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

NCT02855164 | Terminated Phase 2 Results DMC FDA Drug

• 2 other identifiers: CLJN452A22022015-005215-33
• Study Type: interventional
• Target: 350
• Locations: 16 countries
• Sites: 79

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

Conditions

Non-alcoholic Steatohepatitis (NASH)

Keywords

LJN452; non-alcoholic steatohepatitis; NASH; phase 2; adaptive design; randomized

Outcome Measures

Primary Outcomes (4)

• 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 Outcomes (19)

• Change From Baseline in Weight

  48 weeks

• Change in Body Mass Index (BMI)

  12 weeks

• Change From Baseline in Waist to Hip (WTH) Ratio

  12 weeks

• Change From Baseline in Biomarker FGF19

  baseline, week 6

• Change From Baseline in Biomarker C4

  Week 6, 4 hours post dose

Study Arms (8)

LJN452 10 μg

EXPERIMENTAL

Tropifexor (LJN452) Part A

Drug: Tropifexor (LJN452)

LJN452 30 μg

EXPERIMENTAL

Tropifexor (LJN452) Part A

Drug: Tropifexor (LJN452)

LJN452 60 μg

EXPERIMENTAL

Tropifezor (LJN452) Parts A + B

Drug: Tropifexor (LJN452)

LJN452 90 μg

EXPERIMENTAL

Tropifexor (LJN452) Parts A + B

Drug: Tropifexor (LJN452)

Placebo A+ B

PLACEBO COMPARATOR

Placebo Parts A + B

Drug: Placebo

LJN452 140 μg

EXPERIMENTAL

Tropifexor (LJN452) Part C

Drug: Tropifexor (LJN452)

LJN452 200 μg

EXPERIMENTAL

Tropifexor (LJN452) Part B

Drug: Tropifexor (LJN452)

Placebo C

PLACEBO COMPARATOR

Placebo Part C

Drug: Placebo

Interventions

Tropifexor (LJN452) DRUG

Comparison of different doses of drug

LJN452 10 μg; LJN452 140 μg; LJN452 200 μg; LJN452 30 μg; LJN452 60 μg; LJN452 90 μg

Placebo DRUG

Comparator

Placebo A+ B; Placebo C

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (81)

Novartis Investigative Site

Madison, Alabama, 35758, United States

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Novartis Investigative Site

North Little Rock, Arkansas, 72117, United States

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Novartis Investigative Site

Coronado, California, 92118, United States

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Novartis Investigative Site

Los Angeles, California, 90057, United States

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Pasadena, California, 91105, United States

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Rialto, California, 92377, United States

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San Diego, California, 92114, United States

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San Francisco, California, 94115, United States

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Novartis Investigative Site

Lonetree, Colorado, 80124, United States

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Boca Raton, Florida, 33434, United States

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Jacksonville, Florida, 32256, United States

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Lakewood Rch, Florida, 34211, United States

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Miami, Florida, 33136, United States

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Orlando, Florida, 32806, United States

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Pensacola, Florida, 32503, United States

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Athens, Georgia, 30607, United States

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Marietta, Georgia, 30060, United States

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Catonsville, Maryland, 21228, United States

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Worcester, Massachusetts, 01655, United States

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Detroit, Michigan, 48202, United States

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Minneapolis, Minnesota, 55455, United States

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Jefferson City, Missouri, 65109, United States

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Berlin, New Jersey, 08009, United States

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Morehead City, North Carolina, 28557, United States

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Cincinnati, Ohio, 45219, United States

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Hermitage, Tennessee, 37076, United States

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Dallas, Texas, 75208-2312, United States

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Houston, Texas, 77030, United States

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San Antonio, Texas, 78215, United States

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Norfolk, Virginia, 23502, United States

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Richmond, Virginia, 23298, United States

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CABA, Buenos Aires, C1181ACH, Argentina

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Caba, Buenos Aires, C1280AEB, Argentina

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Buenos Aires, C1120AAC, Argentina

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Kingswood, New South Wales, 2747, Australia

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Fitzroy, Victoria, 3065, Australia

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Salzburg, 5020, Austria

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Vienna, 1090, Austria

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Brussels, 1070, Belgium

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Ghent, 9000, Belgium

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Leuven, 3000, Belgium

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London, Ontario, N6A 5A5, Canada

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Toronto, Ontario, M5G 2C4, Canada

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Chicoutimi, Quebec, G7H 7K9, Canada

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Montpellier, 34295, France

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Paris, 75012, France

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Novartis Investigative Site

Paris, 75651, France

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Dresden, 01307, Germany

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Hamburg, 20246, Germany

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Hanover, 30625, Germany

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Leipzig, 04103, Germany

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Novartis Investigative Site

Würzburg, 97080, Germany

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Novartis Investigative Site

New Delhi, National Capital Territory of Delhi, 110070, India

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Bergamo, BG, 24128, Italy

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Bologna, 40138, Italy

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Roma, 00161, Italy

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Hatsukaichi, Hiroshima, 738 8503, Japan

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Yokohama, Kanagawa, 236-0004, Japan

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Novartis Investigative Site

Saga, Saga-ken, 849-8501, Japan

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Izumo, Shimane, 693 8501, Japan

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Utrecht, 3584CX, Netherlands

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Singapore, 169608, Singapore

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Banská Bystrica, 97517, Slovakia

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Bratislava, 82606, Slovakia

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Bratislava, 85101, Slovakia

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Novartis Investigative Site

Nitra, 949 01, Slovakia

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Novartis Investigative Site

Seoul, Korea, 03722, South Korea

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Novartis Investigative Site

Seoul, Korea, 05505, South Korea

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Novartis Investigative Site

Dongjak Gu, Seoul, 07061, South Korea

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Novartis Investigative Site

Busan, 602739, South Korea

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Novartis Investigative Site

Seoul, 03080, South Korea

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Novartis Investigative Site

Seville, Andalusia, 41013, Spain

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Novartis Investigative Site

Barcelona, Catalonia, 08035, Spain

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Novartis Investigative Site

Barcelona, Catalonia, 08036, Spain

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Novartis Investigative Site

Madrid, 28009, Spain

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Novartis Investigative Site

Madrid, 28034, Spain

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Novartis Investigative Site

Kaoshiung, Taiwan, 80756, Taiwan

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Novartis Investigative Site

Keelung, 20401, Taiwan

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Novartis Investigative Site

Taichung, 40447, Taiwan

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Novartis Investigative Site

Taipei, 11217, Taiwan

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Novartis Investigative Site

Taoyuan District, 33305, Taiwan

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Related Publications (2)

• Sanyal AJ, Lopez P, Lawitz EJ, Lucas KJ, Loeffler J, Kim W, Goh GBB, Huang JF, Serra C, Andreone P, Chen YC, Hsia SH, Ratziu V, Aizenberg D, Tobita H, Sheikh AM, Vierling JM, Kim YJ, Hyogo H, Tai D, Goodman Z, Schaefer F, Carbarns IRI, Lamle S, Martic M, Naoumov NV, Brass CA. Tropifexor for nonalcoholic steatohepatitis: an adaptive, randomized, placebo-controlled phase 2a/b trial. Nat Med. 2023 Feb;29(2):392-400. doi: 10.1038/s41591-022-02200-8. Epub 2023 Feb 16.

  PMID: 36797481 DERIVED

• 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.

  PMID: 35779659 DERIVED

Related 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)

MeSH Terms

Conditions

Non-alcoholic Fatty Liver Disease

Interventions

tropifexor

Condition Hierarchy (Ancestors)

Fatty Liver; Liver Diseases; Digestive System Diseases

Limitations and Caveats

No outputs were planned; and are not available for determining the effects of tropifexor on primary endpoints in the subset of patients who had historical biopsy data.

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

novartis.email@novartis.com

+1 (862) 778-8300

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: July 20, 2016
• First Posted: August 4, 2016
• Study Start: August 1, 2016
• Primary Completion: April 6, 2020
• Study Completion: April 6, 2020
• Last Updated: September 5, 2021
• Results First Posted: July 29, 2021

Record last verified: 2021-08

Locations

DE (5); AU (2); JP (4); IT (3); SG (1); TW (5); IN (1); KR (5); CA (3); FR (3); NL (1); SL (4); ES (5); US (31); AR (3); BE (3)