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

Non-alcoholic Steatohepatitis (NASH) Clinical Trial

— FLIGHT-FXR  

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02855164
• Other study ID #: CLJN452A2202
• Secondary ID: 2015-005215-33
• Status: Terminated
• Phase: Phase 2
• Start date: August 1, 2016
• Est. completion date: April 6, 2020

Study information

• Verified date: August 2021
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 350
• Est. completion date: April 6, 2020
• Est. primary completion date: April 6, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Fatty Liver
• Non-alcoholic Fatty Liver Disease
• Non-alcoholic Steatohepatitis (NASH)

Intervention

Drug:
• Tropifexor (LJN452)
Comparison of different doses of drug
• Placebo
Comparator

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Caba	Buenos Aires
Argentina	Novartis Investigative Site	Caba	Buenos Aires
Australia	Novartis Investigative Site	Fitzroy	Victoria
Australia	Novartis Investigative Site	Kingswood	New South Wales
Austria	Novartis Investigative Site	Salzburg
Austria	Novartis Investigative Site	Wien
Belgium	Novartis Investigative Site	Bruxelles
Belgium	Novartis Investigative Site	Gent
Belgium	Novartis Investigative Site	Leuven
Canada	Novartis Investigative Site	Chicoutimi	Quebec
Canada	Novartis Investigative Site	London	Ontario
Canada	Novartis Investigative Site	Toronto	Ontario
France	Novartis Investigative Site	Montpellier
France	Novartis Investigative Site	Paris
France	Novartis Investigative Site	Paris
Germany	Novartis Investigative Site	Dresden
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Hannover
Germany	Novartis Investigative Site	Leipzig
Germany	Novartis Investigative Site	Wuerzburg
India	Novartis Investigative Site	New Delhi	Delhi
Italy	Novartis Investigative Site	Bergamo	BG
Italy	Novartis Investigative Site	Bologna
Italy	Novartis Investigative Site	Roma
Japan	Novartis Investigative Site	Hatsukaichi city	Hiroshima
Japan	Novartis Investigative Site	Izumo-city	Shimane
Japan	Novartis Investigative Site	Saga-city	Saga
Japan	Novartis Investigative Site	Yokohama-city	Kanagawa
Korea, Republic of	Novartis Investigative Site	Busan
Korea, Republic of	Novartis Investigative Site	Dongjak Gu	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul	Korea
Korea, Republic of	Novartis Investigative Site	Seoul	Korea
Netherlands	Novartis Investigative Site	Utrecht
Singapore	Novartis Investigative Site	Singapore
Slovakia	Novartis Investigative Site	Banska Bystrica
Slovakia	Novartis Investigative Site	Bratislava
Slovakia	Novartis Investigative Site	Bratislava
Slovakia	Novartis Investigative Site	Nitra
Spain	Novartis Investigative Site	Barcelona	Cataluna
Spain	Novartis Investigative Site	Barcelona	Cataluna
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Sevilla	Andalucia
Taiwan	Novartis Investigative Site	Kaoshiung
Taiwan	Novartis Investigative Site	Keelung City
Taiwan	Novartis Investigative Site	Taichung
Taiwan	Novartis Investigative Site	Taipei
Taiwan	Novartis Investigative Site	Taoyuan
United States	Novartis Investigative Site	Athens	Georgia
United States	Novartis Investigative Site	Berlin	New Jersey
United States	Novartis Investigative Site	Boca Raton	Florida
United States	Novartis Investigative Site	Catonsville	Maryland
United States	Novartis Investigative Site	Cincinnati	Ohio
United States	Novartis Investigative Site	Coronado	California
United States	Novartis Investigative Site	Dallas	Texas
United States	Novartis Investigative Site	Detroit	Michigan
United States	Novartis Investigative Site	Hermitage	Tennessee
United States	Novartis Investigative Site	Houston	Texas
United States	Novartis Investigative Site	Jacksonville	Florida
United States	Novartis Investigative Site	Jefferson City	Missouri
United States	Novartis Investigative Site	Lakewood Ranch	Florida
United States	Novartis Investigative Site	Lonetree	Colorado
United States	Novartis Investigative Site	Los Angeles	California
United States	Novartis Investigative Site	Madison	Alabama
United States	Novartis Investigative Site	Marietta	Georgia
United States	Novartis Investigative Site	Miami	Florida
United States	Novartis Investigative Site	Minneapolis	Minnesota
United States	Novartis Investigative Site	Morehead City	North Carolina
United States	Novartis Investigative Site	Norfolk	Virginia
United States	Novartis Investigative Site	North Little Rock	Arkansas
United States	Novartis Investigative Site	Orlando	Florida
United States	Novartis Investigative Site	Pasadena	California
United States	Novartis Investigative Site	Pensacola	Florida
United States	Novartis Investigative Site	Rialto	California
United States	Novartis Investigative Site	Richmond	Virginia
United States	Novartis Investigative Site	San Antonio	Texas
United States	Novartis Investigative Site	San Diego	California
United States	Novartis Investigative Site	San Francisco	California
United States	Novartis Investigative Site	Worcester	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belgium,  Canada,  France,  Germany,  India,  Italy,  Japan,  Korea, Republic of,  Netherlands,  Singapore,  Slovakia,  Spain,  Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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)
Primary	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)
Primary	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	Change From Baseline in Weight	Repeated measures for LS mean change in weight after 12 weeks of treatment	48 weeks
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Change From Baseline on Markers of Liver Fibrosis, Fibrotest (Parts A+B)	Fibrosis biomarker test, originally called Fibrotest®/ Fibrosure®, is combines a2-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
Secondary	Change From Baseline on Markers of Liver Fibrosis, Fibrotest, (Part C)	Fibrosis biomarker test, originally called Fibrotest®/ Fibrosure®, is combines a2-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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)

External 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)