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Safety, Tolerability, Pharmacokinetics and Efficacy of LMB763 in Patients With NASH

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02913105
Recruitment Status : Terminated
First Posted : September 23, 2016
Results First Posted : November 26, 2019
Last Update Posted : January 5, 2021
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Description
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Brief Summary:
The purpose of the present study is to assess the effects of LMB763 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: LMB763 Drug: Placebo Phase 2

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 122 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : October 24, 2016
Actual Primary Completion Date : September 19, 2018
Actual Study Completion Date : September 19, 2018

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: LMB763
Oral dose once daily for 12 weeks (84 days)
 Drug: LMB763
Hard Gelatin Capsules
Placebo Comparator: Placebo
Oral dose once daily for 12 weeks (84 days)
 Drug: Placebo
Hard Gelatin Capsule


Outcome Measures
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Primary Outcome Measures :
  1. Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: From date of First Participant First Treatment until Last Patient Last Visit (up to Day 112 (End of Study (EOS)) ]
    An AE is defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. An SAE is defined as any untoward medical occurrence that, at any dose that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect or any other situation as per Medical or scientific judgment. No statistical analysis was planned for this primary outcome measure.

  2. Change From Baseline in Alanine Aminotransferase (ALT) Levels [ Time Frame: Baseline to Day 84 (Week 12) ]
    ALT level assessment is one of the diagnostic parameters in Liver function test (LFT). Baseline was defined as the mean of ALT levels at baseline and pre-dose visits. Geometric Mean and Geometric Coefficient of Variation for change are based on log-transformed ratio to baseline (i.e., change from baseline in the log domain).


Secondary Outcome Measures :
  1. Observed Maximum Plasma Concentration (Cmax) of LMB763 [ Time Frame: 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose on Days 1 and 42 ]
    No statistical analysis was planned for this outcome measure.

  2. Time to Reach Maximum Concentration (Tmax) of LMB763 [ Time Frame: 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose on Days 1 and 42 ]
    No statistical analysis was planned for this outcome measure.

  3. Area Under Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUClast) of LMB763 [ Time Frame: 0 to 96 hours post-dose on Days 1 and 42 ]
    No statistical analysis was planned for this outcome measure.

  4. Accumulation Ratio (Racc) of LMB763 [ Time Frame: Day 42 ]

    The drug accumulation ratio (Racc) is the ratio of accumulation of drug going from a single dose to steady state with repeated administration.

    No statistical analysis was planned for this outcome measure.


  5. Change From Baseline in Percentage of Liver Fat as Measured by Magnetic Resonance Imaging (MRI) [ Time Frame: Baseline to Day 84 (Week 12) ]
    Participants were to undergo MRI twice (Baseline and End of Treatment) during the course of the study to quantitate liver fat. Baseline was defined as the last available measurement prior to the first dose. Geometric Mean and Geometric Coefficient of Variation for change are based on log-transformed ratio to baseline (i.e., change from baseline in the log domain).

  6. Change From Baseline in Weight [ Time Frame: Baseline to Days 28, 42, 56, 84 and 112 (EOS) ]
    Baseline was defined as the last available measurement prior to the first dose.

  7. Change From Baseline in Body Mass Index (BMI) [ Time Frame: Baseline to Days 28, 42, 56, 84 and 112 (EOS) ]
    Baseline was defined as the last available measurement prior to the first dose at specified visit (day).

  8. Change From Baseline in Waist to Hip Ratio [ Time Frame: Baseline to Days 28, 42, 56, 84 and 112 (EOS) ]
    Baseline was defined as the last available measurement prior to the first dose.

  9. Change From to Baseline in Liver Stiffness [ Time Frame: Baseline to Day 84 (Week 12) ]
    Fibroscan® was performed where available to assess liver stiffness. Baseline was defined as the last available measurement prior to the first dose. Geometric Mean and Geometric Coefficient of Variation for change are based on log-transformed ratio to baseline (i.e., change from baseline in the log domain).

  10. Change From Baseline in Enhanced Liver Fibrosis (ELF) Test Panel [ Time Frame: Baseline to Days 42 and 84 ]

    The ADVIA CentaurR systems' ELF™ test is an in vitro diagnostic multivariate index assay that provides a single score by combining quantitative measurements of hyaluronic acid (HA), amino-terminal propeptide of type III procollagen (PIIINP), and tissue inhibitor of metalloproteinase 1 (TIMP-1) in human serum using the ADVIA Centaur XP, ADVIA Centaur XPT, and ADVIA Centaur CP systems in an algorithm. ELF score for the ADVIA Centaur systems is calculated by, first obtaining results for the ADVIA Centaur HA, PIIINP, and TIMP-1 assays and then using the following equation/algorithm:

    ADVIA Centaur XP/XPT:

    ELF score = 2.278 + 0.851 ln(CHA) + 0.751 ln(CP3NP) + 0.394 ln(CTIMP1)

    ADVIA Centaur CP:

    ELF score = 2.494 + 0.846 ln(CHA) + 0.735 ln(CP3NP) + 0.391 ln(CTIMP1) Concentrations (C) of each assay are in ng/mL

    Interpretation of ELF score is as follows:

    < 7.7 None to mild

    • 7.7 to < 9.8 Moderate
    • 9.8 Severe

  11. Change From Baseline in Fibrosis Biomarker Test [ Time Frame: Baseline to Days 42 and 84 ]
    Fibrosis Biomarker test included hyaluronic acid (HA), amino-terminal pro-peptide of procollagen type III (PIIINP), and tissue inhibitor of metalloproteinases (TIMP-1) as markers of liver fibrosis. Baseline was defined as the last available measurement prior to the first dose. Geometric Mean and Geometric Coefficient of Variation for change are based on log-transformed ratio to baseline (i.e., change from baseline in the log domain).

  12. Change From Baseline in Fasting Lipid Profile: Cholesterol (Chol) and Triglycerides (TG) [ Time Frame: Baseline to Days 7, 14, 28, 42, 56, 84 and 112 (EOS) ]
    Lipid measurements were collected under fasted conditions. Baseline was defined as the last available measurement prior to the first dose. Geometric Mean and Geometric Coefficient of Variation for change are based on log-transformed ratio to baseline (i.e., change from baseline in the log domain).

  13. Change From Baseline in Fasting Lipid Profile: High-density Lipoprotein (HDL) and Low-density Lipoprotein (LDL) Cholesterol [ Time Frame: Baseline to Days 7, 14, 28, 42, 56, 84 and 112 (EOS) ]
    Baseline was defined as the last available measurement prior to the first dose. Geometric Mean and Geometric Coefficient of Variation for change are based on log-transformed ratio to baseline (i.e., change from baseline in the log domain).

  14. Change From Baseline in Visual Analog Scale (VAS) for Itching of Skin [ Time Frame: Baseline to Day 84 (Week 12) ]
    A 10 cm VAS was used to assess the severity of participants itch (ranging from 0 = no itch at all to 10 = the worst imaginable itch). The score (distance from left) on the VAS was recorded by the participant marking with a line and used to test for an effect of LMB763 over placebo. Baseline was defined as the last available measurement prior to the first dose. A positive change from Baseline indicates improvement.


Eligibility Criteria
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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
  • Presence of NASH by histologic evidence (liver biopsy) and elevated alanine aminotransferase (ALT), OR phenotypic diagnosis of NASH based on elevated ALT, BMI and diagnosis of Type 2 diabetes mellitus

Exclusion Criteria:

  • Current use of obeticholic acid (OCA)
  • New initiation GLP-1 agonists such as liraglutide, exenatide , lixisenatide, albiglutide or dulaglutide within 3 months of screening
  • Pregnant or nursing (lactating) women
  • Women of child-bearing potential, unless they are using highly effective methods of contraception during dosing and for 5 days after stopping study medication
  • Current or history of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to screening
  • Clinical evidence of hepatic decompensation or severe liver impairment
  • Previous diagnosis of other forms of chronic liver disease
  • Uncontrolled diabetes mellitus
  • History or current diagnosis of ECG abnormalities
  • Patients with contraindications to MRI imaging
Contacts and Locations
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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): NCT02913105


Locations
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United States, California
Novartis Investigative Site
Culver City, California, United States, 90230
Novartis Investigative Site
Cypress, California, United States, 90630
United States, Florida
Novartis Investigative Site
Gainesville, Florida, United States, 32610-0277
Novartis Investigative Site
Miami Springs, Florida, United States, 33166
Novartis Investigative Site
Orlando, Florida, United States, 32803
Novartis Investigative Site
Orlando, Florida, United States, 32806
United States, Hawaii
Novartis Investigative Site
Honolulu, Hawaii, United States, 96814
United States, Louisiana
Novartis Investigative Site
Baton Rouge, Louisiana, United States, 70808
United States, Massachusetts
Novartis Investigative Site
Boston, Massachusetts, United States, 02114
United States, North Carolina
Novartis Investigative Site
High Point, North Carolina, United States, 27265
United States, Tennessee
Novartis Investigative Site
Nashville, Tennessee, United States, 37211
United States, Texas
Novartis Investigative Site
Arlington, Texas, United States, 76012
Novartis Investigative Site
Houston, Texas, United States, 77081
United States, Virginia
Novartis Investigative Site
Newport News, Virginia, United States, 23602
Australia, New South Wales
Novartis Investigative Site
New Lambton, New South Wales, Australia, 2305
Australia, Western Australia
Novartis Investigative Site
Nedlands, Western Australia, Australia, 6009
Georgia
Novartis Investigative Site
Tbilisi, Georgia, 0112
Jordan
Novartis Investigative Site
Amman, Jordan, 11941
New Zealand
Novartis Investigative Site
Papatoetoe, Auckland, New Zealand, 2025
Novartis Investigative Site
Auckland, New Zealand
Novartis Investigative Site
Christchurch, New Zealand, 8024
Novartis Investigative Site
Tauranga, New Zealand, 3110
Novartis Investigative Site
Wellington, New Zealand, 6021
Puerto Rico
Novartis Investigative Site
San Juan, Puerto Rico, 00927
Switzerland
Novartis Investigative Site
Bern, Switzerland, 3010
Novartis Investigative Site
Geneve 14, Switzerland, 1211
Novartis Investigative Site
Lugano, Switzerland, 6900
United Kingdom
Novartis Investigative Site
Plymouth, Devon, United Kingdom, PL6 8DH
Novartis Investigative Site
Glasgow, United Kingdom, G31 2ER
Novartis Investigative Site
Portsmouth, United Kingdom, PO6 3LY
Sponsors and Collaborators
Novartis Pharmaceuticals
  Study Documents (Full-Text)

Documents provided by Novartis ( Novartis Pharmaceuticals ):
Study Protocol  [PDF] October 2, 2017
Statistical Analysis Plan  [PDF] November 9, 2018

More Information
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Additional Information:

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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02913105    
Other Study ID Numbers: CLMB763X2201
First Posted: September 23, 2016    Key Record Dates
Results First Posted: November 26, 2019
Last Update Posted: January 5, 2021
Last Verified: January 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description:

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect 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

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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 ):
Non-alcoholic Steatohepatitis
NASH
Fatty liver disease
Additional relevant MeSH terms:
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Fatty Liver
Non-alcoholic Fatty Liver Disease
Liver Diseases
Digestive System Diseases