Different Doses of BI 1467335 Compared to Placebo in Patients With Clinical Evidence of NASH
- Conditions
- Non-alcoholic Fatty Liver Disease
- Interventions
- Drug: BI 1467335Drug: Placebo
- Registration Number
- NCT03166735
- Lead Sponsor
- Boehringer Ingelheim
- Brief Summary
The primary objective of this study is the proof of mechanism and support of dose finding, together with the safety evaluation in patients with clinical evidence of NASH.
To gain further insight into clinical effects of AOC3 inhibition on NASH further exploratory analyses of biomarkers related to NASH and liver fibrosis will be performed. This will include the effect of BI 1467335 on reduction of secondary biomarker endpoints (ALT, AST, AP, γ-GT and CK18 fragments). Safety will be assessed throughout the study to provide key information regarding the use of BI 1467335 in patients with NASH.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 114
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description BI 1467335 dose 1 BI 1467335 - BI 1467335 dose 2 BI 1467335 - BI 1467335 dose 3 BI 1467335 - BI 1467335 dose 4 BI 1467335 - Placebo Placebo -
- Primary Outcome Measures
Name Time Method Plasma Amine Oxidase Copper-containing 3 (AOC3) Activity After 12 Weeks of Treatment, Relative to Baseline in Percent Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335. The patient-specific plasma AOC3 activity at time t (24 hours after the last dose in week 12) relative to baseline in percentage was calculated as follows:
%AOC3at = \[(AOC3at - AOC3at,back) ⁄ (AOC3abase - AOC3abase,back)\]\*100
With AOC3at the AOC3 activity measured at time t, AOC3at,back the background noise at time t, AOC3abase the AOC3 activity measured at baseline and AOC3abase,back the background noise at baseline.
A dose-response relationship was analysed using a non-linear regression model to estimate the daily dosage needed to reach 10% of AOC3 activity (i.e. 90% inhibition) 12 weeks after treatment.
- Secondary Outcome Measures
Name Time Method Percentage of Participants With Drug-related Adverse Events (AEs) Start of treatment till end of treatment + 28 days, up to 113 days. Percentage of participants with drug-related adverse events (AEs). Percentages are calculated using total number of patients per treatment as the denominator.
Alanine Aminotransaminase (ALT) After 12 Weeks of Treatment, Relative to Baseline in Percent Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335. Alanine aminotransaminase (ALT) after 12 weeks of treatment, relative to baseline in percent. Number analyzed lower than N in PPS if there is missing data for specific timepoints.
The unit of measure is: percentage relative to baseline = \[post baseline (time t)/baseline\]\*100%
Statistical analyses description: A Mixed effects Model for Repeated Measurements (MMRM) over time including fixed effects for 'base', 'treatment', 'time', 'base\*time' interaction, and 'treatment\*time' interaction was performed. The MMRM estimates for the treatment effects at Week 12 and the corresponding covariance matrix were used to analyse the dose-response relationship using the Multiple contrast test (MCPMod). A test for non-flat dose-response relationship was first performed. If this relationship could be shown, the best fitting model out of a set of candidate models (Sigmoidal Emax, Logistic, Quadratic, Linear, Exponential, Linear logistic, Emax and Betamod) was to be selected and fitted.Aspartate Aminotransferase (AST) After 12 Weeks of Treatment, Relative to Baseline in Percent Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335. Aspartate aminotransferase (AST) after 12 weeks of treatment, relative to baseline in percent. Number analyzed lower than N in PPS if there is missing data for specific timepoints.
The unit of measure is: percentage relative to baseline = \[post baseline (time t)/baseline\]\*100%
Statistical analyses description: A Mixed effects Model for Repeated Measurements (MMRM) over time including fixed effects for 'base', 'treatment', 'time', 'base\*time' interaction, and 'treatment\*time' interaction was performed. The MMRM estimates for the treatment effects at Week 12 and the corresponding covariance matrix were used to analyse the dose-response relationship using the Multiple contrast test (MCPMod). A test for non-flat dose-response relationship was first performed. If this relationship could be shown, the best fitting model out of a set of candidate models (Sigmoidal Emax, Logistic, Quadratic, Linear, Exponential, Linear logistic, Emax and Betamod) was to be selected and fitted.Alkaline Phosphatase (AP) After 12 Weeks of Treatment, Relative to Baseline in Percent Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335. Alkaline phosphatase (AP) after 12 weeks of treatment, relative to baseline in percent. Number analyzed lower than N in PPS if there is missing data for specific timepoints.
The unit of measure is: percentage relative to baseline = \[post baseline (time t)/baseline\]\*100%
Statistical analyses description: A Mixed effects Model for Repeated Measurements (MMRM) over time including fixed effects for 'base', 'treatment', 'time', 'base\*time' interaction, and 'treatment\*time' interaction was performed. The MMRM estimates for the treatment effects at Week 12 and the corresponding covariance matrix were used to analyse the dose-response relationship using the Multiple contrast test (MCPMod). A test for non-flat dose-response relationship was first performed. If this relationship could be shown, the best fitting model out of a set of candidate models (Sigmoidal Emax, Logistic, Quadratic, Linear, Exponential, Linear logistic, Emax and Betamod) was to be selected and fitted.Gamma-glutamyltransferase (GGT) After 12 Weeks of Treatment, Relative to Baseline in Percent Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335. Gamma-glutamyltransferase (GGT) after 12 weeks of treatment, relative to baseline in percent. Number analyzed lower than N in PPS if there is missing data for specific timepoints.
The unit of measure is: percentage relative to baseline = \[post baseline (time t)/baseline\]\*100%
Statistical analyses description: A Mixed effects Model for Repeated Measurements (MMRM) over time including fixed effects for 'base', 'treatment', 'time', 'base\*time' interaction, and 'treatment\*time' interaction was performed. The MMRM estimates for the treatment effects at Week 12 and the corresponding covariance matrix were used to analyse the dose-response relationship using the Multiple contrast test (MCPMod). A test for non-flat dose-response relationship was first performed. If this relationship could be shown, the best fitting model out of a set of candidate models (Sigmoidal Emax, Logistic, Quadratic, Linear, Exponential, Linear logistic, Emax and Betamod) was to be selected and fitted.Caspase-cleaved Cytokeratin 18 (CK-18 Caspase) After 12 Weeks of Treatment, Relative to Baseline in Percent Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335. Caspase-cleaved cytokeratin 18 (CK-18 caspase) after 12 weeks of treatment, relative to baseline in percent. Number analyzed lower than N in PPS if there is missing data for specific timepoints.
The unit of measure is: percentage relative to baseline = \[post baseline (time t)/baseline\]\*100%
Statistical analyses description: A MMRM over time including fixed effects for 'base', 'treatment', 'time', 'base\*time' interaction, and 'treatment\*time' interaction was performed. The MMRM estimates for the treatment effects at Week 12 and the corresponding covariance matrix were used to analyse the dose-response relationship using the Multiple contrast test (MCPMod). A test for non-flat dose-response relationship was first performed. If this relationship could be shown, the best fitting model out of a set of candidate models (Sigmoidal Emax, Logistic, Quadratic, Linear, Exponential, Linear logistic, Emax and Betamod) was to be selected and fitted.Total Cytokeratin 18 (CK-18 Total) After 12 Weeks of Treatment, Relative to Baseline in Percent Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335. Total cytokeratin 18 (CK-18 total) after 12 weeks of treatment, relative to baseline in percent. Number analyzed lower than N in PPS if there is missing data for specific timepoints.
The unit of measure is: percentage relative to baseline = \[post baseline (time t)/baseline\]\*100%.
Statistical analyses description: A Mixed effects Model for Repeated Measurements (MMRM) over time including fixed effects for 'base', 'treatment', 'time', 'base\*time' interaction, and 'treatment\*time' interaction was performed. The MMRM estimates for the treatment effects at Week 12 and the corresponding covariance matrix were used to analyse the dose-response relationship using the Multiple contrast test (MCPMod). A test for non-flat dose-response relationship was first performed. If this relationship could be shown, the best fitting model out of a set of candidate models (Sigmoidal Emax, Logistic, Quadratic, Linear, Exponential, Linear logistic, Emax and Betamod) was to be selected and fitted.
Trial Locations
- Locations (43)
Toronto Liver Centre
🇨🇦Toronto, Ontario, Canada
Radboud Universitair Medisch Centrum
🇳🇱Nijmegen, Netherlands
National Research Institute
🇺🇸Los Angeles, California, United States
The University of North Carolina at Chapel Hill
🇺🇸Chapel Hill, North Carolina, United States
American Research Corporation at the Texas Liver Institute
🇺🇸San Antonio, Texas, United States
Amsterdam UMC, Locatie AMC
🇳🇱Amsterdam, Netherlands
Maastricht Universitair Medisch Centrum
🇳🇱Maastricht, Netherlands
AZ Maria Middelares
🇧🇪Gent, Belgium
Universitätsklinikum Leipzig
🇩🇪Leipzig, Germany
Manchester Royal Infirmary
🇬🇧Manchester, United Kingdom
Aintree University Hospital
🇬🇧Liverpool, United Kingdom
eStudySite
🇺🇸La Mesa, California, United States
Southern California Research Center
🇺🇸Coronado, California, United States
University of California San Diego
🇺🇸La Jolla, California, United States
Florida Research Institute
🇺🇸Lakewood Ranch, Florida, United States
Quest Clinical Research
🇺🇸San Francisco, California, United States
Genoma Research Group, Inc
🇺🇸Miami, Florida, United States
Edegem - UNIV UZ Antwerpen
🇧🇪Edegem, Belgium
Pinnacle Clinical Research
🇺🇸Live Oak, Texas, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
Dallas Diabetes and Endocrine Center
🇺🇸Dallas, Texas, United States
Diabetes and Endocrinology Consultants, PC
🇺🇸Morehead City, North Carolina, United States
Virginia Commonwealth University
🇺🇸Richmond, Virginia, United States
HOP La Pitié Salpêtrière
🇫🇷Paris, France
Universitätsklinikum Aachen, AöR
🇩🇪Aachen, Germany
Universitätsmedizin der Johannes Gutenberg-Universität Mainz
🇩🇪Mainz, Germany
Universitätsklinikum Frankfurt
🇩🇪Frankfurt am Main, Germany
Universitätsklinikum Köln (AöR)
🇩🇪Köln, Germany
St James's Hospital
🇮🇪Dublin, Ireland
Universitätsklinikum Würzburg
🇩🇪Würzburg, Germany
Hospital Virgen de la Victoria
🇪🇸Malaga, Spain
Hospital Universitario Marqués de Valdecilla
🇪🇸Santander, Spain
Hospital Vall d'Hebron
🇪🇸Barcelona, Spain
Queen Elizabeth Hospital
🇬🇧Birmingham, United Kingdom
Hospital Virgen del Rocío
🇪🇸Sevilla, Spain
Hospital General Universitario de Valencia
🇪🇸Valencia, Spain
Royal Stoke University Hospital
🇬🇧Stoke on Trent, United Kingdom
Rutgers Robert Wood Johnson Medical School
🇺🇸New Brunswick, New Jersey, United States
HOP Claude Huriez
🇫🇷Lille, France
Northwell Health
🇺🇸Manhasset, New York, United States
University of Calgary
🇨🇦Calgary, Alberta, Canada
UZ Leuven
🇧🇪Leuven, Belgium
Centre Hospitalier Universitaire de Liège
🇧🇪Liège, Belgium