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

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)

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

Study Overview

• Status: Terminated
• Conditions: Non-alcoholic Steatohepatitis NASH
• Intervention / Treatment: Drug: LMB763; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 122
• Phase: Phase 2

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	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.	From date of First Participant First Treatment until Last Patient Last Visit (up to Day 112 (End of Study (EOS))
Change From Baseline in Alanine Aminotransferase (ALT) Levels	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).	Baseline to Day 84 (Week 12)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Observed Maximum Plasma Concentration (Cmax) of LMB763	No statistical analysis was planned for this outcome measure.	0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose on Days 1 and 42
Time to Reach Maximum Concentration (Tmax) of LMB763	No statistical analysis was planned for this outcome measure.	0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose on Days 1 and 42
Area Under Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUClast) of LMB763	No statistical analysis was planned for this outcome measure.	0 to 96 hours post-dose on Days 1 and 42
Accumulation Ratio (Racc) of LMB763	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.	Day 42
Change From Baseline in Percentage of Liver Fat as Measured by Magnetic Resonance Imaging (MRI)	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).	Baseline to Day 84 (Week 12)
Change From Baseline in Weight	Baseline was defined as the last available measurement prior to the first dose.	Baseline to Days 28, 42, 56, 84 and 112 (EOS)
Change From Baseline in Body Mass Index (BMI)	Baseline was defined as the last available measurement prior to the first dose at specified visit (day).	Baseline to Days 28, 42, 56, 84 and 112 (EOS)
Change From Baseline in Waist to Hip Ratio	Baseline was defined as the last available measurement prior to the first dose.	Baseline to Days 28, 42, 56, 84 and 112 (EOS)
Change From to Baseline in Liver Stiffness	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).	Baseline to Day 84 (Week 12)
Change From Baseline in Enhanced Liver Fibrosis (ELF) Test Panel	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	Baseline to Days 42 and 84
Change From Baseline in Fibrosis Biomarker Test	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).	Baseline to Days 42 and 84
Change From Baseline in Fasting Lipid Profile: Cholesterol (Chol) and Triglycerides (TG)	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).	Baseline to Days 7, 14, 28, 42, 56, 84 and 112 (EOS)
Change From Baseline in Fasting Lipid Profile: High-density Lipoprotein (HDL) and Low-density Lipoprotein (LDL) Cholesterol	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).	Baseline to Days 7, 14, 28, 42, 56, 84 and 112 (EOS)
Change From Baseline in Visual Analog Scale (VAS) for Itching of Skin	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.	Baseline to Day 84 (Week 12)

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• A Plain Language Trial Summary is available on novartisclinicatrials.com

Study record dates

Study Major Dates

• Study Start (Actual): October 24, 2016
• Primary Completion (Actual): September 19, 2018
• Study Completion (Actual): September 19, 2018

Study Registration Dates

• First Submitted: September 13, 2016
• First Submitted That Met QC Criteria: September 21, 2016
• First Posted (Estimate): September 23, 2016

Study Record Updates

• Last Update Posted (Actual): January 5, 2021
• Last Update Submitted That Met QC Criteria: December 9, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Keywords: NASH; Fatty liver disease; Non-alcoholic Steatohepatitis
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
• Other Study ID Numbers: CLMB763X2201

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

IPD 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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No