Trial Status	GB - no longer in EU/EEA

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