Back to resultsStudy of Various Treatments in Non-alcoholic Fatty Liver Disease (NAFLD) Patients Who Have Aspects of Non-alcoholic Steatohepatitis (NASH) (NEXSCOT)
Primary Purpose
Non-alcoholic Fatty Liver Disease, Nonalcoholic Steatohepatitis
Status
Terminated
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
LYS006
Tropifexor
Sponsored by
About this trial
This is an interventional treatment trial for Non-alcoholic Fatty Liver Disease focused on measuring Non-alcoholic fatty liver disease, NAFLD, Non-alcoholic steatohepatitis, NASH, Platform design, LYS006, LJN452, Tropifexor
Eligibility Criteria
Inclusion Criteria:
- Phenotypic diagnosis of NASH based on the presence of all of the following:
- ALT ≥ 43 IU/L (males) or ≥ 28 IU/L (females) at screening
- BMI ≥ 27 kg/m2 (race other than Asian) or ≥ 23 kg/m2 (Asian race)
- History of type 2 diabetes mellitus with HbA1c ≤ 9%
- ELF test score ≥ 8.5 and ≤ 10.5
- Liver fat ≥ 8%
- Patients must weigh between 40 kg (88 lbs.) and 150 kg (330 lbs.)
Exclusion Criteria:
- Use of other investigational drugs within 5 half-lives of enrollment or within 3 months, whichever is longer
- Use of obeticholic acid (OCA) or pharmacologically-active weight loss drugs within 1 month of enrollment and until end-of-study
- Use of strong CYP3A4/5 inhibitors or strong CYP3A4 inducers within 5 half-lives or 7 days of enrollment, whichever is longer, and until end-of-study
- History or presence of other concomitant liver diseases
- History or current diagnosis of ECG abnormalities
- Patients with contraindications to MRI imaging
- Current or history of significant alcohol consumption
- Clinical evidence of hepatic decompensation or severe liver impairment
- Women of child bearing potential (unless on highly effective methods of contraception)
- Presence of liver cirrhosis
- For Cohort 1, use of OAT3 inhibitors or BRCP inhibitors within 5 half-lives or 7 days of enrollment, whichever is longer and until the end of study.
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
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
LYS006
LYS006 + LJN452
Arm Description
LYS006 20 mg was administered orally twice per day (b.i.d) for 12 weeks
LYS006 20 mg was administered orally twice per day (b.i.d) in addition to LJN452 200ug administered orally once daily for 12 weeks
Outcomes
Primary Outcome Measures
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Number of participants with AEs and SAEs including significant changes from baseline in vital signs, electrocardiograms and laboratory parameters qualifying and reported as AEs. The number of participants in each category is reported in the table.
Secondary Outcome Measures
Change From Baseline in Non-invasive Markers of Hepatic Fibrosis: Enhanced Liver Fibrosis Test (ELF) Score
The markers of fibrosis assessed in this test comprised hyaluronic acid (HA), tissue inhibitor of metalloproteinase (TIMP1) and procollagen III N-terminal peptide (PIIINP); these are components of the extracellular matrix and basement sinusoidal membrane of the liver and are elevated during fibrogenesis as a result of activation of the hepatic stellate cell. The ELF test is a composite score: < 7.7: no to mild fibrosis; ≥ 7.7 - < 9.8: Moderate fibrosis; ≥ 9.8 - < 11.3: Severe fibrosis; ≥ 11.3: Cirrhosis.
Baseline is defined as the last non-missing measurement taken at the Screening and Baseline visits (prior to the first dose of study drug administered at the Day 1). A negative change from Baseline indicates decreased fibrosis.
Change From Baseline in Cholesterol: Fasting Lipid Profile Endpoint
Fasting lipid profile (total cholesterol) was examined as a cardiometabolic risk parameter. Total cholesterol was measured on blood samples under fasted conditions and analyzed at a central laboratory.
Baseline is defined as the last non-missing measurement taken at the Screening and Baseline visits (prior to the first dose of study drug administered at the Day 1). A negative change from Baseline indicates cardiovascular risk.
Change From Baseline in Percent Liver Fat at Day 85
Percent (%) Liver fat was measured by Magnetic Resonance Imaging Proton Density Liver Fat Fraction (MRIPDFF). Participants underwent magnetic resonance imaging twice during the course of the study (baseline and end of treatment) to quantitate liver fat.
Baseline is defined as the last non-missing measurement taken at the Screening and Baseline visits (prior to the first dose of study drug administered at the Day 1). A negative change from Baseline indicates a reduction in a component of NAFLD.
Change From Baseline in Total Body Weight
Body weight (to the nearest 0.1 kilogram [kg] was measured on a calibrated scale. The measurement was performed with the study participant in underwear and without shoes; or while wearing minimal indoor clothing.
Baseline is defined as the last non-missing measurement taken at the Screening and Baseline visits (prior to the first dose of study drug administered at the Day 1). A negative change from Baseline indicates improvement in obesity.
Change From Baseline in Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) at Day 85
HOMA-IR is a test that uses a simultaneous fasting blood glucose test and fasting insulin test to accurately estimate the degree of insulin resistance (IR) and β-cell function (the cells of the pancreas that produce insulin). HOMA-IR scores are classified as follows: Insulin sensitive is considered less than 1.0, Healthy is considered 0.5-1.4, Above 1.8 is early insulin resistance and Above 2.7 is considered significant insulin resistance
HOMA-IR= [Fasting glucose (mmol/L) x (fasting insulin (pmol/L)/6)] / 22.5
Baseline is defined as the last non-missing measurement taken at the Screening and Baseline visits (prior to the first dose of study drug administered at the Day 1). A negative change from Baseline indicates improvement in insulin sensitivity.
Change From Baseline in Fasting Glucose
Fasting Glucose was examined as a cardiometabolic risk parameter. Total fasting glucose was measured on blood samples under fasted conditions and analyzed at a central laboratory.
Baseline is defined as the last non-missing measurement taken at the Screening and Baseline visits (prior to the first dose of study drug administered at the Day 1). A negative change from Baseline indicates improvement in glycemic control.
Change From Baseline in Fasting Insulin at Day 85
Fasting insulin was examined as a cardiometabolic risk parameter. Total fasting insulin was measured on blood samples under fasted conditions and analyzed at a central laboratory.
Baseline is defined as the last non-missing measurement taken at the Screening and Baseline visits (prior to the first dose of study drug administered at the Day 1). A negative change from Baseline indicates improvement in insulin sensitivity.
Change From Baseline in Hemoglobin A1c (HbA1c)
HbA1c was examined as a cardiometabolic risk parameter. HbA1c was measured on blood samples under fasted conditions and analyzed at a central laboratory.
Baseline is defined as the last non-missing measurement taken at the Screening and Baseline visits (prior to the first dose of study drug administered at the Day 1). A negative change from Baseline indicates improvement in glycemic control.
Change From Baseline in Alanine Aminotransferase (ALT)
Alanine aminotransferase (ALT) is an enzyme found primarily in the liver. ALT is increased with liver damage. In this study, the blood levels of ALT was used to detect liver inflammation.
Baseline is defined as the mean of the last 2 non-missing measurements taken at the Screening and Baseline visits (prior to the first dose of study drug administered at the Day 1). A negative change from Baseline indicates a reduction in liver inflammation.
Change From Baseline in High-sensitivity C-reactive Protein (hsCRP)
High-sensitivity C-reactive protein is a blood test marker for inflammation in the body. HsCRP was measured from a blood sample and analyzed at a central laboratory.
Baseline is defined as the last non-missing measurement taken at the Screening and Baseline visits (prior to the first dose of study drug administered at the Day 1). A negative change from Baseline indicates a reduction in liver inflammation.
LYS006 Plasma Concentration
LYS006 plasma concentrations were determined by a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. No methods for imputation of missing data were used.
Maximum Observed Plasma Concentration (Cmax) of LYS006
LYS006 plasma concentrations were determined by a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. Cmax of LYS006 was determined with Phoenix WinNonlin (Version 8.0 or higher). No methods for imputation of missing data were used.
Full Information
NCT ID
NCT04147195
First Posted
October 22, 2019
Last Updated
August 16, 2023
Sponsor
Novartis Pharmaceuticals
1. Study Identification
Unique Protocol Identification Number
NCT04147195
Brief Title
Study of Various Treatments in Non-alcoholic Fatty Liver Disease (NAFLD) Patients Who Have Aspects of Non-alcoholic Steatohepatitis (NASH)
Acronym
NEXSCOT
Official Title
NASH EXploratory Single and COmbination Treatment (NEXSCOT): An Open Label, Multicenter, Platform Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Efficacy of Various Single and Combination Treatments in Patients With Non-alcoholic Fatty Liver Disease (NAFLD) Who Manifest a Non-alcoholic Steatohepatitis (NASH)-Like Biomarker Phenotype
Study Type
Interventional
2. Study Status
Record Verification Date
August 2023
Overall Recruitment Status
Terminated
Why Stopped
Sponsor Decision
Study Start Date
June 4, 2020 (Actual)
Primary Completion Date
January 6, 2022 (Actual)
Study Completion Date
January 6, 2022 (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
Yes
5. Study Description
Brief Summary
This clinical study was designed to evaluate the safety, tolerability, pharmacokinetics and efficacy of various single and combination treatments in adult patients with non-alcoholic fatty liver disease (NAFLD) who manifest a non-alcoholic steatohepatitis (NASH)-like biomarker phenotype.
Detailed Description
This was a Phase II, non-confirmatory, multicenter, open label, platform study in NAFLD participants with a NASH-like biomarker phenotype to examine the effects of single and combination therapies over 12 weeks of treatment. The study consisted of four distinct study periods:
Screening Period (Day -60 to -28): Lasted up to a maximum of 33 days where participants were assessed for inclusion and exclusion criteria prior the baseline assessments.
Baseline Period (Day -27 to -1): Lasted up to a maximum of 27 days and comprised baseline assessments and randomization.
Treatment Period (Day 1 to 85): Participants were randomized in a 1:1 ratio to LYS006 20 mg (twice a day) arm or to LYS006 20 mg (twice a day) and tropifexor 200ug (once a day). Participants were treated daily during 12 weeks.
Follow-up Period (Day 85 to 113): After completion of the treatment period, participants were observed until the End Of Study (EOS) visit at Day 113.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Non-alcoholic Fatty Liver Disease, Nonalcoholic Steatohepatitis
Keywords
Non-alcoholic fatty liver disease, NAFLD, Non-alcoholic steatohepatitis, NASH, Platform design, LYS006, LJN452, Tropifexor
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
41 (Actual)
8. Arms, Groups, and Interventions
Arm Title
LYS006
Arm Type
Experimental
Arm Description
LYS006 20 mg was administered orally twice per day (b.i.d) for 12 weeks
Arm Title
LYS006 + LJN452
Arm Type
Experimental
Arm Description
LYS006 20 mg was administered orally twice per day (b.i.d) in addition to LJN452 200ug administered orally once daily for 12 weeks
Intervention Type
Drug
Intervention Name(s)
LYS006
Intervention Description
5 mg LYS006 capsules orally administered 20 mg b.i.d for 12 weeks
Intervention Type
Drug
Intervention Name(s)
Tropifexor
Other Intervention Name(s)
LJN452
Intervention Description
100 ug LJN452 capsules orally administered 200ug once daily for 12 weeks
Primary Outcome Measure Information:
Title
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description
Number of participants with AEs and SAEs including significant changes from baseline in vital signs, electrocardiograms and laboratory parameters qualifying and reported as AEs. The number of participants in each category is reported in the table.
Time Frame
From the start of treatment to 28 days after end of treatment, assessed up to maximum duration of 113 Days
Secondary Outcome Measure Information:
Title
Change From Baseline in Non-invasive Markers of Hepatic Fibrosis: Enhanced Liver Fibrosis Test (ELF) Score
Description
The markers of fibrosis assessed in this test comprised hyaluronic acid (HA), tissue inhibitor of metalloproteinase (TIMP1) and procollagen III N-terminal peptide (PIIINP); these are components of the extracellular matrix and basement sinusoidal membrane of the liver and are elevated during fibrogenesis as a result of activation of the hepatic stellate cell. The ELF test is a composite score: < 7.7: no to mild fibrosis; ≥ 7.7 - < 9.8: Moderate fibrosis; ≥ 9.8 - < 11.3: Severe fibrosis; ≥ 11.3: Cirrhosis.
Baseline is defined as the last non-missing measurement taken at the Screening and Baseline visits (prior to the first dose of study drug administered at the Day 1). A negative change from Baseline indicates decreased fibrosis.
Time Frame
Baseline and Days 57, 85 and EOS (Day 113)
Title
Change From Baseline in Cholesterol: Fasting Lipid Profile Endpoint
Description
Fasting lipid profile (total cholesterol) was examined as a cardiometabolic risk parameter. Total cholesterol was measured on blood samples under fasted conditions and analyzed at a central laboratory.
Baseline is defined as the last non-missing measurement taken at the Screening and Baseline visits (prior to the first dose of study drug administered at the Day 1). A negative change from Baseline indicates cardiovascular risk.
Time Frame
Baseline and Days 15, 29, 43, 57, 85 and EOS (Day 113)
Title
Change From Baseline in Percent Liver Fat at Day 85
Description
Percent (%) Liver fat was measured by Magnetic Resonance Imaging Proton Density Liver Fat Fraction (MRIPDFF). Participants underwent magnetic resonance imaging twice during the course of the study (baseline and end of treatment) to quantitate liver fat.
Baseline is defined as the last non-missing measurement taken at the Screening and Baseline visits (prior to the first dose of study drug administered at the Day 1). A negative change from Baseline indicates a reduction in a component of NAFLD.
Time Frame
Baseline and Day 85
Title
Change From Baseline in Total Body Weight
Description
Body weight (to the nearest 0.1 kilogram [kg] was measured on a calibrated scale. The measurement was performed with the study participant in underwear and without shoes; or while wearing minimal indoor clothing.
Baseline is defined as the last non-missing measurement taken at the Screening and Baseline visits (prior to the first dose of study drug administered at the Day 1). A negative change from Baseline indicates improvement in obesity.
Time Frame
Baseline and Days 15, 29, 43, 57, 85 and EOS (Day 113)
Title
Change From Baseline in Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) at Day 85
Description
HOMA-IR is a test that uses a simultaneous fasting blood glucose test and fasting insulin test to accurately estimate the degree of insulin resistance (IR) and β-cell function (the cells of the pancreas that produce insulin). HOMA-IR scores are classified as follows: Insulin sensitive is considered less than 1.0, Healthy is considered 0.5-1.4, Above 1.8 is early insulin resistance and Above 2.7 is considered significant insulin resistance
HOMA-IR= [Fasting glucose (mmol/L) x (fasting insulin (pmol/L)/6)] / 22.5
Baseline is defined as the last non-missing measurement taken at the Screening and Baseline visits (prior to the first dose of study drug administered at the Day 1). A negative change from Baseline indicates improvement in insulin sensitivity.
Time Frame
Baseline and Day 85
Title
Change From Baseline in Fasting Glucose
Description
Fasting Glucose was examined as a cardiometabolic risk parameter. Total fasting glucose was measured on blood samples under fasted conditions and analyzed at a central laboratory.
Baseline is defined as the last non-missing measurement taken at the Screening and Baseline visits (prior to the first dose of study drug administered at the Day 1). A negative change from Baseline indicates improvement in glycemic control.
Time Frame
Baseline and Days 15, 29, 43, 57, 85 and EOS (Day 113)
Title
Change From Baseline in Fasting Insulin at Day 85
Description
Fasting insulin was examined as a cardiometabolic risk parameter. Total fasting insulin was measured on blood samples under fasted conditions and analyzed at a central laboratory.
Baseline is defined as the last non-missing measurement taken at the Screening and Baseline visits (prior to the first dose of study drug administered at the Day 1). A negative change from Baseline indicates improvement in insulin sensitivity.
Time Frame
Baseline and Day 85
Title
Change From Baseline in Hemoglobin A1c (HbA1c)
Description
HbA1c was examined as a cardiometabolic risk parameter. HbA1c was measured on blood samples under fasted conditions and analyzed at a central laboratory.
Baseline is defined as the last non-missing measurement taken at the Screening and Baseline visits (prior to the first dose of study drug administered at the Day 1). A negative change from Baseline indicates improvement in glycemic control.
Time Frame
Baseline and Days 15, 29, 43, 57, 85 and EOS (Day 113)
Title
Change From Baseline in Alanine Aminotransferase (ALT)
Description
Alanine aminotransferase (ALT) is an enzyme found primarily in the liver. ALT is increased with liver damage. In this study, the blood levels of ALT was used to detect liver inflammation.
Baseline is defined as the mean of the last 2 non-missing measurements taken at the Screening and Baseline visits (prior to the first dose of study drug administered at the Day 1). A negative change from Baseline indicates a reduction in liver inflammation.
Time Frame
Baseline and days 15, 29, 43, 57, 85 and EOS (Day 113)
Title
Change From Baseline in High-sensitivity C-reactive Protein (hsCRP)
Description
High-sensitivity C-reactive protein is a blood test marker for inflammation in the body. HsCRP was measured from a blood sample and analyzed at a central laboratory.
Baseline is defined as the last non-missing measurement taken at the Screening and Baseline visits (prior to the first dose of study drug administered at the Day 1). A negative change from Baseline indicates a reduction in liver inflammation.
Time Frame
Baseline and Days 57, 85 and EOS (Day 113)
Title
LYS006 Plasma Concentration
Description
LYS006 plasma concentrations were determined by a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. No methods for imputation of missing data were used.
Time Frame
pre-dose at Days 1, 29, 57 and 85 and post-dose (1, 2, 3 and 4 hours) at Days 29 and 57
Title
Maximum Observed Plasma Concentration (Cmax) of LYS006
Description
LYS006 plasma concentrations were determined by a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. Cmax of LYS006 was determined with Phoenix WinNonlin (Version 8.0 or higher). No methods for imputation of missing data were used.
Time Frame
pre-dose and post-dose (1, 2, 3 and 4 hours) at Days 29 and 57
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Phenotypic diagnosis of NASH based on the presence of all of the following:
ALT ≥ 43 IU/L (males) or ≥ 28 IU/L (females)
BMI ≥ 27 kg/m2 (race other than Asian) or ≥ 23 kg/m2 (Asian race)
History of type 2 diabetes mellitus with HbA1c ≤ 9%
ELF test score ≥ 8.5 and ≤ 10.5
Liver fat ≥ 8%
Patients must weigh between 40 kg (88 lbs.) and 150 kg (330 lbs.)
Exclusion Criteria:
Use of other investigational drugs within 5 half-lives of randomization or within 3 months, whichever is longer
Use of obeticholic acid (OCA) or pharmacologically-active weight loss drugs within 1 month of randomization
Use of strong CYP3A4/5 inhibitors or strong CYP3A4 inducers within 5 half-lives or 7 days of randomization, whichever is longer
History or presence of other concomitant liver diseases
History or current diagnosis of ECG abnormalities
Patients with contraindications to MRI imaging
Current or history of significant alcohol consumption
Clinical evidence of hepatic decompensation or severe liver impairment
Women of child bearing potential (unless on highly effective methods of contraception)
Presence of liver cirrhosis
Use of OAT3 inhibitors within 5 half-lives or 7 days of randomization, whichever is longer
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Novartis Investigative Site
City
Coronado
State/Province
California
ZIP/Postal Code
92118
Country
United States
Facility Name
Novartis Investigative Site
City
Los Angeles
State/Province
California
ZIP/Postal Code
90057
Country
United States
Facility Name
Novartis Investigative Site
City
Miami Lakes
State/Province
Florida
ZIP/Postal Code
33014
Country
United States
Facility Name
Novartis Investigative Site
City
Marietta
State/Province
Georgia
ZIP/Postal Code
30060
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
South Bend
State/Province
Indiana
ZIP/Postal Code
46635
Country
United States
Facility Name
Novartis Investigative Site
City
Morehead City
State/Province
North Carolina
ZIP/Postal Code
28557
Country
United States
Facility Name
Novartis Investigative Site
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78215
Country
United States
Facility Name
Novartis Investigative Site
City
Buenos Aires
ZIP/Postal Code
C1012AAR
Country
Argentina
Facility Name
Novartis Investigative Site
City
Essen
State/Province
Nordrhine Westphalia
ZIP/Postal Code
45136
Country
Germany
12. IPD Sharing Statement
Plan to Share IPD
Yes
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=1455
Description
A Plain Language Trial Summary is available on novctrd.com
Learn more about this trial
Study of Various Treatments in Non-alcoholic Fatty Liver Disease (NAFLD) Patients Who Have Aspects of Non-alcoholic Steatohepatitis (NASH)
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