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

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

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

Study Overview

• Status: Terminated
• Conditions: Non-alcoholic Steatohepatitis (NASH)
• Intervention / Treatment: Drug: Placebo; Drug: Tropifexor (LJN452)

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 Type: Interventional
• Enrollment (Actual): 350
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1120AAC
    • Novartis Investigative Site
  • Buenos Aires
    • Caba, Buenos Aires, Argentina, C1280AEB
      • Novartis Investigative Site
    • Caba, Buenos Aires, Argentina, C1181ACH
      • Novartis Investigative Site
• Australia
  • New South Wales
    • Kingswood, New South Wales, Australia, 2747
      • Novartis Investigative Site
  • Victoria
    • Fitzroy, Victoria, Australia, 3065
      • Novartis Investigative Site
• Austria
  • Salzburg, Austria, 5020
    • Novartis Investigative Site
  • Wien, Austria, 1090
    • Novartis Investigative Site
• Belgium
  • Bruxelles, Belgium, 1070
    • Novartis Investigative Site
  • Gent, Belgium, 9000
    • Novartis Investigative Site
  • Leuven, Belgium, 3000
    • Novartis Investigative Site
• Canada
  • Ontario
    • London, Ontario, Canada, N6A 5A5
      • Novartis Investigative Site
    • Toronto, Ontario, Canada, M5G 2C4
      • Novartis Investigative Site
  • Quebec
    • Chicoutimi, Quebec, Canada, G7H 7K9
      • Novartis Investigative Site
• France
  • Montpellier, France, 34295
    • Novartis Investigative Site
  • Paris, France, 75012
    • Novartis Investigative Site
  • Paris, France, 75651
    • Novartis Investigative Site
• Germany
  • Dresden, Germany, 01307
    • Novartis Investigative Site
  • Hamburg, Germany, 20246
    • Novartis Investigative Site
  • Hannover, Germany, 30625
    • Novartis Investigative Site
  • Leipzig, Germany, 04103
    • Novartis Investigative Site
  • Wuerzburg, Germany, 97080
    • Novartis Investigative Site
• India
  • Delhi
    • New Delhi, Delhi, India, 110070
      • Novartis Investigative Site
• Italy
  • Bologna, Italy, 40138
    • Novartis Investigative Site
  • Roma, Italy, 00161
    • Novartis Investigative Site
  • BG
    • Bergamo, BG, Italy, 24128
      • Novartis Investigative Site
• Japan
  • Hiroshima
    • Hatsukaichi city, Hiroshima, Japan, 738 8503
      • Novartis Investigative Site
  • Kanagawa
    • Yokohama-city, Kanagawa, Japan, 236-0004
      • Novartis Investigative Site
  • Saga
    • Saga-city, Saga, Japan, 849-8501
      • Novartis Investigative Site
  • Shimane
    • Izumo-city, Shimane, Japan, 693 8501
      • Novartis Investigative Site
• Korea, Republic of
  • Busan, Korea, Republic of, 602739
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 03080
    • Novartis Investigative Site
  • Korea
    • Seoul, Korea, Korea, Republic of, 05505
      • Novartis Investigative Site
    • Seoul, Korea, Korea, Republic of, 03722
      • Novartis Investigative Site
  • Seoul
    • Dongjak Gu, Seoul, Korea, Republic of, 07061
      • Novartis Investigative Site
• Netherlands
  • Utrecht, Netherlands, 3584CX
    • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 169608
    • Novartis Investigative Site
• Slovakia
  • Banska Bystrica, Slovakia, 97517
    • Novartis Investigative Site
  • Bratislava, Slovakia, 85101
    • Novartis Investigative Site
  • Bratislava, Slovakia, 82606
    • Novartis Investigative Site
  • Nitra, Slovakia, 949 01
    • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28034
    • Novartis Investigative Site
  • Madrid, Spain, 28009
    • Novartis Investigative Site
  • Andalucia
    • Sevilla, Andalucia, Spain, 41013
      • Novartis Investigative Site
  • Cataluna
    • Barcelona, Cataluna, Spain, 08036
      • Novartis Investigative Site
    • Barcelona, Cataluna, Spain, 08035
      • Novartis Investigative Site
• Taiwan
  • Kaoshiung, Taiwan, 80756
    • Novartis Investigative Site
  • Keelung City, Taiwan, 20401
    • Novartis Investigative Site
  • Taichung, Taiwan, 40447
    • Novartis Investigative Site
  • Taipei, Taiwan, 11217
    • Novartis Investigative Site
  • Taoyuan, Taiwan, 33305
    • Novartis Investigative Site
• United States
  • Alabama
    • Madison, Alabama, United States, 35758
      • Novartis Investigative Site
  • Arkansas
    • North Little Rock, Arkansas, United States, 72117
      • Novartis Investigative Site
  • California
    • Coronado, California, United States, 92118
      • Novartis Investigative Site
    • Los Angeles, California, United States, 90057
      • Novartis Investigative Site
    • Pasadena, California, United States, 91105
      • Novartis Investigative Site
    • Rialto, California, United States, 92377
      • Novartis Investigative Site
    • San Diego, California, United States, 92114
      • Novartis Investigative Site
    • San Francisco, California, United States, 94115
      • Novartis Investigative Site
  • Colorado
    • Lonetree, Colorado, United States, 80124
      • Novartis Investigative Site
  • Florida
    • Boca Raton, Florida, United States, 33434
      • Novartis Investigative Site
    • Jacksonville, Florida, United States, 32256
      • Novartis Investigative Site
    • Lakewood Ranch, Florida, United States, 34211
      • Novartis Investigative Site
    • Miami, Florida, United States, 33136
      • Novartis Investigative Site
    • Orlando, Florida, United States, 32806
      • Novartis Investigative Site
    • Pensacola, Florida, United States, 32503
      • Novartis Investigative Site
  • Georgia
    • Athens, Georgia, United States, 30607
      • Novartis Investigative Site
    • Marietta, Georgia, United States, 30060
      • Novartis Investigative Site
  • Maryland
    • Catonsville, Maryland, United States, 21228
      • Novartis Investigative Site
  • Massachusetts
    • Worcester, Massachusetts, United States, 01655
      • Novartis Investigative Site
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Novartis Investigative Site
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Novartis Investigative Site
  • Missouri
    • Jefferson City, Missouri, United States, 65109
      • Novartis Investigative Site
  • New Jersey
    • Berlin, New Jersey, United States, 08009
      • Novartis Investigative Site
  • North Carolina
    • Morehead City, North Carolina, United States, 28557
      • Novartis Investigative Site
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • Novartis Investigative Site
  • Tennessee
    • Hermitage, Tennessee, United States, 37076
      • Novartis Investigative Site
  • Texas
    • Dallas, Texas, United States, 75208-2312
      • Novartis Investigative Site
    • Houston, Texas, United States, 77030
      • Novartis Investigative Site
    • San Antonio, Texas, United States, 78215
      • Novartis Investigative Site
  • Virginia
    • Norfolk, Virginia, United States, 23502
      • Novartis Investigative Site
    • Richmond, Virginia, United States, 23298
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

8

Arms and Interventions

Participant Group / 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

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Naoumov NV, Brees D, Loeffler J, Chng E, Ren Y, Lopez P, Tai D, Lamle S, Sanyal AJ. Digital pathology with artificial intelligence analyses provides greater insights into treatment-induced fibrosis regression in NASH. J Hepatol. 2022 Nov;77(5):1399-1409. doi: 10.1016/j.jhep.2022.06.018. Epub 2022 Jun 30.

Helpful Links

• 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)

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2016
• Primary Completion (Actual): April 6, 2020
• Study Completion (Actual): April 6, 2020

Study Registration Dates

• First Submitted: July 20, 2016
• First Submitted That Met QC Criteria: August 1, 2016
• First Posted (Estimate): August 4, 2016

Study Record Updates

• Last Update Posted (Actual): September 5, 2021
• Last Update Submitted That Met QC Criteria: August 11, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: NASH; non-alcoholic steatohepatitis; randomized; phase 2; LJN452; adaptive design
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
• Other Study ID Numbers: CLJN452A2202; 2015-005215-33 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

IPD Plan Description

Novartis is committed to sharing access to patient-level data and supporting clinical documents from eligible studies with qualified external researchers. Requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to protect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No