FLIGHT-FXR: Study of Safety and Efficacy of Tropifexor (LJN452) in Patients With Non-alcoholic Steatohepatitis (NASH)

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Terminated

CT.gov ID

NCT02855164

Collaborator

(none)

350

Enrollment

Locations

Arms

44.2

Actual Duration (Months)

4.3

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of the study was to assess the effects of different doses of tropifexor (LJN452) with respect to safety, tolerability, and on markers of liver inflammation in patients with NASH

Condition or Disease	Intervention/Treatment	Phase
Non-alcoholic Steatohepatitis (NASH)	Drug: Tropifexor (LJN452) Drug: Placebo	Phase 2

Detailed Description

Part A In Part A, 77 subjects were randomized at baseline to receive tropifexor (10 μg, 30 μg, 60 μg or 90 μg) or placebo (Arms A, B, C, D and E) for 12 weeks. After ≥ 90% of the subjects from Part A completed 8 weeks of treatment, the first interim analysis of all Part A data was performed and the Data Monitoring Committee (DMC) recommended evaluation of 90 μg tropifexor (safe andefficacious) in Part B. The treatment arms of Part A were completed through Week 16 without adaptation.

Part B Randomization for Part B was started after the DMC recommendations on the dose to be used in Part B were implemented by the sponsor. As planned in the study protocol, since the first interim analysis selected one active dose (90 μg) to be tested in Part B, one of the other originally planned active treatment arms (60 μg) was included with a smaller sample size to confirm the earlier findings of this dose observed in Part A. Therefore, in Part B, 121 subjects, were randomized at baseline to receive tropifexor (90 μg and 60 μg) or placebo (Arms F, G and H) for 12 weeks.

Part C was introduced as a result of the DMC recommendation to pursue doses > 90 μg. Randomization in Part C started once the Part B randomization was completed. In Part C, 152 subjects were randomized at baseline to receive 140 μg or 200 μg tropifexor or placebo (Arms I, J and K) for 48 weeks.

One patient was treated at 2 sites but is still only one patient. 350 total enrollment, and not 351.

Study Design

Study Type:

Interventional

Actual Enrollment :

350 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

This was a randomized, double-blind, placebo-controlled, multicenter, parallel-group, dose finding, 3-part (Parts A, B, and C), adaptive design study to assess the safety, tolerability, and efficacy of six doses of tropifexor as compared to placebo in subjects with NASH. Each study part had a screening period followed by a double-blind, randomized, treatment period, and a post-treatment follow-up period. This study was extended based on safety and efficacy results in Part A and available long-term toxicology coverage; Part C was added to explore 48 weeks of treatment at higher doses with paired biopsies in F2/3 NASH patients.This was a randomized, double-blind, placebo-controlled, multicenter, parallel-group, dose finding, 3-part (Parts A, B, and C), adaptive design study to assess the safety, tolerability, and efficacy of six doses of tropifexor as compared to placebo in subjects with NASH. Each study part had a screening period followed by a double-blind, randomized, treatment period, and a post-treatment follow-up period. This study was extended based on safety and efficacy results in Part A and available long-term toxicology coverage; Part C was added to explore 48 weeks of treatment at higher doses with paired biopsies in F2/3 NASH patients.

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Aug 1, 2016

Actual Primary Completion Date :

Apr 6, 2020

Actual Study Completion Date :

Apr 6, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LJN452 10 μg Tropifexor (LJN452) Part A	Drug: Tropifexor (LJN452) Comparison of different doses of drug
Experimental: LJN452 30 μg Tropifexor (LJN452) Part A	Drug: Tropifexor (LJN452) Comparison of different doses of drug
Experimental: LJN452 60 μg Tropifezor (LJN452) Parts A + B	Drug: Tropifexor (LJN452) Comparison of different doses of drug
Experimental: LJN452 90 μg Tropifexor (LJN452) Parts A + B	Drug: Tropifexor (LJN452) Comparison of different doses of drug
Placebo Comparator: Placebo A+ B Placebo Parts A + B	Drug: Placebo Comparator
Experimental: LJN452 140 μg Tropifexor (LJN452) Part C	Drug: Tropifexor (LJN452) Comparison of different doses of drug
Experimental: LJN452 200 μg Tropifexor (LJN452) Part B	Drug: Tropifexor (LJN452) Comparison of different doses of drug
Placebo Comparator: Placebo C Placebo Part C	Drug: Placebo Comparator

Outcome Measures

Primary Outcome Measures

Number of Nonalcoholic Steatohepatitis (NASH) Patients With Treatment Emergent Adverse Events (TEAE) [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)]
Number of Nonalcoholic steatohepatitis (NASH) patients with TEAEs
Change in Transaminase Levels (ALT) [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)]
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 from baseline to week 12 Summary statistics of change in ALT from baseline to EOT by treatment
Change in Aspartate Transaminase (AST) [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)]
To determine the dose relationship of tropifexor (LJN452) on markers of hepatic inflammation (AST) in NASH from baseline to Week 12 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)
Change From Baseline in % of Fat in the Liver Assessed Using Magnetic Resonance Imaging (MRI) [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)]
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)

Secondary Outcome Measures

Change From Baseline in Weight [48 weeks]
Repeated measures for LS mean change in weight after 12 weeks of treatment
Change in Body Mass Index (BMI) [12 weeks]
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
Change From Baseline in Waist to Hip (WTH) Ratio [12 weeks]
The LS mean change in waist to hip ratio after 12 weeks of treatment
Change From Baseline in Biomarker FGF19 [baseline, week 6]
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 Value at 6 weeks minus value at baseline
Change From Baseline in Biomarker C4 [Week 6, 4 hours post dose]
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
Change From Baseline on Markers of Liver Fibrosis, Fibroscan [End of Treatment (EoT): For Parts A&B, EoT was Week 12. For Part C, EoT was Week 48]
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 Scores range from 0-4 with zero being no liver scarring and 4 being advanced liver scarring (cirrhosis)
Change From Baseline on Markers of Liver Fibrosis Panel (ELF) Score [End of Treatment (EoT): For Parts A&B, EoT was Week 12. For Part C, EoT was Week 48]
ANCOVA: LS Mean Change in Enhanced liver fibrosis panel (ELF) score from baseline by visit up to EOT. The total ELF score reference range calculated non-parametrically is 6.72 (90% CI 6.58-6.84) to 9.79 (90% CI 9.45-10.01); Journal of Hepatology 2013 vol. 59 j 236-242. Enhanced liver fibrosis Test (ELF) panel: the following was assessed: hyaluronic acid (HA), tissue inhibitor of metalloproteinases (TIMP-1), and amino-terminal pro-peptide of procollagen type III (PIIINP). The Enhanced Liver Fibrosis score is a linear combination of TIMP-1, PIIINP, and HA with the following formula: ELF score = 2.494+0.846 x ln(HA) + 0.735 x ln (PIIINP) + 0.391 x ln (TIMP-1).
Change From Baseline on Markers of Liver Fibrosis, Fibrotest (Parts A+B) [End of Treatment (EoT):12 weeks]
Fibrosis biomarker test, originally called Fibrotest®/ Fibrosure®, is combines α2-macroglobulin (a2m), apolipoprotein A1 (aA1), total bilirubin (BIL), haptoglobin (h), GGT, and ALT. The coefficient for the score is calculated as: z = 4.467 x log(a2m) - 1.357 x log(h) + 1.017 x log(GGT) + 0.0281 x Age + 1.737 x log(BIL) - 1.184 x (aA1) + 0.301 x Gender - 5.54 where Gender = 1 for male and Gender = 0 for female. The score is then: 1/(1+e^-z). Calculated scores range from 0.00 (no fibrosis) to 1.00 (severe fibrosis or cirrhosis) (See Part C in separate outcomes that follows)
Change From Baseline on Markers of Liver Fibrosis, Fibrotest, (Part C) [End of Treatment (EoT) was 48 weeks]
Fibrosis biomarker test, originally called Fibrotest®/ Fibrosure®, is combines α2-macroglobulin (a2m), apolipoprotein A1 (aA1), total bilirubin (BIL), haptoglobin (h), GGT, and ALT. The coefficient for the score is calculated as: z = 4.467 x log(a2m) - 1.357 x log(h) + 1.017 x log(GGT) + 0.0281 x Age + 1.737 x log(BIL) - 1.184 x (aA1) + 0.301 x Gender - 5.54 where Gender = 1 for male and Gender = 0 for female. The score is then: 1/(1+e^-z). Calculated scores range from 0.00 (no fibrosis) to 1.00 (severe fibrosis or cirrhosis)
Change From Baseline on Gamma-glutamyl Transferase (GGT) [EoT for Parts A+B=12 weeks; EoT for Part C = 48 weeks]
Summary statistics of change in GGT (IU/L) from baseline by visit up to EoT
Change From Baseline on Fasting Lipid Profile [End of Treatment (EoT): For Parts A&B, EoT was Week 12. For Part C, EoT was Week 48]
Repeated measures analysis: LS geometric mean ratio of fasting lipids to baseline by visit up to EOT
Itch Based on a Visual Analog Scale (VAS) Rating Scale [EoT for Parts A+B=12 weeks; EoT for Part C = 48 weeks]
Repeated measures analysis: Change in VAS for Itch from baseline by visit up to EoT VAS score 0 = no disease; and 9 is severely advanced disease
Pre-dose Trough Concentration (Ctrough) of LJN452 [In Parts A and B, LJN452 Ctrough was measured on Study Days 7, 14, 28, 42, 56, and 84. In Part C LJN452 Ctrough was measured on Study Days 42, 84, 168, 280 and 336]
Pre-dose Trough Concentration (Ctrough) of tropifexor (LJN452)
C2h (Steady-state Drug Levels 2 Hours Postdose) of LJN452 [Days 7 and 14 (10 and 30μg LJN452 C2h was not measured day 14)]
Summary C2h of tropifexor (LJN452)
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 [EoT (Week 48)]
Number of patients who have at least one point improvement in fibrosis (NASH CRN staging) without worsening of steatohepatitis (total score)
Biopsy-based Response at Week 48 Compared to Baseline: At Least One Point Improvement in Fibrosis (NASH CRN Staging) Without Worsening - FDA [EoT (Week 48)]
Number of patients who have at least one point improvement in fibrosis (NASH CRN staging) without worsening of steatohepatitis (FDA)
Biopsy-based Response at Week 48 Compared to Baseline: At Least One Point Improvement in Fibrosis (NASH CRN Staging) Without Worsening - EMA [EoT (Week 48)]
Number of patients who have at least one point improvement in fibrosis (NASH CRN staging) without worsening of steatohepatitis (EMA)
Biopsy-based Response at Week 48 Compared to Baseline: Difference Between Treatment Groups (Part C) - Resolution of Steatohepatitis (Diagnostic Category) [EoT (Week 48)]
Resolution of steatohepatitis (diagnostic category) without worsening of fibrosis (NASH CRN staging)
Biopsy-based Response at Week 48 Compared to Baseline: Difference Between Treatment Groups (Part C) - Resolution of Steatohepatitis (FDA, EMA) [EoT (Week 48)]
Resolution of steatohepatitis (diagnostic category) without worsening of fibrosis (NASH CRN staging)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

male/female patients, 18 years or older
written informed consent
Part A and B patients : presence of NASH by histological evidence (liver biopsy obtained 2 years or less prior to randomization) with fibrosis level of F1, F2 or F3 (fibrosis in the absence of cirrhosis) and no diagnosis of chronic liver disease and elevated alanine aminotransferase (ALT) OR phenotypic diagnosis based on elevated ALT, BMI and diagnosis of Type 2 diabetes mellitus (DM)
Part C patients: presence of NASH by histological evidence (liver biopsy obtained during the Screening period or 6 months or less prior to randomization) with fibrosis level of F2 or F3 and no diagnosis of chronic liver disease

And ( All Parts):

ALT ≥ 43 IU/L (males) or ≥ 28 IU/L (females)
Liver fat equal to or higher than 10% by MRI

Exclusion Criteria:

previous exposure to OCA
patients taking prohibited medications
patients taking the following medicines UNLESS on a stable dose (within 25% of baseline dose) for at least 1 month before randomization: (for Part C patients, dose must be stable for at least 1 month prior to biopsy through Screening : anti- diabetic medications, insulin, beta-blockers, thiazide diuretics, fibrates, statins, niacin, ezetimibe, vitamin E (if doses > 200 IU/day; doses > 800 IU/day are prohibited), thyroid hormone, psychotropic medications, estrogen or estrogen containing birth control
pregnant or nursing (lactating) women
current or history of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to screening
uncontrolled diabetes mellitus
new use of GLP-1 agonists such as liraglutide, exenatide, lixisenatide, albiglutide or dulaglutide within 3 months of screening
presence of cirrhosis
hepatic decompensation or severe liver impairment
previous diagnosis of other forms of chronic liver disease
patients with contraindications to MRI imaging

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Madison	Alabama	United States	35758
2	Novartis Investigative Site	North Little Rock	Arkansas	United States	72117
3	Novartis Investigative Site	Coronado	California	United States	92118
4	Novartis Investigative Site	Los Angeles	California	United States	90057
5	Novartis Investigative Site	Pasadena	California	United States	91105
6	Novartis Investigative Site	Rialto	California	United States	92377
7	Novartis Investigative Site	San Diego	California	United States	92114
8	Novartis Investigative Site	San Francisco	California	United States	94115
9	Novartis Investigative Site	Lonetree	Colorado	United States	80124
10	Novartis Investigative Site	Boca Raton	Florida	United States	33434
11	Novartis Investigative Site	Jacksonville	Florida	United States	32256
12	Novartis Investigative Site	Lakewood Ranch	Florida	United States	34211
13	Novartis Investigative Site	Miami	Florida	United States	33136
14	Novartis Investigative Site	Orlando	Florida	United States	32806
15	Novartis Investigative Site	Pensacola	Florida	United States	32503
16	Novartis Investigative Site	Athens	Georgia	United States	30607
17	Novartis Investigative Site	Marietta	Georgia	United States	30060
18	Novartis Investigative Site	Catonsville	Maryland	United States	21228
19	Novartis Investigative Site	Worcester	Massachusetts	United States	01655
20	Novartis Investigative Site	Detroit	Michigan	United States	48202
21	Novartis Investigative Site	Minneapolis	Minnesota	United States	55455
22	Novartis Investigative Site	Jefferson City	Missouri	United States	65109
23	Novartis Investigative Site	Berlin	New Jersey	United States	08009
24	Novartis Investigative Site	Morehead City	North Carolina	United States	28557
25	Novartis Investigative Site	Cincinnati	Ohio	United States	45219
26	Novartis Investigative Site	Hermitage	Tennessee	United States	37076
27	Novartis Investigative Site	Dallas	Texas	United States	75208-2312
28	Novartis Investigative Site	Houston	Texas	United States	77030
29	Novartis Investigative Site	San Antonio	Texas	United States	78215
30	Novartis Investigative Site	Norfolk	Virginia	United States	23502
31	Novartis Investigative Site	Richmond	Virginia	United States	23298
32	Novartis Investigative Site	Caba	Buenos Aires	Argentina	C1181ACH
33	Novartis Investigative Site	Caba	Buenos Aires	Argentina	C1280AEB
34	Novartis Investigative Site	Buenos Aires		Argentina	C1120AAC
35	Novartis Investigative Site	Kingswood	New South Wales	Australia	2747
36	Novartis Investigative Site	Fitzroy	Victoria	Australia	3065
37	Novartis Investigative Site	Salzburg		Austria	5020
38	Novartis Investigative Site	Wien		Austria	1090
39	Novartis Investigative Site	Bruxelles		Belgium	1070
40	Novartis Investigative Site	Gent		Belgium	9000
41	Novartis Investigative Site	Leuven		Belgium	3000
42	Novartis Investigative Site	London	Ontario	Canada	N6A 5A5
43	Novartis Investigative Site	Toronto	Ontario	Canada	M5G 2C4
44	Novartis Investigative Site	Chicoutimi	Quebec	Canada	G7H 7K9
45	Novartis Investigative Site	Montpellier		France	34295
46	Novartis Investigative Site	Paris		France	75012
47	Novartis Investigative Site	Paris		France	75651
48	Novartis Investigative Site	Dresden		Germany	01307
49	Novartis Investigative Site	Hamburg		Germany	20246
50	Novartis Investigative Site	Hannover		Germany	30625
51	Novartis Investigative Site	Leipzig		Germany	04103
52	Novartis Investigative Site	Wuerzburg		Germany	97080
53	Novartis Investigative Site	New Delhi	Delhi	India	110070
54	Novartis Investigative Site	Bergamo	BG	Italy	24128
55	Novartis Investigative Site	Bologna		Italy	40138
56	Novartis Investigative Site	Roma		Italy	00161
57	Novartis Investigative Site	Hatsukaichi city	Hiroshima	Japan	738 8503
58	Novartis Investigative Site	Yokohama-city	Kanagawa	Japan	236-0004
59	Novartis Investigative Site	Saga-city	Saga	Japan	849-8501
60	Novartis Investigative Site	Izumo-city	Shimane	Japan	693 8501
61	Novartis Investigative Site	Seoul	Korea	Korea, Republic of	03722
62	Novartis Investigative Site	Seoul	Korea	Korea, Republic of	05505
63	Novartis Investigative Site	Dongjak Gu	Seoul	Korea, Republic of	07061
64	Novartis Investigative Site	Busan		Korea, Republic of	602739
65	Novartis Investigative Site	Seoul		Korea, Republic of	03080
66	Novartis Investigative Site	Utrecht		Netherlands	3584CX
67	Novartis Investigative Site	Singapore		Singapore	169608
68	Novartis Investigative Site	Banska Bystrica		Slovakia	97517
69	Novartis Investigative Site	Bratislava		Slovakia	82606
70	Novartis Investigative Site	Bratislava		Slovakia	85101
71	Novartis Investigative Site	Nitra		Slovakia	949 01
72	Novartis Investigative Site	Sevilla	Andalucia	Spain	41013
73	Novartis Investigative Site	Barcelona	Cataluna	Spain	08035
74	Novartis Investigative Site	Barcelona	Cataluna	Spain	08036
75	Novartis Investigative Site	Madrid		Spain	28009
76	Novartis Investigative Site	Madrid		Spain	28034
77	Novartis Investigative Site	Kaoshiung		Taiwan	80756
78	Novartis Investigative Site	Keelung City		Taiwan	20401
79	Novartis Investigative Site	Taichung		Taiwan	40447
80	Novartis Investigative Site	Taipei		Taiwan	11217
81	Novartis Investigative Site	Taoyuan		Taiwan	33305

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

More Information

Additional Information:

A Randomized, Patient and Investigator Blinded, Placebo Controlled, Multicenter Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of LMB763 in Patients With Non-alcoholic Steatohepatitis (NASH)

Publications

None provided.

Responsible Party:

Novartis Pharmaceuticals

ClinicalTrials.gov Identifier:

NCT02855164

Other Study ID Numbers:

CLJN452A2202
2015-005215-33

First Posted:

Aug 4, 2016

Last Update Posted:

Sep 5, 2021

Last Verified:

Aug 1, 2021

Individual Participant Data (IPD) Sharing Statement:

Undecided

Plan to Share IPD:

Undecided

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Keywords provided by Novartis Pharmaceuticals

LJN452

non-alcoholic steatohepatitis

Additional relevant MeSH terms:

Fatty Liver

Non-alcoholic Fatty Liver Disease

Study Results

Participant Flow

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

Pre-assignment Detail

In Part A, 77 were randomized at baseline to receive tropifexor 10 μg (n=14), 30μg (n=16), 60 μg (n=16) or 90 μg (n=15) or placebo (n=16) In Part B, 121 were randomized at baseline to receive tropifexor 90 μg (n=70) and 60 μg (n=21) or placebo (n=30) 780 were screened in Part C. Of these 152 met eligibility criteria and were randomized to receive tropifexor 140 μg (n=50) or 200 μg (n=51) or placebo (n=51)

Arm/Group Title	LJN452 10 μg	LJN452 30 μg	LJN452 60 μg	LJN452 90 μg	Placebo A+B	LJN452 140 μg	LJN452 200 μg	Placebo C
Arm/Group Description	10 micrograms of Tropifexor (Part A)	30 micrograms of Tropifexor (Part A)	60 micrograms of Tropifexor (Parts A+B)	90 micrograms of Tropifexor (Parts A + B)	Placebo A+B	140 micrograms of Tropifexor (Part C)	200 micrograms of Tropifexor (Part C)	Placebo (Part C)
Period Title: Parts A + B (Randomized Set)
STARTED	14	16	37	85	46	0	0	0
COMPLETED	14	16	36	77	45	0	0	0
NOT COMPLETED	0	0	1	8	1	0	0	0
Period Title: Parts A + B (Randomized Set)
STARTED	0	0	0	0	0	50	51	51
COMPLETED	0	0	0	0	0	38	37	44
NOT COMPLETED	0	0	0	0	0	12	14	7

Baseline Characteristics

Arm/Group Title	LJN452 10 μg	LJN452 30 μg	LJN452 60 μg	LJN452 90 μg	Placebo A+B	LJN452 140 μg	LJN452 200 μg	Placebo C	Total
Arm/Group Description	10 micrograms of Tropifexor (Part A)	30 micrograms of Tropifexor (Part A)	60 micrograms of Tropifexor (Parts A+B)	90 micrograms of Tropifexor (Parts A + B)	Placebo (Parts A+B)	140 micrograms of Tropifexor (Part C)	200 micrograms of Tropifexor (Part C)	Placebo (Part C)	Total of all reporting groups
Overall Participants	14	16	37	85	46	50	51	51	350
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	14 100%	14 87.5%	33 89.2%	72 84.7%	41 89.1%	0 0%	0 0%	0 0%	174 49.7%
>=65 years	0 0%	2 12.5%	4 10.8%	13 15.3%	5 10.9%	0 0%	0 0%	0 0%	24 6.9%
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	0 0%	40 250%	41 110.8%	43 50.6%	124 269.6%
>=65 years	0 0%	10 62.5%	10 27%	8 9.4%	28 60.9%
Age (years) [Mean (Standard Deviation) ]
Parts A + B	48 (11.7)	49 (14.4)	50 (12.5)	51 (13.4)	51 (12.3)	51 (12.8)
Part C	56 (11.41)	55 (10.8)	54 (11.0)	55 (11.0)
Sex: Female, Male (Count of Participants)
Female	9 64.3%	7 43.8%	20 54.1%	47 55.3%	21 45.7%	0 0%	0 0%	0 0%	104 29.7%
Male	5 35.7%	9 56.3%	17 45.9%	38 44.7%	25 54.3%	0 0%	0 0%	0 0%	94 26.9%
Female	0 0%	0 0%	0 0%	0 0%	0 0%	36 72%	29 56.9%	32 62.7%	97 27.7%
Male	0 0%	0 0%	0 0%	0 0%	0 0%	14 28%	22 43.1%	19 37.3%	55 15.7%
Race/Ethnicity, Customized (Count of Participants)
Caucasian (Parts A + B)	12 85.7%	11 68.8%	24 64.9%	50 58.8%	25 54.3%	122 244%
Black (Parts A + B)	0 0%	0 0%	0 0%	1 1.2%	0 0%	1 2%
Asian (Parts A + B)	2 14.3%	5 31.3%	12 32.4%	31 36.5%	20 43.5%	70 140%
Pacific Islander (Parts A + B)	0 0%	0 0%	0 0%	0 0%	1 2.2%	1 2%
Other (Parts A + B)	0 0%	0 0%	0 0%	2 2.4%	0 0%	2 4%
Unknown (Parts A+B)	0 0%	1 6.3%	1 2.7%	1 1.2%	3 6.5%
Caucasian (Part C)	37 264.3%	38 237.5%	38 102.7%	113 132.9%
Black (Part C)	0 0%	0 0%	1 2.7%	1 1.2%
Asian (Part C)	10 71.4%	10 62.5%	8 21.6%	28 32.9%
Pacific Islander (Part C)	1 7.1%	0 0%	0 0%	1 1.2%
Other (Part C)	2 14.3%	3 18.8%	4 10.8%	9 10.6%

Outcome Measures

1. Primary Outcome

Title	Number of Nonalcoholic Steatohepatitis (NASH) Patients With Treatment Emergent Adverse Events (TEAE)
Description	Number of Nonalcoholic steatohepatitis (NASH) patients with TEAEs
Time Frame	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)

Outcome Measure Data

Analysis Population Description
Safety analysis set (SAS) is all subjects who received at least one dose of drug and had at least one post-baseline safety assessment.

Arm/Group Title	LJN452 10 μg	LJN452 30 μg	LJN452 60 μg	LJN452 90 μg	Placebo A+B	LJN452 140 μg	LNJ452 200 μg	Placebo Part C
Arm/Group Description	10 micrograms of Tropifexor (Part A)	30 micrograms of Tropifexor (Part A)	60 micrograms of Tropifexor (Parts A+B)	90 micrograms of Tropifexor (Parts A+B)	Placebo (Parts A+B)	140 micrograms of Tropifexor (Part C)	200 micrograms of Tropifexor (Part C)	Placebo (Part C)
Measure Participants	13	17	37	85	46	50	51	51
Count of Participants [Participants]	5 35.7%	11 68.8%	24 64.9%	61 71.8%	31 67.4%	49 98%	49 96.1%	46 90.2%

2. Primary Outcome

Title	Change in Transaminase Levels (ALT)
Description	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 from baseline to week 12 Summary statistics of change in ALT from baseline to EOT by treatment
Time Frame	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)

Outcome Measure Data

Analysis Population Description
Full analysis set (FAS): All subjects to whom study treatment had been assigned. Following the intent-to-treat (ITT) principle, subjects were analyzed according to the treatment they have been assigned to at randomization.

Arm/Group Title	LJN452 10 μg	LJN452 30 μg	LJN452 60 μg	LJN452 90 μg	Placebo A+B	LJN452 140 μg	LNJ452 200 μg	Placebo Part C
Arm/Group Description	10 micrograms of Tropifexor (Part A)	30 micrograms of Tropifexor (Part A)	60 micrograms of Tropifexor (Parts A + B)	90 micrograms of Tropifexor (Parts A + B)	Placebo (Parts A+B)	140 micrograms of Tropifexor (Part C)	200 micrograms of Tropifexor (Part C)	Placebo (Part C)
Measure Participants	14	16	37	85	46	50	51	51
Mean (Standard Deviation) [IU/L]	-16.7 (17.53)	-12.0 (35.99)	-17.3 (28.12)	-15.4 (30.32)	-8.1 (29.37)	-27.0 (30.24)	-28.7 (25.40)	-11.7 (61.64)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LJN452 10 μg, Placebo A+B
	Comments	10 micrograms of Tropifexor vs placebo (Part A)
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: ALT (U/L) change from baseline up to EOT (Parts A + B) (Full analysis set)

Statistical Test of Hypothesis	p-Value	0.362
	Comments
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	LS mean change
	Estimated Value	-15.9
	Confidence Interval	(2-Sided) 95% -31.2 to -0.6
	Parameter Dispersion	Type: Standard Error of the Mean Value: 7.76
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LJN452 30 μg, Placebo A+B
	Comments	30 micrograms of Tropifexor vs placebo (Part A)
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: ALT (U/L) change from baseline up to EOT (Parts A + B) (Full analysis set)

Statistical Test of Hypothesis	p-Value	0.729
	Comments
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	LS mean change
	Estimated Value	-10.7
	Confidence Interval	(2-Sided) 95% -24.8 to 3.3
	Parameter Dispersion	Type: Standard Error of the Mean Value: 7.12
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	LJN452 60 μg, Placebo A+B
	Comments	60 micrograms of Tropifexor vs placebo (Parts A + B)
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: ALT (U/L) change from baseline up to EOT (Parts A + B) (Full analysis set)

Statistical Test of Hypothesis	p-Value	0.173
	Comments
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Least Square Mean Change
	Estimated Value	-16.5
	Confidence Interval	(2-Sided) 95% -25.8 to -7.1
	Parameter Dispersion	Type: Standard Error of the Mean Value: 4.73
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	LJN452 90 μg, Placebo A+B
	Comments	90 micrograms of Tropifexor vs placebo (Parts A + B)
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: ALT (U/L) change from baseline up to EOT (Parts A + B) (Full analysis set)

Statistical Test of Hypothesis	p-Value	0.185
	Comments
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Least Square Mean Change
	Estimated Value	-14.9
	Confidence Interval	(2-Sided) 95% -21.3 to -8.5
	Parameter Dispersion	Type: Standard Error of the Mean Value: 3.25
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	LJN452 140 μg, Placebo Part C
	Comments	140 micrograms of Tropifexor (Part C) vs placebo
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: ALT (U/L) change from baseline up to EOT (Part C) (Full analysis set)

Statistical Test of Hypothesis	p-Value	0.020
	Comments
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	LS Mean Change
	Estimated Value	-31.6
	Confidence Interval	(2-Sided) 95% -46.9 to -16.3
	Parameter Dispersion	Type: Standard Error of the Mean Value: 7.71
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	LNJ452 200 μg, Placebo Part C
	Comments	200 micrograms of Tropifexor vs placebo (Part C)
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: ALT (U/L) change from baseline up to EOT (Part C) (Full analysis set)

Statistical Test of Hypothesis	p-Value	0.030
	Comments
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	LS Mean Change
	Estimated Value	-32.5
	Confidence Interval	(2-Sided) 95% -50.6 to -14.5
	Parameter Dispersion	Type: Standard Error of the Mean Value: 9.10
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	LJN452 10 μg, Placebo A+B, Placebo Part C
	Comments	10 micrograms of Tropifexor vs placebo (Parts A + B + C)
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: ALT (U/L) change from baseline to Week 12 (Parts A+B+C) Full analysis set (FAS)

Statistical Test of Hypothesis	p-Value	0.456
	Comments
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-13.4
	Confidence Interval	(2-Sided) 95% -26.3 to -0.4
	Parameter Dispersion	Type: Standard Error of the Mean Value: 7.86
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	LJN452 30 μg, Placebo A+B, Placebo Part C
	Comments	30 micrograms of Tropifexor vs placebo (Parts A + B + C)
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: ALT (U/L) change from baseline to Week 12 (Parts A+B+C) Full analysis set (FAS)

Statistical Test of Hypothesis	p-Value	0.966
	Comments
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-7.5
	Confidence Interval	(2-Sided) 95% -19.5 to 4.4
	Parameter Dispersion	Type: Standard Error of the Mean Value: 7.27
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	LJN452 60 μg, Placebo A+B, Placebo Part C
	Comments	60 micrograms of Tropifexor vs placebo (Parts A + B + C)
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: ALT (U/L) change from baseline to Week 12 (Parts A+B+C) Full analysis set (FAS)

Statistical Test of Hypothesis	p-Value	0.275
	Comments
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-13.3
	Confidence Interval	(2-Sided) 95% -21.4 to -5.2
	Parameter Dispersion	Type: Standard Error of the Mean Value: 4.93
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	LJN452 90 μg, Placebo A+B, Placebo Part C
	Comments	90 micrograms of Tropifexor vs placebo (Parts A + B + C)
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: ALT (U/L) change from baseline to Week 12 (Parts A+B+C) Full analysis set (FAS)

Statistical Test of Hypothesis	p-Value	0.304
	Comments
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-11.8
	Confidence Interval	(2-Sided) 95% -17.6 to -5.9
	Parameter Dispersion	Type: Standard Error of the Mean Value: 3.56
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Placebo A+B, LJN452 140 μg, Placebo Part C
	Comments	140 micrograms of Tropifexor vs placebo (Parts A + B + C)
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: ALT (U/L) change from baseline up to EOT (Parts A + B) FAS

Statistical Test of Hypothesis	p-Value	0.057
	Comments
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-17.1
	Confidence Interval	(2-Sided) 95% -24.5 to -9.8
	Parameter Dispersion	Type: Standard Error of the Mean Value: 4.45
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Placebo A+B, LNJ452 200 μg, Placebo Part C
	Comments	200 micrograms of Tropifexor vs placebo (Parts A + B + C)
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: ALT (U/L) change from baseline up to EOT (Parts A + B + C) FAS

Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-23.0
	Confidence Interval	(2-Sided) 95% -30.5 to -15.6
	Parameter Dispersion	Type: Standard Error of the Mean Value: 4.49
	Estimation Comments

3. Primary Outcome

Title	Change in Aspartate Transaminase (AST)
Description	To determine the dose relationship of tropifexor (LJN452) on markers of hepatic inflammation (AST) in NASH from baseline to Week 12 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)
Time Frame	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)

Outcome Measure Data

Analysis Population Description
Full Analysis Set (FAS)

Arm/Group Title	LJN452 10 μg	LJN452 30 μg	LJN452 60 μg	LJN452 90 μg	Placebo A+B	LJN452 140 μg	LJN452 200 μg	Placebo Part C
Arm/Group Description	10 micrograms of Tropifexor (Part A)	30 micrograms of Tropifexor (Part A)	60 micrograms of Tropifexor (Parts A + B)	90 micrograms of Tropifexor (Parts A + B)	Placebo (Parts A+B)	140 micrograms of Tropifexor (Part C)	200 micrograms of Tropifexor (Part C)	Placebo (Part C)
Measure Participants	14	16	37	85	46	50	51	51
Mean (Standard Deviation) [U/L]	-11.3 (12.09)	-2.1 (29.62)	-10.2 (25.03)	-2.5 (24.60)	-7.1 (23.85)	-16.7 (23.36)	-13.3 (20.14)	-13.1 (29.00)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LJN452 10 μg, Placebo A+B
	Comments	10 micrograms of Tropifexor vs placebo (Part A)
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: AST (U/L) change from baseline up to EOT (Full analysis set)

Statistical Test of Hypothesis	p-Value	0.722
	Comments
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-9.9
	Confidence Interval	(2-Sided) 95% -22.9 to 3.0
	Parameter Dispersion	Type: Standard Error of the Mean Value: 6.56
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LJN452 30 μg, Placebo A+B
	Comments	30 micrograms of Tropifexor vs placebo (Part A)
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: AST (U/L) change from baseline up to EOT (Full analysis set)

Statistical Test of Hypothesis	p-Value	0.468
	Comments
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-2.2
	Confidence Interval	(2-Sided) 95% -14.0 to 9.5
	Parameter Dispersion	Type: Standard Error of the Mean Value: 5.96
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	LJN452 60 μg, Placebo A+B
	Comments	60 micrograms of Tropifexor vs placebo (Parts A+B)
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: AST (U/L) change from baseline up to EOT (Parts A+B) (Full analysis set)

Statistical Test of Hypothesis	p-Value	0.774
	Comments
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-8.8
	Confidence Interval	(2-Sided) 95% -16.7 to -1.0
	Parameter Dispersion	Type: Standard Error of the Mean Value: 3.97
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	LJN452 90 μg, Placebo A+B
	Comments	90 micrograms of Tropifexor vs placebo (Parts A+B)
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: AST (U/L) change from baseline up to EOT (Parts A+B) (Full analysis set)

Statistical Test of Hypothesis	p-Value	0.136
	Comments
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-0.6
	Confidence Interval	(2-Sided) 95% -6.0 to 4.9
	Parameter Dispersion	Type: Standard Error of the Mean Value: 2.76
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	LJN452 140 μg, Placebo Part C
	Comments	140 micrograms of Tropifexor vs placebo (Part C)
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: AST (U/L) change from baseline up to EOT (Part C) (Full analysis set)

Statistical Test of Hypothesis	p-Value	0.145
	Comments
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-16.0
	Confidence Interval	(2-Sided) 95% -23.9 to -8.2
	Parameter Dispersion	Type: Standard Error of the Mean Value: 3.97
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	LNJ452 200 μg, Placebo Part C
	Comments	200 micrograms of Tropifexor vs placebo (Part C)
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: AST (U/L) change from baseline up to EOT (Part C) (Full analysis set)

Statistical Test of Hypothesis	p-Value	0.236
	Comments
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-15.3
	Confidence Interval	(2-Sided) 95% -24.2 to -6.4
	Parameter Dispersion	Type: Standard Error of the Mean Value: 4.49
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	LJN452 10 μg, Placebo A+B, Placebo Part C
	Comments	10 micrograms of Tropifexor vs placebo (Parts A+B+ C)
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: AST (U/L) change from baseline up to EOT (Parts A+B+C) Full analysis set (FAS)

Statistical Test of Hypothesis	p-Value	0.788
	Comments
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-7.1
	Confidence Interval	(2-Sided) 95% -18.7 to 4.4
	Parameter Dispersion	Type: Standard Error of the Mean Value: 7.00
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	LJN452 30 μg, Placebo A+B, Placebo Part C
	Comments	30 micrograms of Tropifexor vs placebo (Parts A+B+ C)
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: AST (U/L) change from baseline up to EOT (Parts A+B+C) Full analysis set (FAS)

Statistical Test of Hypothesis	p-Value	0.413
	Comments
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	0.4
	Confidence Interval	(2-Sided) 95% -10.2 to 11.0
	Parameter Dispersion	Type: Standard Error of the Mean Value: 6.43
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	LJN452 60 μg, Placebo A+B, Placebo Part C
	Comments	60 micrograms of Tropifexor vs placebo (Parts A+B+ C)
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: AST (U/L) change from baseline up to EOT (Parts A+B+C) Full analysis set (FAS)

Statistical Test of Hypothesis	p-Value	0.833
	Comments
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-6.2
	Confidence Interval	(2-Sided) 95% -13.4 to 1.0
	Parameter Dispersion	Type: Standard Error of the Mean Value: 4.38
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	LJN452 90 μg, Placebo A+B, Placebo Part C
	Comments	90 micrograms of Tropifexor vs placebo (Parts A+B+ C)
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: AST (U/L) change from baseline up to EOT (Parts A+B+C) Full analysis set (FAS)

Statistical Test of Hypothesis	p-Value	0.068
	Comments
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	2.0
	Confidence Interval	(2-Sided) 95% -3.2 to 7.3
	Parameter Dispersion	Type: Standard Error of the Mean Value: 3.19
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Placebo A+B, LJN452 140 μg, Placebo Part C
	Comments	140 micrograms of Tropifexor vs placebo (Parts A+B+ C)
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: AST (U/L) change from baseline up to EOT (Parts A+B+C) Full analysis set (FAS)

Statistical Test of Hypothesis	p-Value	0.269
	Comments
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95% -6.6 to 6.5
	Parameter Dispersion	Type: Standard Error of the Mean Value: 3.98
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Placebo A+B, LNJ452 200 μg, Placebo Part C
	Comments	200 micrograms of Tropifexor vs placebo (Parts A+B+ C)
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: AST (U/L) change from baseline up to EOT (Parts A+B+C) Full analysis set (FAS)

Statistical Test of Hypothesis	p-Value	0.777
	Comments
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-3.8
	Confidence Interval	(2-Sided) 95% -10.5 to 2.9
	Parameter Dispersion	Type: Standard Error of the Mean Value: 4.05
	Estimation Comments

4. Primary Outcome

Title	Change From Baseline in % of Fat in the Liver Assessed Using Magnetic Resonance Imaging (MRI)
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)
Time Frame	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)

Outcome Measure Data

Analysis Population Description
FAS

Arm/Group Title	LJN452 10 μg	LJN452 30 μg	LJN452 60 μg	LJN452 90 μg	Placebo A+B	LJN452 140 μg	LJN452 200 μg	Placebo Part C
Arm/Group Description	10 micrograms of Tropifexor (Part A)	30 micrograms of Tropifexor (Part A)	60 micrograms of Tropifexor (Parts A + B)	90 micrograms of Tropifexor (Parts A + B)	Placebo (Parts A+B)	140 micrograms of Tropifexor (Part C)	200 micrograms of Tropifexor (Part C)	Placebo (Part C)
Measure Participants	14	16	37	85	46	50	51	51
Mean (Standard Error) [percentage of fat in the liver]	-7.48 (6.174)	-14.07 (5.661)	-15.04 (3.754)	-12.34 (2.482)	-6.19 (3.381)	-31.25 (5.228)	-39.54 (4.968)	-3.58 (4.718)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LJN452 10 μg, Placebo A+B
	Comments	10 microgramsof Tropifexor - Change in percentage of fat in the liver Part A
	Type of Statistical Test	Superiority
	Comments	ANCOVA: Relative change in percentage of fat in the liver from baseline to Week 12

Statistical Test of Hypothesis	p-Value	0.853
	Comments
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-7.48
	Confidence Interval	(2-Sided) 95% -19.66 to 4.70
	Parameter Dispersion	Type: Standard Error of the Mean Value: 6.174
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LJN452 30 μg, Placebo A+B
	Comments	30 micrograms of Tropifexor - Change in percentage of fat in the liver Part A
	Type of Statistical Test	Superiority
	Comments	ANCOVA: Relative change in percentage of fat in the liver from baseline to Week 12

Statistical Test of Hypothesis	p-Value	0.232
	Comments
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-14.07
	Confidence Interval	(2-Sided) 95% -25.24 to -2.91
	Parameter Dispersion	Type: Standard Error of the Mean Value: 5.661
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	LJN452 60 μg, Placebo A+B
	Comments	60 micrograms of Tropifexor - Change in percentage of fat in the liver Parts A+B
	Type of Statistical Test	Superiority
	Comments	ANCOVA: Relative change in percentage of fat in the liver from baseline to Week 12

Statistical Test of Hypothesis	p-Value	0.077
	Comments
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-15.04
	Confidence Interval	(2-Sided) 95% -22.45 to -7.64
	Parameter Dispersion	Type: Standard Error of the Mean Value: 3.754
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	LJN452 90 μg, Placebo A+B
	Comments	90 micrograms of Tropifexor - Change in percentage of fat in the liver Parts A+B
	Type of Statistical Test	Superiority
	Comments	ANCOVA: Relative change in percentage of fat in the liver from baseline

Statistical Test of Hypothesis	p-Value	0.141
	Comments
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-12.34
	Confidence Interval	(2-Sided) 95% -17.23 to -7.44
	Parameter Dispersion	Type: Standard Error of the Mean Value: 2.482
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	LJN452 140 μg, Placebo Part C
	Comments	140 micrograms of Tropifexor - Change in percentage of fat in the liver Part C
	Type of Statistical Test	Superiority
	Comments	ANCOVA: Relative change in percentage of fat in the liver from baseline to Week 12

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-31.25
	Confidence Interval	(2-Sided) 95% -41.58 to -20.92
	Parameter Dispersion	Type: Standard Error of the Mean Value: 5.228
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	LNJ452 200 μg, Placebo Part C
	Comments	200 micrograms of Tropifexor - Change in percentage of fat in the liver Part C
	Type of Statistical Test	Superiority
	Comments	ANCOVA: Relative change in percentage of fat in the liver from baseline to Week 12 (Parts A+B+C)

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-39.54
	Confidence Interval	(2-Sided) 95% -49.37 to -29.71
	Parameter Dispersion	Type: Standard Error of the Mean Value: 4.968
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	LJN452 10 μg, Placebo A+B, Placebo Part C
	Comments	10 micrograms of Tropifexor - Change in percentage of fat in the liver Parts A+B+C
	Type of Statistical Test	Superiority
	Comments	ANCOVA: Relative change in percentage of fat in the liver from baseline to Week 12 (Parts A+B+C)

Statistical Test of Hypothesis	p-Value	0.872
	Comments
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-8.09
	Confidence Interval	(2-Sided) 95% -19.06 to 2.88
	Parameter Dispersion	Type: Standard Error of the Mean Value: 6.650
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	LJN452 30 μg, Placebo A+B, Placebo Part C
	Comments	30 micrograms of Tropifexor - Change in percentage of fat in the liver Parts A+B+C
	Type of Statistical Test	Superiority
	Comments	ANCOVA: Relative change in percentage of fat in the liver from baseline to Week 12 (Parts A+B+C)

Statistical Test of Hypothesis	p-Value	0.465
	Comments
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-14.14
	Confidence Interval	(2-Sided) 95% -24.36 to -3.91
	Parameter Dispersion	Type: Standard Error of the Mean Value: 6.198
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	LJN452 60 μg, Placebo A+B, Placebo Part C
	Comments	60 micrograms of Tropifexor - Change in percentage of fat in the liver Parts A+B+C
	Type of Statistical Test	Superiority
	Comments	ANCOVA: Relative change in percentage of fat in the liver from baseline to Week 12 (Parts A+B+C)

Statistical Test of Hypothesis	p-Value	0.228
	Comments
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-15.02
	Confidence Interval	(2-Sided) 95% -21.75 to -8.29
	Parameter Dispersion	Type: Standard Error of the Mean Value: 4.078
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	LJN452 90 μg, Placebo A+B, Placebo Part C
	Comments	90 micrograms - Change in percentage of fat in the liver Parts A+B+C
	Type of Statistical Test	Superiority
	Comments	ANCOVA: Relative change in percentage of fat in the liver from baseline to Week 12 (Parts A+B+C)

Statistical Test of Hypothesis	p-Value	0.370
	Comments
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-12.56
	Confidence Interval	(2-Sided) 95% -17.04 to -8.08
	Parameter Dispersion	Type: Standard Error of the Mean Value: 2.717
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Placebo A+B, LJN452 140 μg, Placebo Part C
	Comments	140 micrograms - Change in percentage of fat in the liver Parts A+B+C
	Type of Statistical Test	Superiority
	Comments	ANCOVA: Relative change in percentage of fat in the liver from baseline to Week 12 (Parts A+B+C)

Statistical Test of Hypothesis	p-Value	0.029
	Comments
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-18.71
	Confidence Interval	(2-Sided) 95% -24.51 to -12.91
	Parameter Dispersion	Type: Standard Error of the Mean Value: 3.517
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Placebo A+B, LNJ452 200 μg, Placebo Part C
	Comments	200 micrograms of Tropifexor - Change in percentage of fat in the liver Parts A+B+C
	Type of Statistical Test	Superiority
	Comments	ANCOVA: Relative change in percentage of fat in the liver from baseline to Week 12 (Parts A+B+C)

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-34.38
	Confidence Interval	(2-Sided) 95% -40.13 to -28.64
	Parameter Dispersion	Type: Standard Error of the Mean Value: 3.482
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline in Weight
Description	Repeated measures for LS mean change in weight after 12 weeks of treatment
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description
FAS

Arm/Group Title	LJN452 10 μg	LJN452 30 μg	LJN452 60 μg	LJN452 90 μg	Placebo A+B	LJN452 140 μg	LJN452 200 μg	Placebo Part C
Arm/Group Description	10 micrograms of Tropifexor (Part A)	30 micrograms of Tropifexor (Part A) vs placebo	60 micrograms of Tropifexor (Parts A + B)	90 micrograms of Tropifexor (Parts A + B)	Placebo (Parts A+B)	140 micrograms of Tropifexor (Part C)	200 micrograms of Tropifexor (Part C)	Placebo (Part C)
Measure Participants	14	16	36	84	46	50	51	51
Mean (Standard Error) [kg]	-1.79 (0.608)	-0.78 (0.567)	-1.05 (0.377)	-1.15 (0.253)	0.00 (0.338)	-5.10 (0.988)	-5.89 (1.002)	-2.48 (0.915)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LJN452 10 μg, Placebo A+B
	Comments	10 micrograms of Tropifexor (Part A) vs Placebo
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: Change in weight from baseline to EOT (Parts A + B) (Full analysis set)

Statistical Test of Hypothesis	p-Value	0.010
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-1.79
	Confidence Interval	(2-Sided) 95% -2.99 to 0.59
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.608
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LJN452 30 μg, Placebo A+B
	Comments	30 micrograms of Tropifexor (Part A) vs Placebo
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: Change in weight from baseline to EOT (Parts A + B) (Full analysis set)

Statistical Test of Hypothesis	p-Value	0.237
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-0.78
	Confidence Interval	(2-Sided) 95% -1.90 to 0.34
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.567
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	LJN452 60 μg, Placebo A+B
	Comments	60 micrograms of Tropifexor (Parts A + B) vs Placebo
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: Change in weight from baseline to EOT (Parts A + B) (Full analysis set)

Statistical Test of Hypothesis	p-Value	0.037
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-1.05
	Confidence Interval	(2-Sided) 95% -1.80 to 0.31
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.377
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	LJN452 90 μg, Placebo A+B
	Comments	90 micrograms of Tropifexor (Parts A + B) vs Placebo
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: Change in weight from baseline to EOT (Parts A + B) (Full analysis set)

Statistical Test of Hypothesis	p-Value	0.007
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-1.15
	Confidence Interval	(2-Sided) 95% -1.65 to 0.65
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.253
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	LJN452 140 μg, Placebo Part C
	Comments	140 micrograms of Tropifexor (Part C) vs Placebo
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: Change in weight from baseline to EOT (Parts C) (Full analysis set)

Statistical Test of Hypothesis	p-Value	0.053
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-5.10
	Confidence Interval	(2-Sided) 95% -7.05 to -3.14
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.988
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	LNJ452 200 μg, Placebo Part C
	Comments	200 micrograms of Tropifexor (Part C) vs Placebo
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: Change in weight from baseline to EOT (Parts C) (Full analysis set)

Statistical Test of Hypothesis	p-Value	0.013
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-5.89
	Confidence Interval	(2-Sided) 95% -7.87 to -3.91
	Parameter Dispersion	Type: Standard Error of the Mean Value: 1.002
	Estimation Comments

6. Secondary Outcome

Title	Change in Body Mass Index (BMI)
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
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description
FAS

Arm/Group Title	LJN452 10 μg	LJN452 30 μg	LJN452 60 μg	LJN452 90 μg	Placebo A+B	LJN452 140 μg	LJN452 200 μg	Placebo Part C
Arm/Group Description	10 micrograms of Tropifexor (Part A)	30 micrograms of Tropifexor (Part A)	60 micrograms of Tropifexor (Parts A + B)	90 micrograms of Tropifexor (Parts A + B)	Placebo (Parts A+B)	140 micrograms of Tropifexor (Part C)	200 micrograms of Tropifexor (Part C)	Placebo (Part C)
Measure Participants	14	16	37	84	46	50	51	51
Mean (Standard Error) [kg/m2]	-0.64 (0.208)	-0.29 (0.194)	-0.35 (0.129)	-0.42 (0.087)	0.02 (0.116)	-1.88 (0.322)	-2.11 (0.327)	-0.80 (0.299)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LJN452 10 μg, Placebo A+B
	Comments	10 micrograms of Tropifexor (Part A) vs Placebo
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: Change in BMI from baseline to EOT (Full analysis set)

Statistical Test of Hypothesis	p-Value	0.006
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-0.64
	Confidence Interval	(2-Sided) 95% -1.05 to 0.23
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.208
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LJN452 30 μg, Placebo A+B
	Comments	30 micrograms of Tropifexor (Part A) vs Placebo
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: Change in BMI from baseline to EOT (Full analysis set)

Statistical Test of Hypothesis	p-Value	0.177
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-0.29
	Confidence Interval	(2-Sided) 95% -0.67 to 0.09
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.194
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	LJN452 60 μg, Placebo A+B
	Comments	60 micrograms of Tropifexor (Parts A + B) vs Placebo
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: Change in BMI from baseline to EOT (Parts C) (Full analysis set)

Statistical Test of Hypothesis	p-Value	0.032
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-0.35
	Confidence Interval	(2-Sided) 95% -0.61 to 0.10
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.129
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	LJN452 90 μg, Placebo A+B
	Comments	90 micrograms of Tropifexor (Parts A + B) vs Placebo
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: Change in BMI from baseline to EOT (Full analysis set)

Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-0.42
	Confidence Interval	(2-Sided) 95% -0.59 to 0.25
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.087
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	LJN452 140 μg, Placebo Part C
	Comments	140 micrograms of Tropifexor (Part C) vs Placebo
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: Change in BMI from baseline to EOT (Full analysis set)

Statistical Test of Hypothesis	p-Value	0.015
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-1.88
	Confidence Interval	(2-Sided) 95% -2.51 to -1.24
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.322
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	LNJ452 200 μg, Placebo Part C
	Comments	200 micrograms of Tropifexor (Part C) vs Placebo
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: Change in BMI from baseline to EOT (Parts C) (Full analysis set)

Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-2.11
	Confidence Interval	(2-Sided) 95% -2.75 to -1.46
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.327
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline in Waist to Hip (WTH) Ratio
Description	The LS mean change in waist to hip ratio after 12 weeks of treatment
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description
FAS

Arm/Group Title	LJN452 10 μg	LJN452 30 μg	LJN452 60 μg	LJN452 90 μg	Placebo A+B	LJN452 140 μg	LJN452 200 μg	Placebo Part C
Arm/Group Description	10 micrograms of Tropifexor (Part A)	30 micrograms of Tropifexor (Part A)	60 micrograms of Tropifexor (Parts A + B)	90 micrograms of Tropifexor (Parts A + B)	Placebo (Parts A+B)	140 micrograms of Tropifexor (Part C)	200 micrograms of Tropifexor (Part C)	Placebo (Part C)
Measure Participants	13	15	37	84	46	49	37	51
Mean (Standard Error) [ratio]	-0.01 (0.009)	0.00 (0.008)	-0.01 (0.005)	0.00 (0.004)	0.00 (0.005)	0.00 (0.008)	-0.01 (0.007)	-0.02 (0.007)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LJN452 10 μg, Placebo A+B
	Comments	10 micrograms of Tropifexor (Part A) vs Placebo
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: Change in WTH ratio from baseline to EOT (Parts A+B) (Full analysis set)

Statistical Test of Hypothesis	p-Value	0.530
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95% -0.03 to 0.01
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.009
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LJN452 30 μg, Placebo A+B
	Comments	30 micrograms of Tropifexor (Part A) vs Placebo
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: Change in WTH ratio from baseline to EOT (Parts A+B) (Full analysis set)

Statistical Test of Hypothesis	p-Value	0.857
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	0.00
	Confidence Interval	(2-Sided) 95% -0.02 to 0.01
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.008
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	LJN452 60 μg, Placebo A+B
	Comments	60 micrograms of Tropifexor (Part A) vs Placebo
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: Change in WTH ratio from baseline to EOT (Parts A+B) (Full analysis set)

Statistical Test of Hypothesis	p-Value	0.262
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95% -0.02 to 0.00
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.005
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	LJN452 90 μg, Placebo A+B
	Comments	90 micrograms of Tropifexor (Parts A + B) vs Placebo
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: Change in WTH ratio from baseline to EOT (Parts A+B) (Full analysis set)

Statistical Test of Hypothesis	p-Value	0.323
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	0.00
	Confidence Interval	(2-Sided) 95% 0.00 to 0.01
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.004
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	LJN452 140 μg, Placebo Part C
	Comments	140 micrograms of Tropifexor (Part C) vs Placebo
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: Change in WTH ratio from baseline to EOT (Part C) (Full analysis set)

Statistical Test of Hypothesis	p-Value	0.100
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 95% -0.02 to 0.01
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.008
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	LNJ452 200 μg, Placebo Part C
	Comments	200 micrograms of Tropifexor (Part C) vs Placebo
	Type of Statistical Test	Superiority
	Comments	Repeated measures analysis: Change in WTH ratio from baseline to EOT (Part C) (Full analysis set)

Statistical Test of Hypothesis	p-Value	0.693
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	LS Mean change
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95% -0.03 to 0.00
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.007
	Estimation Comments

8. Secondary Outcome

Title	Change From Baseline in Biomarker FGF19
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 Value at 6 weeks minus value at baseline
Time Frame	baseline, week 6

Outcome Measure Data

Analysis Population Description
FAS

Arm/Group Title	LJN452 10 μg	LJN452 30 μg	LJN452 60 μg	LJN452 90 μg	Placebo A+B	LJN452 140 μg	LJN452 200 μg	Placebo Part C
Arm/Group Description	10 micrograms of Tropifexor (Part A)	30 micrograms of Tropifexor (Part A)	60 micrograms of Tropifexor (Parts A + B)	90 micrograms of Tropifexor (Parts A + B)	Placebo (Parts A+B)	140 micrograms of Tropifexor (Part C)	200 micrograms of Tropifexor (Part C)	Placebo (Part C)
Measure Participants	14	15	34	78	42	47	42	42
Geometric Least Squares Mean (95% Confidence Interval) [pg/mL]	1.45	1.53	3.82	5.78	1.33	1.97	2.23	1.22

9. Secondary Outcome

Title	Change From Baseline in Biomarker C4
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
Time Frame	Week 6, 4 hours post dose

Outcome Measure Data

Analysis Population Description
FAS

Arm/Group Title	LJN452 10 μg	LJN452 30 μg	LJN452 60 μg	LJN452 90 μg	Placebo A+B	LJN452 140 μg	LJN452 200 μg	Placebo Part C
Arm/Group Description	10 micrograms of Tropifexor (Part A)	30 micrograms of Tropifexor (Part A)	60 micrograms of Tropifexor (Parts A + B)	90 micrograms of Tropifexor (Parts A + B)	Placebo (Parts A+B)	140 micrograms of Tropifexor (Part C)	200 micrograms of Tropifexor (Part C)	Placebo (Part C)
Measure Participants	14	15	37	85	46	47	42	51
Mean (Standard Deviation) [ng/mL]	38.82 (25.765)	32.75 (23.360)	28.38 (13.394)	40.19 (31.356)	47.70 (25.524)	14.97 (20.232)	8.54 (9.583)	38.40 (24.552)

10. Secondary Outcome

Title	Change From Baseline on Markers of Liver Fibrosis, Fibroscan
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 Scores range from 0-4 with zero being no liver scarring and 4 being advanced liver scarring (cirrhosis)
Time Frame	End of Treatment (EoT): For Parts A&B, EoT was Week 12. For Part C, EoT was Week 48

Outcome Measure Data

Analysis Population Description
FAS

Arm/Group Title	LJN452 10 μg	LJN452 30 μg	LJN452 60 μg	LJN452 90 μg	Placebo A+B	LJN452 140 μg	LJN452 200 μg	Placebo (Part C)
Arm/Group Description	10 micrograms of Tropifexor (Part A)	30 micrograms of Tropifexor (Part A)	60 micrograms of Tropifexor (Parts A + B)	90 micrograms of Tropifexor (Parts A + B)	Placebo (Parts A+B)	140 micrograms of Tropifexor (Part C)	200 micrograms of Tropifexor (Part C)	Placebo (Part C)
Measure Participants	14	16	37	85	46	46	42	51
Mean (Standard Deviation) [scores]	10.94 (5.314)	10.40 (7.663)	9.90 (4.095)	9.00 (4.152)	9.30 (4.676)	11.29 (3.677)	12.03 (4.804)	11.26 (4.027)

11. Secondary Outcome

Title	Change From Baseline on Markers of Liver Fibrosis Panel (ELF) Score
Description	ANCOVA: LS Mean Change in Enhanced liver fibrosis panel (ELF) score from baseline by visit up to EOT. The total ELF score reference range calculated non-parametrically is 6.72 (90% CI 6.58-6.84) to 9.79 (90% CI 9.45-10.01); Journal of Hepatology 2013 vol. 59 j 236-242. Enhanced liver fibrosis Test (ELF) panel: the following was assessed: hyaluronic acid (HA), tissue inhibitor of metalloproteinases (TIMP-1), and amino-terminal pro-peptide of procollagen type III (PIIINP). The Enhanced Liver Fibrosis score is a linear combination of TIMP-1, PIIINP, and HA with the following formula: ELF score = 2.494+0.846 x ln(HA) + 0.735 x ln (PIIINP) + 0.391 x ln (TIMP-1).
Time Frame	End of Treatment (EoT): For Parts A&B, EoT was Week 12. For Part C, EoT was Week 48

Outcome Measure Data

Analysis Population Description
FAS

Arm/Group Title	LJN452 10 μg	LJN452 30 μg	LJN452 60 μg	LJN452 90 μg	Placebo A+B	LJN452 140 μg	LJN452 200 μg	Placebo Part C
Arm/Group Description	10 micrograms of Tropifexor (Part A)	30 micrograms of Tropifexor (Parts A + B)	60 micrograms of Tropifexor (Parts A + B)	90 micrograms of Tropifexor (Parts A + B)	Placebo (Parts A+B)	140 micrograms of Tropifexor (Part C) vs placebo	200 micrograms of Tropifexor (Part C)	(Part C)
Measure Participants	14	16	34	78	46	47	42	51
Least Squares Mean (Standard Error) [scores on a scale]	0.05 (0.158)	0.00 (0.146)	-0.19 (0.097)	0.20 (0.064)	0.08 (0.087)	-0.34 (0.132)	-0.24 (0.122)	-0.08 (0.115)

12. Secondary Outcome

Title	Change From Baseline on Markers of Liver Fibrosis, Fibrotest (Parts A+B)
Description	Fibrosis biomarker test, originally called Fibrotest®/ Fibrosure®, is combines α2-macroglobulin (a2m), apolipoprotein A1 (aA1), total bilirubin (BIL), haptoglobin (h), GGT, and ALT. The coefficient for the score is calculated as: z = 4.467 x log(a2m) - 1.357 x log(h) + 1.017 x log(GGT) + 0.0281 x Age + 1.737 x log(BIL) - 1.184 x (aA1) + 0.301 x Gender - 5.54 where Gender = 1 for male and Gender = 0 for female. The score is then: 1/(1+e^-z). Calculated scores range from 0.00 (no fibrosis) to 1.00 (severe fibrosis or cirrhosis) (See Part C in separate outcomes that follows)
Time Frame	End of Treatment (EoT):12 weeks

Outcome Measure Data

Analysis Population Description
FAS

Arm/Group Title	LJN452 10 μg	LJN452 30 μg	LJN452 60 μg	LJN452 90 μg	Placebo (A+B)
Arm/Group Description	10 micrograms of Tropifexor (Part A)	30 micrograms of Tropifexor (Part A)	60 micrograms of Tropifexor (Parts A + B)	90 micrograms of Tropifexor (Parts A + B)	Placebo (Parts A+B)
Measure Participants	14	16	37	85	46
Mean (Standard Deviation) [scores]	-0.23 (0.284)	-1.49 (0.852)	-1.44 (1.080)	-1.34 (1.222)	-1.23 (1.088)

13. Secondary Outcome

Title	Change From Baseline on Markers of Liver Fibrosis, Fibrotest, (Part C)
Description	Fibrosis biomarker test, originally called Fibrotest®/ Fibrosure®, is combines α2-macroglobulin (a2m), apolipoprotein A1 (aA1), total bilirubin (BIL), haptoglobin (h), GGT, and ALT. The coefficient for the score is calculated as: z = 4.467 x log(a2m) - 1.357 x log(h) + 1.017 x log(GGT) + 0.0281 x Age + 1.737 x log(BIL) - 1.184 x (aA1) + 0.301 x Gender - 5.54 where Gender = 1 for male and Gender = 0 for female. The score is then: 1/(1+e^-z). Calculated scores range from 0.00 (no fibrosis) to 1.00 (severe fibrosis or cirrhosis)
Time Frame	End of Treatment (EoT) was 48 weeks

Outcome Measure Data

Analysis Population Description
FAS

Arm/Group Title	LJN452 140 μg	LJN452 200 μg	Placebo A+B
Arm/Group Description	140 micrograms of Tropifexor (Part C)	200 micrograms of Tropifexor (Part C)	Placebo A+B
Measure Participants	34	28	37
Least Squares Mean (Standard Error) [scores]	-0.42 (0.131)	-0.44 (0.135)	-0.17 (0.119)

14. Secondary Outcome

Title	Change From Baseline on Gamma-glutamyl Transferase (GGT)
Description	Summary statistics of change in GGT (IU/L) from baseline by visit up to EoT
Time Frame	EoT for Parts A+B=12 weeks; EoT for Part C = 48 weeks

Outcome Measure Data

Analysis Population Description
FAS

Arm/Group Title	LJN452 10 μg	LJN452 30 μg	LJN452 60 μg	LJN452 90 μg	Placebo A+B	LJN452 140 μg	LJN452 200 μg	Placebo C
Arm/Group Description	10 micrograms of Tropifexor (Part A)	30 micrograms of Tropifexor (Part A)	60 micrograms of Tropifexor (Parts A + B)	90 micrograms of Tropifexor (Parts A + B)	Placebo (Parts A+B)	140 micrograms of Tropifexor (Part C)	200 micrograms of Tropifexor (Part C)	Placebo (Part C)
Measure Participants	14	15	37	84	78	51	42	36
Least Squares Mean (Standard Error) [IU/L]	1.6 (10.93)	-29.9 (10.11)	-34.2 (6.70)	-45.7 (4.52)	-5.0 (6.10)	-35.2 (11.58)	-29.9 (11.65)	9.0 (10.72)

15. Secondary Outcome

Title	Change From Baseline on Fasting Lipid Profile
Description	Repeated measures analysis: LS geometric mean ratio of fasting lipids to baseline by visit up to EOT
Time Frame	End of Treatment (EoT): For Parts A&B, EoT was Week 12. For Part C, EoT was Week 48

Outcome Measure Data

Analysis Population Description
FAS

Arm/Group Title	LJN452 10 μg	LJN452 30 μg	LJN452 60 μg	LJN452 90 μg	Placebo A+B	LJN452 140 μg	LJN452 200 μg	Placebo Part C
Arm/Group Description	10 micrograms of Tropifexor (Part A)	30 micrograms of Tropifexor (Part A)	60 micrograms of Tropifexor (Parts A + B)	90 micrograms of Tropifexor (Parts A + B)	Placebo (Parts A+B)	140 micrograms of Tropifexor (Part C)	200 micrograms of Tropifexor (Part C)	Placebo (Part C)
Measure Participants	14	16	37	50	46	46	42	37
Cholesterol	0.949	1.003	1.029	1.029	0.956	1.032	1.071	0.977
Triglycerides	0.920	0.919	0.960	1.048	0.991	1.070	1.068	0.883
LDL Cholesterol	0.923	1.044	1.092	1.104	0.943	1.056	1.200	0.973
HDL Cholesterol	1.019	1.001	0.961	0.897	0.959	0.855	0.824	1.033
LDL/HDL Ratio	0.921	1.058	1.139	1.227	0.980	1.252	1.478	0.947
Free Glycerol	1.0563	0.9376	0.9128	0.9915	0.9604	1.1115	0.9808	0.9846
Free Fatty Acid	1.082	0.864	0.929	0.947	0.936	1.072	0.887	0.977

16. Secondary Outcome

Title	Itch Based on a Visual Analog Scale (VAS) Rating Scale
Description	Repeated measures analysis: Change in VAS for Itch from baseline by visit up to EoT VAS score 0 = no disease; and 9 is severely advanced disease
Time Frame	EoT for Parts A+B=12 weeks; EoT for Part C = 48 weeks

Outcome Measure Data

Analysis Population Description
FAS

Arm/Group Title	LJN452 10 μg	LJN452 30 μg	LJN452 60 μg	LJN452 90 μg	Placebo A+B	LJN452 140 μg	LJN452 200 μg	Placebo Part C
Arm/Group Description	10 micrograms of Tropifexor (Part A)	30 micrograms of Tropifexor (Part A) vs placebo	60 micrograms of Tropifexor (Parts A + B) vs placebo	90 micrograms of Tropifexor (Parts A + B)	Placebo for parts A + B	140 micrograms of Tropifexor (Part C)	200 micrograms of Tropifexor (Part C)	Placebo (Part C)
Measure Participants	14	16	36	78	39	47	42	37
Least Squares Mean (Standard Error) [scores]	-0.3 (0.48)	0.2 (0.43)	0.4 (0.28)	0.1 (0.19)	0.6 (0.27)	0.6 (0.37)	1.1 (0.35)	0.3 (0.33)

17. Secondary Outcome

Title	Pre-dose Trough Concentration (Ctrough) of LJN452
Description	Pre-dose Trough Concentration (Ctrough) of tropifexor (LJN452)
Time Frame	In Parts A and B, LJN452 Ctrough was measured on Study Days 7, 14, 28, 42, 56, and 84. In Part C LJN452 Ctrough was measured on Study Days 42, 84, 168, 280 and 336

Outcome Measure Data

Analysis Population Description
FAS

Arm/Group Title	LJN452 10 μg	LJN452 30 μg	LJN452 60 μg	LJN452 90 μg	LJN452 140 μg	LJN452 200 μg
Arm/Group Description	10 micrograms of Tropifexor (Parts A + B)	30 micrograms of Tropifexor (Parts A + B)	60 micrograms of Tropifexor (Parts A + B)	90 micrograms of Tropifexor (Parts A + B)	140 micrograms of Tropifexor (Part C)	200 micrograms of Tropifexor (Part C)
Measure Participants	14	16	37	85	37	51
Profile day 7	0.142 (0.119)	0.355 (0.194)	0.638 (0.453)	1.215 (0.593)
Profile day 14	0.216 (0.127)	0.505 (0.328)	0.626 (0.281)	1.115 (0.693)
Profile day 28	0.118 (0.087)	0.411 (0.250)	0.639 (0.265)	1.027 (0.700)
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)
Profile day 56	0.168 (0.088)	0.474 (0.273)	0.637 (0.278)	1.041 (0.701)
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)
Profile day 168	1.889 (1.340)	2.146 (1.383)
Profile day 280	2.129 (1.257)	1.990 (1.053)
Profile day 336	1.444 (1.077)	1.979 (1.153)

18. Secondary Outcome

Title	C2h (Steady-state Drug Levels 2 Hours Postdose) of LJN452
Description	Summary C2h of tropifexor (LJN452)
Time Frame	Days 7 and 14 (10 and 30μg LJN452 C2h was not measured day 14)

Outcome Measure Data

Analysis Population Description
FAS

Arm/Group Title	LJN452 10 μg	LJN452 30 μg	LJN452 60 μg	LJN452 90 μg
Arm/Group Description	10 micrograms of Tropifexor (Parts A + B)	30 micrograms of Tropifexor (Parts A + B)	60 micrograms of Tropifexor (Parts A + B)	90 micrograms of Tropifexor (Parts A + B)
Measure Participants	14	16	37	85
Profile day 7	0.190 (0.143)	0.702 (0.399)	1.228 (0.598)	2.193 (1.003)
Profile day 14	1.344 (0.727)	2.001 (1.053)

19. Secondary Outcome

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
Description	Number of patients who have at least one point improvement in fibrosis (NASH CRN staging) without worsening of steatohepatitis (total score)
Time Frame	EoT (Week 48)

Outcome Measure Data

Analysis Population Description
Full analysis set (FAS)

Arm/Group Title	LJN452 140 μg	LNJ452 200 μg	Placebo C
Arm/Group Description	140 micrograms of Tropifexor (Part C)	200 micrograms of Tropifexor (Part C)	Placebo (Part C)
Measure Participants	39	35	42
Count of Participants [Participants]	11 78.6%	11 68.8%	12 32.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LJN452 10 μg, LJN452 60 μg
	Comments	At least one point improvement in fibrosis (NASH CRN staging) without worsening of steatohepatitis (total score)
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	1.0000
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.004
	Confidence Interval	(2-Sided) 95% -0.214 to 0.223
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LJN452 30 μg, LJN452 60 μg
	Comments	At least one point improvement in fibrosis (NASH CRN staging) without worsening of steatohepatitis (total score)
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.8074
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.029
	Confidence Interval	(2-Sided) 95% -0.196 to 0.251
	Parameter Dispersion	Type: Value:
	Estimation Comments

20. Secondary Outcome

Title	Biopsy-based Response at Week 48 Compared to Baseline: At Least One Point Improvement in Fibrosis (NASH CRN Staging) Without Worsening - FDA
Description	Number of patients who have at least one point improvement in fibrosis (NASH CRN staging) without worsening of steatohepatitis (FDA)
Time Frame	EoT (Week 48)

Outcome Measure Data

Analysis Population Description
Full analysis set (FAS)

Arm/Group Title	LJN452 140 μg	LNJ452 200 μg	Placebo A+B
Arm/Group Description	140 micrograms of Tropifexor (Part C)	200 micrograms of Tropifexor (Part C)	Placebo A+B
Measure Participants	38	35	42
Count of Participants [Participants]	11 78.6%	11 68.8%	11 29.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LJN452 10 μg, LJN452 60 μg
	Comments	At least one point improvement in fibrosis (NASH CRN staging) without worsening of steatohepatitis (FDA)
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.8070
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.028
	Confidence Interval	(2-Sided) 95% -0.191 to 0.246
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LJN452 30 μg, LJN452 60 μg
	Comments	At least one point improvement in fibrosis (NASH CRN staging) without worsening of steatohepatitis (FDA)
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.6233
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.052
	Confidence Interval	(2-Sided) 95% -0.173 to 0.273
	Parameter Dispersion	Type: Value:
	Estimation Comments

21. Secondary Outcome

Title	Biopsy-based Response at Week 48 Compared to Baseline: At Least One Point Improvement in Fibrosis (NASH CRN Staging) Without Worsening - EMA
Description	Number of patients who have at least one point improvement in fibrosis (NASH CRN staging) without worsening of steatohepatitis (EMA)
Time Frame	EoT (Week 48)

Outcome Measure Data

Analysis Population Description
Full analysis set (FAS)

Arm/Group Title	LJN452 140 μg	LNJ452 200 μg	Placebo A+B
Arm/Group Description	140 micrograms of Tropifexor (Part C)	200 micrograms of Tropifexor (Part C)	Placebo A+B
Measure Participants	38	35	42
Count of Participants [Participants]	11 78.6%	11 68.8%	12 32.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LJN452 10 μg, LJN452 60 μg
	Comments	At least one point improvement in fibrosis (NASH CRN staging) without worsening of steatohepatitis (EMA)
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	1.0000
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.004
	Confidence Interval	(2-Sided) 95% -0.214 to 0.233
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LJN452 30 μg, LJN452 60 μg
	Comments	At least one point improvement in fibrosis (NASH CRN staging) without worsening of steatohepatitis (EMA)
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.8074
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.029
	Confidence Interval	(2-Sided) 95% -0.196 to 0.251
	Parameter Dispersion	Type: Value:
	Estimation Comments

22. Secondary Outcome

Title	Biopsy-based Response at Week 48 Compared to Baseline: Difference Between Treatment Groups (Part C) - Resolution of Steatohepatitis (Diagnostic Category)
Description	Resolution of steatohepatitis (diagnostic category) without worsening of fibrosis (NASH CRN staging)
Time Frame	EoT (Week 48)

Outcome Measure Data

Analysis Population Description
Full analysis set (FAS)

Arm/Group Title	LJN452 140 μg	LNJ452 200 μg	Placebo A+B
Arm/Group Description	140 micrograms of Tropifexor (Part C)	200 micrograms of Tropifexor (Part C)	Placebo A+B
Measure Participants	38	35	42
Count of Participants [Participants]	4 28.6%	7 43.8%	3 8.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LJN452 10 μg, LJN452 60 μg
	Comments	Resolution of steatohepatitis (diagnostic category) without worsening of fibrosis (NASH CRN staging)
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.7028
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.034
	Confidence Interval	(2-Sided) 95% -0.184 to 0.252
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LJN452 30 μg, LJN452 60 μg
	Comments	Resolution of steatohepatitis (diagnostic category) without worsening of fibrosis (NASH CRN staging)
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.1713
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.129
	Confidence Interval	(2-Sided) 95% -0.098 to 0.345
	Parameter Dispersion	Type: Value:
	Estimation Comments

23. Secondary Outcome

Title	Biopsy-based Response at Week 48 Compared to Baseline: Difference Between Treatment Groups (Part C) - Resolution of Steatohepatitis (FDA, EMA)
Description	Resolution of steatohepatitis (diagnostic category) without worsening of fibrosis (NASH CRN staging)
Time Frame	EoT (Week 48)

Outcome Measure Data

Analysis Population Description
Full analysis set (FAS)

Arm/Group Title	LJN452 140 μg	LNJ452 200 μg	Placebo A+B
Arm/Group Description	140 micrograms of Tropifexor (Part C)	200 micrograms of Tropifexor (Part C)	Placebo A+B
Measure Participants	38	35	42
Count of Participants [Participants]	0 0%	2 12.5%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LJN452 30 μg, LJN452 60 μg
	Comments	Resolution of steatohepatitis (FDA, EMA) without worsening of fibrosis (NASH CRN staging)
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.2033
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.057
	Confidence Interval	(2-Sided) 95% -0.168 to 0.278
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

	LJN452 10 μg		LJN452 30 μg		LJN452 60 μg		LJN452 90 μg		LJN452 140 μg		LJN452 200 μg		Placebo		Total
Time Frame	To End of Treatment (EoT): For Parts A&B, EoT was Week 12; For Part C, EoT was Week 48
Adverse Event Reporting Description	AEs are any untoward sign or symptom that occurred during the study treatment period 350 patients were randomized. One patient was treated at 2 sites, so 351 enrolled may appearr in some places.

Arm/Group Title	LJN452 10 μg		LJN452 30 μg		LJN452 60 μg		LJN452 90 μg		LJN452 140 μg		LJN452 200 μg		Placebo		Total
Arm/Group Description	LJN452 10 mcg (Part A)		30 micrograms of Tropifexor (Part A)		LJN452 60 mcg (Parts A+B)		90 micrograms of Tropifexor (Parts A + B)		LJN452 140 mcg (Part C)		LJN452 200 mcg (Part C)		Placebo A+B+C		Total
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/17 (0%)		0/37 (0%)		0/85 (0%)		0/50 (0%)		0/51 (0%)		0/97 (0%)		0/350 (0%)
Serious Adverse Events
	LJN452 10 μg		LJN452 30 μg		LJN452 60 μg		LJN452 90 μg		LJN452 140 μg		LJN452 200 μg		Placebo		Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/17 (0%)		0/37 (0%)		4/85 (4.7%)		5/50 (10%)		3/51 (5.9%)		6/97 (6.2%)		18/350 (5.1%)
Cardiac disorders
Angina pectoris	0/13 (0%)		0/17 (0%)		0/37 (0%)		0/85 (0%)		1/50 (2%)		1/51 (2%)		0/97 (0%)		2/350 (0.6%)
Tachycardia	0/13 (0%)		0/17 (0%)		0/37 (0%)		0/85 (0%)		1/50 (2%)		0/51 (0%)		0/97 (0%)		1/350 (0.3%)
Gastrointestinal disorders
Haematochezia	0/13 (0%)		0/17 (0%)		0/37 (0%)		1/85 (1.2%)		0/50 (0%)		0/51 (0%)		0/97 (0%)		1/350 (0.3%)
General disorders
Non-cardiac chest pain	0/13 (0%)		0/17 (0%)		0/37 (0%)		0/85 (0%)		1/50 (2%)		0/51 (0%)		0/97 (0%)		1/350 (0.3%)
Hepatobiliary disorders
Cholecystitis acute	0/13 (0%)		0/17 (0%)		0/37 (0%)		0/85 (0%)		0/50 (0%)		0/51 (0%)		1/97 (1%)		1/350 (0.3%)
Infections and infestations
Gastroenteritis	0/13 (0%)		0/17 (0%)		0/37 (0%)		0/85 (0%)		0/50 (0%)		0/51 (0%)		1/97 (1%)		1/350 (0.3%)
Injury, poisoning and procedural complications
Animal bite	0/13 (0%)		0/17 (0%)		0/37 (0%)		0/85 (0%)		1/50 (2%)		0/51 (0%)		0/97 (0%)		1/350 (0.3%)
Multiple injuries	0/13 (0%)		0/17 (0%)		0/37 (0%)		0/85 (0%)		0/50 (0%)		0/51 (0%)		1/97 (1%)		1/350 (0.3%)
Investigations
Blood creatine phosphokinase increased	0/13 (0%)		0/17 (0%)		0/37 (0%)		1/85 (1.2%)		0/50 (0%)		0/51 (0%)		0/97 (0%)		1/350 (0.3%)
Metabolism and nutrition disorders
Hyperglycaemia	0/13 (0%)		0/17 (0%)		0/37 (0%)		0/85 (0%)		0/50 (0%)		1/51 (2%)		0/97 (0%)		1/350 (0.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/13 (0%)		0/17 (0%)		0/37 (0%)		1/85 (1.2%)		0/50 (0%)		0/51 (0%)		0/97 (0%)		1/350 (0.3%)
Synovial cyst	0/13 (0%)		0/17 (0%)		0/37 (0%)		0/85 (0%)		1/50 (2%)		0/51 (0%)		0/97 (0%)		1/350 (0.3%)
Trigger finger	0/13 (0%)		0/17 (0%)		0/37 (0%)		0/85 (0%)		1/50 (2%)		0/51 (0%)		0/97 (0%)		1/350 (0.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant melanoma	0/13 (0%)		0/17 (0%)		0/37 (0%)		0/85 (0%)		0/50 (0%)		0/51 (0%)		1/97 (1%)		1/350 (0.3%)
Nervous system disorders
Transient ischaemic attack	0/13 (0%)		0/17 (0%)		0/37 (0%)		0/85 (0%)		0/50 (0%)		0/51 (0%)		1/97 (1%)		1/350 (0.3%)
Product Issues
Device dislocation	0/13 (0%)		0/17 (0%)		0/37 (0%)		0/85 (0%)		0/50 (0%)		0/51 (0%)		1/97 (1%)		1/350 (0.3%)
Renal and urinary disorders
Nephrolithiasis	0/13 (0%)		0/17 (0%)		0/37 (0%)		0/85 (0%)		0/50 (0%)		1/51 (2%)		0/97 (0%)		1/350 (0.3%)
Renal impairment	0/13 (0%)		0/17 (0%)		0/37 (0%)		1/85 (1.2%)		0/50 (0%)		0/51 (0%)		0/97 (0%)		1/350 (0.3%)
Reproductive system and breast disorders
Endometrial thickening	0/13 (0%)		0/17 (0%)		0/37 (0%)		0/85 (0%)		1/50 (2%)		0/51 (0%)		0/97 (0%)		1/350 (0.3%)
Respiratory, thoracic and mediastinal disorders
Haemothorax	0/13 (0%)		0/17 (0%)		0/37 (0%)		0/85 (0%)		0/50 (0%)		0/51 (0%)		1/97 (1%)		1/350 (0.3%)
Other (Not Including Serious) Adverse Events
	LJN452 10 μg		LJN452 30 μg		LJN452 60 μg		LJN452 90 μg		LJN452 140 μg		LJN452 200 μg		Placebo		Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/13 (38.5%)		11/17 (64.7%)		16/37 (43.2%)		50/85 (58.8%)		43/50 (86%)		45/51 (88.2%)		63/97 (64.9%)		233/350 (66.6%)
Blood and lymphatic system disorders
Anaemia	0/13 (0%)		1/17 (5.9%)		0/37 (0%)		0/85 (0%)		1/50 (2%)		0/51 (0%)		1/97 (1%)		3/350 (0.9%)
Gastrointestinal disorders
Abdominal distension	0/13 (0%)		0/17 (0%)		1/37 (2.7%)		3/85 (3.5%)		5/50 (10%)		2/51 (3.9%)		4/97 (4.1%)		15/350 (4.3%)
Abdominal pain	0/13 (0%)		0/17 (0%)		0/37 (0%)		1/85 (1.2%)		2/50 (4%)		3/51 (5.9%)		8/97 (8.2%)		14/350 (4%)
Abdominal pain lower	0/13 (0%)		1/17 (5.9%)		0/37 (0%)		0/85 (0%)		1/50 (2%)		0/51 (0%)		0/97 (0%)		2/350 (0.6%)
Abdominal pain upper	0/13 (0%)		2/17 (11.8%)		0/37 (0%)		2/85 (2.4%)		6/50 (12%)		2/51 (3.9%)		3/97 (3.1%)		15/350 (4.3%)
Constipation	0/13 (0%)		1/17 (5.9%)		1/37 (2.7%)		2/85 (2.4%)		3/50 (6%)		3/51 (5.9%)		5/97 (5.2%)		15/350 (4.3%)
Diarrhoea	0/13 (0%)		1/17 (5.9%)		1/37 (2.7%)		4/85 (4.7%)		3/50 (6%)		7/51 (13.7%)		6/97 (6.2%)		22/350 (6.3%)
Dry mouth	0/13 (0%)		1/17 (5.9%)		1/37 (2.7%)		2/85 (2.4%)		0/50 (0%)		2/51 (3.9%)		2/97 (2.1%)		8/350 (2.3%)
Dyspepsia	0/13 (0%)		0/17 (0%)		0/37 (0%)		4/85 (4.7%)		2/50 (4%)		3/51 (5.9%)		4/97 (4.1%)		13/350 (3.7%)
Flatulence	0/13 (0%)		0/17 (0%)		0/37 (0%)		1/85 (1.2%)		5/50 (10%)		2/51 (3.9%)		2/97 (2.1%)		10/350 (2.9%)
Gastrooesophageal reflux disease	0/13 (0%)		1/17 (5.9%)		0/37 (0%)		1/85 (1.2%)		2/50 (4%)		2/51 (3.9%)		1/97 (1%)		7/350 (2%)
Nausea	0/13 (0%)		0/17 (0%)		1/37 (2.7%)		4/85 (4.7%)		6/50 (12%)		10/51 (19.6%)		11/97 (11.3%)		32/350 (9.1%)
Vomiting	0/13 (0%)		2/17 (11.8%)		0/37 (0%)		3/85 (3.5%)		3/50 (6%)		4/51 (7.8%)		2/97 (2.1%)		14/350 (4%)
General disorders
Fatigue	0/13 (0%)		3/17 (17.6%)		1/37 (2.7%)		5/85 (5.9%)		7/50 (14%)		3/51 (5.9%)		9/97 (9.3%)		28/350 (8%)
Pyrexia	1/13 (7.7%)		0/17 (0%)		0/37 (0%)		1/85 (1.2%)		2/50 (4%)		1/51 (2%)		1/97 (1%)		6/350 (1.7%)
Infections and infestations
Body tinea	0/13 (0%)		0/17 (0%)		0/37 (0%)		0/85 (0%)		3/50 (6%)		0/51 (0%)		0/97 (0%)		3/350 (0.9%)
Bronchitis	0/13 (0%)		1/17 (5.9%)		0/37 (0%)		0/85 (0%)		3/50 (6%)		0/51 (0%)		6/97 (6.2%)		10/350 (2.9%)
Influenza	0/13 (0%)		0/17 (0%)		0/37 (0%)		9/85 (10.6%)		1/50 (2%)		3/51 (5.9%)		4/97 (4.1%)		17/350 (4.9%)
Laryngitis	0/13 (0%)		1/17 (5.9%)		0/37 (0%)		0/85 (0%)		0/50 (0%)		0/51 (0%)		0/97 (0%)		1/350 (0.3%)
Nasopharyngitis	0/13 (0%)		0/17 (0%)		2/37 (5.4%)		6/85 (7.1%)		6/50 (12%)		5/51 (9.8%)		10/97 (10.3%)		29/350 (8.3%)
Periodontitis	0/13 (0%)		1/17 (5.9%)		0/37 (0%)		0/85 (0%)		1/50 (2%)		0/51 (0%)		0/97 (0%)		2/350 (0.6%)
Rhinitis	0/13 (0%)		1/17 (5.9%)		0/37 (0%)		3/85 (3.5%)		0/50 (0%)		0/51 (0%)		1/97 (1%)		5/350 (1.4%)
Sinusitis	0/13 (0%)		0/17 (0%)		0/37 (0%)		1/85 (1.2%)		3/50 (6%)		0/51 (0%)		7/97 (7.2%)		11/350 (3.1%)
Tonsillitis	1/13 (7.7%)		0/17 (0%)		0/37 (0%)		1/85 (1.2%)		0/50 (0%)		0/51 (0%)		0/97 (0%)		2/350 (0.6%)
Upper respiratory tract infection	0/13 (0%)		0/17 (0%)		2/37 (5.4%)		8/85 (9.4%)		9/50 (18%)		3/51 (5.9%)		10/97 (10.3%)		32/350 (9.1%)
Urinary tract infection	1/13 (7.7%)		0/17 (0%)		0/37 (0%)		1/85 (1.2%)		9/50 (18%)		0/51 (0%)		3/97 (3.1%)		14/350 (4%)
Viral sinusitis	0/13 (0%)		1/17 (5.9%)		0/37 (0%)		0/85 (0%)		0/50 (0%)		0/51 (0%)		0/97 (0%)		1/350 (0.3%)
Injury, poisoning and procedural complications
Contusion	0/13 (0%)		0/17 (0%)		0/37 (0%)		0/85 (0%)		3/50 (6%)		0/51 (0%)		2/97 (2.1%)		5/350 (1.4%)
Investigations
Alanine aminotransferase increased	0/13 (0%)		0/17 (0%)		0/37 (0%)		3/85 (3.5%)		1/50 (2%)		3/51 (5.9%)		3/97 (3.1%)		10/350 (2.9%)
Aspartate aminotransferase increased	0/13 (0%)		0/17 (0%)		0/37 (0%)		2/85 (2.4%)		4/50 (8%)		4/51 (7.8%)		2/97 (2.1%)		12/350 (3.4%)
Blood alkaline phosphatase increased	0/13 (0%)		0/17 (0%)		0/37 (0%)		0/85 (0%)		1/50 (2%)		5/51 (9.8%)		0/97 (0%)		6/350 (1.7%)
Blood creatinine increased	1/13 (7.7%)		0/17 (0%)		0/37 (0%)		0/85 (0%)		0/50 (0%)		1/51 (2%)		0/97 (0%)		2/350 (0.6%)
Platelet count decreased	1/13 (7.7%)		0/17 (0%)		0/37 (0%)		0/85 (0%)		0/50 (0%)		0/51 (0%)		0/97 (0%)		1/350 (0.3%)
Metabolism and nutrition disorders
Decreased appetite	0/13 (0%)		2/17 (11.8%)		1/37 (2.7%)		2/85 (2.4%)		1/50 (2%)		2/51 (3.9%)		1/97 (1%)		9/350 (2.6%)
Diabetes mellitus	1/13 (7.7%)		0/17 (0%)		0/37 (0%)		2/85 (2.4%)		2/50 (4%)		1/51 (2%)		1/97 (1%)		7/350 (2%)
Type 2 diabetes mellitus	0/13 (0%)		0/17 (0%)		0/37 (0%)		2/85 (2.4%)		2/50 (4%)		3/51 (5.9%)		2/97 (2.1%)		9/350 (2.6%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/13 (0%)		0/17 (0%)		0/37 (0%)		1/85 (1.2%)		3/50 (6%)		1/51 (2%)		3/97 (3.1%)		8/350 (2.3%)
Back pain	0/13 (0%)		1/17 (5.9%)		0/37 (0%)		3/85 (3.5%)		1/50 (2%)		2/51 (3.9%)		7/97 (7.2%)		14/350 (4%)
Musculoskeletal pain	0/13 (0%)		1/17 (5.9%)		0/37 (0%)		0/85 (0%)		1/50 (2%)		0/51 (0%)		1/97 (1%)		3/350 (0.9%)
Nervous system disorders
Headache	1/13 (7.7%)		1/17 (5.9%)		1/37 (2.7%)		4/85 (4.7%)		3/50 (6%)		3/51 (5.9%)		6/97 (6.2%)		19/350 (5.4%)
Poor quality sleep	0/13 (0%)		1/17 (5.9%)		0/37 (0%)		0/85 (0%)		0/50 (0%)		0/51 (0%)		0/97 (0%)		1/350 (0.3%)
Psychiatric disorders
Anxiety	0/13 (0%)		1/17 (5.9%)		0/37 (0%)		0/85 (0%)		1/50 (2%)		0/51 (0%)		0/97 (0%)		2/350 (0.6%)
Insomnia	0/13 (0%)		1/17 (5.9%)		1/37 (2.7%)		0/85 (0%)		4/50 (8%)		3/51 (5.9%)		2/97 (2.1%)		11/350 (3.1%)
Loss of libido	0/13 (0%)		1/17 (5.9%)		0/37 (0%)		0/85 (0%)		0/50 (0%)		0/51 (0%)		0/97 (0%)		1/350 (0.3%)
Renal and urinary disorders
Haematuria	1/13 (7.7%)		1/17 (5.9%)		1/37 (2.7%)		0/85 (0%)		0/50 (0%)		2/51 (3.9%)		1/97 (1%)		6/350 (1.7%)
Proteinuria	1/13 (7.7%)		1/17 (5.9%)		0/37 (0%)		1/85 (1.2%)		1/50 (2%)		3/51 (5.9%)		0/97 (0%)		7/350 (2%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	1/13 (7.7%)		3/17 (17.6%)		1/37 (2.7%)		3/85 (3.5%)		0/50 (0%)		0/51 (0%)		0/97 (0%)		8/350 (2.3%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	0/13 (0%)		1/17 (5.9%)		0/37 (0%)		0/85 (0%)		0/50 (0%)		0/51 (0%)		0/97 (0%)		1/350 (0.3%)
Neurodermatitis	1/13 (7.7%)		0/17 (0%)		0/37 (0%)		0/85 (0%)		0/50 (0%)		0/51 (0%)		0/97 (0%)		1/350 (0.3%)
Pruritus	0/13 (0%)		0/17 (0%)		5/37 (13.5%)		7/85 (8.2%)		26/50 (52%)		35/51 (68.6%)		15/97 (15.5%)		88/350 (25.1%)
Rash	0/13 (0%)		0/17 (0%)		1/37 (2.7%)		2/85 (2.4%)		5/50 (10%)		3/51 (5.9%)		4/97 (4.1%)		15/350 (4.3%)
Rash pruritic	0/13 (0%)		0/17 (0%)		2/37 (5.4%)		0/85 (0%)		2/50 (4%)		0/51 (0%)		0/97 (0%)		4/350 (1.1%)

Limitations/Caveats

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.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.

Results Point of Contact

Name/Title	Study Director
Organization	Novartis Pharmaceuticals
Phone	+1 (862) 778-8300
Email	novartis.email@novartis.com

Responsible Party:

Novartis Pharmaceuticals

ClinicalTrials.gov Identifier:

NCT02855164

Other Study ID Numbers:

CLJN452A2202
2015-005215-33

First Posted:

Aug 4, 2016

Last Update Posted:

Sep 5, 2021

Last Verified:

Aug 1, 2021