TANDEM: Study of Safety, Tolerability, and Efficacy of a Combination Treatment of LJN452 and CVC in Adult Patients With NASH and Liver Fibrosis

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03517540
• Collaborator: Allergan (Industry)
• Enrollment: 193
• Locations: 65
• Arms: 4
• Actual Duration (Months): 25.1
• Patients Per Site: 3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study was to assess the safety, tolerability, and efficacy of a combination treatment of tropifexor (LJN452) and cenicriviroc (CVC) in adult patients with nonalcoholic steatohepatitis (NASH) and liver fibrosis.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 193 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Multicenter Study to Assess the Safety, Tolerability, and Efficacy of a Combination Treatment of Tropifexor (LJN452) and Cenicriviroc (CVC) in Adult Patients With Nonalcoholic Steatohepatitis (NASH) and Liver Fibrosis
• Actual Study Start Date: Sep 11, 2018
• Actual Primary Completion Date: Sep 15, 2020
• Actual Study Completion Date: Oct 15, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm A: Tropifexor (LJN452) - Dose 1 tropifexor 140 mcg, once daily; given orally	Drug: Tropifexor (LJN452); Comparison with monotherapy and different combination doses; Other Names: LJN452
Experimental: Arm B: Cenicriviroc (CVC) CVC 150 mg, once daily; given orally	Drug: Cenicriviroc (CVC); Comparison with monotherapy and different combination doses; Other Names: CVC
Experimental: Arm C: Tropifexor (LJN452) Dose 1 + CVC tropifexor 140 mcg + CVC 150 mg, once daily; given orally	Drug: Tropifexor (LJN452); Comparison with monotherapy and different combination doses; Other Names: LJN452 ; Drug: Cenicriviroc (CVC); Comparison with monotherapy and different combination doses; Other Names: CVC
Experimental: Arm D: Tropifexor Dose 2 + CVC tropifexor 90 mcg + CVC 150 mg, once daily; given orally	Drug: Tropifexor (LJN452); Comparison with monotherapy and different combination doses; Other Names: LJN452 ; Drug: Cenicriviroc (CVC); Comparison with monotherapy and different combination doses; Other Names: CVC

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Adverse Events [AEs were collected from first dose of study treatment until end of study treatment at week 48 and then up to maximum duration of 66 weeks]

   Occurrence of adverse events and serious adverse events Adverse Events (AEs) are any untoward sign or symptom that occurs during the study treatment and then up to 66 weeks

Secondary Outcome Measures

1. Proportion of Participants Who Have at Least a One Point Improvement in Fibrosis [baseline to 48 Weeks]

   Efficacy of tropifexor + CVC in patients with Nonalcoholic steatohepatitis (NASH) with fibrosis stage F2/F3 as assessed by histological improvement after 48 weeks of treatment compared to monotherapies (tropifexor and CVC) compared to baseline biopsy

2. Proportion of Participants With Resolution of Steatohepatitis [baseline to 48 weeks]

   Efficacy of tropifexor + CVC in patients with Nonalcoholic steatohepatitis (NASH) with fibrosis stage F2/F3 as assessed by histological improvement after 48 weeks of treatment compared to monotherapies (tropifexor and CVC) compared to baseline biopsy

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Written informed consent Male and female patients 18 years or older (at the time of the screening visit). Patients must weigh at least 50 kg (110 lb) and no more than 200 kg (440 lb) to participate in the study.

Able to communicate well with the investigator, to understand and comply with the requirements of the study.

Adequate liver biopsy sample for evaluation by Central Reader. Presence of NASH as demonstrated by histologic evidence based on liver biopsy - NASH with fibrosis stage F2/F3, demonstrated on liver biopsy during the screening period. Alternatively, a historical biopsy can be used if performed within 6 months prior to screening.

Exclusion Criteria:

Use of other investigational drugs within 5 half-lives of enrollment or within 30 days whichever is longer.

History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar chemical classes.

Previous exposure to elafibranor, CVC, tropifexor, obeticholic acid (OCA), LMB763 or other FXR agonist.

Participated in a clinical trial and treated with any investigational product being evaluated for the treatment of liver fibrosis or NASH in the 6 months before screening.

Patients taking medications prohibited by the protocol. History of treated or untreated malignancy of any organ system, other than localized basal cell carcinoma of the skin or treated cervical intraepithelial neoplasia, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases .

Pregnant or nursing (lactating) women. Women of child-bearing potential. Current or history of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to screening (significant alcohol consumption is defined as more than 20 g/day in females and more than 30 g/day in males, on average) and/or a score on the modified AUDIT questionnaire ≥ 8.

Inability to reliably quantify alcohol consumption. History or evidence of ongoing drug abuse, within the last 6 months prior to randomization.

Prior or planned (during the study) bariatric surgery. Uncontrolled diabetes defined as HbA1c ≥ 9% at screening Clinical evidence of hepatic decompensation or severe liver impairment. Previous diagnosis of other forms of chronic liver disease. Calculated eGFR less than 60 mL/min (using the MDRD formula). History of biliary diversion History of liver transplantation or planned liver transplant. Known positivity for HIV. History or current diagnosis of ECG abnormalities indicating significant risk of safety for the patient to participate.

History of inflammatory bowel disease. Patients who are not candidates for liver biopsy. Presence of cirrhosis on liver biopsy (F4 by NASH CRN System) or medical history Patients with an abnormal platelet count (referring to reference ranges from the central lab).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Chandler	Arizona	United States	85224
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	90048
5	Novartis Investigative Site	Los Angeles	California	United States	90057
6	Novartis Investigative Site	Pasadena	California	United States	91105
7	Novartis Investigative Site	Rialto	California	United States	92377
8	Novartis Investigative Site	Atlanta	Georgia	United States	30309
9	Novartis Investigative Site	Atlanta	Georgia	United States	30312
10	Novartis Investigative Site	Marietta	Georgia	United States	30060
11	Novartis Investigative Site	Chicago	Illinois	United States	60637-1470
12	Novartis Investigative Site	Indianapolis	Indiana	United States	46237
13	Novartis Investigative Site	Metairie	Louisiana	United States	70006
14	Novartis Investigative Site	Shreveport	Louisiana	United States	71103
15	Novartis Investigative Site	Concord	North Carolina	United States	28027
16	Novartis Investigative Site	Durham	North Carolina	United States	27710
17	Novartis Investigative Site	Morehead City	North Carolina	United States	28557
18	Novartis Investigative Site	Providence	Rhode Island	United States	02905
19	Novartis Investigative Site	Chattanooga	Tennessee	United States	37404
20	Novartis Investigative Site	Germantown	Tennessee	United States	38138
21	Novartis Investigative Site	Hermitage	Tennessee	United States	37076
22	Novartis Investigative Site	Dallas	Texas	United States	75208-2312
23	Novartis Investigative Site	San Antonio	Texas	United States	78215
24	Novartis Investigative Site	Murray	Utah	United States	84107
25	Novartis Investigative Site	Richmond	Virginia	United States	23249
26	Novartis Investigative Site	Richmond	Virginia	United States	23298
27	Novartis Investigative Site	Seattle	Washington	United States	98104
28	Novartis Investigative Site	Caba	Buenos Aires	Argentina	C1181ACH
29	Novartis Investigative Site	Caba	Buenos Aires	Argentina	C1280AEB
30	Novartis Investigative Site	Florencio Varela	Buenos Aires	Argentina	C1073ABA
31	Novartis Investigative Site	Edegem	Antwerpen	Belgium	2650
32	Novartis Investigative Site	Leuven		Belgium	3000
33	Novartis Investigative Site	Vancouver	British Columbia	Canada	V6Z 2K5
34	Novartis Investigative Site	Toronto	Ontario	Canada	M5G 2C4
35	Novartis Investigative Site	Toronto	Ontario	Canada	M6H 3MI
36	Novartis Investigative Site	Chicoutimi	Quebec	Canada	G7H 7K9
37	Novartis Investigative Site	Montreal	Quebec	Canada	H4A 3J1
38	Novartis Investigative Site	Prague		Czechia	128 08
39	Novartis Investigative Site	Shebeen El-Kom		Egypt
40	Novartis Investigative Site	Paris Cedex 13		France	75651
41	Novartis Investigative Site	Pessac Cedex		France	33604
42	Novartis Investigative Site	Strasbourg		France	67098
43	Novartis Investigative Site	Mainz		Germany	55131
44	Novartis Investigative Site	Wuerzburg		Germany	97080
45	Novartis Investigative Site	New Delhi	Delhi	India	110070
46	Novartis Investigative Site	Tel Aviv		Israel	6423906
47	Novartis Investigative Site	Modena	Itlay	Italy	41126
48	Novartis Investigative Site	Palermo	PA	Italy	90127
49	Novartis Investigative Site	Roma	RM	Italy	00168
50	Novartis Investigative Site	Verona	VR	Italy	37126
51	Novartis Investigative Site	Milan		Italy	20112
52	Novartis Investigative Site	Riga		Latvia	LV-1006
53	Novartis Investigative Site	Moscow		Russian Federation	101990
54	Novartis Investigative Site	Moscow		Russian Federation	109544
55	Novartis Investigative Site	Singapore		Singapore	117549
56	Novartis Investigative Site	Singapore		Singapore	169608
57	Novartis Investigative Site	Santander	Cantabria	Spain	39008
58	Novartis Investigative Site	Barcelona	Catalunya	Spain	08035
59	Novartis Investigative Site	Barcelona	Catalunya	Spain	08036
60	Novartis Investigative Site	Valencia	Comunidad Valenciana	Spain	46026
61	Novartis Investigative Site	Izmir		Turkey	35100
62	Novartis Investigative Site	Pendik / Istanbul		Turkey	34899
63	Novartis Investigative Site	High Heaton	Newcastle Upon Tyne	United Kingdom	NE7 7DN
64	Novartis Investigative Site	Aberdeen		United Kingdom	AB25 2ZN
65	Novartis Investigative Site	Torquay		United Kingdom	TQ2 7AA

Sponsors and Collaborators

• Novartis Pharmaceuticals
• Allergan

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Study Protocol - May 7, 2020
• Statistical Analysis Plan - Nov 11, 2020

More Information

Additional Information:

• A Plain Language Trial Summary is available on novctrd.com

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03517540
• Other Study ID Numbers: CLJC242A2201J; 2017-004208-24; LJC242A2201J
• First Posted: May 7, 2018
• Last Update Posted: Apr 29, 2022
• Last Verified: Apr 1, 2022

• 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: No
• Keywords provided by Novartis Pharmaceuticals: Steatohepatitis; NASH; NAFLD; Fatty Liver Disease; Liver; Liver fibrosis
• Additional relevant MeSH terms: Fatty Liver; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease; Fibrosis; Cenicriviroc

Study Results

Participant Flow

Recruitment Details	193 participants enrolled at 65 sites in 17 countries
Pre-assignment Detail	450 of 643 subjects discontinued during screening phase

Arm/Group Title	Arm A: Tropifexor (LJN452) - Dose 1	Arm B: Cenicriviroc (CVC)	Arm C: Tropifexor (LJN452) Dose 1 + CVC	Arm D: Tropifexor Dose 2 + CVC
Arm/Group Description	tropifexor 140 mg, once daily	CVC 150 mg, once daily	tropifexor 140 mg + CVC 150 mg, once daily	tropifexor 90 mg + CVC 150 mg, once daily
Period Title: Overall Study
STARTED	50	48	47	48
COMPLETED	36	41	38	43
NOT COMPLETED	14	7	9	5

Baseline Characteristics

Arm/Group Title	Arm A: Tropifexor (LJN452) - Dose 1	Arm B: Cenicriviroc (CVC)	Arm C: Tropifexor (LJN452) Dose 1 + CVC	Arm D: Tropifexor Dose 2 + CVC	Total
Arm/Group Description	tropifexor 140 mg, once daily	CVC 150 mg, once daily	tropifexor 140 mg + CVC 150 mg, once daily	tropifexor 90 mg + CVC 150 mg, once daily	Total of all reporting groups
Overall Participants	50	48	47	48	193
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.8 (13.35)	53.7 (11.79)	54.7 (12.65)	54.9 (12.29)	54.5 (12.52)
Age, Customized (Count of Participants)
<65	35 70%	39 81.3%	37 78.7%	38 79.2%	149 77.2%
>=65	15 30%	9 18.8%	10 21.3%	10 20.8%	44 22.8%
Sex/Gender, Customized (Count of Participants)
Male	20 40%	17 35.4%	18 38.3%	25 52.1%	80 41.5%
Female	30 60%	31 64.6%	29 61.7%	23 47.9%	113 58.5%
Race/Ethnicity, Customized (Count of Participants)
White	41 82%	44 91.7%	40 85.1%	43 89.6%	168 87%
Asian	7 14%	4 8.3%	5 10.6%	5 10.4%	21 10.9%
Black	1 2%	0 0%	2 4.3%	0 0%	3 1.6%
Unknown	1 2%	0 0%	0 0%	0 0%	1 0.5%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adverse Events
Description	Occurrence of adverse events and serious adverse events Adverse Events (AEs) are any untoward sign or symptom that occurs during the study treatment and then up to 66 weeks
Time Frame	AEs were collected from first dose of study treatment until end of study treatment at week 48 and then up to maximum duration of 66 weeks

Outcome Measure Data

Analysis Population Description

Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-baseline safety assessment. Of note, the statement that a patient had no AEs also constituted a safety assessment. Patients were analyzed according to the treatment received

Arm/Group Title	Arm A: Tropifexor (LJN452) - Dose 1	Arm B: Cenicriviroc (CVC)	Arm C: Tropifexor (LJN452) Dose 1 + CVC	Arm D: Tropifexor Dose 2 + CVC
Arm/Group Description	tropifexor 140 mg, once daily	CVC 150 mg, once daily	tropifexor 140 mg + CVC 150 mg, once daily	tropifexor 90 mg + CVC 150 mg, once daily
Measure Participants	50	48	47	48
Number of participants with at least one Adverse Event (AE)	42 84%	41 85.4%	40 85.1%	42 87.5%
Number of participants with at least one Serious Adverse Events (SAEs)	5 10%	3 6.3%	4 8.5%	10 20.8%
Deaths	0 0%	0 0%	0 0%	0 0%

2. Secondary Outcome

Title	Proportion of Participants Who Have at Least a One Point Improvement in Fibrosis
Description	Efficacy of tropifexor + CVC in patients with Nonalcoholic steatohepatitis (NASH) with fibrosis stage F2/F3 as assessed by histological improvement after 48 weeks of treatment compared to monotherapies (tropifexor and CVC) compared to baseline biopsy
Time Frame	baseline to 48 Weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - All participants to whom study treatment was assigned (excluding patients who were mis-randomized and did not take investigational drug. Mis-randomized participants were those who were not qualified for randomization but were inadvertently randomized into the study). Following the intent-to-treat (ITT) principle, patients were analyzed according to the treatment they had been assigned to at randomization.

Arm/Group Title	Arm A: Tropifexor (LJN452) - Dose 1	Arm B: Cenicriviroc (CVC)	Arm C: Tropifexor (LJN452) Dose 1 + CVC	Arm D: Tropifexor Dose 2 + CVC
Arm/Group Description	tropifexor 140 mg, once daily	CVC 150 mg, once daily	tropifexor 140 mg + CVC 150 mg, once daily	tropifexor 90 mg + CVC 150 mg, once daily
Measure Participants	31	38	37	40
Count of Participants [Participants]	10 20%	12 25%	11 23.4%	13 27.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: Tropifexor (LJN452) - Dose 1, Arm C: Tropifexor (LJN452) Dose 1 + CVC
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.688
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.8
	Confidence Interval	(2-Sided) 95%; 0.25 to 2.63
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm A: Tropifexor (LJN452) - Dose 1, Arm D: Tropifexor Dose 2 + CVC
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.985
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.01
	Confidence Interval	(2-Sided) 95%; 0.51 to 1.99
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Arm C: Tropifexor (LJN452) Dose 1 + CVC, Arm D: Tropifexor Dose 2 + CVC
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.870
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.92
	Confidence Interval	(2-Sided) 95%; 0.3 to 2.84
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Arm B: Cenicriviroc (CVC), Arm D: Tropifexor Dose 2 + CVC
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.710
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.21
	Confidence Interval	(2-Sided) 95%; 0.41 to 3.61
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Proportion of Participants With Resolution of Steatohepatitis
Description	Efficacy of tropifexor + CVC in patients with Nonalcoholic steatohepatitis (NASH) with fibrosis stage F2/F3 as assessed by histological improvement after 48 weeks of treatment compared to monotherapies (tropifexor and CVC) compared to baseline biopsy
Time Frame	baseline to 48 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - All participants to whom study treatment was assigned (excluding patients who were mis-randomized and did not take investigational drug. Mis-randomized participants were those who were not qualified for randomization but were inadvertently randomized into the study). Following the intent-to-treat (ITT) principle, patients were analyzed according to the treatment they had been assigned to at randomization.

Arm/Group Title	Arm A: Tropifexor (LJN452) - Dose 1	Arm B: Cenicriviroc (CVC)	Arm C: Tropifexor (LJN452) Dose 1 + CVC	Arm D: Tropifexor Dose 2 + CVC
Arm/Group Description	tropifexor 140 mg, once daily	CVC 150 mg, once daily	tropifexor 140 mg + CVC 150 mg, once daily	tropifexor 90 mg + CVC 150 mg, once daily
Measure Participants	31	38	37	40
Count of Participants [Participants]	8 16%	8 16.7%	5 10.6%	9 18.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: Tropifexor (LJN452) - Dose 1, Arm C: Tropifexor (LJN452) Dose 1 + CVC
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.136
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.37
	Confidence Interval	(2-Sided) 95%; 0.08 to 1.61
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm A: Tropifexor (LJN452) - Dose 1, Arm D: Tropifexor Dose 2 + CVC
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.747
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.83
	Confidence Interval	(2-Sided) 95%; 0.24 to 2.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Arm B: Cenicriviroc (CVC), Arm C: Tropifexor (LJN452) Dose 1 + CVC
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.784
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 95%; 0.18 to 3.63
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Arm B: Cenicriviroc (CVC), Arm D: Tropifexor Dose 2 + CVC
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.521
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.45
	Confidence Interval	(2-Sided) 95%; 0.4 to 5.69
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	AEs were collected from first dose of study treatment until end of study treatment at week 48 and then up to maximum duration of 66 weeks
Adverse Event Reporting Description	Adverse Events (AEs) are any untoward sign or symptom that occurs during the study treatment and up to of 66 weeks
Arm/Group Title	Tropifexor 140mg		CVC 150mg		Tropifexor 140mcg + CVC 150mg		Tropifexor 90 mg + CVC 150 mg
Arm/Group Description	Tropifexor 140mg		CVC 150mg		Tropifexor 140mg + CVC 150mg		Tropifexor 90 mg + CVC 150 mg
All Cause Mortality
	Tropifexor 140mg		CVC 150mg		Tropifexor 140mcg + CVC 150mg		Tropifexor 90 mg + CVC 150 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/50 (0%)		0/48 (0%)		0/47 (0%)		0/48 (0%)
Serious Adverse Events
	Tropifexor 140mg		CVC 150mg		Tropifexor 140mcg + CVC 150mg		Tropifexor 90 mg + CVC 150 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/50 (10%)		3/48 (6.3%)		4/47 (8.5%)		10/48 (20.8%)
Cardiac disorders
Coronary artery disease	0/50 (0%)		1/48 (2.1%)		0/47 (0%)		0/48 (0%)
Myocardial infarction	0/50 (0%)		0/48 (0%)		0/47 (0%)		1/48 (2.1%)
Gastrointestinal disorders
Duodenal ulcer	1/50 (2%)		0/48 (0%)		0/47 (0%)		0/48 (0%)
Gastritis	1/50 (2%)		0/48 (0%)		0/47 (0%)		0/48 (0%)
Oesophageal ulcer	1/50 (2%)		0/48 (0%)		0/47 (0%)		0/48 (0%)
Pancreatitis acute	0/50 (0%)		1/48 (2.1%)		0/47 (0%)		0/48 (0%)
General disorders
Non-cardiac chest pain	1/50 (2%)		0/48 (0%)		0/47 (0%)		0/48 (0%)
Hepatobiliary disorders
Biliary dyskinesia	0/50 (0%)		0/48 (0%)		0/47 (0%)		1/48 (2.1%)
Gallbladder polyp	1/50 (2%)		0/48 (0%)		0/47 (0%)		0/48 (0%)
Infections and infestations
Appendicitis	0/50 (0%)		0/48 (0%)		0/47 (0%)		1/48 (2.1%)
COVID-19	0/50 (0%)		0/48 (0%)		0/47 (0%)		2/48 (4.2%)
COVID-19 pneumonia	1/50 (2%)		0/48 (0%)		0/47 (0%)		0/48 (0%)
Sepsis	0/50 (0%)		0/48 (0%)		0/47 (0%)		1/48 (2.1%)
Injury, poisoning and procedural complications
Anaesthetic complication	0/50 (0%)		0/48 (0%)		0/47 (0%)		1/48 (2.1%)
Cervical vertebral fracture	0/50 (0%)		1/48 (2.1%)		0/47 (0%)		0/48 (0%)
Road traffic accident	0/50 (0%)		1/48 (2.1%)		0/47 (0%)		0/48 (0%)
Spinal compression fracture	0/50 (0%)		1/48 (2.1%)		0/47 (0%)		0/48 (0%)
Metabolism and nutrition disorders
Euglycaemic diabetic ketoacidosis	0/50 (0%)		1/48 (2.1%)		0/47 (0%)		0/48 (0%)
Musculoskeletal and connective tissue disorders
Spondylitis	1/50 (2%)		0/48 (0%)		0/47 (0%)		0/48 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute lymphocytic leukaemia	0/50 (0%)		0/48 (0%)		1/47 (2.1%)		0/48 (0%)
Colon cancer	1/50 (2%)		0/48 (0%)		0/47 (0%)		0/48 (0%)
Nervous system disorders
Cerebrovascular accident	0/50 (0%)		0/48 (0%)		1/47 (2.1%)		1/48 (2.1%)
Syncope	1/50 (2%)		0/48 (0%)		0/47 (0%)		0/48 (0%)
Psychiatric disorders
Depression suicidal	0/50 (0%)		0/48 (0%)		1/47 (2.1%)		0/48 (0%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	0/50 (0%)		0/48 (0%)		1/47 (2.1%)		0/48 (0%)
Respiratory, thoracic and mediastinal disorders
Pneumonitis	0/50 (0%)		0/48 (0%)		0/47 (0%)		1/48 (2.1%)
Surgical and medical procedures
Cataract operation	0/50 (0%)		0/48 (0%)		0/47 (0%)		1/48 (2.1%)
Other (Not Including Serious) Adverse Events
	Tropifexor 140mg		CVC 150mg		Tropifexor 140mcg + CVC 150mg		Tropifexor 90 mg + CVC 150 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	39/50 (78%)		30/48 (62.5%)		33/47 (70.2%)		32/48 (66.7%)
Eye disorders
Cataract	0/50 (0%)		3/48 (6.3%)		0/47 (0%)		0/48 (0%)
Gastrointestinal disorders
Abdominal distension	2/50 (4%)		3/48 (6.3%)		1/47 (2.1%)		4/48 (8.3%)
Abdominal pain	5/50 (10%)		3/48 (6.3%)		5/47 (10.6%)		2/48 (4.2%)
Abdominal pain upper	3/50 (6%)		2/48 (4.2%)		5/47 (10.6%)		2/48 (4.2%)
Constipation	5/50 (10%)		2/48 (4.2%)		6/47 (12.8%)		3/48 (6.3%)
Diarrhoea	2/50 (4%)		7/48 (14.6%)		4/47 (8.5%)		0/48 (0%)
Dyspepsia	1/50 (2%)		0/48 (0%)		3/47 (6.4%)		2/48 (4.2%)
Flatulence	1/50 (2%)		1/48 (2.1%)		3/47 (6.4%)		2/48 (4.2%)
Nausea	2/50 (4%)		6/48 (12.5%)		7/47 (14.9%)		6/48 (12.5%)
General disorders
Asthenia	4/50 (8%)		2/48 (4.2%)		5/47 (10.6%)		3/48 (6.3%)
Fatigue	7/50 (14%)		4/48 (8.3%)		5/47 (10.6%)		4/48 (8.3%)
Oedema peripheral	0/50 (0%)		0/48 (0%)		0/47 (0%)		4/48 (8.3%)
Infections and infestations
Bronchitis	1/50 (2%)		0/48 (0%)		3/47 (6.4%)		1/48 (2.1%)
Ear infection	0/50 (0%)		0/48 (0%)		3/47 (6.4%)		0/48 (0%)
Gastroenteritis	1/50 (2%)		1/48 (2.1%)		3/47 (6.4%)		3/48 (6.3%)
Nasopharyngitis	2/50 (4%)		3/48 (6.3%)		2/47 (4.3%)		2/48 (4.2%)
Sinusitis	2/50 (4%)		1/48 (2.1%)		4/47 (8.5%)		3/48 (6.3%)
Upper respiratory tract infection	3/50 (6%)		2/48 (4.2%)		5/47 (10.6%)		5/48 (10.4%)
Urinary tract infection	7/50 (14%)		3/48 (6.3%)		2/47 (4.3%)		4/48 (8.3%)
Injury, poisoning and procedural complications
Ligament sprain	2/50 (4%)		0/48 (0%)		0/47 (0%)		3/48 (6.3%)
Investigations
Blood alkaline phosphatase increased	3/50 (6%)		0/48 (0%)		1/47 (2.1%)		0/48 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	6/50 (12%)		3/48 (6.3%)		6/47 (12.8%)		1/48 (2.1%)
Back pain	1/50 (2%)		3/48 (6.3%)		5/47 (10.6%)		4/48 (8.3%)
Muscle spasms	1/50 (2%)		2/48 (4.2%)		3/47 (6.4%)		1/48 (2.1%)
Osteoarthritis	1/50 (2%)		0/48 (0%)		3/47 (6.4%)		0/48 (0%)
Pain in extremity	0/50 (0%)		3/48 (6.3%)		0/47 (0%)		1/48 (2.1%)
Nervous system disorders
Dizziness	2/50 (4%)		3/48 (6.3%)		2/47 (4.3%)		1/48 (2.1%)
Psychiatric disorders
Insomnia	1/50 (2%)		1/48 (2.1%)		3/47 (6.4%)		1/48 (2.1%)
Skin and subcutaneous tissue disorders
Pruritus	20/50 (40%)		10/48 (20.8%)		15/47 (31.9%)		10/48 (20.8%)

Limitations/Caveats

[Not Specified]

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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 (ie, data from all sites) in the clinical trial.