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

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ClinicalTrials.gov Identifier: NCT02855164
Recruitment Status : Recruiting
First Posted : August 4, 2016
Last Update Posted : June 11, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
The purpose of the study is 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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 345 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: This study was extended based on safety and efficacy results in Part A and available long-term toxicology coverage; Part C is added exploring 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 : August 1, 2016
Estimated Primary Completion Date : July 31, 2019
Estimated Study Completion Date : April 3, 2020


Arm Intervention/treatment
Experimental: Part A - Arm A
Tropifexor (LJN452)- - dose 1
Drug: Tropifexor (LJN452)
Comparison of different doses of drug

Experimental: Part A - Arm B
Tropifexor (LJN452)- - dose 2
Drug: Tropifexor (LJN452)
Comparison of different doses of drug

Experimental: Part A - Arm C
Tropifezor (LJN452)- - dose 3
Drug: Tropifexor (LJN452)
Comparison of different doses of drug

Experimental: Part A - Arm D
Tropifexor (LJN452)- - dose 4
Drug: Tropifexor (LJN452)
Comparison of different doses of drug

Placebo Comparator: Part A - Arm E
Placebo
Drug: Placebo
Comparator

Experimental: Part B - Arm F
Tropifexor (LJN452)- - dose to be determined
Drug: Tropifexor (LJN452)
Comparison of different doses of drug

Experimental: Part B - Arm G
Tropifexor (LJN452)- - dose to be determined
Drug: Tropifexor (LJN452)
Comparison of different doses of drug

Placebo Comparator: Part B - Arm H
Placebo
Drug: Placebo
Comparator

Experimental: Part C- Arm I
Tropifexor (LJN452)- dose 9
Drug: Tropifexor (LJN452)
Comparison of different doses of drug

Experimental: Part C- Arm J
Tropifexor (LJN452)- dose 10
Drug: Tropifexor (LJN452)
Comparison of different doses of drug

Placebo Comparator: Part C- Arm K
Placebo
Drug: Placebo
Comparator




Primary Outcome Measures :
  1. Adverse event profile of different doses of tropifexor (LJN452) in patients with NASH [ Time Frame: 12 weeks ]
    Occurrence of Serious Adverse Event (SAE), Adverse Event (AE) resulting in treatment discontinuation and/or dose reductions, and AE of special interest, from baseline to week 12

  2. Change in Transaminase levels [ Time Frame: 12 weeks ]
    To determine the dose relationship of tropifexor (LJN452) on markers of hepatic inflammation in NASH (ALT and AST) from baseline to Week 12.

  3. Change from baseline in % of fat in the liver assessed using MRI [ Time Frame: 12 weeks ]
    To determine the dose-response relationship of tropifexor (LJN452) on liver fat content by changes in quantitative MRI determined fat from baseline to Week 12.


Secondary Outcome Measures :
  1. Change from baseline in weight [ Time Frame: 12 weeks ]
    To determine the effect of different doses of tropifexor (LJN452) on weight, after 12 weeks of treatment

  2. Change from baseline in biomarker FGF19 [ Time Frame: 12 weeks ]
    To determine the dose-response relationship of tropifexor (LJN452) on FGF19 over time, a marker of FXR target engagement in the gut.

  3. Change from baseline on on markers of liver fibrosis [ Time Frame: 12 weeks ]
    To determine the dose-response relationship of tropifexor (LJN452) on markers of liver fibrosis commonly available such as Fibroscan®, enhanced liver fibrosis panel (ELF), and fibrosis biomarker test (originally known as Fibrotest®/ FibroSure®)

  4. Change from baseline on gamma-glutamyl transferase (GGT) [ Time Frame: 12 weeks ]
    To determine the dose-response relationship of tropifexor (LJN452) on GGT, a marker of cholestasis

  5. Change from baseline on fasting lipid profile [ Time Frame: 12 weeks ]
    To determine the effect of tropifexor (LJN452) on fasting lipid profile

  6. Determine Ctrough of LJN452 [ Time Frame: 12 weeks ]
    To determine the ctrough of tropifexor (LJN452)

  7. Itch based on a visual analog scale (VAS) rating scale [ Time Frame: 12 weeks ]
    The score (distance from left) on the VAS will be recorded by the patient marking with a line. The distance marked will be converted to a score between 0 and 10

  8. Change from baseline in BMI [ Time Frame: 12 weeks ]
    To determine the effect of different doses of tropifexor (LJN452) on BMI, after 12 weeks of treatment

  9. Change from baseline in waist-to-hip (WTH) ratio [ Time Frame: 12 weeks ]
    To determine the effect of different doses of tropifexor (LJN452) on waist-to-hip (WTH) ratio after 12 weeks of treatment

  10. Change from baseline in biomarker C4 [ Time Frame: 12 weeks ]
    To determine the dose-response relationship of LJN452 on C4, a marker of hepatic target engagement.

  11. Determine C2h of LJN452 [ Time Frame: 12 weeks ]
    To determine the pharmacokinetics (PK) of LJN452.

  12. Effects on above mentioned primary outcome measures in a subset of patients with history of biopsy data [ Time Frame: 12 weeks ]
    To determine the dose-response relationship of tropifexor (LJN452) in a subset of patients with historical biopsy data (both overall and by subsets defined by fibrosis score and/or NAS score) on the following primary outcome measures: adverse event profile; change in transaminase levels; on liver fat content by changes in quantitative MRI


Other Outcome Measures:
  1. Change in baseline on fibrosis level , as assessed by liver biopsy [ Time Frame: 48 weeks ]
    To demonstrate the efficacy of tropifexor (LJN452) in patients with NASH and F2/F3 fibrosis, as assessed by improvement in liver biopsy from baseline to Week 48.

  2. Adverse event profile of different doses of tropifexor (LJN452) in patients with NASH [ Time Frame: 48 weeks ]
    SAE), Adverse Event (AE) resulting in treatment discontinuation and/or dose reductions, and AE of special interest, from baseline to Week 48.

  3. Change from baseline in % of fat in the liver assessed using MRI [ Time Frame: 48 weeks ]
    To determine the dose-response relationship of tropifexor (LJN452) on liver fat content by changes in quantitative MRI determined fat from baseline to Week 48.

  4. Change in Transaminase levels [ Time Frame: 48 weeks ]
    To determine the dose relationship of tropifexor (LJN452) on markers of hepatic inflammation in NASH (ALT and AST) from baseline to Week 48.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02855164


Contacts
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Contact: Novartis Pharmaceuticals 1-888-669-6682
Contact: Novartis Pharmaceuticals +41613241111

  Show 109 Study Locations
Sponsors and Collaborators
Novartis Pharmaceuticals

Additional Information:
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02855164     History of Changes
Other Study ID Numbers: CLJN452A2202
2015-005215-33 ( EudraCT Number )
First Posted: August 4, 2016    Key Record Dates
Last Update Posted: June 11, 2019
Last Verified: June 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):
LJN452
non-alcoholic steatohepatitis
NASH
phase 2
adaptive design
randomized

Additional relevant MeSH terms:
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Fatty Liver
Non-alcoholic Fatty Liver Disease
Liver Diseases
Digestive System Diseases