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

Phase 2

Terminated

• Conditions: Non-alcoholic Steatohepatitis (NASH)
• Interventions: Drug: Tropifexor (LJN452); Drug: Placebo

• Registration Number: NCT02855164
• Lead Sponsor: Novartis Pharmaceuticals

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

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 Timeline

• Study First Submitted: 2016-07-20
• Study Start: 2016-08-01
• Study First Submitted QC: 2016-08-01
• Study First Posted: 2016-08-04
• Primary Completion: 2020-04-06
• Study Completion: 2020-04-06
• Results First Submitted: 2021-04-06
• Results First Submitted QC: 2021-07-07
• Results First Posted: 2021-07-29
• Status Verified: 2021-08
• Last Update Submitted: 2021-08-11
• Last Update Posted: 2021-09-05

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 350

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
LJN452 10 μg	Tropifexor (LJN452)	Tropifexor (LJN452) Part A
LJN452 30 μg	Tropifexor (LJN452)	Tropifexor (LJN452) Part A
LJN452 60 μg	Tropifexor (LJN452)	Tropifezor (LJN452) Parts A + B
Placebo A+ B	Placebo	Placebo Parts A + B
LJN452 90 μg	Tropifexor (LJN452)	Tropifexor (LJN452) Parts A + B
LJN452 140 μg	Tropifexor (LJN452)	Tropifexor (LJN452) Part C
LJN452 200 μg	Tropifexor (LJN452)	Tropifexor (LJN452) Part B
Placebo C	Placebo	Placebo Part C

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
Change From Baseline in Weight	48 weeks	Repeated measures for LS mean change in weight 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
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 - 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)
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 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, 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 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, (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 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 - FDA	EoT (Week 48)	Number of patients who have at least one point improvement in fibrosis (NASH CRN staging) without worsening of steatohepatitis (FDA)
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
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)

Trial Locations

Locations (1)

Novartis Investigative Site; 🇨🇳 Taoyuan, Taiwan