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

Primary Purpose

Non-alcoholic Steatohepatitis NASH

Status
Terminated
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
LMB763
Placebo
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Non-alcoholic Steatohepatitis NASH focused on measuring Non-alcoholic Steatohepatitis, NASH, Fatty liver disease

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

LMB763

Placebo

Arm Description

Oral dose once daily for 12 weeks (84 days)

Oral dose once daily for 12 weeks (84 days)

Outcomes

Primary Outcome Measures

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.
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).

Secondary Outcome Measures

Observed Maximum Plasma Concentration (Cmax) of LMB763
No statistical analysis was planned for this outcome measure.
Time to Reach Maximum Concentration (Tmax) of LMB763
No statistical analysis was planned for this outcome measure.
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.
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.
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).
Change From Baseline in Weight
Baseline was defined as the last available measurement prior to the first dose.
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).
Change From Baseline in Waist to Hip Ratio
Baseline was defined as the last available measurement prior to the first dose.
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).
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
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).
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).
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).
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.

Full Information

First Posted
September 13, 2016
Last Updated
December 9, 2020
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT02913105
Brief Title
Safety, Tolerability, Pharmacokinetics and Efficacy of LMB763 in Patients With NASH
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)
Study Type
Interventional

2. Study Status

Record Verification Date
January 2020
Overall Recruitment Status
Terminated
Study Start Date
October 24, 2016 (Actual)
Primary Completion Date
September 19, 2018 (Actual)
Study Completion Date
September 19, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Non-alcoholic Steatohepatitis NASH
Keywords
Non-alcoholic Steatohepatitis, NASH, Fatty liver disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
122 (Actual)

8. Arms, Groups, and Interventions

Arm Title
LMB763
Arm Type
Experimental
Arm Description
Oral dose once daily for 12 weeks (84 days)
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Oral dose once daily for 12 weeks (84 days)
Intervention Type
Drug
Intervention Name(s)
LMB763
Intervention Description
Hard Gelatin Capsules
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Hard Gelatin Capsule
Primary Outcome Measure Information:
Title
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description
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.
Time Frame
From date of First Participant First Treatment until Last Patient Last Visit (up to Day 112 (End of Study (EOS))
Title
Change From Baseline in Alanine Aminotransferase (ALT) Levels
Description
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).
Time Frame
Baseline to Day 84 (Week 12)
Secondary Outcome Measure Information:
Title
Observed Maximum Plasma Concentration (Cmax) of LMB763
Description
No statistical analysis was planned for this outcome measure.
Time Frame
0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose on Days 1 and 42
Title
Time to Reach Maximum Concentration (Tmax) of LMB763
Description
No statistical analysis was planned for this outcome measure.
Time Frame
0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose on Days 1 and 42
Title
Area Under Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUClast) of LMB763
Description
No statistical analysis was planned for this outcome measure.
Time Frame
0 to 96 hours post-dose on Days 1 and 42
Title
Accumulation Ratio (Racc) of LMB763
Description
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.
Time Frame
Day 42
Title
Change From Baseline in Percentage of Liver Fat as Measured by Magnetic Resonance Imaging (MRI)
Description
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).
Time Frame
Baseline to Day 84 (Week 12)
Title
Change From Baseline in Weight
Description
Baseline was defined as the last available measurement prior to the first dose.
Time Frame
Baseline to Days 28, 42, 56, 84 and 112 (EOS)
Title
Change From Baseline in Body Mass Index (BMI)
Description
Baseline was defined as the last available measurement prior to the first dose at specified visit (day).
Time Frame
Baseline to Days 28, 42, 56, 84 and 112 (EOS)
Title
Change From Baseline in Waist to Hip Ratio
Description
Baseline was defined as the last available measurement prior to the first dose.
Time Frame
Baseline to Days 28, 42, 56, 84 and 112 (EOS)
Title
Change From to Baseline in Liver Stiffness
Description
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).
Time Frame
Baseline to Day 84 (Week 12)
Title
Change From Baseline in Enhanced Liver Fibrosis (ELF) Test Panel
Description
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
Time Frame
Baseline to Days 42 and 84
Title
Change From Baseline in Fibrosis Biomarker Test
Description
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).
Time Frame
Baseline to Days 42 and 84
Title
Change From Baseline in Fasting Lipid Profile: Cholesterol (Chol) and Triglycerides (TG)
Description
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).
Time Frame
Baseline to Days 7, 14, 28, 42, 56, 84 and 112 (EOS)
Title
Change From Baseline in Fasting Lipid Profile: High-density Lipoprotein (HDL) and Low-density Lipoprotein (LDL) Cholesterol
Description
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).
Time Frame
Baseline to Days 7, 14, 28, 42, 56, 84 and 112 (EOS)
Title
Change From Baseline in Visual Analog Scale (VAS) for Itching of Skin
Description
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.
Time Frame
Baseline to Day 84 (Week 12)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Facility Information:
Facility Name
Novartis Investigative Site
City
Culver City
State/Province
California
ZIP/Postal Code
90230
Country
United States
Facility Name
Novartis Investigative Site
City
Cypress
State/Province
California
ZIP/Postal Code
90630
Country
United States
Facility Name
Novartis Investigative Site
City
Gainesville
State/Province
Florida
ZIP/Postal Code
32610-0277
Country
United States
Facility Name
Novartis Investigative Site
City
Miami Springs
State/Province
Florida
ZIP/Postal Code
33166
Country
United States
Facility Name
Novartis Investigative Site
City
Orlando
State/Province
Florida
ZIP/Postal Code
32803
Country
United States
Facility Name
Novartis Investigative Site
City
Orlando
State/Province
Florida
ZIP/Postal Code
32806
Country
United States
Facility Name
Novartis Investigative Site
City
Honolulu
State/Province
Hawaii
ZIP/Postal Code
96814
Country
United States
Facility Name
Novartis Investigative Site
City
Baton Rouge
State/Province
Louisiana
ZIP/Postal Code
70808
Country
United States
Facility Name
Novartis Investigative Site
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Novartis Investigative Site
City
High Point
State/Province
North Carolina
ZIP/Postal Code
27265
Country
United States
Facility Name
Novartis Investigative Site
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37211
Country
United States
Facility Name
Novartis Investigative Site
City
Arlington
State/Province
Texas
ZIP/Postal Code
76012
Country
United States
Facility Name
Novartis Investigative Site
City
Houston
State/Province
Texas
ZIP/Postal Code
77081
Country
United States
Facility Name
Novartis Investigative Site
City
Newport News
State/Province
Virginia
ZIP/Postal Code
23602
Country
United States
Facility Name
Novartis Investigative Site
City
New Lambton
State/Province
New South Wales
ZIP/Postal Code
2305
Country
Australia
Facility Name
Novartis Investigative Site
City
Nedlands
State/Province
Western Australia
ZIP/Postal Code
6009
Country
Australia
Facility Name
Novartis Investigative Site
City
Tbilisi
ZIP/Postal Code
0112
Country
Georgia
Facility Name
Novartis Investigative Site
City
Amman
ZIP/Postal Code
11941
Country
Jordan
Facility Name
Novartis Investigative Site
City
Papatoetoe
State/Province
Auckland
ZIP/Postal Code
2025
Country
New Zealand
Facility Name
Novartis Investigative Site
City
Auckland
Country
New Zealand
Facility Name
Novartis Investigative Site
City
Christchurch
ZIP/Postal Code
8024
Country
New Zealand
Facility Name
Novartis Investigative Site
City
Tauranga
ZIP/Postal Code
3110
Country
New Zealand
Facility Name
Novartis Investigative Site
City
Wellington
ZIP/Postal Code
6021
Country
New Zealand
Facility Name
Novartis Investigative Site
City
San Juan
ZIP/Postal Code
00927
Country
Puerto Rico
Facility Name
Novartis Investigative Site
City
Bern
ZIP/Postal Code
3010
Country
Switzerland
Facility Name
Novartis Investigative Site
City
Geneve 14
ZIP/Postal Code
1211
Country
Switzerland
Facility Name
Novartis Investigative Site
City
Lugano
ZIP/Postal Code
6900
Country
Switzerland
Facility Name
Novartis Investigative Site
City
Plymouth
State/Province
Devon
ZIP/Postal Code
PL6 8DH
Country
United Kingdom
Facility Name
Novartis Investigative Site
City
Glasgow
ZIP/Postal Code
G31 2ER
Country
United Kingdom
Facility Name
Novartis Investigative Site
City
Portsmouth
ZIP/Postal Code
PO6 3LY
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
Undecided
IPD Sharing 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
Links:
URL
https://www.novctrd.com/ctrdweb/patientsummary/patientsummaries?patientSummaryId=493
Description
A Plain Language Trial Summary is available on novartisclinicatrials.com

Learn more about this trial

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

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