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Clinical Trial Results:
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

Summary
EudraCT number	2019-000204-14
Trial protocol	FI BE AT GB DK FR ES IT
Global end of trial date	23 Dec 2022

Results information
Results version number	v1(current)
This version publication date	16 Dec 2023
First version publication date	16 Dec 2023
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

GS-US-428-4194

ISRCTN number

US NCT number

NCT03890120

WHO universal trial number (UTN)

Other trial identifiers

jRCT2080224728: Japan Registry of Clinical Trials

Sponsor organisation name

Gilead Sciences

Sponsor organisation address

333 Lakeside Drive, Foster City, CA, United States, 94404

Public contact

Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.com

Scientific contact

Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

23 Dec 2022

Is this the analysis of the primary completion data?

Yes

Primary completion date

10 Nov 2022

Global end of trial reached?

Yes

Global end of trial date

23 Dec 2022

Was the trial ended prematurely?

Yes

Main objective of the trial

The primary objective of this study was to evaluate whether cilofexor reduces the risk of fibrosis progression among non-cirrhotic adults with primary sclerosing cholangitis (PSC).

Protection of trial subjects

The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.

Background therapy

Evidence for comparator

Actual start date of recruitment

27 Mar 2019

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 31

Country: Number of subjects enrolled

Austria: 4

Country: Number of subjects enrolled

Belgium: 6

Country: Number of subjects enrolled

Canada: 38

Country: Number of subjects enrolled

Denmark: 7

Country: Number of subjects enrolled

Finland: 19

Country: Number of subjects enrolled

France: 14

Country: Number of subjects enrolled

Germany: 18

Country: Number of subjects enrolled

Israel: 11

Country: Number of subjects enrolled

Italy: 23

Country: Number of subjects enrolled

Japan: 27

Country: Number of subjects enrolled

New Zealand: 6

Country: Number of subjects enrolled

Spain: 16

Country: Number of subjects enrolled

Switzerland: 6

Country: Number of subjects enrolled

United Kingdom: 19

Country: Number of subjects enrolled

United States: 174

Worldwide total number of subjects

419

EEA total number of subjects

107

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

395

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Participants were enrolled at study sites in Europe, North America, Oceania, and Asia.

Screening details

587 participants were screened.

Period 1 title

Blinded Treatment Phase (100.3 weeks)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Cilofexor 100 mg (Blinded Phase)

Arm description

Participants received cilofexor 100 mg tablet, orally, once daily for up to 100.3 weeks.

Arm type

Experimental

Investigational medicinal product name

Cilofexor

Investigational medicinal product code

Other name

GS-9674

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

100 mg tablet administered orally once daily for up to 100.3 weeks.

Placebo (Blinded Phase)

Arm description

Participants received placebo to match cilofexor 100 mg tablet, orally, once daily for up to 98.1 weeks.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

placebo to match cilofexor 100 mg tablet administered orally once daily for up to 98.1 weeks.

Number of subjects in period 1	Cilofexor 100 mg (Blinded Phase)	Placebo (Blinded Phase)
Started	278	141
Completed	123	66
Not completed	155	75
Adverse event, non-fatal	17	7
Death	1	-
Pregnancy	-	1
Study terminated by sponsor	119	57
Non-compliance with study drug	-	1
Withdrew consent	12	4
Lost to follow-up	4	1
Investigator's discretion	1	2
Randomized but never treated	1	2

Period 2 title

Open-Label Extension Phase (45 weeks)

Is this the baseline period?

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Cilofexor From Cilofexor 100 mg (OLE Phase)

Arm description

Participants who received cilofexor in blinded phase and had entered the open-label extension (OLE) phase received open-label cilofexor 100 mg tablet, orally, once daily for up to 44.7 weeks.

Arm type

Experimental

Investigational medicinal product name

Cilofexor

Investigational medicinal product code

Other name

GS-9674

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

100 mg tablet administered orally once daily for up to 44.7 weeks.

Cilofexor From Placebo (OLE Phase)

Arm description

Participants who received placebo in blinded phase and had entered the OLE phase received open-label cilofexor 100 mg tablet, orally, once daily for up to 45.0 weeks.

Arm type

Experimental

Investigational medicinal product name

Cilofexor

Investigational medicinal product code

Other name

GS-9674

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

100 mg tablet administered orally once daily for up to 45.0 weeks.

Number of subjects in period 2 ^[1]	Cilofexor From Cilofexor 100 mg (OLE Phase)	Cilofexor From Placebo (OLE Phase)
Started	80	45
Completed	0	0
Not completed	80	45
Adverse event, non-fatal	3	1
Study terminated by sponsor	76	42
Withdrew consent	1	-
Lost to follow-up	-	2

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Participants who consented to enter the OLE Phase and completed the Blinded Study Phase Week 96 with an evaluable biopsy (noncirrhotic F0, F1, F2, and F3) as determined by the central reader and Blinded Study Phase follow-up visit entered OLE Phase.

Baseline characteristics

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Reporting group title

Cilofexor 100 mg (Blinded Phase)

Reporting group description

Participants received cilofexor 100 mg tablet, orally, once daily for up to 100.3 weeks.

Reporting group title

Placebo (Blinded Phase)

Reporting group description

Participants received placebo to match cilofexor 100 mg tablet, orally, once daily for up to 98.1 weeks.

Reporting group values	Cilofexor 100 mg (Blinded Phase)	Placebo (Blinded Phase)	Total
Number of subjects	278	141	419
Age categorical
Units: Subjects
18 – 64 Years	260	135	395
65 – 84 Years	18	6	24
Gender categorical
Units: Subjects
Female	107	54	161
Male	171	87	258
Race
Units: Subjects
White	228	117	345
Asian	28	10	38
Black or African American	11	9	20
Unknown or Not Reported	6	5	11
Other or More Than One Race	5	0	5
Ethnicity
Units: Subjects
Hispanic or Latino	11	3	14
Not Hispanic or Latino	259	132	391
Unknown or Not Reported	8	6	14
Alkaline Phosphatase (ALP)
Units: units per liter (U/L)
arithmetic mean (standard deviation)	( )	( )	-
Aspartate Aminotransferase (AST)
Units: U/L
arithmetic mean (standard deviation)	( )	( )	-
Fasting Total Bile Acids
Units: micromoles per liter (μmol/L)
arithmetic mean (standard deviation)	( )	( )	-
Enhanced Liver Fibrosis (ELF™) Test Score
The Enhanced Liver Fibrosis (ELF™) test is a composite of three serum biomarkers of hepatobiliary fibrosis: hyaluronic acid, procollagen III amino‐terminal peptide, and tissue inhibitor of metalloproteinase. A typical range for ELF™ test scores in PSC is between 6 and 14. Higher ELF™ test scores are associated with more severe liver disease.
Units: score on a scale
arithmetic mean (standard deviation)	( )	( )	-
Fibroscan Score
Change in liver stiffness was measured by FibroScan® scores. FibroScan measures liver scarring by measuring the stiffness of the liver. It's normally between 2 and 6 kPa. Many people with liver disease(s) have a result that's higher than the normal range. Higher scores indicate increased scarring of the liver.
Units: kilopascals (kPa)
arithmetic mean (standard deviation)	( )	( )	-

Subject analysis set title

Cilofexor 100 mg (Blinded Phase)

Subject analysis set type

Safety analysis

Subject analysis set description

Participants received cilofexor 100 mg tablet, orally, once daily for up to 100.3 weeks. Safety Analysis Set included all participants who took at least 1 dose of study drug.

Subject analysis set title

Placebo (Blinded Phase)

Subject analysis set type

Safety analysis

Subject analysis set description

Participants received placebo to match cilofexor 100 mg tablet, orally, once daily for up to 98.1 weeks. Participants in the Safety Analysis Set were analyzed.

Subject analysis set title

Cilofexor 100 mg (Blinded Phase)

Subject analysis set type

Safety analysis

Subject analysis set description

Participants received cilofexor 100 mg tablet, orally, once daily for up to 100.3 weeks. Participants in the Safety Analysis Set with available data were analyzed.

Subject analysis set title

Placebo (Blinded Phase)

Subject analysis set type

Safety analysis

Subject analysis set description

Participants received placebo to match cilofexor 100 mg tablet, orally, once daily for up to 98.1 weeks. Participants in the Safety Analysis Set with available data were analyzed.

Subject analysis set title

Cilofexor 100 mg (Blinded Phase)

Subject analysis set type

Safety analysis

Subject analysis set description

Participants received cilofexor 100 mg tablet, orally, once daily for up to 100.3 weeks. Participants in the Safety Analysis Set with available data were analyzed.

Subject analysis set title

Placebo (Blinded Phase)

Subject analysis set type

Safety analysis

Subject analysis set description

Participants received placebo to match cilofexor 100 mg tablet, orally, once daily for up to 98.1 weeks. Participants in the Safety Analysis Set with available data were analyzed.

Subject analysis set title

Cilofexor 100 mg (Blinded Phase)

Subject analysis set type

Safety analysis

Subject analysis set description

Participants received cilofexor 100 mg tablet, orally, once daily for up to 100.3 weeks. Participants in the Safety Analysis Set with available data were analyzed.

Subject analysis set title

Placebo (Blinded Phase)

Subject analysis set type

Safety analysis

Subject analysis set description

Participants received placebo to match cilofexor 100 mg tablet, orally, once daily for up to 98.1 weeks. Participants in the Safety Analysis Set with available data were analyzed.

Subject analysis sets values	Cilofexor 100 mg (Blinded Phase)	Placebo (Blinded Phase)	Cilofexor 100 mg (Blinded Phase)	Placebo (Blinded Phase)	Cilofexor 100 mg (Blinded Phase)	Placebo (Blinded Phase)	Cilofexor 100 mg (Blinded Phase)	Placebo (Blinded Phase)
Number of subjects	277	139	262	132	276	137	253	125
Age categorical
Units: Subjects
18 – 64 Years
65 – 84 Years
Age continuous
Units: years
arithmetic mean (standard deviation)	( )	( )	( )	( )	( )	( )	( )	( )
Gender categorical
Units: Subjects
Female
Male
Race
Units: Subjects
White
Asian
Black or African American
Unknown or Not Reported
Other or More Than One Race
Ethnicity
Units: Subjects
Hispanic or Latino
Not Hispanic or Latino
Unknown or Not Reported
Alkaline Phosphatase (ALP)
Units: units per liter (U/L)
arithmetic mean (standard deviation)	223 ( 177.7 )	243 ( 189.5 )	( )	( )	( )	( )	( )	( )
Aspartate Aminotransferase (AST)
Units: U/L
arithmetic mean (standard deviation)	49 ( 34.1 )	51 ( 34.6 )	( )	( )	( )	( )	( )	( )
Fasting Total Bile Acids
Units: micromoles per liter (μmol/L)
arithmetic mean (standard deviation)	( )	( )	24.2 ( 37.57 )	18.6 ( 22.49 )	( )	( )	( )	( )
Enhanced Liver Fibrosis (ELF™) Test Score
The Enhanced Liver Fibrosis (ELF™) test is a composite of three serum biomarkers of hepatobiliary fibrosis: hyaluronic acid, procollagen III amino‐terminal peptide, and tissue inhibitor of metalloproteinase. A typical range for ELF™ test scores in PSC is between 6 and 14. Higher ELF™ test scores are associated with more severe liver disease.
Units: score on a scale
arithmetic mean (standard deviation)	( )	( )	( )	( )	9.14 ( 0.910 )	9.13 ( 0.963 )	( )	( )
Fibroscan Score
Change in liver stiffness was measured by FibroScan® scores. FibroScan measures liver scarring by measuring the stiffness of the liver. It's normally between 2 and 6 kPa. Many people with liver disease(s) have a result that's higher than the normal range. Higher scores indicate increased scarring of the liver.
Units: kilopascals (kPa)
arithmetic mean (standard deviation)	( )	( )	( )	( )	( )	( )	7.8 ( 4.91 )	8.0 ( 4.07 )

End points

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Reporting group title

Cilofexor 100 mg (Blinded Phase)

Reporting group description

Participants received cilofexor 100 mg tablet, orally, once daily for up to 100.3 weeks.

Reporting group title

Placebo (Blinded Phase)

Reporting group description

Participants received placebo to match cilofexor 100 mg tablet, orally, once daily for up to 98.1 weeks.

Reporting group title

Cilofexor From Cilofexor 100 mg (OLE Phase)

Reporting group description

Participants who received cilofexor in blinded phase and had entered the open-label extension (OLE) phase received open-label cilofexor 100 mg tablet, orally, once daily for up to 44.7 weeks.

Reporting group title

Cilofexor From Placebo (OLE Phase)

Reporting group description

Participants who received placebo in blinded phase and had entered the OLE phase received open-label cilofexor 100 mg tablet, orally, once daily for up to 45.0 weeks.

Subject analysis set title

Cilofexor 100 mg (Blinded Phase)

Subject analysis set type

Safety analysis

Subject analysis set description

Participants received cilofexor 100 mg tablet, orally, once daily for up to 100.3 weeks. Safety Analysis Set included all participants who took at least 1 dose of study drug.

Subject analysis set title

Placebo (Blinded Phase)

Subject analysis set type

Safety analysis

Subject analysis set description

Participants received placebo to match cilofexor 100 mg tablet, orally, once daily for up to 98.1 weeks. Participants in the Safety Analysis Set were analyzed.

Subject analysis set title

Cilofexor 100 mg (Blinded Phase)

Subject analysis set type

Safety analysis

Subject analysis set description

Participants received cilofexor 100 mg tablet, orally, once daily for up to 100.3 weeks. Participants in the Safety Analysis Set with available data were analyzed.

Subject analysis set title

Placebo (Blinded Phase)

Subject analysis set type

Safety analysis

Subject analysis set description

Participants received placebo to match cilofexor 100 mg tablet, orally, once daily for up to 98.1 weeks. Participants in the Safety Analysis Set with available data were analyzed.

Subject analysis set title

Cilofexor 100 mg (Blinded Phase)

Subject analysis set type

Safety analysis

Subject analysis set description

Participants received cilofexor 100 mg tablet, orally, once daily for up to 100.3 weeks. Participants in the Safety Analysis Set with available data were analyzed.

Subject analysis set title

Placebo (Blinded Phase)

Subject analysis set type

Safety analysis

Subject analysis set description

Participants received placebo to match cilofexor 100 mg tablet, orally, once daily for up to 98.1 weeks. Participants in the Safety Analysis Set with available data were analyzed.

Subject analysis set title

Cilofexor 100 mg (Blinded Phase)

Subject analysis set type

Safety analysis

Subject analysis set description

Participants received cilofexor 100 mg tablet, orally, once daily for up to 100.3 weeks. Participants in the Safety Analysis Set with available data were analyzed.

Subject analysis set title

Placebo (Blinded Phase)

Subject analysis set type

Safety analysis

Subject analysis set description

Participants received placebo to match cilofexor 100 mg tablet, orally, once daily for up to 98.1 weeks. Participants in the Safety Analysis Set with available data were analyzed.

Primary: Percentage of Participants With Progression of Liver Fibrosis at Blinded Phase Week 96

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End point title

Percentage of Participants With Progression of Liver Fibrosis at Blinded Phase Week 96

End point description

Progression of liver fibrosis was defined as having a ≥ 1-stage increase from baseline in fibrosis according to the Ludwig classification at Blinded Phase Week 96. The stages of fibrosis was assessed according to Ludwig classification. Ludwig classification fibrosis stages range from 0 to 4, with higher scores indicating greater fibrosis (0=no fibrosis, 4=cirrhosis). Full Analysis Set included all randomized participants who took at least 1 dose of study drug. Participants in the Full Analysis Set who had nonmissing data at both baseline and Week 96 in the Blinded Study Phase were analyzed.

End point type

Primary

End point timeframe

Blinded Phase Week 96

End point values	Cilofexor 100 mg (Blinded Phase)	Placebo (Blinded Phase)
Number of subjects analysed	133	64
Units: percentage of participants
number (not applicable)	30.8	32.8

Cilofexor 100 mg vs Placebo

Comparison groups

Cilofexor 100 mg (Blinded Phase) v Placebo (Blinded Phase)

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4186 ^[1]

Method

Mantel-Haenszel

Parameter type

Difference in Percentages

Point estimate

-1.4

Confidence interval

level

95%

sides

2-sided

lower limit

-15.2

upper limit

12.3

Notes
[1] - The difference of cilofexor and placebo,95% confidence interval(CI),and P value(1-sided)were obtained by the stratum-adjusted Mantel-Haenszel (MH) method,with baseline ursodeoxycholic acid(UDCA)use and Ludwig fibrosis stage as stratification factors.

Secondary: Percentage of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) in The Blinded Phase

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End point title

Percentage of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) in The Blinded Phase

End point description

An AE was any untoward medical occurrence in a clinical study participant administered a study drug that does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use of a study drug, whether or not the AE is considered related to the study drug. For Blinded Study Phase and OLE Phase, TEAEs were defined as 1 or both of the following: Any AEs with an onset date on or after the study drug start date and no later than 30 days after permanent discontinuation of study drug and/or any AEs leading to premature discontinuation of study drug. Safety Analysis Set included all participants who took at least 1 dose of study drug.

End point type

Secondary

End point timeframe

First dose date in the Blinded Phase up to 100.3 weeks plus 30 days

End point values	Cilofexor 100 mg (Blinded Phase)	Placebo (Blinded Phase)
Number of subjects analysed	277	139
Units: percentage of participants
number (not applicable)	97.1	95.0

No statistical analyses for this end point

Secondary: Percentage of Participants Who Experienced TEAEs in The OLE Phase

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End point title

Percentage of Participants Who Experienced TEAEs in The OLE Phase

End point description

An AE was any untoward medical occurrence in a clinical study participant administered a study drug that does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use of a study drug, whether or not the AE is considered related to the study drug. For Blinded Study Phase and OLE Phase, TEAEs were defined as 1 or both of the following: Any AEs with an onset date on or after the study drug start date and no later than 30 days after permanent discontinuation of study drug and/or any AEs leading to premature discontinuation of study drug. OLE Analysis Set included all participants who took at least 1 dose of study drug in the OLE Phase.

End point type

Secondary

End point timeframe

First dose date in the OLE Phase up to 45 weeks plus 30 days

End point values	Cilofexor From Cilofexor 100 mg (OLE Phase)	Cilofexor From Placebo (OLE Phase)
Number of subjects analysed	80	45
Units: percentage of participants
number (not applicable)	66.3	73.3

No statistical analyses for this end point

Secondary: Percentage of Participants Who Experienced Treatment-emergent Serious Adverse Events (SAEs) in the Blinded Phase

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End point title

Percentage of Participants Who Experienced Treatment-emergent Serious Adverse Events (SAEs) in the Blinded Phase

End point description

An SAE was defined as an event that, at any dose, results in the following: death, a life-threatening situation; in-patient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, a congenital anomaly/birth defect or a medically important event or reaction. Participants in the Safety Analysis Set were analyzed.

End point type

Secondary

End point timeframe

First dose date in the Blinded Phase up to 100.3 weeks plus 30 days

End point values	Cilofexor 100 mg (Blinded Phase)	Placebo (Blinded Phase)
Number of subjects analysed	277	139
Units: percentage of participants
number (not applicable)	19.1	18.7

No statistical analyses for this end point

Secondary: Percentage of Participants Who Experienced Treatment-emergent SAEs in the OLE Phase

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End point title

Percentage of Participants Who Experienced Treatment-emergent SAEs in the OLE Phase

End point description

End point type

Secondary

End point timeframe

First dose date in the OLE Phase up to 45 weeks plus 30 days

End point values	Cilofexor From Cilofexor 100 mg (OLE Phase)	Cilofexor From Placebo (OLE Phase)
Number of subjects analysed	80	45
Units: percentage of participants
number (not applicable)	11.3	2.2

No statistical analyses for this end point

Secondary: Change From Baseline in Serum Concentrations of Alkaline Phosphatase (ALP) at Blinded Phase Week 96

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End point title

Change From Baseline in Serum Concentrations of Alkaline Phosphatase (ALP) at Blinded Phase Week 96

End point description

Participants in the Full Analysis Set with available data were analyzed.

End point type

Secondary

End point timeframe

Baseline, Blinded Phase Week 96

End point values	Cilofexor 100 mg (Blinded Phase)	Placebo (Blinded Phase)
Number of subjects analysed	146	74
Units: units per liter (U/L)
least squares mean (confidence interval 95%)	0 (-17 to 16)	3 (-19 to 25)

Cilofexor 100 mg vs Placebo

Comparison groups

Cilofexor 100 mg (Blinded Phase) v Placebo (Blinded Phase)

Number of subjects included in analysis

220

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3884 ^[2]

Method

ANCOVA

Parameter type

Difference in Least Squares Mean (LSM)

Point estimate

-4

Confidence interval

level

95%

sides

2-sided

lower limit

-28

upper limit

Notes
[2] - The LSM,95% CI and P-value(1-sided) were obtained by an analysis of covariance(ANCOVA)model with change at Week 96 as dependent variable,baseline value of outcome measure,baseline UDCA use, and baseline Ludwig fibrosis stage as independent variables.

Secondary: Change From Baseline in Serum Concentrations of Alanine Aminotransferase (ALT) at Blinded Phase Week 96

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End point title

Change From Baseline in Serum Concentrations of Alanine Aminotransferase (ALT) at Blinded Phase Week 96

End point description

Participants in the Full Analysis Set with available data were analyzed.

End point type

Secondary

End point timeframe

Baseline, Blinded Phase Week 96

End point values	Cilofexor 100 mg (Blinded Phase)	Placebo (Blinded Phase)
Number of subjects analysed	145	74
Units: U/L
least squares mean (confidence interval 95%)	-13 (-20 to -6)	-3 (-12 to 6)

Cilofexor 100 mg vs Placebo

Comparison groups

Cilofexor 100 mg (Blinded Phase) v Placebo (Blinded Phase)

Number of subjects included in analysis

219

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.039 ^[3]

Method

ANCOVA

Parameter type

Difference in LSM

Point estimate

-9

Confidence interval

level

95%

sides

2-sided

lower limit

-20

upper limit

Notes
[3] - The LSM, 95% CI and P-value (1-sided) were obtained by ANCOVA model to evaluate change at Week 96 as the dependent variable, baseline value of the outcome measure, baseline UDCA use, and baseline Ludwig fibrosis stage as independent variables.

Secondary: Change From Baseline in Serum Concentrations of Fasting Total Bile Acids at Blinded Phase Week 96

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End point title

Change From Baseline in Serum Concentrations of Fasting Total Bile Acids at Blinded Phase Week 96

End point description

Participants in the Full Analysis Set with available data were analyzed.

End point type

Secondary

End point timeframe

Baseline, Blinded Phase Week 96

End point values	Cilofexor 100 mg (Blinded Phase)	Placebo (Blinded Phase)
Number of subjects analysed	147	74
Units: micromoles per liter (μmol/L)
least squares mean (confidence interval 95%)	7.2 (0.9 to 13.5)	9.8 (1.8 to 17.9)

Cilofexor 100 mg vs Placebo

Comparison groups

Cilofexor 100 mg (Blinded Phase) v Placebo (Blinded Phase)

Number of subjects included in analysis

221

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2845 ^[4]

Method

ANCOVA

Parameter type

Difference in LSM

Point estimate

-2.6

Confidence interval

level

95%

sides

2-sided

lower limit

-11.6

upper limit

6.4

Notes
[4] - The LSM, 95% CI and P-value (1-sided) were obtained by ANCOVA model to evaluate change at Week 96 as the dependent variable, baseline value of the outcome measure, baseline UDCA use, and baseline Ludwig fibrosis stage as independent variables.

Secondary: Percentage of Participants With ≥ 25% Relative Reduction in Serum ALP Concentration From Baseline and No Worsening of Fibrosis According to the Ludwig Classification at Blinded Phase Week 96

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End point title

Percentage of Participants With ≥ 25% Relative Reduction in Serum ALP Concentration From Baseline and No Worsening of Fibrosis According to the Ludwig Classification at Blinded Phase Week 96

End point description

The stages of fibrosis was assessed according to Ludwig classification. Ludwig classification fibrosis stages range from 0 to 4, with higher scores indicating greater fibrosis (0=no fibrosis, 4=cirrhosis).The percentage of participants with ≥ 25% reduction in serum ALP Concentration from baseline and no increase in fibrosis according to the Ludwig Classification at Blinded Phase Week 96 was analyzed. Participants in the Full Analysis Set with available data who had nonmissing data at both baseline and Week 96 in the blinded phase were analyzed.

End point type

Secondary

End point timeframe

Baseline, Blinded Phase Week 96

End point values	Cilofexor 100 mg (Blinded Phase)	Placebo (Blinded Phase)
Number of subjects analysed	122	61
Units: percentage of participants
number (not applicable)	9.8	6.6

Cilofexor 100 mg vs Placebo

Comparison groups

Placebo (Blinded Phase) v Cilofexor 100 mg (Blinded Phase)

Number of subjects included in analysis

183

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1978 ^[5]

Method

Mantel-Haenszel

Parameter type

Difference in Percentages

Point estimate

4.1

Confidence interval

level

95%

sides

2-sided

lower limit

-5.3

upper limit

13.5

Notes
[5] - The difference between cilofexor and Placebo, 95% CI, and the p-value (1-sided) were obtained by the stratum-adjusted MH method, with baseline UDCA use and Ludwig fibrosis stage as stratification factors.

Secondary: Percentage of Participants With Fibrosis Improvement According to the Ludwig Classification at Blinded Phase Week 96

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End point title

Percentage of Participants With Fibrosis Improvement According to the Ludwig Classification at Blinded Phase Week 96

End point description

Fibrosis improvement was defined as ≥ 1-stage decrease from baseline in the Ludwig classification score at Blinded Study Phase Week 96. The stages of fibrosis was assessed according to Ludwig classification. Ludwig classification fibrosis stages range from 0 to 4, with higher scores indicating greater fibrosis (0=no fibrosis, 4=cirrhosis). Participants in the Full Analysis Set with available data who had nonmissing data at both baseline and Week 96 in the blinded phase were analyzed.

End point type

Secondary

End point timeframe

Blinded Phase Week 96

End point values	Cilofexor 100 mg (Blinded Phase)	Placebo (Blinded Phase)
Number of subjects analysed	133	64
Units: percentage of participants
number (not applicable)	25.6	17.2

Cilofexor 100 mg vs Placebo

Comparison groups

Cilofexor 100 mg (Blinded Phase) v Placebo (Blinded Phase)

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0797 ^[6]

Method

Mantel-Haenszel

Parameter type

Difference in Percentages

Point estimate

8.9

Confidence interval

level

95%

sides

2-sided

lower limit

-3.5

upper limit

21.2

Notes
[6] - The difference between cilofexor and Placebo, 95% CI, and the p-value (1-sided) were obtained by the stratum-adjusted MH method, with baseline UDCA use and Ludwig fibrosis stage as stratification factors.

Secondary: Change From Baseline in Primary Sclerosing Cholangitis (PSC) Symptoms - Module 1 based on disease-specific Patient Reported Outcome (PSC-PRO) at Blinded Phase Week 96

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End point title

Change From Baseline in Primary Sclerosing Cholangitis (PSC) Symptoms - Module 1 based on disease-specific Patient Reported Outcome (PSC-PRO) at Blinded Phase Week 96

End point description

The PSC-PRO addressed the severity of common everyday symptoms of PSC (eg, pruritus, fatigue, and right upper quadrant abdominal discomfort); and their functional impact (eg, on physical function, activities of daily living, and work productivity, etc). PSC-PRO module 1 – PSC symptoms contains a total of 12 questions asking about the severity of specific PSC symptoms on a scale of 0 (no symptoms) to 10 (symptoms as bad as you could imagine) with a 24-hour recall period. The total score, which is computed as 12 times the average of nonmissing scores of the 12 questions, can potentially range between 0 and 120, with higher scores indicating more severe symptoms. A positive change from baseline indicates worsening of symptoms. Participants in the Full Analysis Set with available data were analyzed.

End point type

Secondary

End point timeframe

Baseline, Blinded Phase Week 96

End point values	Cilofexor 100 mg (Blinded Phase)	Placebo (Blinded Phase)
Number of subjects analysed	274	137
Units: score on a scale
arithmetic mean (standard deviation)
Baseline	11 ( 11.0 )	11 ( 11.8 )
Change at Blinded Phase Wk 96 (N=163, 78)	1 ( 9.0 )	0 ( 6.8 )

Cilofexor 100 mg vs Placebo

Comparison groups

Cilofexor 100 mg (Blinded Phase) v Placebo (Blinded Phase)

Number of subjects included in analysis

411

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7275 ^[7]

Method

ANCOVA

Parameter type

Difference in LSM

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Notes
[7] - The LSM, 95% CI and P-value (1-sided) were obtained by ANCOVA model to evaluate change at Week 96 as the dependent variable, baseline value of the outcome measure, baseline UDCA use, and baseline Ludwig fibrosis stage as independent variables.

Secondary: Change From Baseline in Enhanced Liver Fibrosis (ELF™ ) Test Score at Blinded Phase Week 96

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End point title

Change From Baseline in Enhanced Liver Fibrosis (ELF™ ) Test Score at Blinded Phase Week 96

End point description

The Enhanced Liver Fibrosis (ELF™) test is a composite of three serum biomarkers of hepatobiliary fibrosis: hyaluronic acid, procollagen III amino‐terminal peptide, and tissue inhibitor of metalloproteinase. A typical range for ELF™ test scores in PSC is between 6 and 14. Higher ELF™ test scores are associated with more severe liver disease. A positive change from baseline indicated worsening of fibrosis. Participants in the Full Analysis Set with available data were analyzed.

End point type

Secondary

End point timeframe

Baseline, Blinded Phase Week 96

End point values	Cilofexor 100 mg (Blinded Phase)	Placebo (Blinded Phase)
Number of subjects analysed	163	78
Units: score on a scale
least squares mean (confidence interval 95%)	0.27 (0.16 to 0.38)	0.30 (0.15 to 0.45)

Cilofexor 100 mg vs Placebo

Comparison groups

Cilofexor 100 mg (Blinded Phase) v Placebo (Blinded Phase)

Number of subjects included in analysis

241

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3636 ^[8]

Method

ANCOVA

Parameter type

Difference in LSM

Point estimate

-0.03

Confidence interval

level

95%

sides

2-sided

lower limit

-0.2

upper limit

0.14

Notes
[8] - The LSM, 95% CI and P-value (1-sided) were obtained by ANCOVA model to evaluate change at Week 96 as the dependent variable, baseline value of the outcome measure, baseline UDCA use, and baseline Ludwig fibrosis stage as independent variables.

Secondary: Change From Baseline in Liver Stiffness by FibroScan® at Blinded Phase Week 96

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End point title

Change From Baseline in Liver Stiffness by FibroScan® at Blinded Phase Week 96

End point description

Change in liver stiffness was measured by FibroScan® scores. FibroScan measures liver scarring by measuring the stiffness of the liver. It's normally between 2 and 6 kPa. Many people with liver disease(s) have a result that's higher than the normal range. Higher scores indicate increased scarring of the liver. A positive change from baseline indicates severe liver disease(s). Participants in the Full Analysis Set with available data were analyzed.

End point type

Secondary

End point timeframe

Baseline, Blinded Phase Week 96

End point values	Cilofexor 100 mg (Blinded Phase)	Placebo (Blinded Phase)
Number of subjects analysed	154	73
Units: kilopascals (kPa)
least squares mean (confidence interval 95%)	2.4 (1.2 to 3.6)	2.8 (1.1 to 4.4)

Cilofexor 100 mg vs Placebo

Comparison groups

Cilofexor 100 mg (Blinded Phase) v Placebo (Blinded Phase)

Number of subjects included in analysis

227

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3595 ^[9]

Method

ANCOVA

Parameter type

Difference in LSM

Point estimate

-0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-2.2

upper limit

1.5

Notes
[9] - The LSM, 95% CI and P-value (1-sided) were obtained by ANCOVA model to evaluate change at Week 96 as the dependent variable, baseline value of the outcome measure, baseline UDCA use, and baseline Ludwig fibrosis stage as independent variables.

Adverse events

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Timeframe for reporting adverse events

All-cause mortality: Randomization up to 3.4 years; Adverse events: Blinded Phase: First dose date in the Blinded Phase up to 100.3 weeks plus 30 days; Open-Label Extension (OLE) Phase: First dose date in the OLE Phase up to 45 weeks plus 30 days

Adverse event reporting additional description

All-cause mortality: All Randomized Analysis Set included all participants who were randomized in the study. Adverse Events: Safety Analysis Set included all participants who took at least 1 dose of study drug.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

25.1

Reporting group title

Cilofexor 100 mg (Blinded Phase)

Reporting group description

Participants received cilofexor 100 mg tablet, orally, once daily for up to 100.3 weeks.

Reporting group title

Placebo (Blinded Phase)

Reporting group description

Participants received placebo to match cilofexor 100 mg tablet, orally, once daily for up to 98.1 weeks.

Reporting group title

Cilofexor From Cilofexor 100 mg (OLE Phase)

Reporting group description

Participants who received cilofexor in blinded phase and had entered the OLE phase received open-label cilofexor 100 mg tablet, orally, once daily for up to 44.7 weeks.

Reporting group title

Cilofexor From Placebo (OLE Phase)

Reporting group description

Participants who received placebo in blinded phase and had entered the OLE phase received open-label cilofexor 100 mg tablet, orally, once daily for up to 45.0 weeks.

Serious adverse events	Cilofexor 100 mg (Blinded Phase)	Placebo (Blinded Phase)	Cilofexor From Cilofexor 100 mg (OLE Phase)	Cilofexor From Placebo (OLE Phase)
Total subjects affected by serious adverse events
subjects affected / exposed	53 / 277 (19.13%)	26 / 139 (18.71%)	9 / 80 (11.25%)	1 / 45 (2.22%)
number of deaths (all causes)	2	0	0	0
number of deaths resulting from adverse events	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cholangiocarcinoma
subjects affected / exposed	0 / 277 (0.00%)	2 / 139 (1.44%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Adenocarcinoma of colon
subjects affected / exposed	0 / 277 (0.00%)	0 / 139 (0.00%)	1 / 80 (1.25%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Breast cancer metastatic
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lung adenocarcinoma
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastric cancer
subjects affected / exposed	0 / 277 (0.00%)	1 / 139 (0.72%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gallbladder cancer
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal neoplasm
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Marginal zone lymphoma
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypotension
subjects affected / exposed	0 / 277 (0.00%)	1 / 139 (0.72%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Cholecystectomy
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colorectostomy
subjects affected / exposed	0 / 277 (0.00%)	0 / 139 (0.00%)	1 / 80 (1.25%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Liver transplant
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ligament operation
subjects affected / exposed	0 / 277 (0.00%)	1 / 139 (0.72%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	4 / 277 (1.44%)	1 / 139 (0.72%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	0 / 277 (0.00%)	1 / 139 (0.72%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chills
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Anaphylactoid reaction
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
General physical condition abnormal
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Alanine aminotransferase increased
subjects affected / exposed	0 / 277 (0.00%)	1 / 139 (0.72%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endoscopic retrograde ~ cholangiopancreatography
subjects affected / exposed	1 / 277 (0.36%)	1 / 139 (0.72%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
International normalised ratio ~ increased
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic enzyme abnormal
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Post procedural complication
subjects affected / exposed	0 / 277 (0.00%)	1 / 139 (0.72%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal procedural ~ complication
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Clavicle fracture
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ligament rupture
subjects affected / exposed	1 / 277 (0.36%)	1 / 139 (0.72%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Procedural pain
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	0 / 277 (0.00%)	1 / 139 (0.72%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peroneal nerve palsy
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Migraine with aura
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 277 (0.00%)	0 / 139 (0.00%)	1 / 80 (1.25%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 277 (0.00%)	1 / 139 (0.72%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	3 / 277 (1.08%)	0 / 139 (0.00%)	1 / 80 (1.25%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Crohn's disease
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	2 / 277 (0.72%)	0 / 139 (0.00%)	1 / 80 (1.25%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea haemorrhagic
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Large intestine polyp
subjects affected / exposed	0 / 277 (0.00%)	1 / 139 (0.72%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Obstructive pancreatitis
subjects affected / exposed	0 / 277 (0.00%)	0 / 139 (0.00%)	1 / 80 (1.25%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 277 (0.00%)	1 / 139 (0.72%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 277 (0.00%)	1 / 139 (0.72%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pouchitis
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholangitis
subjects affected / exposed	10 / 277 (3.61%)	7 / 139 (5.04%)	2 / 80 (2.50%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	1 / 17	1 / 10	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bile duct stenosis
subjects affected / exposed	1 / 277 (0.36%)	2 / 139 (1.44%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	4 / 277 (1.44%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	2 / 5	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholangitis acute
subjects affected / exposed	4 / 277 (1.44%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	1 / 4	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bile duct stone
subjects affected / exposed	2 / 277 (0.72%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperbilirubinaemia
subjects affected / exposed	2 / 277 (0.72%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	2 / 277 (0.72%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholangitis sclerosing
subjects affected / exposed	2 / 277 (0.72%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Jaundice
subjects affected / exposed	1 / 277 (0.36%)	1 / 139 (0.72%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Jaundice cholestatic
subjects affected / exposed	1 / 277 (0.36%)	1 / 139 (0.72%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Biliary colic
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Biliary dilatation
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic haematoma
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhagic cholecystitis
subjects affected / exposed	0 / 277 (0.00%)	1 / 139 (0.72%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Drug-induced liver injury
subjects affected / exposed	0 / 277 (0.00%)	1 / 139 (0.72%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	2 / 277 (0.72%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	1 / 80 (1.25%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Abdominal abscess
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	0 / 277 (0.00%)	1 / 139 (0.72%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholangitis infective
subjects affected / exposed	0 / 277 (0.00%)	1 / 139 (0.72%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Febrile infection
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 277 (0.00%)	0 / 139 (0.00%)	1 / 80 (1.25%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis salmonella
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	0 / 277 (0.00%)	1 / 139 (0.72%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Klebsiella infection
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Liver abscess
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	0 / 277 (0.00%)	1 / 139 (0.72%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Meningitis
subjects affected / exposed	0 / 277 (0.00%)	1 / 139 (0.72%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pharyngitis
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural sepsis
subjects affected / exposed	0 / 277 (0.00%)	1 / 139 (0.72%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Postoperative abscess
subjects affected / exposed	0 / 277 (0.00%)	1 / 139 (0.72%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Wound infection
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Streptococcal sepsis
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Soft tissue infection
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Type 1 diabetes mellitus
subjects affected / exposed	1 / 277 (0.36%)	0 / 139 (0.00%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Cilofexor 100 mg (Blinded Phase)	Placebo (Blinded Phase)	Cilofexor From Cilofexor 100 mg (OLE Phase)	Cilofexor From Placebo (OLE Phase)
Total subjects affected by non serious adverse events
subjects affected / exposed	232 / 277 (83.75%)	109 / 139 (78.42%)	34 / 80 (42.50%)	24 / 45 (53.33%)
Investigations
Aspartate aminotransferase increased
subjects affected / exposed	8 / 277 (2.89%)	7 / 139 (5.04%)	0 / 80 (0.00%)	0 / 45 (0.00%)
occurrences all number	10	8	0	0
Nervous system disorders
Headache
subjects affected / exposed	32 / 277 (11.55%)	18 / 139 (12.95%)	1 / 80 (1.25%)	0 / 45 (0.00%)
occurrences all number	44	21	1	0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	34 / 277 (12.27%)	24 / 139 (17.27%)	3 / 80 (3.75%)	0 / 45 (0.00%)
occurrences all number	37	28	3	0
Pyrexia
subjects affected / exposed	33 / 277 (11.91%)	9 / 139 (6.47%)	3 / 80 (3.75%)	2 / 45 (4.44%)
occurrences all number	48	12	3	4
Gastrointestinal disorders
Abdominal pain upper
subjects affected / exposed	40 / 277 (14.44%)	20 / 139 (14.39%)	1 / 80 (1.25%)	2 / 45 (4.44%)
occurrences all number	50	22	1	2
Abdominal pain
subjects affected / exposed	38 / 277 (13.72%)	17 / 139 (12.23%)	1 / 80 (1.25%)	0 / 45 (0.00%)
occurrences all number	52	20	1	0
Nausea
subjects affected / exposed	34 / 277 (12.27%)	16 / 139 (11.51%)	4 / 80 (5.00%)	0 / 45 (0.00%)
occurrences all number	42	19	4	0
Diarrhoea
subjects affected / exposed	21 / 277 (7.58%)	11 / 139 (7.91%)	2 / 80 (2.50%)	1 / 45 (2.22%)
occurrences all number	24	12	2	1
Abdominal distension
subjects affected / exposed	9 / 277 (3.25%)	9 / 139 (6.47%)	0 / 80 (0.00%)	2 / 45 (4.44%)
occurrences all number	10	9	0	2
Vomiting
subjects affected / exposed	12 / 277 (4.33%)	7 / 139 (5.04%)	1 / 80 (1.25%)	0 / 45 (0.00%)
occurrences all number	12	7	1	0
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	135 / 277 (48.74%)	50 / 139 (35.97%)	14 / 80 (17.50%)	11 / 45 (24.44%)
occurrences all number	184	58	14	13
Rash
subjects affected / exposed	16 / 277 (5.78%)	7 / 139 (5.04%)	1 / 80 (1.25%)	0 / 45 (0.00%)
occurrences all number	17	8	2	0
Psychiatric disorders
Insomnia
subjects affected / exposed	14 / 277 (5.05%)	2 / 139 (1.44%)	1 / 80 (1.25%)	2 / 45 (4.44%)
occurrences all number	15	2	1	2
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	15 / 277 (5.42%)	14 / 139 (10.07%)	2 / 80 (2.50%)	0 / 45 (0.00%)
occurrences all number	18	14	2	0
Back pain
subjects affected / exposed	21 / 277 (7.58%)	8 / 139 (5.76%)	3 / 80 (3.75%)	0 / 45 (0.00%)
occurrences all number	22	9	3	0
Infections and infestations
Covid-19
subjects affected / exposed	65 / 277 (23.47%)	26 / 139 (18.71%)	11 / 80 (13.75%)	11 / 45 (24.44%)
occurrences all number	68	27	11	11
Nasopharyngitis
subjects affected / exposed	15 / 277 (5.42%)	12 / 139 (8.63%)	0 / 80 (0.00%)	1 / 45 (2.22%)
occurrences all number	22	13	0	1
Upper respiratory tract infection
subjects affected / exposed	14 / 277 (5.05%)	7 / 139 (5.04%)	1 / 80 (1.25%)	2 / 45 (4.44%)
occurrences all number	17	8	1	2
Urinary tract infection
subjects affected / exposed	8 / 277 (2.89%)	5 / 139 (3.60%)	5 / 80 (6.25%)	0 / 45 (0.00%)
occurrences all number	11	5	5	0

More information

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Were there any global substantial amendments to the protocol? Yes

25 Mar 2019

- In various sections within the protocol, liver stiffness by FibroScan® will be assessed if available. - In various sections within the protocol, sample size power was calculated using the “Pearson’s” Chi-square test for clarity. - In various sections within the protocol, “study procedures manual” and “study reference binder” were revised to “Site Operations Manual” for alignment.

23 Oct 2019

- In various sections within the protocol, GS-9674 was updated to use the study drug name cilofexor, abbreviated as CILO

07 Apr 2020

- Clarified that IBD includes ulcerative colitis, Crohn’s disease, and indeterminant colitis - Clarified that Partial Mayo score collection is not required for subjects using external ostomy bags - The term study medication has been updated to study drug - The term medicinal product has been updated to investigational product - Appendix 2.: Study Procedures Table and the associated footnotes updated to align with the key changes

30 Jun 2021

- Section 1.2.7 and 1.2.8 have been updated with final results from study GS-US-428-4025. - The terminology for the Blinded Study Phase was added and the corresponding sections were updated accordingly. - The protocol synopsis and the study procedure table(s) were updated to align with the updates to the body of the protocol. - Administrative changes throughout, including abbreviations, updates to terminology, updates to section headings, consistency with revised protocol template, language and additional minor edits.

16 Mar 2022

- Objectives and endpoints were updated (Section 2): • Time point “Blinded Study Phase Week 96” was added to the primary objective (Sections 2 and 8.1.1). • Evaluation of GGT was moved from secondary objectives/endpoints to exploratory objectives/endpoints (Sections 2, 8.1.1, 8.1.3, and 8.5.2). • Secondary objective/endpoint “To evaluate changes in liver fibrosis including hepatic collagen content and progression to cirrhosis at Blinded Study Phase Week 96” was moved to the exploratory objectives/endpoints” (Sections 2, 8.1.1, and 8.5.2). • Text updated to clarify that change in primary sclerosing cholangitis (PSC) symptoms will be evaluated based on the disease-specific PSC-patient-reported outcome (PSC-PRO) Module 1 at Blinded Study Phase Week 96 (Sections 2, 8.1.1, 8.1.3, and 8.5.2). - Text added to clarify that if the Blinded Study Phase follow-up visit and the OLE Phase baseline/Day 1 visit occur on the same day, study assessment procedures should be performed according to the OLE Phase baseline/Day 1 visit (Sections 3.1, and 6.4.7).

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
26 Sep 2022	Following recommendation of the external Data Monitoring Committee, after it reviewed the results of a planned interim futility analysis.	-

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: 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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Participants With Progression of Liver Fibrosis at Blinded Phase Week 96

Primary: Percentage of Participants With Progression of Liver Fibrosis at Blinded Phase Week 96

Secondary: Percentage of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) in The Blinded Phase

Secondary: Percentage of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) in The Blinded Phase

Secondary: Percentage of Participants Who Experienced TEAEs in The OLE Phase

Secondary: Percentage of Participants Who Experienced TEAEs in The OLE Phase

Secondary: Percentage of Participants Who Experienced Treatment-emergent Serious Adverse Events (SAEs) in the Blinded Phase

Secondary: Percentage of Participants Who Experienced Treatment-emergent Serious Adverse Events (SAEs) in the Blinded Phase

Secondary: Percentage of Participants Who Experienced Treatment-emergent SAEs in the OLE Phase

Secondary: Percentage of Participants Who Experienced Treatment-emergent SAEs in the OLE Phase

Secondary: Change From Baseline in Serum Concentrations of Alkaline Phosphatase (ALP) at Blinded Phase Week 96

Secondary: Change From Baseline in Serum Concentrations of Alkaline Phosphatase (ALP) at Blinded Phase Week 96

Secondary: Change From Baseline in Serum Concentrations of Alanine Aminotransferase (ALT) at Blinded Phase Week 96

Secondary: Change From Baseline in Serum Concentrations of Alanine Aminotransferase (ALT) at Blinded Phase Week 96

Secondary: Change From Baseline in Serum Concentrations of Fasting Total Bile Acids at Blinded Phase Week 96

Secondary: Change From Baseline in Serum Concentrations of Fasting Total Bile Acids at Blinded Phase Week 96

Secondary: Percentage of Participants With ≥ 25% Relative Reduction in Serum ALP Concentration From Baseline and No Worsening of Fibrosis According to the Ludwig Classification at Blinded Phase Week 96

Secondary: Percentage of Participants With ≥ 25% Relative Reduction in Serum ALP Concentration From Baseline and No Worsening of Fibrosis According to the Ludwig Classification at Blinded Phase Week 96

Secondary: Percentage of Participants With Fibrosis Improvement According to the Ludwig Classification at Blinded Phase Week 96

Secondary: Percentage of Participants With Fibrosis Improvement According to the Ludwig Classification at Blinded Phase Week 96

Secondary: Change From Baseline in Primary Sclerosing Cholangitis (PSC) Symptoms - Module 1 based on disease-specific Patient Reported Outcome (PSC-PRO) at Blinded Phase Week 96

Secondary: Change From Baseline in Primary Sclerosing Cholangitis (PSC) Symptoms - Module 1 based on disease-specific Patient Reported Outcome (PSC-PRO) at Blinded Phase Week 96

Secondary: Change From Baseline in Enhanced Liver Fibrosis (ELF™ ) Test Score at Blinded Phase Week 96

Secondary: Change From Baseline in Enhanced Liver Fibrosis (ELF™ ) Test Score at Blinded Phase Week 96

Secondary: Change From Baseline in Liver Stiffness by FibroScan® at Blinded Phase Week 96

Secondary: Change From Baseline in Liver Stiffness by FibroScan® at Blinded Phase Week 96

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
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