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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Non-alcoholic Steatohepatitis (NASH)

Intervention / Treatment
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* Drug: Tropifexor (LJN452)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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.
Masking: Triple


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Nonalcoholic Steatohepatitis (NASH) Patients With Treatment Emergent Adverse Events (TEAE) | Number of Nonalcoholic steatohepatitis (NASH) patients with TEAEs | 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) | 
| Change in Transaminase Levels (ALT) | 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 | 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) | 
| Change in Aspartate Transaminase (AST) | 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) | 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) | 
| Change From Baseline in % of Fat in the Liver Assessed Using Magnetic Resonance Imaging (MRI) | Repeated measures analysis: Relative change in percentage of fat in the liver assessed using MRI from baseline by visit up to EOT (Full analysis set) | End of Treatment (EoT): For Parts A&B, EoT was Week 12 (Primary Outcome Measure). For Part C, EoT was Week 48 (Secondary Outcome Measure) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Weight | Repeated measures for LS mean change in weight after 12 weeks of treatment | 48 weeks | 
| Change in Body Mass Index (BMI) | 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 | 12 weeks | 
| Change From Baseline in Waist to Hip (WTH) Ratio | The LS mean change in waist to hip ratio after 12 weeks of treatment | 12 weeks | 
| Change From Baseline in Biomarker FGF19 | 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 | baseline, week 6 | 
| Change From Baseline in Biomarker C4 | 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 | Week 6, 4 hours post dose | 
| Change From Baseline on Markers of Liver Fibrosis, Fibroscan | 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) | End of Treatment (EoT): For Parts A&B, EoT was Week 12. For Part C, EoT was Week 48 | 
| Change From Baseline on Markers of Liver Fibrosis Panel (ELF) Score | 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). | End of Treatment (EoT): For Parts A&B, EoT was Week 12. For Part C, EoT was Week 48 | 
| Change From Baseline on Markers of Liver Fibrosis, Fibrotest (Parts A+B) | 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) | End of Treatment (EoT):12 weeks | 
| Change From Baseline on Markers of Liver Fibrosis, Fibrotest, (Part C) | 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) | End of Treatment (EoT) was 48 weeks | 
| Change From Baseline on Gamma-glutamyl Transferase (GGT) | Summary statistics of change in GGT (IU/L) from baseline by visit up to EoT | EoT for Parts A+B=12 weeks; EoT for Part C = 48 weeks | 
| Change From Baseline on Fasting Lipid Profile | Repeated measures analysis: LS geometric mean ratio of fasting lipids to baseline by visit up to EOT | End of Treatment (EoT): For Parts A&B, EoT was Week 12. For Part C, EoT was Week 48 | 
| Itch Based on a Visual Analog Scale (VAS) Rating Scale | 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 | EoT for Parts A+B=12 weeks; EoT for Part C = 48 weeks | 
| Pre-dose Trough Concentration (Ctrough) of LJN452 | Pre-dose Trough Concentration (Ctrough) of tropifexor (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 | 
| C2h (Steady-state Drug Levels 2 Hours Postdose) of LJN452 | Summary C2h of tropifexor (LJN452) | Days 7 and 14 (10 and 30μg LJN452 C2h was not measured day 14) | 
| 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 | Number of patients who have at least one point improvement in fibrosis (NASH CRN staging) without worsening of steatohepatitis (total score) | EoT (Week 48) | 
| Biopsy-based Response at Week 48 Compared to Baseline: At Least One Point Improvement in Fibrosis (NASH CRN Staging) Without Worsening - FDA | Number of patients who have at least one point improvement in fibrosis (NASH CRN staging) without worsening of steatohepatitis (FDA) | EoT (Week 48) | 
| Biopsy-based Response at Week 48 Compared to Baseline: At Least One Point Improvement in Fibrosis (NASH CRN Staging) Without Worsening - EMA | Number of patients who have at least one point improvement in fibrosis (NASH CRN staging) without worsening of steatohepatitis (EMA) | EoT (Week 48) | 
| Biopsy-based Response at Week 48 Compared to Baseline: Difference Between Treatment Groups (Part C) - Resolution of Steatohepatitis (Diagnostic Category) | Resolution of steatohepatitis (diagnostic category) without worsening of fibrosis (NASH CRN staging) | EoT (Week 48) | 
| Biopsy-based Response at Week 48 Compared to Baseline: Difference Between Treatment Groups (Part C) - Resolution of Steatohepatitis (FDA, EMA) | Resolution of steatohepatitis (diagnostic category) without worsening of fibrosis (NASH CRN staging) | EoT (Week 48) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LJN452, non-alcoholic steatohepatitis, NASH, phase 2, adaptive design, randomized