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Clinical Trial Results:
A randomized, double-blind, placebo controlled, 3-part, adaptive design, multicenter study to assess safety, tolerability and efficacy of tropifexor (LJN452) in patients with non-alcoholic steatohepatitis (NASH) FLIGHT-FXR

Summary
EudraCT number	2015-005215-33
Trial protocol	SK IT DE NL BE AT ES
Global end of trial date	06 Apr 2020

Results information
Results version number	v1(current)
This version publication date	28 Apr 2021
First version publication date	28 Apr 2021
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

CLJN452A2202

ISRCTN number

US NCT number

NCT02855164

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Pharma AG

Sponsor organisation address

CH-4002, Basel, Switzerland,

Public contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.com

Scientific contact

Study Director, Novartis Pharma AG, 1 8627788300, novartis.email@novartis.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

06 Apr 2020

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

06 Apr 2020

Was the trial ended prematurely?

Main objective of the trial

To determine safety and tolerability of different doses of tropifexor To determine the dose-response relationship of tropifexor on markers of hepatic inflammation in NASH (ALT and AST) To determine the dose response relationship of tropifexor on liver fat content by changes in quantitative MRI determined fat

Protection of trial subjects

This study complies with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of this trial.

Background therapy

Evidence for comparator

Actual start date of recruitment

01 Aug 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 10

Country: Number of subjects enrolled

Austria: 5

Country: Number of subjects enrolled

Belgium: 7

Country: Number of subjects enrolled

Canada: 5

Country: Number of subjects enrolled

France: 12

Country: Number of subjects enrolled

Germany: 7

Country: Number of subjects enrolled

India: 2

Country: Number of subjects enrolled

Italy: 16

Country: Number of subjects enrolled

Japan: 21

Country: Number of subjects enrolled

Korea, Republic of: 28

Country: Number of subjects enrolled

Netherlands: 1

Country: Number of subjects enrolled

Singapore: 13

Country: Number of subjects enrolled

Slovakia: 8

Country: Number of subjects enrolled

Spain: 10

Country: Number of subjects enrolled

Taiwan: 26

Country: Number of subjects enrolled

United States: 168

Country: Number of subjects enrolled

Argentina: 11

Worldwide total number of subjects

350

EEA total number of subjects

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)

298

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

In total, 411 subjects were screened in Parts A and B of the study together. Of these, 198 subjects were deemed eligible to participate in the study and were subsequently randomized

Screening details

In Part A, 77 were randomized at baseline; 121 in Part B; and 780 were screened in Part C. Of these 152 met eligibility criteria and were randomized in nearly to receive tropifexor 140 μg (n=50) or 200 μg (n=51) or placebo (n=51)

Period 1 title

Parts A + B (Randomized Set)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Blinding implementation details

This was a double-blind study. Subjects, investigator staff, persons performing the assessments, and Novartis clinical trial team and CRO associates involved with continued direct study site conduct (or delegates), remained blinded to the identity of study treatments from the time of randomization (until final database lock)

Are arms mutually exclusive

Yes

LJN452 10 μg

Arm description

10 micrograms of Tropifexor (Part A)

Arm type

Experimental

Investigational medicinal product name

Tropifexor

Investigational medicinal product code

Other name

LJN452

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

10 microgram tropifexor tablet

LJN452 30 μg

Arm description

30 micrograms of Tropifexor (Part A)

Arm type

Experimental

Investigational medicinal product name

Tropifexor

Investigational medicinal product code

Other name

LJN452

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

30 microgram tropifexor tablet

LJN452 60 μg

Arm description

60 micrograms of Tropifexor (Parts A+B)

Arm type

Experimental

Investigational medicinal product name

Tropifexor

Investigational medicinal product code

Other name

LJN452

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

60 microgram tropifexor tablet

LJN452 90 μg

Arm description

90 micrograms of Tropifexor (Parts A+B)

Arm type

Experimental

Investigational medicinal product name

Tropifexor

Investigational medicinal product code

Other name

LJN452

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

90 microgram tropifexor tablet

Placebo

Arm description

Placebo A+B

Arm type

Placebo

Investigational medicinal product name

placebo

Investigational medicinal product code

Parts A+B

Other name

placebo

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

placebo tablet

Number of subjects in period 1 ^[1]	LJN452 10 μg	LJN452 30 μg	LJN452 60 μg	LJN452 90 μg	Placebo
Started	14	16	37	85	46
Completed	14	16	36	77	45
Not completed	0	0	1	8	1
Consent withdrawn by subject	-	-	1	2	1
Physician decision	-	-	-	2	-
Adverse event, non-fatal	-	-	-	4	-

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Numbers are consistent

Period 2 title

Part C (Randomized Set)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Are arms mutually exclusive

Yes

LJN452 140 μg

Arm description

140 micrograms of Tropifexor (Part C)

Arm type

Experimental

Investigational medicinal product name

Tropifexor

Investigational medicinal product code

Other name

LJN452

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

140 microgram tropifexor tablet

LJN452 200 μg

Arm description

200 micrograms of Tropifexor (Part C)

Arm type

Experimental

Investigational medicinal product name

Tropifexor

Investigational medicinal product code

Other name

LJN452

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

200 microgram tropifexor tablet

Placebo

Arm description

Placebo A+B

Arm type

Placebo

Investigational medicinal product name

placebo

Investigational medicinal product code

Part C

Other name

LJN452

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

placebo tablet

Number of subjects in period 2 ^[2]	LJN452 140 μg	LJN452 200 μg	Placebo
Started	50	51	51
Completed	38	37	44
Not completed	12	14	7
Physician decision	1	-	1
Consent withdrawn by subject	5	4	3
Adverse event, non-fatal	5	9	2
Lost to follow-up	1	1	1

Notes
[2] - 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: Numbers are consistent

Baseline characteristics

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Reporting group title

LJN452 10 μg

Reporting group description

10 micrograms of Tropifexor (Part A)

Reporting group title

LJN452 30 μg

Reporting group description

30 micrograms of Tropifexor (Part A)

Reporting group title

LJN452 60 μg

Reporting group description

60 micrograms of Tropifexor (Parts A+B)

Reporting group title

LJN452 90 μg

Reporting group description

90 micrograms of Tropifexor (Parts A+B)

Reporting group title

Placebo

Reporting group description

Placebo A+B

Reporting group values	LJN452 10 μg	LJN452 30 μg	LJN452 60 μg	LJN452 90 μg	Placebo	Total
Number of subjects	14	16	37	85	46	198
Age Categorical
Units: participants
Parts A + B\|<=18 years	0	0	0	0	0	0
Part C\|<=18 years	0	0	0	0	0	0
Parts A + B\|Between 18 and 65 years	14	14	33	72	41	174
Part C\|Between 18 and 65 years	0	0	0	0	0	0
Parts A + B\|>=65 years	0	2	4	13	5	24
Part C\|>=65 years	0	0	0	0	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	48 ± 11.7	49 ± 14.4	50 ± 12.5	51 ± 13.4	51 ± 12.3	-
Sex: Female, Male
Sex of participant by treatment
Units: participants
Parts A + B\|Female	9	7	20	47	21	104
Part C\|Female	0	0	0	0	0	0
Parts A + B\|Male	5	9	17	38	25	94
Part C\|Male	0	0	0	0	0	0
Race/Ethnicity, Customized
Units: Subjects
Caucasian (Parts A + B)	12	11	24	50	25	122
Black (Parts A + B)	0	0	0	1	0	1
Asian (Parts A + B)	2	5	12	31	20	70
Pacific Islander (Parts A + B)	0	0	0	0	1	1
Other (Parts A + B)	0	0	0	2	0	2
Unknown (Parts A+B)	0	0	1	1	0	2
Caucasian (Part C)	0	0	0	0	0	0
Black (Part C)	0	0	0	0	0	0
Asian (Part C)	0	0	0	0	0	0
Pacific Islander (Part C)	0	0	0	0	0	0
Other (Part C)	0	0	0	0	0	0
Unknown (Part C)	0	0	0	0	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	48 ± 11.7	49 ± 14.4	50 ± 12.5	51 ± 13.4	54 ± 11.0	-

Subject analysis set title

Placebo C

Subject analysis set type

Intention-to-treat

Subject analysis set description

Placebo Part C

Subject analysis set title

Placebo A+B

Subject analysis set type

Intention-to-treat

Subject analysis set description

Placebo Parts A+B

Subject analysis sets values	Placebo C	Placebo A+B
Number of subjects	51	46
Age Categorical
Units: participants
Parts A + B\|<=18 years	0	0
Part C\|<=18 years	0	0
Parts A + B\|Between 18 and 65 years	0	41
Part C\|Between 18 and 65 years	38	0
Parts A + B\|>=65 years	0	5
Part C\|>=65 years	8	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	54 ± 11.00	51 ± 12.3
Sex: Female, Male
Sex of participant by treatment
Units: participants
Parts A + B\|Female	0	0
Part C\|Female	32	21
Parts A + B\|Male	0	0
Part C\|Male	19	25
Race/Ethnicity, Customized
Units: Subjects
Caucasian (Parts A + B)	0	25
Black (Parts A + B)	0	0
Asian (Parts A + B)	0	20
Pacific Islander (Parts A + B)	0	1
Other (Parts A + B)	0	0
Unknown (Parts A+B)	0	0
Caucasian (Part C)	38	0
Black (Part C)	1	0
Asian (Part C)	8	0
Pacific Islander (Part C)	0	0
Other (Part C)	4	0
Unknown (Part C)	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	54 ± 11.0	51 ± 12.3

End points

Top of page

Reporting group title

LJN452 10 μg

Reporting group description

10 micrograms of Tropifexor (Part A)

Reporting group title

LJN452 30 μg

Reporting group description

30 micrograms of Tropifexor (Part A)

Reporting group title

LJN452 60 μg

Reporting group description

60 micrograms of Tropifexor (Parts A+B)

Reporting group title

LJN452 90 μg

Reporting group description

90 micrograms of Tropifexor (Parts A+B)

Reporting group title

Placebo

Reporting group description

Placebo A+B

Reporting group title

LJN452 140 μg

Reporting group description

140 micrograms of Tropifexor (Part C)

Reporting group title

LJN452 200 μg

Reporting group description

200 micrograms of Tropifexor (Part C)

Reporting group title

Placebo

Reporting group description

Placebo A+B

Subject analysis set title

Placebo C

Subject analysis set type

Intention-to-treat

Subject analysis set description

Placebo Part C

Subject analysis set title

Placebo A+B

Subject analysis set type

Intention-to-treat

Subject analysis set description

Placebo Parts A+B

Primary: Number of Nonalcoholic steatohepatitis (NASH) patients with Treatment Emergent Adverse Events (TEAE)

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End point title

Number of Nonalcoholic steatohepatitis (NASH) patients with Treatment Emergent Adverse Events (TEAE) ^[1] ^[2]

End point description

Number of Nonalcoholic steatohepatitis (NASH) patients with TEAEs

End point type

Primary

End point timeframe

End of Treatment (EoT): For Parts A&B, EoT was Week 12 (Primary Outcome Measure). For Part C, EoT was Week 48 (Secondary Outcome Measure)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was planned

End point values	LJN452 10 μg	LJN452 30 μg	LJN452 60 μg	LJN452 90 μg	LJN452 140 μg	LJN452 200 μg	Placebo C	Placebo A+B
Number of subjects analysed	13	16	37	85	50	51	51	46
Units: participants	5	11	24	61	49	49	46	31

No statistical analyses for this end point

Primary: Change in Transaminase levels (ALT)

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End point title

Change in Transaminase levels (ALT) ^[3]

End point description

Summary statistics of change in ALT from baseline to EOT by treatment. The alanine aminotransferase (ALT) test is a blood test that checks for liver damage. High levels of ALT may indicate liver damage. Normal range for ALT is typically 10 to 45 U/L or so (varies a little by age and gender). Elevation of these values indicate more liver inflammation/damage. ALT elevation is not unexpected in this patient population. Dose relationship of tropifexor (LJN452) on ALT marker of hepatic inflammation in NASH

End point type

Primary

End point timeframe

End of Treatment (EoT): For Parts A&B, EoT was Week 12 (Primary Outcome Measure). For Part C, EoT was Week 48 (Secondary Outcome Measure)

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was planned

End point values	LJN452 10 μg	LJN452 30 μg	LJN452 60 μg	LJN452 90 μg	LJN452 140 μg	LJN452 200 μg	Placebo C	Placebo A+B
Number of subjects analysed	14	16	37	85	50	51	51	46
Units: scores
arithmetic mean (standard deviation)	-16.7 ± 17.53	-12.0 ± 35.99	-17.3 ± 28.12	-15.4 ± 30.32	-27.0 ± 30.24	-28.7 ± 25.40	-11.7 ± 61.64	-8.1 ± 29.37

Change in ALT

Statistical analysis description

10 micrograms of Tropifexor vs placebo (Part A)

Comparison groups

LJN452 10 μg v Placebo A+B

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[4]

P-value

= 0.362

Method

ANCOVA

Parameter type

LS mean change

Point estimate

-15.9

Confidence interval

level

95%

sides

2-sided

lower limit

-31.2

upper limit

-0.6

Variability estimate

Standard error of the mean

Dispersion value

7.76

Notes
[4] - Repeated measures analysis: ALT (U/L) change from baseline up to EOT (Parts A + B) (Full analysis set)

Change in ALT

Statistical analysis description

30 micrograms of Tropifexor vs placebo (Part A)

Comparison groups

LJN452 30 μg v Placebo A+B

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[5]

P-value

= 0.729

Method

ANCOVA

Parameter type

LS mean change

Point estimate

-10.7

Confidence interval

level

95%

sides

2-sided

lower limit

-24.8

upper limit

3.3

Variability estimate

Standard error of the mean

Dispersion value

7.12

Notes
[5] - ANCOVA: ALT (U/L) change from baseline up to EOT (Parts A + B) (Full analysis set)

Change in ALT

Statistical analysis description

60 micrograms of Tropifexor vs placebo (Parts A + B)

Comparison groups

LJN452 60 μg v Placebo A+B

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[6]

P-value

= 0.173

Method

ANCOVA

Parameter type

Least Square Mean Change

Point estimate

-16.5

Confidence interval

level

95%

sides

2-sided

lower limit

-25.8

upper limit

-7.1

Variability estimate

Standard error of the mean

Dispersion value

4.73

Notes
[6] - ANCOVA: ALT (U/L) change from baseline up to EOT (Parts A + B) (Full analysis set)

Change in ALT

Statistical analysis description

90 micrograms of Tropifexor vs placebo (Parts A + B)

Comparison groups

LJN452 90 μg v Placebo A+B

Number of subjects included in analysis

131

Analysis specification

Pre-specified

Analysis type

^[7]

P-value

= 0.185

Method

ANCOVA

Parameter type

Least Square Mean Change

Point estimate

-14.9

Confidence interval

level

95%

sides

2-sided

lower limit

-21.3

upper limit

-8.5

Variability estimate

Standard error of the mean

Dispersion value

3.25

Notes
[7] - Repeated measures analysis: ALT (U/L) change from baseline up to EOT (Parts A + B) (Full analysis set)

Change in ALT

Statistical analysis description

140 micrograms of Tropifexor (Part C) vs placebo

Comparison groups

LJN452 140 μg v Placebo C

Number of subjects included in analysis

101

Analysis specification

Pre-specified

Analysis type

superiority ^[8]

P-value

= 0.02

Method

ANCOVA

Parameter type

LS Mean Change

Point estimate

-31.6

Confidence interval

level

95%

sides

2-sided

lower limit

-46.9

upper limit

-16.3

Variability estimate

Standard error of the mean

Dispersion value

7.71

Notes
[8] - ANCOVA: Relative change of ALT (U/L) up to EOT (Part C) (Full analysis set)

Change in ALT

Statistical analysis description

200 micrograms of Tropifexor vs placebo (Part C)

Comparison groups

LJN452 200 μg v Placebo C

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

superiority ^[9]

P-value

= 0.03

Method

ANCOVA

Parameter type

LS Mean Change

Point estimate

-32.5

Confidence interval

level

95%

sides

2-sided

lower limit

-50.6

upper limit

-14.5

Variability estimate

Standard error of the mean

Dispersion value

9.1

Notes
[9] - ANCOVA: ALT (U/L) change from baseline up to EOT (Part C) (Full analysis set)

Change in ALT

Statistical analysis description

10 micrograms of Tropifexor vs placebo (Parts A + B + C)

Comparison groups

LJN452 10 μg v Placebo C

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[10]

P-value

= 0.456

Method

ANCOVA

Parameter type

LS Mean change

Point estimate

-13.4

Confidence interval

level

95%

sides

2-sided

lower limit

-26.3

upper limit

-0.4

Variability estimate

Standard error of the mean

Dispersion value

7.86

Notes
[10] - ANCOVA: ALT (U/L) change from baseline to Week 12 (Parts A+B+C) Full analysis set (FAS)

Change in ALT

Statistical analysis description

30 micrograms of Tropifexor vs placebo (Parts A + B + C)

Comparison groups

LJN452 30 μg v Placebo C

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[11]

P-value

= 0.966

Method

ANCOVA

Parameter type

LS Mean change

Point estimate

-7.5

Confidence interval

level

95%

sides

2-sided

lower limit

-19.5

upper limit

4.4

Variability estimate

Standard error of the mean

Dispersion value

7.27

Notes
[11] - ANCOVA: ALT (U/L) change from baseline to Week 12 (Parts A + B + C) Full analysis set (FAS)

Change in ALT

Statistical analysis description

60 micrograms of Tropifexor vs placebo (Parts A + B + C)

Comparison groups

LJN452 60 μg v Placebo C

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[12]

P-value

= 0.275

Method

ANCOVA

Parameter type

LS Mean change

Point estimate

-13.3

Confidence interval

level

95%

sides

2-sided

lower limit

-21.4

upper limit

-5.2

Variability estimate

Standard error of the mean

Dispersion value

4.93

Notes
[12] - ANCOVA: ALT (U/L) change from baseline to Week 12 (Parts A + B + C) Full analysis set (FAS)

Change in ALT

Statistical analysis description

90 micrograms of Tropifexor vs placebo (Parts A + B + C)

Comparison groups

LJN452 90 μg v Placebo C

Number of subjects included in analysis

136

Analysis specification

Pre-specified

Analysis type

superiority ^[13]

P-value

= 0.304

Method

ANCOVA

Parameter type

LS Mean change

Point estimate

-11.8

Confidence interval

level

95%

sides

2-sided

lower limit

-17.6

upper limit

-5.9

Variability estimate

Standard error of the mean

Dispersion value

3.56

Notes
[13] - ANCOVA: ALT (U/L) change from baseline to Week 12 (Parts A+B + C) Full analysis set (FAS)

Change in ALT

Statistical analysis description

140 micrograms of Tropifexor vs placebo (Parts A + B)

Comparison groups

LJN452 140 μg v Placebo C

Number of subjects included in analysis

101

Analysis specification

Pre-specified

Analysis type

superiority ^[14]

P-value

= 0.057

Method

ANCOVA

Parameter type

LS Mean change

Point estimate

-17.1

Confidence interval

level

95%

sides

2-sided

lower limit

-24.5

upper limit

-9.8

Variability estimate

Standard error of the mean

Dispersion value

4.45

Notes
[14] - ANCOVA: ALT (U/L) change from baseline up to EOT (Parts A + B) FAS

Change in ALT

Statistical analysis description

200 micrograms of Tropifexor vs placebo (Parts A + B + C)

Comparison groups

LJN452 200 μg v Placebo C

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

superiority ^[15]

P-value

= 0.003

Method

ANCOVA

Parameter type

LS Mean change

Point estimate

-23

Confidence interval

level

95%

sides

2-sided

lower limit

-30.5

upper limit

-15.6

Variability estimate

Standard error of the mean

Dispersion value

4.49

Notes
[15] - ANCOVA: ALT (U/L) change from baseline up to EOT (Parts A + B + C) FAS

Primary: Change in Aspartate transaminase (AST)

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End point title

Change in Aspartate transaminase (AST) ^[16]

End point description

To determine the dose relationship of tropifexor (LJN452) on markers of hepatic inflammation (AST) in NASH from baseline to EoT The alanine aminotransferase (AST) test is a blood test that checks for liver damage. High levels of AST may indicate liver damage. Normal range for AST is typically 10 to 45 U/L or so (varies a little by age and gender). Elevation of these values indicate more liver inflammation/damage AST elevation is not unexpected in this patient population The aspartate aminotransferase (AST) test is a blood test that checks for liver damage. Higher levels indicate more possible liver damage Summary statistics of change in AST from baseline up to end of treatment (EOT)

End point type

Primary

End point timeframe

End of Treatment (EoT): For Parts A&B, EoT was Week 12 (Primary Outcome Measure). For Part C, EoT was Week 48 (Secondary Outcome Measure)

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was planned

End point values	LJN452 10 μg	LJN452 30 μg	LJN452 60 μg	LJN452 90 μg	LJN452 140 μg	LJN452 200 μg	Placebo C	Placebo A+B
Number of subjects analysed	14	16	37	85	50	51	51	46
Units: scores
arithmetic mean (standard deviation)	-11.3 ± 12.09	-2.1 ± 29.62	-10.2 ± 25.03	-2.5 ± 24.60	-16.7 ± 23.36	-13.3 ± 20.14	-13.1 ± 29.00	-7.1 ± 23.85

Change in AST

Statistical analysis description

10 micrograms of Tropifexor vs placebo (Part A)

Comparison groups

LJN452 10 μg v Placebo A+B

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[17]

P-value

= 0.722

Method

ANCOVA

Parameter type

LS Mean change

Point estimate

-9.9

Confidence interval

level

95%

sides

2-sided

lower limit

-22.9

upper limit

Variability estimate

Standard error of the mean

Dispersion value

6.56

Notes
[17] - ANCOVA: AST (U/L) change from baseline up to EOT (Full analysis set)

Change in AST

Statistical analysis description

30 micrograms of Tropifexor vs placebo (Part A)

Comparison groups

LJN452 30 μg v Placebo A+B

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[18]

P-value

= 0.468

Method

ANCOVA

Parameter type

LS Mean change

Point estimate

-2.2

Confidence interval

level

95%

sides

2-sided

lower limit

-14

upper limit

9.5

Variability estimate

Standard error of the mean

Dispersion value

5.96

Notes
[18] - ANCOVA: AST (U/L) change from baseline up to EOT (Full analysis set)

Change in AST

Statistical analysis description

60 micrograms of Tropifexor vs placebo (Parts A+B)

Comparison groups

LJN452 60 μg v Placebo A+B

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[19]

P-value

= 0.774

Method

ANCOVA

Parameter type

LS Mean change

Point estimate

-8.8

Confidence interval

level

95%

sides

2-sided

lower limit

-16.7

upper limit

-1

Variability estimate

Standard error of the mean

Dispersion value

3.97

Notes
[19] - Repeated measures analysis: AST (U/L) change from baseline up to EOT (Parts A+B) (Full analysis set)

Change in AST

Statistical analysis description

90 micrograms of Tropifexor vs placebo (Parts A+B)

Comparison groups

LJN452 90 μg v Placebo A+B

Number of subjects included in analysis

131

Analysis specification

Pre-specified

Analysis type

superiority ^[20]

P-value

= 0.136

Method

ANCOVA

Parameter type

LS Mean change

Point estimate

-0.6

Confidence interval

level

95%

sides

2-sided

lower limit

-6

upper limit

4.9

Variability estimate

Standard error of the mean

Dispersion value

2.76

Notes
[20] - ANCOVA: AST (U/L) change from baseline up to EOT (Parts A+B) (Full analysis set)

Change in AST

Statistical analysis description

140 micrograms of Tropifexor vs placebo (Part C)

Comparison groups

LJN452 140 μg v Placebo C

Number of subjects included in analysis

101

Analysis specification

Pre-specified

Analysis type

superiority ^[21]

P-value

= 0.145

Method

ANCOVA

Parameter type

LS Mean change

Point estimate

-16

Confidence interval

level

95%

sides

2-sided

lower limit

-23.9

upper limit

-8.2

Variability estimate

Standard error of the mean

Dispersion value

3.97

Notes
[21] - Repeated measures analysis: AST (U/L) change from baseline up to EOT (Part C) (Full analysis set)

Change in AST

Statistical analysis description

200 micrograms of Tropifexor vs placebo (Part C)

Comparison groups

LJN452 200 μg v Placebo C

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

superiority ^[22]

P-value

= 0.236

Method

ANCOVA

Parameter type

LS Mean change

Point estimate

-15.3

Confidence interval

level

95%

sides

2-sided

lower limit

-24.2

upper limit

-6.4

Variability estimate

Standard error of the mean

Dispersion value

4.49

Notes
[22] - Repeated measures analysis: AST (U/L) change from baseline up to EOT (Part C) (Full analysis set)

Change in AST

Statistical analysis description

10 micrograms of Tropifexor vs placebo (Parts A+B+ C)

Comparison groups

LJN452 10 μg v Placebo C

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[23]

P-value

= 0.788

Method

ANCOVA

Parameter type

LS Mean change

Point estimate

-7.1

Confidence interval

level

95%

sides

2-sided

lower limit

-18.7

upper limit

4.4

Variability estimate

Standard error of the mean

Dispersion value

Notes
[23] - Repeated measures analysis: AST (U/L) change from baseline up to EOT (Parts A+B+C) Full analysis set (FAS)

Change in AST

Statistical analysis description

30 micrograms of Tropifexor vs placebo (Parts A+B+ C)

Comparison groups

LJN452 30 μg v Placebo C

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[24]

P-value

= 0.413

Method

ANCOVA

Parameter type

LS Mean change

Point estimate

0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-10.2

upper limit

Variability estimate

Standard error of the mean

Dispersion value

6.43

Notes
[24] - Repeated measures analysis: AST (U/L) change from baseline up to EOT (Parts A+B+C) Full analysis set (FAS)

Change in AST

Statistical analysis description

60 micrograms of Tropifexor vs placebo (Parts A+B+ C)

Comparison groups

LJN452 60 μg v Placebo C

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[25]

P-value

= 0.833

Method

ANCOVA

Parameter type

LS Mean change

Point estimate

-6.2

Confidence interval

level

95%

sides

2-sided

lower limit

-13.4

upper limit

Variability estimate

Standard error of the mean

Dispersion value

4.38

Notes
[25] - ANCOVA: AST (U/L) change from baseline up to EOT (Parts A+B+C) Full analysis set (FAS)

Change in AST

Statistical analysis description

90 micrograms of Tropifexor vs placebo (Parts A+B+ C)

Comparison groups

LJN452 90 μg v Placebo C

Number of subjects included in analysis

136

Analysis specification

Pre-specified

Analysis type

superiority ^[26]

P-value

= 0.068

Method

ANCOVA

Parameter type

LS Mean change

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-3.2

upper limit

7.3

Variability estimate

Standard error of the mean

Dispersion value

3.19

Notes
[26] - ANCOVA: AST (U/L) change from baseline up to EOT (Parts A+B+C) Full analysis set (FAS)

Change in AST

Statistical analysis description

140 micrograms of Tropifexor vs placebo (Parts A+B+ C)

Comparison groups

LJN452 140 μg v Placebo C

Number of subjects included in analysis

101

Analysis specification

Pre-specified

Analysis type

superiority ^[27]

P-value

= 0.269

Method

ANCOVA

Parameter type

LS Mean change

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-6.6

upper limit

6.5

Variability estimate

Standard error of the mean

Dispersion value

3.98

Notes
[27] - ANCOVA: AST (U/L) change from baseline up to EOT (Parts A+B+C) Full analysis set (FAS)

Change in AST

Statistical analysis description

200 micrograms of Tropifexor vs placebo (Parts A+B+ C)

Comparison groups

LJN452 200 μg v Placebo C

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

superiority ^[28]

P-value

= 0.777

Method

ANCOVA

Parameter type

LS Mean change

Point estimate

-3.8

Confidence interval

level

95%

sides

2-sided

lower limit

-10.5

upper limit

2.9

Variability estimate

Standard error of the mean

Dispersion value

4.05

Notes
[28] - Repeated measures analysis: AST (U/L) change from baseline up to EOT (Parts A+B+C) Full analysis set (FAS)

Primary: Change from baseline in percent of fat in the liver assessed using Magnetic resonance imaging (MRI)

Top of page

End point title

Change from baseline in percent of fat in the liver assessed using Magnetic resonance imaging (MRI) ^[29]

End point description

Repeated measures analysis: Relative change in percentage of fat in the liver assessed using MRI from baseline by visit up to EOT (Full analysis set)

End point type

Primary

End point timeframe

End of Treatment (EoT): For Parts A&B, EoT was Week 12 (Primary Outcome Measure). For Part C, EoT was Week 48 (Secondary Outcome Measure)

Notes
[29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was planned

End point values	LJN452 10 μg	LJN452 30 μg	LJN452 60 μg	LJN452 90 μg	LJN452 140 μg	LJN452 200 μg	Placebo C	Placebo A+B
Number of subjects analysed	14	16	37	85	50	51	51 ^[30]	46 ^[31]
Units: scores
arithmetic mean (standard error)	-7.48 ± 6.174	-14.07 ± 5.661	-15.04 ± 3.754	-12.34 ± 2.482	-31.25 ± 5.228	-39.54 ± 4.968	0.00 ± 0.00	0.00 ± 0.00

Notes
[30] - Placebo is the reference group for repeated measures
[31] - Placebo is the reference group for repeated measures

Change in percent of fat in the liver

Statistical analysis description

10 microgramsof Tropifexor - Change in percentage of fat in the liver Part A

Comparison groups

LJN452 10 μg v Placebo A+B

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[32]

P-value

= 0.853

Method

ANCOVA

Parameter type

LS Mean change

Point estimate

-7.48

Confidence interval

level

95%

sides

2-sided

lower limit

-19.66

upper limit

4.7

Variability estimate

Standard error of the mean

Dispersion value

6.174

Notes
[32] - ANCOVA: Relative change in percentage of fat in the liver from baseline to Week 12

Change in percent of fat in the liver

Statistical analysis description

30 micrograms of Tropifexor - Change in percentage of fat in the liver Part A

Comparison groups

LJN452 30 μg v Placebo A+B

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[33]

P-value

= 0.232

Method

ANCOVA

Parameter type

LS Mean change

Point estimate

-14.07

Confidence interval

level

95%

sides

2-sided

lower limit

-25.24

upper limit

-2.91

Variability estimate

Standard error of the mean

Dispersion value

5.661

Notes
[33] - ANCOVA: Relative change in percentage of fat in the liver from baseline to Week 12

Change in percent of fat in the liver

Statistical analysis description

60 micrograms of Tropifexor - Change in percentage of fat in the liver Parts A+B

Comparison groups

LJN452 60 μg v Placebo A+B

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[34]

P-value

= 0.077

Method

ANCOVA

Parameter type

LS Mean change

Point estimate

-15.04

Confidence interval

level

95%

sides

2-sided

lower limit

-22.45

upper limit

-7.64

Variability estimate

Standard error of the mean

Dispersion value

3.754

Notes
[34] - ANCOVA: Relative change in percentage of fat in the liver from baseline to Week 12

Change in percent of fat in the liver

Statistical analysis description

90 micrograms of Tropifexor - Change in percentage of fat in the liver Parts A+B

Comparison groups

LJN452 90 μg v Placebo A+B

Number of subjects included in analysis

131

Analysis specification

Pre-specified

Analysis type

superiority ^[35]

P-value

= 0.141

Method

ANCOVA

Parameter type

LS Mean change

Point estimate

-12.34

Confidence interval

level

95%

sides

2-sided

lower limit

-17.23

upper limit

-7.44

Variability estimate

Standard error of the mean

Dispersion value

2.482

Notes
[35] - ANCOVA: Relative change in percentage of fat in the liver from baseline

Change in percent of fat in the liver

Statistical analysis description

140 micrograms of Tropifexor - Change in percentage of fat in the liver Part C

Comparison groups

LJN452 140 μg v Placebo C

Number of subjects included in analysis

101

Analysis specification

Pre-specified

Analysis type

superiority ^[36]

P-value

< 0.001

Method

ANCOVA

Parameter type

LS Mean change

Point estimate

-31.25

Confidence interval

level

95%

sides

2-sided

lower limit

-41.58

upper limit

-20.92

Variability estimate

Standard error of the mean

Dispersion value

5.228

Notes
[36] - ANCOVA: Relative change in percentage of fat in the liver

Change in percent of fat in the liver

Statistical analysis description

200 micrograms of Tropifexor - Change in percentage of fat in the liver Part C

Comparison groups

LJN452 200 μg v Placebo C

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

superiority ^[37]

P-value

< 0.001

Method

ANCOVA

Parameter type

LS Mean change

Point estimate

-39.54

Confidence interval

level

95%

sides

2-sided

lower limit

-49.37

upper limit

-29.71

Variability estimate

Standard error of the mean

Dispersion value

4.968

Notes
[37] - ANCOVA: Relative change in percentage of fat in the liver

Change in percent of fat in the liver

Statistical analysis description

10 micrograms of Tropifexor - Change in percentage of fat in the liver Parts A+B+C

Comparison groups

LJN452 10 μg v Placebo C

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[38]

P-value

= 0.872

Method

ANCOVA

Parameter type

LS Mean change

Point estimate

-8.09

Confidence interval

level

95%

sides

2-sided

lower limit

-19.06

upper limit

2.88

Variability estimate

Standard error of the mean

Dispersion value

6.65

Notes
[38] - ANCOVA: Relative change in percentage of fat in the liver from baseline to Week 12 (Parts A+B+C)

Change in percent of fat in the liver

Statistical analysis description

30 micrograms of Tropifexor - Change in percentage of fat in the liver Parts A+B+C

Comparison groups

LJN452 30 μg v Placebo C

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[39]

P-value

= 0.465

Method

ANCOVA

Parameter type

LS Mean change

Point estimate

-14.14

Confidence interval

level

95%

sides

2-sided

lower limit

-24.36

upper limit

-3.91

Variability estimate

Standard error of the mean

Dispersion value

6.198

Notes
[39] - ANCOVA: Relative change in percentage of fat in the liver from baseline to Week 12 Parts A+B+C

Change in percent of fat in the liver

Statistical analysis description

60 micrograms of Tropifexor - Change in percentage of fat in the liver Parts A+B+C

Comparison groups

LJN452 60 μg v Placebo C

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[40]

P-value

= 0.228

Method

ANCOVA

Parameter type

LS Mean change

Point estimate

-15.02

Confidence interval

level

95%

sides

2-sided

lower limit

-21.75

upper limit

-8.29

Variability estimate

Standard error of the mean

Dispersion value

4.078

Notes
[40] - ANCOVA: Relative change in percentage of fat in the liver from baseline to Week 12 (Parts A+B+C)

Change in percent of fat in the liver

Statistical analysis description

90 micrograms - Change in percentage of fat in the liver Parts A+B+C

Comparison groups

LJN452 90 μg v Placebo C

Number of subjects included in analysis

136

Analysis specification

Pre-specified

Analysis type

superiority ^[41]

P-value

= 0.37

Method

ANCOVA

Parameter type

LS Mean change

Point estimate

-12.56

Confidence interval

level

95%

sides

2-sided

lower limit

-17.04

upper limit

-8.08

Variability estimate

Standard error of the mean

Dispersion value

2.717

Notes
[41] - ANCOVA: Relative change in percentage of fat in the liver from baseline to Week 12 (Parts A+B+C)

Change in percent of fat in the liver

Statistical analysis description

140 micrograms - Change in percentage of fat in the liver Parts A+B+C

Comparison groups

LJN452 140 μg v Placebo C

Number of subjects included in analysis

101

Analysis specification

Pre-specified

Analysis type

superiority ^[42]

P-value

= 0.029

Method

ANCOVA

Parameter type

LS Mean change

Point estimate

-18.71

Confidence interval

level

95%

sides

2-sided

lower limit

-24.51

upper limit

-12.91

Variability estimate

Standard error of the mean

Dispersion value

3.517

Notes
[42] - ANCOVA: Relative change in percentage of fat in the liver (Parts A+B+C)

Change in percent of fat in the liver

Statistical analysis description

200 micrograms of Tropifexor - Change in percentage of fat in the liver Parts A+B+C

Comparison groups

LJN452 200 μg v Placebo C

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

superiority ^[43]

P-value

< 0.001

Method

ANCOVA

Parameter type

LS Mean change

Point estimate

-34.38

Confidence interval

level

95%

sides

2-sided

lower limit

-40.13

upper limit

-28.64

Variability estimate

Standard error of the mean

Dispersion value

3.482

Notes
[43] - ANCOVA: Relative change in percentage of fat in the liver (Parts A+B+C)

Secondary: Change from baseline in weight

Top of page

End point title

Change from baseline in weight ^[44]

End point description

Repeated measures for LS mean change in weight at EoT

End point type

Secondary

End point timeframe

End of Treatment (EoT): For Parts A&B, EoT was Week 12 (Primary Outcome Measure). For Part C, EoT was Week 48 (Secondary Outcome Measure)

Notes
[44] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was planned

End point values	LJN452 10 μg	LJN452 30 μg	LJN452 60 μg	LJN452 90 μg	LJN452 140 μg	LJN452 200 μg	Placebo C	Placebo A+B
Number of subjects analysed	14	16	36	84	50	51	51 ^[45]	46 ^[46]
Units: Mean
arithmetic mean (standard error)	-1.79 ± 0.608	-0.78 ± 0.567	-1.05 ± 0.377	-1.15 ± 0.253	-5.10 ± 0.988	-5.89 ± 1.002	999 ± 999	999 ± 999

Notes
[45] - Placebo is the reference group for repeated measures
[46] - Placebo is the reference group for repeated measures

Change in weight

Statistical analysis description

10 micrograms of Tropifexor (Part A) vs Placebo

Comparison groups

LJN452 10 μg v Placebo A+B

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[47]

P-value

= 0.01

Method

Mixed models analysis

Parameter type

LS Mean change

Point estimate

-1.79

Confidence interval

level

95%

sides

2-sided

lower limit

-2.99

upper limit

0.59

Variability estimate

Standard error of the mean

Dispersion value

0.608

Notes
[47] - Repeated measures analysis: Change in weight from baseline to EOT (Parts A + B) (Full analysis set)

Change in weight

Statistical analysis description

30 micrograms of Tropifexor (Part A) vs Placebo

Comparison groups

LJN452 30 μg v Placebo A+B

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[48]

P-value

= 0.237

Method

Mixed models analysis

Parameter type

LS Mean change

Point estimate

-0.78

Confidence interval

level

95%

sides

2-sided

lower limit

-1.9

upper limit

0.34

Variability estimate

Standard error of the mean

Dispersion value

0.567

Notes
[48] - Repeated measures analysis: Change in weight from baseline to EOT (Parts A + B) (Full analysis set)

Change in weight

Statistical analysis description

60 micrograms of Tropifexor (Parts A + B) vs Placebo

Comparison groups

LJN452 60 μg v Placebo A+B

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[49]

P-value

= 0.037

Method

Mixed models analysis

Parameter type

LS Mean change

Point estimate

-1.05

Confidence interval

level

95%

sides

2-sided

lower limit

-1.8

upper limit

0.31

Variability estimate

Standard error of the mean

Dispersion value

0.377

Notes
[49] - Repeated measures analysis: Change in weight from baseline to EOT (Parts A + B) (Full analysis set)

Change in weight

Statistical analysis description

90 micrograms of Tropifexor (Parts A + B) vs Placebo

Comparison groups

LJN452 90 μg v Placebo A+B

Number of subjects included in analysis

130

Analysis specification

Pre-specified

Analysis type

superiority ^[50]

P-value

= 0.007

Method

Mixed models analysis

Parameter type

LS Mean change

Point estimate

-1.15

Confidence interval

level

95%

sides

2-sided

lower limit

-1.65

upper limit

0.65

Variability estimate

Standard error of the mean

Dispersion value

0.253

Notes
[50] - Repeated measures analysis: Change in weight from baseline to EOT (Parts A + B) (Full analysis set)

Change in weight

Statistical analysis description

140 micrograms of Tropifexor (Part C) vs Placebo

Comparison groups

LJN452 140 μg v Placebo C

Number of subjects included in analysis

101

Analysis specification

Pre-specified

Analysis type

superiority ^[51]

P-value

= 0.053

Method

Mixed models analysis

Parameter type

LS Mean change

Point estimate

-5.1

Confidence interval

level

95%

sides

2-sided

lower limit

-7.05

upper limit

-3.14

Variability estimate

Standard error of the mean

Dispersion value

0.988

Notes
[51] - Repeated measures analysis: Change in weight from baseline to EOT (Parts C) (Full analysis set)

Change in weight

Statistical analysis description

200 micrograms of Tropifexor (Part C) vs Placebo

Comparison groups

LJN452 200 μg v Placebo C

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

superiority ^[52]

P-value

= 0.013

Method

Mixed models analysis

Parameter type

LS Mean change

Point estimate

-5.89

Confidence interval

level

95%

sides

2-sided

lower limit

-7.87

upper limit

-3.91

Variability estimate

Standard error of the mean

Dispersion value

1.002

Notes
[52] - Repeated measures analysis: Change in weight from baseline to EOT (Parts C) (Full analysis set)

Secondary: Change in body mass index (BMI)

Top of page

End point title

Change in body mass index (BMI) ^[53]

End point description

Repeated measures for the LS mean change in BMI after 12 weeks of treatment. Body mass index (BMI) is a measure of body fat based on height and weight

End point type

Secondary

End point timeframe

12 weeks

Notes
[53] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was planned

End point values	LJN452 10 μg	LJN452 30 μg	LJN452 60 μg	LJN452 90 μg	LJN452 140 μg	LJN452 200 μg	Placebo C	Placebo A+B
Number of subjects analysed	14	16	37	84	50	51	51 ^[54]	46 ^[55]
Units: Mean
arithmetic mean (standard error)	-0.64 ± 0.208	-0.29 ± 0.194	-0.35 ± 0.129	-0.42 ± 0.087	-1.88 ± 0.322	-2.11 ± 0.327	9.999 ± 9.999	9.999 ± 9.999

Notes
[54] - Placebo is the reference group for repeated measures
[55] - Placebo is the reference group for repeated measures

Change in BMI

Statistical analysis description

10 micrograms of Tropifexor (Part A) vs Placebo

Comparison groups

LJN452 10 μg v Placebo A+B

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[56]

P-value

= 0.006

Method

Mixed models analysis

Parameter type

LS Mean change

Point estimate

-0.64

Confidence interval

level

95%

sides

2-sided

lower limit

-1.05

upper limit

0.23

Variability estimate

Standard error of the mean

Dispersion value

0.208

Notes
[56] - Repeated measures analysis: Change in BMI from baseline to EoT (Full analysis set)

Change in BMI

Statistical analysis description

30 micrograms of Tropifexor (Part A) vs Placebo

Comparison groups

LJN452 30 μg v Placebo A+B

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[57]

P-value

= 0.177

Method

Mixed models analysis

Parameter type

LS Mean change

Point estimate

-0.29

Confidence interval

level

95%

sides

2-sided

lower limit

-0.67

upper limit

0.09

Variability estimate

Standard error of the mean

Dispersion value

0.194

Notes
[57] - Repeated measures analysis: Change in BMI from baseline to EOT (Full analysis set)

Change in BMI

Statistical analysis description

60 micrograms of Tropifexor (Parts A + B) vs Placebo

Comparison groups

LJN452 60 μg v Placebo A+B

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[58]

P-value

= 0.032

Method

Mixed models analysis

Parameter type

LS Mean change

Point estimate

-0.35

Confidence interval

level

95%

sides

2-sided

lower limit

-0.61

upper limit

0.1

Variability estimate

Standard error of the mean

Dispersion value

0.129

Notes
[58] - Repeated measures analysis: Change in BMI from baseline to EOT (Parts C) (Full analysis set)

Change in BMI

Statistical analysis description

90 micrograms of Tropifexor (Parts A + B) vs Placebo

Comparison groups

LJN452 90 μg v Placebo A+B

Number of subjects included in analysis

130

Analysis specification

Pre-specified

Analysis type

superiority ^[59]

P-value

= 0.003

Method

Mixed models analysis

Parameter type

LS Mean change

Point estimate

-0.42

Confidence interval

level

95%

sides

2-sided

lower limit

-0.59

upper limit

0.25

Variability estimate

Standard error of the mean

Dispersion value

0.087

Notes
[59] - Repeated measures analysis: Change in BMI from baseline to EOT (Full analysis set)

Change in BMI

Statistical analysis description

140 micrograms of Tropifexor (Part C) vs Placebo

Comparison groups

LJN452 140 μg v Placebo C

Number of subjects included in analysis

101

Analysis specification

Pre-specified

Analysis type

superiority ^[60]

P-value

= 0.015

Method

Mixed models analysis

Parameter type

LS Mean change

Point estimate

-1.88

Confidence interval

level

95%

sides

2-sided

lower limit

-2.51

upper limit

-1.24

Variability estimate

Standard error of the mean

Dispersion value

0.322

Notes
[60] - Repeated measures analysis: Change in BMI from baseline to EOT (Full analysis set)

Change in BMI

Statistical analysis description

200 micrograms of Tropifexor (Part C) vs Placebo

Comparison groups

LJN452 200 μg v Placebo C

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

superiority ^[61]

P-value

= 0.004

Method

Mixed models analysis

Parameter type

LS Mean change

Point estimate

-2.11

Confidence interval

level

95%

sides

2-sided

lower limit

-2.75

upper limit

-1.46

Variability estimate

Standard error of the mean

Dispersion value

0.327

Notes
[61] - Repeated measures analysis: Change in BMI from baseline to EOT (Parts C) (Full analysis set)

Secondary: Change from baseline in waist to hip (WTH) ratio

Top of page

End point title

Change from baseline in waist to hip (WTH) ratio ^[62]

End point description

The LS mean change in waist to hip ratio after 12 weeks of treatment

End point type

Secondary

End point timeframe

12 weeks

Notes
[62] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was planned

End point values	LJN452 10 μg	LJN452 30 μg	LJN452 60 μg	LJN452 90 μg	LJN452 140 μg	LJN452 200 μg	Placebo C	Placebo A+B
Number of subjects analysed	13	15	37	84	49	51	51 ^[63]	46 ^[64]
Units: Mean
arithmetic mean (standard error)	-0.01 ± 0.009	0.00 ± 0.008	-0.01 ± 0.005	0.00 ± 0.004	0.00 ± 0.008	-0.01 ± 0.007	9.999 ± 9.999	9.999 ± 9.999

Notes
[63] - 9.999 = Placebo is the reference group for repeated measures
[64] - 9.999=Placebo is the reference group for repeated measures

Change in WTH ratio

Statistical analysis description

10 micrograms of Tropifexor (Part A) vs Placebo

Comparison groups

LJN452 10 μg v Placebo A+B

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[65]

P-value

= 0.53

Method

Mixed models analysis

Parameter type

LS Mean change

Point estimate

-0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.03

upper limit

0.01

Variability estimate

Standard error of the mean

Dispersion value

0.009

Notes
[65] - Repeated measures analysis: Change in WTH ratio from baseline to EOT (Parts A+B) (Full analysis set)

Change in WTH ratio

Statistical analysis description

30 micrograms of Tropifexor (Part A) vs Placebo

Comparison groups

LJN452 30 μg v Placebo A+B

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[66]

P-value

= 0.857

Method

Mixed models analysis

Parameter type

LS Mean change

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.02

upper limit

0.01

Variability estimate

Standard error of the mean

Dispersion value

0.008

Notes
[66] - Repeated measures analysis: Change in WTH ratio from baseline to EOT (Parts A+B) (Full analysis set)

Change in WTH ratio

Statistical analysis description

60 micrograms of Tropifexor (Part A) vs Placebo

Comparison groups

LJN452 60 μg v Placebo A+B

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[67]

P-value

= 0.262

Method

Mixed models analysis

Parameter type

LS Mean change

Point estimate

-0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.02

upper limit

Variability estimate

Standard error of the mean

Dispersion value

0.005

Notes
[67] - Repeated measures analysis: Change in WTH ratio from baseline to EOT (Parts A+B) (Full analysis set)

Change in WTH ratio

Statistical analysis description

90 micrograms of Tropifexor (Parts A + B) vs Placebo

Comparison groups

LJN452 90 μg v Placebo A+B

Number of subjects included in analysis

130

Analysis specification

Pre-specified

Analysis type

superiority ^[68]

P-value

= 0.323

Method

Mixed models analysis

Parameter type

LS Mean change

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

0.01

Variability estimate

Standard error of the mean

Dispersion value

0.004

Notes
[68] - Repeated measures analysis: Change in WTH ratio from baseline to EOT (Parts A+B) (Full analysis set)

Change in WTH ratio

Statistical analysis description

140 micrograms of Tropifexor (Part C) vs Placebo

Comparison groups

LJN452 140 μg v Placebo C

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

superiority ^[69]

P-value

= 0.1

Method

Mixed models analysis

Parameter type

LS Mean change

Point estimate

0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.02

upper limit

0.01

Variability estimate

Standard error of the mean

Dispersion value

0.008

Notes
[69] - Repeated measures analysis: Change in WTH ratio from baseline to EOT (Part C) (Full analysis set)

Change in WTH ratio

Statistical analysis description

200 micrograms of Tropifexor (Part C) vs Placebo

Comparison groups

LJN452 200 μg v Placebo C

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

superiority ^[70]

P-value

= 0.693

Method

Mixed models analysis

Parameter type

LS Mean change

Point estimate

-0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.03

upper limit

Variability estimate

Standard error of the mean

Dispersion value

0.007

Notes
[70] - Repeated measures analysis: Change in WTH ratio from baseline to EOT (Part C) (Full analysis set)

Secondary: Change from baseline in biomarker FGF19

Top of page

End point title

Change from baseline in biomarker FGF19 ^[71]

End point description

Dose-response relationship of tropifexor (LJN452) on FGF19 over time, a marker of FXR target engagement in the gut. ANCOVA: Ratio of FGF19 (pg/mL) post-dose to pre-dose at Week 6

End point type

Secondary

End point timeframe

6 weeks

Notes
[71] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was planned

End point values	LJN452 10 μg	LJN452 30 μg	LJN452 60 μg	LJN452 90 μg	LJN452 140 μg	LJN452 200 μg
Number of subjects analysed	14	15	34	78	47	42
Units: pg/mL
least squares mean (confidence interval 95%)	1.45 (0.93 to 2.26)	1.53 (1.00 to 2.35)	3.82 (2.88 to 5.09)	5.78 (4.78 to 6.98)	1.97 (1.48 to 2.62)	2.23 (1.65 to 3.01)

No statistical analyses for this end point

Secondary: Change from baseline in biomarker C4

Top of page

End point title

Change from baseline in biomarker C4 ^[72]

End point description

Dose-response relationship of LJN452 on C4, a marker of hepatic target engagement at 4 hours post dose C4 (ng/mL): Summary statistics by treatment and visit

End point type

Secondary

End point timeframe

Week 6, 4 hours post dose

Notes
[72] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was planned

End point values	LJN452 10 μg	LJN452 30 μg	LJN452 60 μg	LJN452 90 μg	LJN452 140 μg	LJN452 200 μg
Number of subjects analysed	14	15	37	85	47	42
Units: ng/mL
arithmetic mean (standard deviation)	38.82 ± 25.765	32.75 ± 23.360	28.38 ± 13.394	40.19 ± 31.356	14.97 ± 20.232	8.54 ± 9.583

No statistical analyses for this end point

Secondary: Change from baseline on markers of liver fibrosis, Fibroscan

Top of page

End point title

Change from baseline on markers of liver fibrosis, Fibroscan ^[73]

End point description

Dose-response relationship of tropifexor (LJN452) on markers of liver fibrosis commonly available such as Fibroscan® Liver stiffness (kPa): Summary statistics by treatment and visit FibroScan is a specialized ultrasound machine for measuring fibrosis (scarring) in the liver

End point type

Secondary

End point timeframe

End of Treatment (EoT): For Parts A&B, EoT was Week 12. For Part C, EoT was Week 48

Notes
[73] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was planned

End point values	LJN452 10 μg	LJN452 30 μg	LJN452 60 μg	LJN452 90 μg	LJN452 140 μg	LJN452 200 μg	Placebo A+B
Number of subjects analysed	14	16	37	85	50	51	46
Units: mean change
arithmetic mean (standard deviation)	10.94 ± 5.314	10.40 ± 7.663	9.90 ± 4.095	9.00 ± 4.152	11.29 ± 3.677	12.03 ± 4.804	9.30 ± 4.676

No statistical analyses for this end point

Secondary: Change from baseline on markers of liver fibrosis (ELF)

Top of page

End point title

Change from baseline on markers of liver fibrosis (ELF) ^[74]

End point description

ANCOVA: LS Mean Change in Enhanced liver fibrosis panel (ELF) score from baseline by visit up to EOT

End point type

Secondary

End point timeframe

End of Treatment (EoT): For Parts A&B, EoT was Week 12. For Part C, EoT was Week 48

Notes
[74] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was planned

End point values	LJN452 10 μg	LJN452 30 μg	LJN452 60 μg	LJN452 90 μg	LJN452 140 μg	LJN452 200 μg	Placebo C	Placebo A+B
Number of subjects analysed	14	16	34	78	50	51	51 ^[75]	46 ^[76]
Units: scores on a scale
least squares mean (standard error)	0.05 ± 0.158	0.00 ± 0.146	-0.19 ± 0.097	0.20 ± 0.064	-0.34 ± 0.132	-0.24 ± 0.122	9.999 ± 9.999	9.999 ± 9.999

Notes
[75] - 9.999=Placebo is the reference group for repeated measures
[76] - 9.999=Placebo is the reference group for repeated measures

No statistical analyses for this end point

Secondary: Change from baseline on markers of liver fibrosis, Fibrotest (Parts A+B)

Top of page

End point title

Change from baseline on markers of liver fibrosis, Fibrotest (Parts A+B) ^[77]

End point description

Score of fibrosis biomarker test: Summary statistics by treatment and visit at EoT (See Part C in separate outcomes that follows)

End point type

Secondary

End point timeframe

End of Treatment (EoT):12 weeks

Notes
[77] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was planned

End point values	LJN452 10 μg	LJN452 30 μg	LJN452 60 μg	LJN452 90 μg	Placebo A+B
Number of subjects analysed	14	16	37	85	46
Units: mean change
arithmetic mean (standard deviation)	-0.23 ± 0.284	-1.49 ± 0.852	-1.44 ± 1.080	-1.34 ± 1.222	-1.23 ± 1.088

No statistical analyses for this end point

Secondary: Change from baseline on markers of liver fibrosis, Fibrotest, (Part C)

Top of page

End point title

Change from baseline on markers of liver fibrosis, Fibrotest, (Part C)

End point description

Repeated measures analysis: Change in score of fibrosis biomarker test from baseline by visit up to EOT

End point type

Secondary

End point timeframe

End of Treatment (EoT) was 48 weeks

End point values	LJN452 140 μg	LJN452 200 μg	Placebo C
Number of subjects analysed	50	51	51 ^[78]
Units: mean change
least squares mean (standard error)	-0.42 ± 0.131	-0.44 ± 0.135	9.999 ± 9.999

Notes
[78] - 9.999=Placebo is the reference group for repeated measures

No statistical analyses for this end point

Secondary: Change from baseline on gamma-glutamyl transferase (GGT)

Top of page

End point title

Change from baseline on gamma-glutamyl transferase (GGT) ^[79]

End point description

Summary statistics of change in GGT (U/L) from baseline by visit up to EoT

End point type

Secondary

End point timeframe

EoT for Parts A+B=12 weeks; EoT for Part C = 48 weeks

Notes
[79] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was planned

End point values	LJN452 10 μg	LJN452 30 μg	LJN452 60 μg	LJN452 90 μg	LJN452 140 μg	LJN452 200 μg	Placebo C	Placebo A+B
Number of subjects analysed	14	15	37	84	50	51	51 ^[80]	46 ^[81]
Units: mean
least squares mean (standard error)	1.6 ± 10.93	-29.9 ± 10.11	-34.2 ± 6.70	-45.7 ± 4.52	-35.2 ± 11.58	-29.9 ± 11.65	9.999 ± 9.999	9.999 ± 9.999

Notes
[80] - 9.999=Placebo is the reference group for repeated measures
[81] - 9.999=Placebo is the reference group for repeated measures

No statistical analyses for this end point

Secondary: Change from baseline on fasting lipid profile

Top of page

End point title

Change from baseline on fasting lipid profile ^[82]

End point description

Repeated measures analysis: LS geometric mean ratio of fasting lipids to baseline by visit up to EOT

End point type

Secondary

End point timeframe

End of Treatment (EoT): For Parts A&B, EoT was Week 12. For Part C, EoT was Week 48

Notes
[82] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was planned

End point values	LJN452 10 μg	LJN452 30 μg	LJN452 60 μg	LJN452 90 μg	LJN452 140 μg	LJN452 200 μg	Placebo C	Placebo A+B
Number of subjects analysed	14	16	37	50	50	51	51 ^[83]	46 ^[84]
Units: mmol/L
least squares mean (confidence interval 95%)
Cholesterol	0.949 (0.888 to 1.014)	1.003 (0.945 to 1.065)	1.029 (0.989 to 1.070)	1.029 (1.002 to 1.057)	1.032 (0.975 to 1.093)	1.071 (1.012 to 1.133)	9.999 (9.999 to 9.999)	9.999 (9.999 to 9.999)
Triglycerides	0.920 (0.766 to 1.091)	0.919 (0.789 to 1.071)	0.960 (0.868 to 1.062)	1.048 (0.978 to 1.123)	1.070 (0.934 to 1.226)	1.068 (0.936 to 1.219)	9.999 (9.999 to 9.999)	9.999 (9.999 to 9.999)
LDL Cholesterol	0.923 (0.834 to 1.020)	1.044 (0.953 to 1.142)	1.092 (1.029 to 1.159)	1.104 (1.060 to 1.150)	1.056 (0.972 to 1.147)	1.200 (1.106 to 1.302)	9.999 (9.999 to 9.999)	9.999 (9.999 to 9.999)
HDL Cholesterol	1.019 (0.946 to 1.096)	1.001 (0.937 to 1.069)	0.961 (0.920 to 1.004)	0.897 (0.870 to 0.924)	0.855 (0.800 to 0.913)	0.824 (0.772 to 0.879)	9.999 (9.999 to 9.999)	9.999 (9.999 to 9.999)
LDL/HDL Ratio	0.921 (0.810 to 1.047)	1.058 (0.942 to 1.188)	1.139 (1.055 to 1.229)	1.227 (1.165 to 1.293)	1.252 (1.128 to 1.390)	1.478 (1.332 to 1.639)	9.999 (9.999 to 9.999)	9.999 (9.999 to 9.999)
Free Glycerol	1.0563 (0.8722 to 1.2793)	0.9376 (0.7859 to 1.1185)	0.9128 (0.8112 to 1.0272)	0.9915 (0.9151 to 1.0743)	1.1115 (0.9721 to 1.2709)	0.9808 (0.8571 to 1.1223)	9.999 (9.999 to 9.999)	9.999 (9.999 to 9.999)
Free Fatty Acid	1.082 (0.897 to 1.305)	0.864 (0.726 to 1.028)	0.929 (0.827 to 1.043)	0.947 (0.874 to 1.025)	1.072 (0.951 to 1.208)	0.887 (0.785 to 1.002)	9.999 (9.999 to 9.999)	9.999 (9.999 to 9.999)

Notes
[83] - 9.999=Placebo is the reference group for repeated measures
[84] - 9.999=Placebo is the reference group for repeated measures

No statistical analyses for this end point

Secondary: Itch based on a visual analog scale (VAS) rating scale

Top of page

End point title

Itch based on a visual analog scale (VAS) rating scale ^[85]

End point description

Repeated measures analysis: Change in VAS for Itch from baseline by visit up to EoT

End point type

Secondary

End point timeframe

EoT for Parts A+B=12 weeks; EoT for Part C = 48 weeks

Notes
[85] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was planned

End point values	LJN452 10 μg	LJN452 30 μg	LJN452 60 μg	LJN452 90 μg	LJN452 140 μg	LJN452 200 μg	Placebo C	Placebo A+B
Number of subjects analysed	14	16	36	78	50	51	51 ^[86]	46 ^[87]
Units: mean
least squares mean (standard error)	-0.3 ± 0.48	0.2 ± 0.43	0.4 ± 0.28	0.1 ± 0.19	0.6 ± 0.37	1.1 ± 0.35	9.999 ± 9.999	9.999 ± 9.999

Notes
[86] - 9.999=placebo is not complared to itself
[87] - 9.999=placebo is not complared to itself

No statistical analyses for this end point

Secondary: Ctrough of LJN452

Top of page

End point title

Ctrough of LJN452 ^[88]

End point description

Summary Ctrough of tropifexor (LJN452)

End point type

Secondary

End point timeframe

Scheduled timepoint is zero (Parts A+B) or pre-dose (Part C )

Notes
[88] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was planned

End point values	LJN452 10 μg	LJN452 30 μg	LJN452 60 μg	LJN452 90 μg	LJN452 140 μg	LJN452 200 μg	Placebo C	Placebo A+B
Number of subjects analysed	14	16	37	85	50	51	51 ^[89]	46 ^[90]
Units: ng/mL
arithmetic mean (standard deviation)
Profile day 7	0.142 ± 0.119	0.355 ± 0.194	0.638 ± 0.453	1.215 ± 0.593	0.00 ± 0.0	0.00 ± 0.00	9.999 ± 9.999	9.999 ± 9.999
Profile day 14	0.216 ± 0.127	0.505 ± 0.328	0.626 ± 0.281	1.115 ± 0.693	0.00 ± 0.00	0.00 ± 0.00	9.999 ± 9.999	9.999 ± 9.999
Profile day 28	0.118 ± 0.087	0.411 ± 0.250	0.639 ± 0.265	1.027 ± 0.700	0.00 ± 0.00	0.00 ± 0.00	9.999 ± 9.999	9.999 ± 9.999
Profile day 42	0.161 ± 0.094	0.382 ± 0.150	0.647 ± 0.344	1.032 ± 0.661	2.821 ± 1.659	3.533 ± 2.356	9.999 ± 9.999	9.999 ± 9.999
Profile day 56	0.168 ± 0.088	0.474 ± 0.273	0.637 ± 0.278	1.041 ± 0.701	0.00 ± 0.00	0.00 ± 0.00	9.999 ± 9.999	9.999 ± 9.999
Profile day 84	0.118 ± 0.080	0.366 ± 0.147	0.530 ± 0.357	1.095 ± 0.653	1.685 ± 0.874	2.286 ± 1.259	9.999 ± 9.999	9.999 ± 9.999
Profile day 168	0.00 ± 0.00	0.00 ± 0.00	0.00 ± 0.00	0.00 ± 0.00	1.889 ± 1.340	2.146 ± 1.383	9.999 ± 9.999	9.999 ± 9.999
Profile day 280	0.00 ± 0.00	0.00 ± 0.00	0.00 ± 0.00	0.00 ± 0.00	2.129 ± 1.990	1.990 ± 1.053	9.999 ± 9.999	9.999 ± 9.999
Profile day 336	0.00 ± 0.00	0.00 ± 0.00	0.00 ± 0.00	0.00 ± 0.00	1.444 ± 1.077	1.979 ± 1.153	9.999 ± 9.999	9.999 ± 9.999

Notes
[89] - 9.999=Placebo is the reference group for repeated measures. It is not compared to itself
[90] - 9.999=Placebo is the reference group for repeated measures. It is not compared to itself

No statistical analyses for this end point

Secondary: C2h of LJN452

Top of page

End point title

C2h of LJN452 ^[91]

End point description

Summary C2h of tropifexor (LJN452)

End point type

Secondary

End point timeframe

Scheduled timepoint (Parts A+B) is 2 hours; Part C measured Post-dose

Notes
[91] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was planned

End point values	LJN452 10 μg	LJN452 30 μg	LJN452 60 μg	LJN452 90 μg	Placebo A+B
Number of subjects analysed	14 ^[92]	16 ^[93]	37	85	46 ^[94]
Units: ng/mL
arithmetic mean (standard deviation)
Profile day 7	0.190 ± 0.143	0.702 ± 0.399	1.228 ± 0.598	2.193 ± 1.003	0.00 ± 0.00
Profile day 14	0.00 ± 0.00	0.00 ± 0.00	1.344 ± 0.727	2.001 ± 1.053	0.00 ± 0.00

Notes
[92] - This dosage was not measured at Day 14
[93] - This dosage was not measured at Day 14
[94] - Placebo is the reference group and is not compared to itself

No statistical analyses for this end point

Secondary: Biopsy-based response at Week 48 compared to baseline: At least one point improvement in fibrosis (NASH CRN staging) without worsening of steatohepatitis (Part C) - total score

Top of page

End point title

Biopsy-based response at Week 48 compared to baseline: At least one point improvement in fibrosis (NASH CRN staging) without worsening of steatohepatitis (Part C) - total score

End point description

Number of patients who have at least one point improvement in fibrosis (NASH CRN staging) without worsening of steatohepatitis (total score)

End point type

Secondary

End point timeframe

EoT (Week 48)

End point values	LJN452 140 μg	LJN452 200 μg	Placebo C
Number of subjects analysed	39	35	42
Units: participants	11	11	12

Biopsy-based response total score

Statistical analysis description

At least one point improvement in fibrosis (NASH CRN staging) without worsening of steatohepatitis (total score)

Comparison groups

LJN452 140 μg v Placebo C

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 1

Method

Mixed models analysis

Parameter type

Risk difference (RD)

Point estimate

0.004

Confidence interval

level

95%

sides

2-sided

lower limit

-0.214

upper limit

0.223

Biopsy-based response total score

Statistical analysis description

At least one point improvement in fibrosis (NASH CRN staging) without worsening of steatohepatitis (total score)

Comparison groups

LJN452 200 μg v Placebo C

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8074

Method

Mixed models analysis

Parameter type

Risk difference (RD)

Point estimate

0.029

Confidence interval

level

95%

sides

2-sided

lower limit

-0.196

upper limit

0.251

Secondary: Biopsy-based response at Week 48 compared to baseline: At least one point improvement in fibrosis (NASH CRN staging) without worsening - FDA

Top of page

End point title

Biopsy-based response at Week 48 compared to baseline: At least one point improvement in fibrosis (NASH CRN staging) without worsening - FDA

End point description

Number of patients who have at least one point improvement in fibrosis (NASH CRN staging) without worsening of steatohepatitis (FDA)

End point type

Secondary

End point timeframe

EoT (Week 48)

End point values	LJN452 140 μg	LJN452 200 μg	Placebo C
Number of subjects analysed	38	35	42
Units: participants	11	11	12

Biopsy-based response - FDA

Statistical analysis description

At least one point improvement in fibrosis (NASH CRN staging) without worsening of steatohepatitis (FDA)

Comparison groups

LJN452 140 μg v Placebo C

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.807

Method

Mixed models analysis

Parameter type

Risk difference (RD)

Point estimate

0.028

Confidence interval

level

95%

sides

2-sided

lower limit

-0.191

upper limit

0.246

Biopsy-based response - FDA

Statistical analysis description

At least one point improvement in fibrosis (NASH CRN staging) without worsening of steatohepatitis (FDA)

Comparison groups

LJN452 200 μg v Placebo C

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6233

Method

Mixed models analysis

Parameter type

Risk difference (RD)

Point estimate

0.052

Confidence interval

level

95%

sides

2-sided

lower limit

-0.173

upper limit

0.273

Secondary: Biopsy-based response at Week 48 compared to baseline: At least one point improvement in fibrosis (NASH CRN staging) without worsening - EMA

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End point title

Biopsy-based response at Week 48 compared to baseline: At least one point improvement in fibrosis (NASH CRN staging) without worsening - EMA

End point description

Number of patients who have at least one point improvement in fibrosis (NASH CRN staging) without worsening of steatohepatitis (EMA)

End point type

Secondary

End point timeframe

EoT (Week 48)

End point values	LJN452 140 μg	LJN452 200 μg	Placebo C
Number of subjects analysed	38	35	42
Units: participants	11	11	12

Biopsy-based response - EMA

Statistical analysis description

At least one point improvement in fibrosis (NASH CRN staging) without worsening of steatohepatitis (EMA)

Comparison groups

LJN452 140 μg v Placebo C

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 1

Method

Mixed models analysis

Parameter type

Risk difference (RD)

Point estimate

0.004

Confidence interval

level

95%

sides

2-sided

lower limit

-0.214

upper limit

0.233

Biopsy-based response - EMA

Statistical analysis description

At least one point improvement in fibrosis (NASH CRN staging) without worsening of steatohepatitis (EMA)

Comparison groups

LJN452 200 μg v Placebo C

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8074

Method

Mixed models analysis

Parameter type

Risk difference (RD)

Point estimate

0.029

Confidence interval

level

95%

sides

2-sided

lower limit

-0.196

upper limit

0.251

Secondary: Biopsy-based response at Week 48 compared to baseline: Difference between treatment groups (Part C) - Resolution of steatohepatitis (diagnostic category)

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End point title

Biopsy-based response at Week 48 compared to baseline: Difference between treatment groups (Part C) - Resolution of steatohepatitis (diagnostic category)

End point description

Resolution of steatohepatitis (diagnostic category) without worsening of fibrosis (NASH CRN staging)

End point type

Secondary

End point timeframe

EoT (Week 48)

End point values	LJN452 140 μg	LJN452 200 μg	Placebo C
Number of subjects analysed	38	35	42
Units: participants	4	7	3

Biopsy-based response

Statistical analysis description

Resolution of steatohepatitis (diagnostic category) without worsening of fibrosis (NASH CRN staging)

Comparison groups

LJN452 140 μg v Placebo C

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7028

Method

Mixed models analysis

Parameter type

Risk difference (RD)

Point estimate

0.034

Confidence interval

level

95%

sides

2-sided

lower limit

-0.184

upper limit

0.252

Biopsy-based response

Statistical analysis description

Resolution of steatohepatitis (diagnostic category) without worsening of fibrosis (NASH CRN staging)

Comparison groups

LJN452 200 μg v Placebo C

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1713

Method

Mixed models analysis

Parameter type

Risk difference (RD)

Point estimate

0.129

Confidence interval

level

95%

sides

2-sided

lower limit

-0.098

upper limit

0.345

Secondary: Biopsy-based response at Week 48 compared to baseline: Difference between treatment groups (Part C) - Resolution of steatohepatitis (FDA, EMA)

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End point title

Biopsy-based response at Week 48 compared to baseline: Difference between treatment groups (Part C) - Resolution of steatohepatitis (FDA, EMA)

End point description

Resolution of steatohepatitis (diagnostic category) without worsening of fibrosis (NASH CRN staging)

End point type

Secondary

End point timeframe

EoT (Week 48)

End point values	LJN452 140 μg	LJN452 200 μg	Placebo C
Number of subjects analysed	38	35	42
Units: participants	0	2	0

Biopsy-based response, FDA and EMA

Statistical analysis description

Resolution of steatohepatitis (FDA, EMA) without worsening of fibrosis (NASH CRN staging)

Comparison groups

LJN452 140 μg v Placebo C

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2033

Method

Mixed models analysis

Parameter type

Risk difference (RD)

Point estimate

0.057

Confidence interval

level

95%

sides

2-sided

lower limit

-0.168

upper limit

0.278

Adverse events

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Timeframe for reporting adverse events

Timeframe for AE

Adverse event reporting additional description

AE additional description

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.1

Reporting group title

LJN452 10 mcg

Reporting group description

LJN452 10 mcg

Reporting group title

LJN452 60 mcg

Reporting group description

LJN452 60 mcg

Reporting group title

LJN452 30 mcg

Reporting group description

LJN452 30 mcg

Reporting group title

LJN452 90 mcg

Reporting group description

LJN452 90 mcg

Reporting group title

LJN452 140 mcg

Reporting group description

LJN452 140 mcg

Reporting group title

LJN452 200 mcg

Reporting group description

LJN452 200 mcg

Reporting group title

Placebo

Reporting group description

Placebo

Reporting group title

Total

Reporting group description

Total

Serious adverse events	LJN452 10 mcg	LJN452 60 mcg	LJN452 30 mcg	LJN452 90 mcg	LJN452 140 mcg	LJN452 200 mcg	Placebo	Total
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	0 / 17 (0.00%)	4 / 85 (4.71%)	5 / 50 (10.00%)	3 / 51 (5.88%)	6 / 97 (6.19%)	18 / 350 (5.14%)
number of deaths (all causes)	0	0	0	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant melanoma
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	0 / 17 (0.00%)	0 / 85 (0.00%)	0 / 50 (0.00%)	0 / 51 (0.00%)	1 / 97 (1.03%)	1 / 350 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Non-cardiac chest pain
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	0 / 17 (0.00%)	0 / 85 (0.00%)	1 / 50 (2.00%)	0 / 51 (0.00%)	0 / 97 (0.00%)	1 / 350 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Endometrial thickening
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	0 / 17 (0.00%)	0 / 85 (0.00%)	1 / 50 (2.00%)	0 / 51 (0.00%)	0 / 97 (0.00%)	1 / 350 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Haemothorax
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	0 / 17 (0.00%)	0 / 85 (0.00%)	0 / 50 (0.00%)	0 / 51 (0.00%)	1 / 97 (1.03%)	1 / 350 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Product issues
Device dislocation
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	0 / 17 (0.00%)	0 / 85 (0.00%)	0 / 50 (0.00%)	0 / 51 (0.00%)	1 / 97 (1.03%)	1 / 350 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	0 / 17 (0.00%)	1 / 85 (1.18%)	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 97 (0.00%)	1 / 350 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Animal bite
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	0 / 17 (0.00%)	0 / 85 (0.00%)	1 / 50 (2.00%)	0 / 51 (0.00%)	0 / 97 (0.00%)	1 / 350 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Multiple injuries
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	0 / 17 (0.00%)	0 / 85 (0.00%)	0 / 50 (0.00%)	0 / 51 (0.00%)	1 / 97 (1.03%)	1 / 350 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Angina pectoris
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	0 / 17 (0.00%)	0 / 85 (0.00%)	1 / 50 (2.00%)	1 / 51 (1.96%)	0 / 97 (0.00%)	2 / 350 (0.57%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	0 / 17 (0.00%)	0 / 85 (0.00%)	1 / 50 (2.00%)	0 / 51 (0.00%)	0 / 97 (0.00%)	1 / 350 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Transient ischaemic attack
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	0 / 17 (0.00%)	0 / 85 (0.00%)	0 / 50 (0.00%)	0 / 51 (0.00%)	1 / 97 (1.03%)	1 / 350 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Haematochezia
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	0 / 17 (0.00%)	1 / 85 (1.18%)	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 97 (0.00%)	1 / 350 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis acute
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	0 / 17 (0.00%)	0 / 85 (0.00%)	0 / 50 (0.00%)	0 / 51 (0.00%)	1 / 97 (1.03%)	1 / 350 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	0 / 17 (0.00%)	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 51 (1.96%)	0 / 97 (0.00%)	1 / 350 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal impairment
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	0 / 17 (0.00%)	1 / 85 (1.18%)	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 97 (0.00%)	1 / 350 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	0 / 17 (0.00%)	1 / 85 (1.18%)	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 97 (0.00%)	1 / 350 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Synovial cyst
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	0 / 17 (0.00%)	0 / 85 (0.00%)	1 / 50 (2.00%)	0 / 51 (0.00%)	0 / 97 (0.00%)	1 / 350 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Trigger finger
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	0 / 17 (0.00%)	0 / 85 (0.00%)	1 / 50 (2.00%)	0 / 51 (0.00%)	0 / 97 (0.00%)	1 / 350 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Gastroenteritis
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	0 / 17 (0.00%)	0 / 85 (0.00%)	0 / 50 (0.00%)	0 / 51 (0.00%)	1 / 97 (1.03%)	1 / 350 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hyperglycaemia
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	0 / 17 (0.00%)	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 51 (1.96%)	0 / 97 (0.00%)	1 / 350 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	LJN452 10 mcg	LJN452 60 mcg	LJN452 30 mcg	LJN452 90 mcg	LJN452 140 mcg	LJN452 200 mcg	Placebo	Total
Total subjects affected by non serious adverse events
subjects affected / exposed	5 / 13 (38.46%)	16 / 37 (43.24%)	11 / 17 (64.71%)	50 / 85 (58.82%)	43 / 50 (86.00%)	45 / 51 (88.24%)	63 / 97 (64.95%)	233 / 350 (66.57%)
General disorders and administration site conditions
Fatigue
subjects affected / exposed	0 / 13 (0.00%)	1 / 37 (2.70%)	3 / 17 (17.65%)	5 / 85 (5.88%)	7 / 50 (14.00%)	3 / 51 (5.88%)	9 / 97 (9.28%)	28 / 350 (8.00%)
occurrences all number	0	1	3	5	7	4	9	29
Pyrexia
subjects affected / exposed	1 / 13 (7.69%)	0 / 37 (0.00%)	0 / 17 (0.00%)	1 / 85 (1.18%)	2 / 50 (4.00%)	1 / 51 (1.96%)	1 / 97 (1.03%)	6 / 350 (1.71%)
occurrences all number	1	0	0	1	2	1	1	6
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain
subjects affected / exposed	1 / 13 (7.69%)	1 / 37 (2.70%)	3 / 17 (17.65%)	3 / 85 (3.53%)	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 97 (0.00%)	8 / 350 (2.29%)
occurrences all number	1	1	3	3	0	0	0	8
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	1 / 17 (5.88%)	0 / 85 (0.00%)	1 / 50 (2.00%)	0 / 51 (0.00%)	0 / 97 (0.00%)	2 / 350 (0.57%)
occurrences all number	0	0	1	0	1	0	0	2
Insomnia
subjects affected / exposed	0 / 13 (0.00%)	1 / 37 (2.70%)	1 / 17 (5.88%)	0 / 85 (0.00%)	4 / 50 (8.00%)	3 / 51 (5.88%)	2 / 97 (2.06%)	11 / 350 (3.14%)
occurrences all number	0	1	1	0	4	3	2	11
Loss of libido
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	1 / 17 (5.88%)	0 / 85 (0.00%)	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 97 (0.00%)	1 / 350 (0.29%)
occurrences all number	0	0	1	0	0	0	0	1
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	0 / 17 (0.00%)	3 / 85 (3.53%)	1 / 50 (2.00%)	3 / 51 (5.88%)	3 / 97 (3.09%)	10 / 350 (2.86%)
occurrences all number	0	0	0	3	2	3	3	11
Aspartate aminotransferase increased
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	0 / 17 (0.00%)	2 / 85 (2.35%)	4 / 50 (8.00%)	4 / 51 (7.84%)	2 / 97 (2.06%)	12 / 350 (3.43%)
occurrences all number	0	0	0	2	5	4	2	13
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	0 / 17 (0.00%)	0 / 85 (0.00%)	1 / 50 (2.00%)	5 / 51 (9.80%)	0 / 97 (0.00%)	6 / 350 (1.71%)
occurrences all number	0	0	0	0	1	6	0	7
Blood creatinine increased
subjects affected / exposed	1 / 13 (7.69%)	0 / 37 (0.00%)	0 / 17 (0.00%)	0 / 85 (0.00%)	0 / 50 (0.00%)	1 / 51 (1.96%)	0 / 97 (0.00%)	2 / 350 (0.57%)
occurrences all number	1	0	0	0	0	1	0	2
Platelet count decreased
subjects affected / exposed	1 / 13 (7.69%)	0 / 37 (0.00%)	0 / 17 (0.00%)	0 / 85 (0.00%)	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 97 (0.00%)	1 / 350 (0.29%)
occurrences all number	1	0	0	0	0	0	0	1
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	0 / 17 (0.00%)	0 / 85 (0.00%)	3 / 50 (6.00%)	0 / 51 (0.00%)	2 / 97 (2.06%)	5 / 350 (1.43%)
occurrences all number	0	0	0	0	3	0	2	5
Nervous system disorders
Headache
subjects affected / exposed	1 / 13 (7.69%)	1 / 37 (2.70%)	1 / 17 (5.88%)	4 / 85 (4.71%)	3 / 50 (6.00%)	3 / 51 (5.88%)	6 / 97 (6.19%)	19 / 350 (5.43%)
occurrences all number	1	1	1	7	3	6	6	25
Poor quality sleep
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	1 / 17 (5.88%)	0 / 85 (0.00%)	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 97 (0.00%)	1 / 350 (0.29%)
occurrences all number	0	0	1	0	0	0	0	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	1 / 17 (5.88%)	0 / 85 (0.00%)	1 / 50 (2.00%)	0 / 51 (0.00%)	1 / 97 (1.03%)	3 / 350 (0.86%)
occurrences all number	0	0	1	0	1	0	1	3
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	0 / 13 (0.00%)	1 / 37 (2.70%)	0 / 17 (0.00%)	3 / 85 (3.53%)	5 / 50 (10.00%)	2 / 51 (3.92%)	4 / 97 (4.12%)	15 / 350 (4.29%)
occurrences all number	0	1	0	3	6	3	4	17
Abdominal pain
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	0 / 17 (0.00%)	1 / 85 (1.18%)	2 / 50 (4.00%)	3 / 51 (5.88%)	8 / 97 (8.25%)	14 / 350 (4.00%)
occurrences all number	0	0	0	1	2	3	9	15
Abdominal pain lower
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	1 / 17 (5.88%)	0 / 85 (0.00%)	1 / 50 (2.00%)	0 / 51 (0.00%)	0 / 97 (0.00%)	2 / 350 (0.57%)
occurrences all number	0	0	1	0	1	0	0	2
Abdominal pain upper
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	2 / 17 (11.76%)	2 / 85 (2.35%)	6 / 50 (12.00%)	2 / 51 (3.92%)	3 / 97 (3.09%)	15 / 350 (4.29%)
occurrences all number	0	0	2	2	8	2	3	17
Constipation
subjects affected / exposed	0 / 13 (0.00%)	1 / 37 (2.70%)	1 / 17 (5.88%)	2 / 85 (2.35%)	3 / 50 (6.00%)	3 / 51 (5.88%)	5 / 97 (5.15%)	15 / 350 (4.29%)
occurrences all number	0	1	1	2	3	3	6	16
Diarrhoea
subjects affected / exposed	0 / 13 (0.00%)	1 / 37 (2.70%)	1 / 17 (5.88%)	4 / 85 (4.71%)	3 / 50 (6.00%)	7 / 51 (13.73%)	6 / 97 (6.19%)	22 / 350 (6.29%)
occurrences all number	0	1	3	4	5	7	9	29
Dry mouth
subjects affected / exposed	0 / 13 (0.00%)	1 / 37 (2.70%)	1 / 17 (5.88%)	2 / 85 (2.35%)	0 / 50 (0.00%)	2 / 51 (3.92%)	2 / 97 (2.06%)	8 / 350 (2.29%)
occurrences all number	0	1	1	2	0	2	2	8
Dyspepsia
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	0 / 17 (0.00%)	4 / 85 (4.71%)	2 / 50 (4.00%)	3 / 51 (5.88%)	4 / 97 (4.12%)	13 / 350 (3.71%)
occurrences all number	0	0	0	5	2	3	4	14
Flatulence
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	0 / 17 (0.00%)	1 / 85 (1.18%)	5 / 50 (10.00%)	2 / 51 (3.92%)	2 / 97 (2.06%)	10 / 350 (2.86%)
occurrences all number	0	0	0	1	5	4	2	12
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	1 / 17 (5.88%)	1 / 85 (1.18%)	2 / 50 (4.00%)	2 / 51 (3.92%)	1 / 97 (1.03%)	7 / 350 (2.00%)
occurrences all number	0	0	1	1	2	2	1	7
Nausea
subjects affected / exposed	0 / 13 (0.00%)	1 / 37 (2.70%)	0 / 17 (0.00%)	4 / 85 (4.71%)	6 / 50 (12.00%)	10 / 51 (19.61%)	11 / 97 (11.34%)	32 / 350 (9.14%)
occurrences all number	0	1	0	5	9	12	13	40
Vomiting
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	2 / 17 (11.76%)	3 / 85 (3.53%)	3 / 50 (6.00%)	4 / 51 (7.84%)	2 / 97 (2.06%)	14 / 350 (4.00%)
occurrences all number	0	0	3	6	6	5	2	22
Skin and subcutaneous tissue disorders
Hyperhidrosis
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	1 / 17 (5.88%)	0 / 85 (0.00%)	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 97 (0.00%)	1 / 350 (0.29%)
occurrences all number	0	0	1	0	0	0	0	1
Neurodermatitis
subjects affected / exposed	1 / 13 (7.69%)	0 / 37 (0.00%)	0 / 17 (0.00%)	0 / 85 (0.00%)	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 97 (0.00%)	1 / 350 (0.29%)
occurrences all number	1	0	0	0	0	0	0	1
Pruritus
subjects affected / exposed	0 / 13 (0.00%)	5 / 37 (13.51%)	0 / 17 (0.00%)	7 / 85 (8.24%)	26 / 50 (52.00%)	35 / 51 (68.63%)	15 / 97 (15.46%)	88 / 350 (25.14%)
occurrences all number	0	6	0	7	33	45	17	108
Rash
subjects affected / exposed	0 / 13 (0.00%)	1 / 37 (2.70%)	0 / 17 (0.00%)	2 / 85 (2.35%)	5 / 50 (10.00%)	3 / 51 (5.88%)	4 / 97 (4.12%)	15 / 350 (4.29%)
occurrences all number	0	1	0	2	7	4	4	18
Rash pruritic
subjects affected / exposed	0 / 13 (0.00%)	2 / 37 (5.41%)	0 / 17 (0.00%)	0 / 85 (0.00%)	2 / 50 (4.00%)	0 / 51 (0.00%)	0 / 97 (0.00%)	4 / 350 (1.14%)
occurrences all number	0	2	0	0	2	0	0	4
Renal and urinary disorders
Haematuria
subjects affected / exposed	1 / 13 (7.69%)	1 / 37 (2.70%)	1 / 17 (5.88%)	0 / 85 (0.00%)	0 / 50 (0.00%)	2 / 51 (3.92%)	1 / 97 (1.03%)	6 / 350 (1.71%)
occurrences all number	2	1	1	0	0	2	3	9
Proteinuria
subjects affected / exposed	1 / 13 (7.69%)	0 / 37 (0.00%)	1 / 17 (5.88%)	1 / 85 (1.18%)	1 / 50 (2.00%)	3 / 51 (5.88%)	0 / 97 (0.00%)	7 / 350 (2.00%)
occurrences all number	2	0	1	1	1	3	0	8
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	0 / 17 (0.00%)	1 / 85 (1.18%)	3 / 50 (6.00%)	1 / 51 (1.96%)	3 / 97 (3.09%)	8 / 350 (2.29%)
occurrences all number	0	0	0	1	4	1	3	9
Back pain
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	1 / 17 (5.88%)	3 / 85 (3.53%)	1 / 50 (2.00%)	2 / 51 (3.92%)	7 / 97 (7.22%)	14 / 350 (4.00%)
occurrences all number	0	0	1	3	2	2	7	15
Musculoskeletal pain
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	1 / 17 (5.88%)	0 / 85 (0.00%)	1 / 50 (2.00%)	0 / 51 (0.00%)	1 / 97 (1.03%)	3 / 350 (0.86%)
occurrences all number	0	0	1	0	1	0	1	3
Infections and infestations
Body tinea
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	0 / 17 (0.00%)	0 / 85 (0.00%)	3 / 50 (6.00%)	0 / 51 (0.00%)	0 / 97 (0.00%)	3 / 350 (0.86%)
occurrences all number	0	0	0	0	3	0	0	3
Bronchitis
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	1 / 17 (5.88%)	0 / 85 (0.00%)	3 / 50 (6.00%)	0 / 51 (0.00%)	6 / 97 (6.19%)	10 / 350 (2.86%)
occurrences all number	0	0	1	0	3	0	7	11
Influenza
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	0 / 17 (0.00%)	9 / 85 (10.59%)	1 / 50 (2.00%)	3 / 51 (5.88%)	4 / 97 (4.12%)	17 / 350 (4.86%)
occurrences all number	0	0	0	9	1	3	4	17
Laryngitis
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	1 / 17 (5.88%)	0 / 85 (0.00%)	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 97 (0.00%)	1 / 350 (0.29%)
occurrences all number	0	0	1	0	0	0	0	1
Nasopharyngitis
subjects affected / exposed	0 / 13 (0.00%)	2 / 37 (5.41%)	0 / 17 (0.00%)	6 / 85 (7.06%)	6 / 50 (12.00%)	5 / 51 (9.80%)	10 / 97 (10.31%)	29 / 350 (8.29%)
occurrences all number	0	2	0	7	8	10	11	38
Periodontitis
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	1 / 17 (5.88%)	0 / 85 (0.00%)	1 / 50 (2.00%)	0 / 51 (0.00%)	0 / 97 (0.00%)	2 / 350 (0.57%)
occurrences all number	0	0	1	0	1	0	0	2
Rhinitis
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	1 / 17 (5.88%)	3 / 85 (3.53%)	0 / 50 (0.00%)	0 / 51 (0.00%)	1 / 97 (1.03%)	5 / 350 (1.43%)
occurrences all number	0	0	1	3	0	0	1	5
Sinusitis
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	0 / 17 (0.00%)	1 / 85 (1.18%)	3 / 50 (6.00%)	0 / 51 (0.00%)	7 / 97 (7.22%)	11 / 350 (3.14%)
occurrences all number	0	0	0	1	3	0	7	11
Tonsillitis
subjects affected / exposed	1 / 13 (7.69%)	0 / 37 (0.00%)	0 / 17 (0.00%)	1 / 85 (1.18%)	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 97 (0.00%)	2 / 350 (0.57%)
occurrences all number	1	0	0	1	0	0	0	2
Upper respiratory tract infection
subjects affected / exposed	0 / 13 (0.00%)	2 / 37 (5.41%)	0 / 17 (0.00%)	8 / 85 (9.41%)	9 / 50 (18.00%)	3 / 51 (5.88%)	10 / 97 (10.31%)	32 / 350 (9.14%)
occurrences all number	0	3	0	8	11	3	10	35
Urinary tract infection
subjects affected / exposed	1 / 13 (7.69%)	0 / 37 (0.00%)	0 / 17 (0.00%)	1 / 85 (1.18%)	9 / 50 (18.00%)	0 / 51 (0.00%)	3 / 97 (3.09%)	14 / 350 (4.00%)
occurrences all number	1	0	0	1	13	0	3	18
Viral sinusitis
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	1 / 17 (5.88%)	0 / 85 (0.00%)	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 97 (0.00%)	1 / 350 (0.29%)
occurrences all number	0	0	1	0	0	0	0	1
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 13 (0.00%)	1 / 37 (2.70%)	2 / 17 (11.76%)	2 / 85 (2.35%)	1 / 50 (2.00%)	2 / 51 (3.92%)	1 / 97 (1.03%)	9 / 350 (2.57%)
occurrences all number	0	1	2	2	1	2	1	9
Diabetes mellitus
subjects affected / exposed	1 / 13 (7.69%)	0 / 37 (0.00%)	0 / 17 (0.00%)	2 / 85 (2.35%)	2 / 50 (4.00%)	1 / 51 (1.96%)	1 / 97 (1.03%)	7 / 350 (2.00%)
occurrences all number	1	0	0	2	2	1	1	7
Type 2 diabetes mellitus
subjects affected / exposed	0 / 13 (0.00%)	0 / 37 (0.00%)	0 / 17 (0.00%)	2 / 85 (2.35%)	2 / 50 (4.00%)	3 / 51 (5.88%)	2 / 97 (2.06%)	9 / 350 (2.57%)
occurrences all number	0	0	0	2	2	3	2	9

More information

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Were there any global substantial amendments to the protocol? Yes

21 Jun 2016

To implement recommendations from the US FDA to modify certain details of study CLJN452A2202.

07 Mar 2017

To ensure that the protocol text clearly outlines that a second interim analysis of Part A, to include data collected up to Week 16, would be conducted. Additionally, the eligibility criteria were updated based on the accumulating experience from ongoing Part A, other NASH studies, input from study investigators, and review of recent literature.

05 Oct 2017

To add Part C to the protocol to explore doses of tropifexor (LJN452) > 90 μg. Part C enrolled patients to be treated for 48 weeks with 140 μg tropifexor or 200 μg tropifexor

Were there any global interruptions to the trial? No

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

No outputs were planned; and are not available for determining the effects of tropifexor on primary endpoints in the subset of patients who had historical biopsy data.

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Clinical trials

Clinical Trial Results: A randomized, double-blind, placebo controlled, 3-part, adaptive design, multicenter study to assess safety, tolerability and efficacy of tropifexor (LJN452) in patients with non-alcoholic steatohepatitis (NASH) FLIGHT-FXR

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Nonalcoholic steatohepatitis (NASH) patients with Treatment Emergent Adverse Events (TEAE)

Primary: Number of Nonalcoholic steatohepatitis (NASH) patients with Treatment Emergent Adverse Events (TEAE)

Primary: Change in Transaminase levels (ALT)

Primary: Change in Transaminase levels (ALT)

Primary: Change in Aspartate transaminase (AST)

Primary: Change in Aspartate transaminase (AST)

Primary: Change from baseline in percent of fat in the liver assessed using Magnetic resonance imaging (MRI)

Primary: Change from baseline in percent of fat in the liver assessed using Magnetic resonance imaging (MRI)

Secondary: Change from baseline in weight

Secondary: Change from baseline in weight

Secondary: Change in body mass index (BMI)

Secondary: Change in body mass index (BMI)

Secondary: Change from baseline in waist to hip (WTH) ratio

Secondary: Change from baseline in waist to hip (WTH) ratio

Secondary: Change from baseline in biomarker FGF19

Secondary: Change from baseline in biomarker FGF19

Secondary: Change from baseline in biomarker C4

Secondary: Change from baseline in biomarker C4

Secondary: Change from baseline on markers of liver fibrosis, Fibroscan

Secondary: Change from baseline on markers of liver fibrosis, Fibroscan

Secondary: Change from baseline on markers of liver fibrosis (ELF)

Secondary: Change from baseline on markers of liver fibrosis (ELF)

Secondary: Change from baseline on markers of liver fibrosis, Fibrotest (Parts A+B)

Secondary: Change from baseline on markers of liver fibrosis, Fibrotest (Parts A+B)

Secondary: Change from baseline on markers of liver fibrosis, Fibrotest, (Part C)

Secondary: Change from baseline on markers of liver fibrosis, Fibrotest, (Part C)

Secondary: Change from baseline on gamma-glutamyl transferase (GGT)

Secondary: Change from baseline on gamma-glutamyl transferase (GGT)

Secondary: Change from baseline on fasting lipid profile

Secondary: Change from baseline on fasting lipid profile

Secondary: Itch based on a visual analog scale (VAS) rating scale

Secondary: Itch based on a visual analog scale (VAS) rating scale

Secondary: Ctrough of LJN452

Secondary: Ctrough of LJN452

Secondary: C2h of LJN452

Secondary: C2h of LJN452

Secondary: Biopsy-based response at Week 48 compared to baseline: At least one point improvement in fibrosis (NASH CRN staging) without worsening of steatohepatitis (Part C) - total score

Secondary: Biopsy-based response at Week 48 compared to baseline: At least one point improvement in fibrosis (NASH CRN staging) without worsening of steatohepatitis (Part C) - total score

Secondary: Biopsy-based response at Week 48 compared to baseline: At least one point improvement in fibrosis (NASH CRN staging) without worsening - FDA

Secondary: Biopsy-based response at Week 48 compared to baseline: At least one point improvement in fibrosis (NASH CRN staging) without worsening - FDA

Secondary: Biopsy-based response at Week 48 compared to baseline: At least one point improvement in fibrosis (NASH CRN staging) without worsening - EMA

Secondary: Biopsy-based response at Week 48 compared to baseline: At least one point improvement in fibrosis (NASH CRN staging) without worsening - EMA

Secondary: Biopsy-based response at Week 48 compared to baseline: Difference between treatment groups (Part C) - Resolution of steatohepatitis (diagnostic category)

Secondary: Biopsy-based response at Week 48 compared to baseline: Difference between treatment groups (Part C) - Resolution of steatohepatitis (diagnostic category)

Secondary: Biopsy-based response at Week 48 compared to baseline: Difference between treatment groups (Part C) - Resolution of steatohepatitis (FDA, EMA)

Secondary: Biopsy-based response at Week 48 compared to baseline: Difference between treatment groups (Part C) - Resolution of steatohepatitis (FDA, EMA)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A randomized, double-blind, placebo controlled, 3-part, adaptive design, multicenter study to assess safety, tolerability and efficacy of tropifexor (LJN452) in patients with non-alcoholic steatohepatitis (NASH) FLIGHT-FXR