Clinical trial NCT02855164: Study of Safety and Efficacy of Tropifexor (LJN452) in Patients With Non-alcoholic Steatohepatitis (NASH)
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Non-alcoholic Steatohepatitis (NASH)
Keywords: LJN452
non-alcoholic steatohepatitis
NASH
phase 2
adaptive design
randomized
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2016-08-04
Enrollment: 350
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: Number of Nonalcoholic Steatohepatitis (NASH) Patients With Treatment Emergent Adverse Events (TEAE)
timeFrame: 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)
measure: Change in Transaminase Levels (ALT)
timeFrame: 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)
measure: Change in Aspartate Transaminase (AST)
timeFrame: 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)
measure: Change From Baseline in % of Fat in the Liver Assessed Using Magnetic Resonance Imaging (MRI)
timeFrame: 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 outcomes:
measure: Change From Baseline in Weight
timeFrame: 48 weeks
measure: Change in Body Mass Index (BMI)
timeFrame: 12 weeks
measure: Change From Baseline in Waist to Hip (WTH) Ratio
timeFrame: 12 weeks
measure: Change From Baseline in Biomarker FGF19
timeFrame: baseline, week 6
measure: Change From Baseline in Biomarker C4
timeFrame: Week 6, 4 hours post dose
measure: Change From Baseline on Markers of Liver Fibrosis, Fibroscan
timeFrame: End of Treatment (EoT): For Parts A&B, EoT was Week 12. For Part C, EoT was Week 48
measure: Change From Baseline on Markers of Liver Fibrosis Panel (ELF) Score
timeFrame: End of Treatment (EoT): For Parts A&B, EoT was Week 12. For Part C, EoT was Week 48
measure: Change From Baseline on Markers of Liver Fibrosis, Fibrotest (Parts A+B)
timeFrame: End of Treatment (EoT):12 weeks
measure: Change From Baseline on Markers of Liver Fibrosis, Fibrotest, (Part C)
timeFrame: End of Treatment (EoT) was 48 weeks
measure: Change From Baseline on Gamma-glutamyl Transferase (GGT)
timeFrame: EoT for Parts A+B=12 weeks; EoT for Part C = 48 weeks
measure: Change From Baseline on Fasting Lipid Profile
timeFrame: End of Treatment (EoT): For Parts A&B, EoT was Week 12. For Part C, EoT was Week 48
measure: Itch Based on a Visual Analog Scale (VAS) Rating Scale
timeFrame: EoT for Parts A+B=12 weeks; EoT for Part C = 48 weeks
measure: Pre-dose Trough Concentration (Ctrough) of LJN452
timeFrame: 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
measure: C2h (Steady-state Drug Levels 2 Hours Postdose) of LJN452
timeFrame: Days 7 and 14 (10 and 30μg LJN452 C2h was not measured day 14)
measure: 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
timeFrame: EoT (Week 48)
measure: Biopsy-based Response at Week 48 Compared to Baseline: At Least One Point Improvement in Fibrosis (NASH CRN Staging) Without Worsening - FDA
timeFrame: EoT (Week 48)
measure: Biopsy-based Response at Week 48 Compared to Baseline: At Least One Point Improvement in Fibrosis (NASH CRN Staging) Without Worsening - EMA
timeFrame: EoT (Week 48)
measure: Biopsy-based Response at Week 48 Compared to Baseline: Difference Between Treatment Groups (Part C) - Resolution of Steatohepatitis (Diagnostic Category)
timeFrame: EoT (Week 48)
measure: Biopsy-based Response at Week 48 Compared to Baseline: Difference Between Treatment Groups (Part C) - Resolution of Steatohepatitis (FDA, EMA)
timeFrame: EoT (Week 48)
Other outcomes:
Locations:
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facility: Novartis Investigative Site
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city: North Little Rock
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city: Los Angeles
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city: Miami
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city: Orlando
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city: Pensacola
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city: Athens
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city: Marietta
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state: Georgia
city: Catonsville
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state: Maryland
city: Worcester
country: United States
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state: Massachusetts
city: Detroit
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facility: Novartis Investigative Site
state: Michigan
city: Minneapolis
country: United States
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state: Minnesota
city: Jefferson City
country: United States
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state: Missouri
city: Berlin
country: United States
facility: Novartis Investigative Site
state: New Jersey
city: Morehead City
country: United States
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state: North Carolina
city: Cincinnati
country: United States
facility: Novartis Investigative Site
state: Ohio
city: Hermitage
country: United States
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state: Tennessee
city: Dallas
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state: Texas
city: Houston
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state: Texas
city: San Antonio
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state: Texas
city: Norfolk
country: United States
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state: Virginia
city: Richmond
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state: Virginia
city: Caba
country: Argentina
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state: Buenos Aires
city: Caba
country: Argentina
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state: Buenos Aires
city: Buenos Aires
country: Argentina
facility: Novartis Investigative Site
city: Kingswood
country: Australia
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state: New South Wales
city: Fitzroy
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state: Victoria
city: Salzburg
country: Austria
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city: Wien
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city: Bruxelles
country: Belgium
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city: Gent
country: Belgium
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city: Leuven
country: Belgium
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city: London
country: Canada
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state: Ontario
city: Toronto
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state: Ontario
city: Chicoutimi
country: Canada
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state: Quebec
city: Montpellier
country: France
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city: Paris
country: France
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city: Paris
country: France
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city: Dresden
country: Germany
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city: Hamburg
country: Germany
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city: Hannover
country: Germany
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city: Leipzig
country: Germany
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city: Wuerzburg
country: Germany
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city: New Delhi
country: India
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state: Delhi
city: Bergamo
country: Italy
facility: Novartis Investigative Site
state: BG
city: Bologna
country: Italy
facility: Novartis Investigative Site
city: Roma
country: Italy
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city: Hatsukaichi city
country: Japan
facility: Novartis Investigative Site
state: Hiroshima
city: Yokohama-city
country: Japan
facility: Novartis Investigative Site
state: Kanagawa
city: Saga-city
country: Japan
facility: Novartis Investigative Site
state: Saga
city: Izumo-city
country: Japan
facility: Novartis Investigative Site
state: Shimane
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Korea
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Korea
city: Dongjak Gu
country: Korea, Republic of
facility: Novartis Investigative Site
state: Seoul
city: Busan
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Utrecht
country: Netherlands
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city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Banska Bystrica
country: Slovakia
facility: Novartis Investigative Site
city: Bratislava
country: Slovakia
facility: Novartis Investigative Site
city: Bratislava
country: Slovakia
facility: Novartis Investigative Site
city: Nitra
country: Slovakia
facility: Novartis Investigative Site
city: Sevilla
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Cataluna
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Cataluna
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Kaoshiung
country: Taiwan
facility: Novartis Investigative Site
city: Keelung City
country: Taiwan
facility: Novartis Investigative Site
city: Taichung
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Taoyuan
country: Taiwan
facility: Novartis Investigative Site
Study officials:
References:
citation: 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.