Non-alcoholic Fatty Liver Disease, Obesity
Conditions
Brief summary
This study is open to adults with overweight or obesity who also have fatty liver disease. The purpose of this study is to find the highest dose of BI 3006337 that people with overweight or obesity and with fatty liver disease can tolerate. Participants are divided into 4 groups of equal size randomly, which means by chance. Different doses of BI 3006337 are given to participants in each group. Participants in each group receive an injection of either BI 3006337 or placebo once a week. Placebo injections look like BI 3006337 injections but do not contain any medicine. Participants are in the study for about 4 months. During this time, they visit the study site 18 times. Three of the visits include overnight stays at the study site. The doctors check the health of the participants and note any health problems that could have been caused by BI 3006337.
Interventions
DRUGBI 3006337
Subject with overweight/obesity and steatosis received subcutaneous solution once weekly.
DRUGPlacebo matching BI 3006337
Subject with overweight/obesity and steatosis received subcutaneous solution once weekly.
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
\- Male or female trial participants ≥18 years and ≤75 years of age at time of consent. Women of child-bearing potential (WOCBP) must be willing and able to use 2 forms of effective contraception where at least 1 form is a highly effective method of birth control per ICH M3 (R2) that results in a low failure rate of less than 1% per year when used consistently and correctly. Male trial participants must be willing and able to use condom if their partner is a WOCBP * Body mass index (BMI) ≥25 - \<40 kg/m\^2 * Liver fat fraction ≥8% as measured by Magnetic resonance imaging proton density fat fraction (MRI-PDFF) * Signed and dated written informed consent in accordance with International Council for Harmonisation-Good Clinical Practice (ICH-GCP) and local legislation prior to admission to the trial
Exclusion criteria
\- Current or past significant alcohol consumption (daily alcohol consumption in women should not exceed more than one standard drink per day and two drinks per day for men, whereby one standard drink is equivalent to 12 oz beer \[5% alcohol\]; 5 ounces of wine \[12% alcohol\], 1.5 ounces of 80 proof \[40% alcohol\]) or inability to reliably quantify alcohol consumption based on Investigator judgement within the last 5 years. The Alcohol Use Disorders Identification Test (AUDIT) shall be used a standardized screening tool for alcohol use disorder * Intake of medications historically associated with liver injury, hepatic steatosis, or steatohepatitis (e.g. oral or intravenous corticosteroids, methotrexate, valproic acid, tamoxifen, tetracycline, amiodarone) for more than 14 consecutive days within 12 weeks prior to the screening visit * Presence of any form of acute or chronic liver disease other than simple steatosis (e.g. viral hepatitis, autoimmune liver disease, primary biliary sclerosis, primary sclerosing cholangitis, Wilson's disease, hemochromatosis, alpha-1 antitrypsin deficiency). Chronic viral hepatitis parameters that would be considered exclusionary for the participation to this trial are (hepatitis B and C testing will be done at the screening visit): * Hepatitis B virus (HBV): trial participants with positive Hepatitis B virus surface antigen (HbsAg) * Hepatitis C virus (HCV): trial participants with positive HCV RNA. Trial participants treated for hepatitis C must have a negative RNA test at screening and also be HCV RNA negative for at least 3 years prior to screening in order to be eligible for the trial * Liver stiffness \>10 Kilopascal (kPa) as measured using Fibroscan. In patients with a non-valid Fibroscan measurement, a Fib-4 score \>1.3 should be considered exclusionary. * Suspicion, confirmed diagnosis, or history of hepatocellular carcinoma * Treatment with vitamin E (at a minimum dose of 800 IU/day) or pioglitazone not stable (in the opinion of the Investigator) within 90 days before screening * History of type 1 diabetes * Use of Glucagon-like peptide 1 (GLP1)-receptor agonists within last 90 days before screening Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Drug-related Adverse Events (AEs) | From drug administration of BI 3006337 until end of the treatment, up to 99 days | Number of subjects with drug-related adverse events (AEs) occurring between first administration of trial medication (BI 3006337 or placebo) and end of study (EOS) is reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of BI 3006337 in Serum Over the Dosing Interval Tau at Steady State (AUCτ,ss) After the Last Dose in Week 12 | 0 hours (prior to drug administration) and 3, 7, 11, 15, 23, 27, 31, 35, 39, 47, 72, 168 and 504 hours after drug administration in week 12 | Area under the concentration-time curve of BI 3006337 in serum over the dosing interval tau at steady state (AUCτ,ss) after the last dose in Week 12 is reported. |
| Maximum Measured Concentration of BI 3006337 in Serum at Steady State (Cmax,ss) After the Last Dose in Week 12 | 0 hours (prior to drug administration) and 3, 7, 11, 15, 23, 27, 31, 35, 39, 47, 72, 168 hours after drug administration in week 12 | Maximum measured concentration of BI 3006337 in serum at steady state (Cmax,ss) after the last dose in Week 12 is reported. |
| Time From Dosing to the Maximum Measured Concentration of BI 3006337 in Serum at Steady State (Tmax,ss) After the Last Dose in Week 12 | 0 hours (prior to drug administration) and 3, 7, 11, 15, 23, 27, 31, 35, 39, 47, 72, 168 hours after drug administration in week 12 | Time from dosing to the maximum measured concentration of BI 3006337 in serum at steady state (tmax,ss) after the last dose in Week 12 is reported. |
| Relative Percentage Change in Liver Steatosis From Baseline After 12 Weeks of Treatment | Baseline (-48 to -4): the last observed measurement prior to drug administration, Day 85 | Relative percentage change in liver steatosis from baseline after 12 weeks of treatment is reported. Liver steatosis is measured by Magnetic resonance imaging proton density fat fraction (MRI-PDFF). |
Countries
United States
Participant flow
Recruitment details
This study was single-blind and randomised trial with placebo matching the dose of BI 3006337 as comparator. Treatment allocation was performed within each dose group in a 5:2 ratio (BI 3006337 to placebo). Participants were included in the trial once they had signed the informed consent. The trial consisted of a screening period of up to 6 weeks to assess participant eligibility, a treatment period of 12 weeks and a follow-up period of 3 weeks.
Pre-assignment details
All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated. Of 64 enrolled, 63 began treatment; one participant in the BI 3006337 150 mg group withdrew consent before Day -1 and underwent no procedures.
Participants by arm
| Arm | Count |
|---|---|
| BI 3006337 50 mg Subject with overweight/obesity and steatosis received subcutaneous solution for administration of 50 milligram of BI 3006337 once weekly. | 11 |
| BI 3006337 100 mg Subjects with overweight/obesity and steatosis received subcutaneous solution for administration of 100 milligram of BI 3006337 once weekly. | 10 |
| BI 3006337 150 mg Subjects with overweight/obesity and steatosis received subcutaneous solution for administration of 150 milligram of BI 3006337 once weekly. | 23 |
| Placebo Subjects with overweight/obesity and steatosis received subcutaneous solution for administration of Placebo once weekly. | 19 |
| Total | 63 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 3 | 1 | 0 |
| Overall Study | Sponsor decision | 0 | 0 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | BI 3006337 50 mg | BI 3006337 100 mg | BI 3006337 150 mg | Total | Placebo |
|---|---|---|---|---|---|
| Age, Continuous | 42.5 years STANDARD_DEVIATION 9.3 | 45.5 years STANDARD_DEVIATION 16.1 | 54.4 years STANDARD_DEVIATION 11.9 | 50.0 years STANDARD_DEVIATION 13.4 | 51.5 years STANDARD_DEVIATION 14 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants | 7 Participants | 22 Participants | 52 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 3 Participants | 1 Participants | 11 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 0 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) White | 11 Participants | 8 Participants | 23 Participants | 59 Participants | 17 Participants |
| Sex: Female, Male Female | 3 Participants | 4 Participants | 9 Participants | 26 Participants | 10 Participants |
| Sex: Female, Male Male | 8 Participants | 6 Participants | 14 Participants | 37 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 10 | 0 / 23 | 0 / 19 |
| other Total, other adverse events | 10 / 11 | 9 / 10 | 18 / 23 | 15 / 19 |
| serious Total, serious adverse events | 0 / 11 | 0 / 10 | 1 / 23 | 0 / 19 |
Outcome results
Primary
Number of Subjects With Drug-related Adverse Events (AEs)
Number of subjects with drug-related adverse events (AEs) occurring between first administration of trial medication (BI 3006337 or placebo) and end of study (EOS) is reported.
Time frame: From drug administration of BI 3006337 until end of the treatment, up to 99 days
Population: Treated set (TS): TS includes all subjects from the randomised set who are treated with at least one dose of study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BI 3006337 50 mg | Number of Subjects With Drug-related Adverse Events (AEs) | 9 Participants |
| BI 3006337 100 mg | Number of Subjects With Drug-related Adverse Events (AEs) | 8 Participants |
| BI 3006337 150 mg | Number of Subjects With Drug-related Adverse Events (AEs) | 14 Participants |
| Placebo | Number of Subjects With Drug-related Adverse Events (AEs) | 5 Participants |
Secondary
Area Under the Concentration-time Curve of BI 3006337 in Serum Over the Dosing Interval Tau at Steady State (AUCτ,ss) After the Last Dose in Week 12
Area under the concentration-time curve of BI 3006337 in serum over the dosing interval tau at steady state (AUCτ,ss) after the last dose in Week 12 is reported.
Time frame: 0 hours (prior to drug administration) and 3, 7, 11, 15, 23, 27, 31, 35, 39, 47, 72, 168 and 504 hours after drug administration in week 12
Population: Pharmacokinetic parameter analysis set (PKS): This set includes all trial participants in the treated set (TS) who provide at least one primary or secondary PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. One subject from the 50 mg arm was excluded from the analysis due to a missing sample, which precluded characterization of the elimination phase.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BI 3006337 50 mg | Area Under the Concentration-time Curve of BI 3006337 in Serum Over the Dosing Interval Tau at Steady State (AUCτ,ss) After the Last Dose in Week 12 | 21000 Hour*Microgram/Liter | Geometric Coefficient of Variation 57.3 |
| BI 3006337 100 mg | Area Under the Concentration-time Curve of BI 3006337 in Serum Over the Dosing Interval Tau at Steady State (AUCτ,ss) After the Last Dose in Week 12 | 38800 Hour*Microgram/Liter | Geometric Coefficient of Variation 81.1 |
| BI 3006337 150 mg | Area Under the Concentration-time Curve of BI 3006337 in Serum Over the Dosing Interval Tau at Steady State (AUCτ,ss) After the Last Dose in Week 12 | 67100 Hour*Microgram/Liter | Geometric Coefficient of Variation 50.4 |
Secondary
Maximum Measured Concentration of BI 3006337 in Serum at Steady State (Cmax,ss) After the Last Dose in Week 12
Maximum measured concentration of BI 3006337 in serum at steady state (Cmax,ss) after the last dose in Week 12 is reported.
Time frame: 0 hours (prior to drug administration) and 3, 7, 11, 15, 23, 27, 31, 35, 39, 47, 72, 168 hours after drug administration in week 12
Population: Pharmacokinetic parameter analysis set (PKS): This set includes all trial participants in the treated set (TS) who provide at least one primary or secondary PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BI 3006337 50 mg | Maximum Measured Concentration of BI 3006337 in Serum at Steady State (Cmax,ss) After the Last Dose in Week 12 | 312 Microgram/Liter | Geometric Coefficient of Variation 87.7 |
| BI 3006337 100 mg | Maximum Measured Concentration of BI 3006337 in Serum at Steady State (Cmax,ss) After the Last Dose in Week 12 | 761 Microgram/Liter | Geometric Coefficient of Variation 64.9 |
| BI 3006337 150 mg | Maximum Measured Concentration of BI 3006337 in Serum at Steady State (Cmax,ss) After the Last Dose in Week 12 | 1060 Microgram/Liter | Geometric Coefficient of Variation 64.2 |
Secondary
Relative Percentage Change in Liver Steatosis From Baseline After 12 Weeks of Treatment
Relative percentage change in liver steatosis from baseline after 12 weeks of treatment is reported. Liver steatosis is measured by Magnetic resonance imaging proton density fat fraction (MRI-PDFF).
Time frame: Baseline (-48 to -4): the last observed measurement prior to drug administration, Day 85
Population: Treated set (TS): The TS includes all subjects from the randomised set who are treated with at least one dose of study medication. The treatment assignment will be determined based on the first treatment the trial subjects received. The TS is the basis for safety analyses. The main efficacy analysis was conducted using the Treated Set and excluded all participants who discontinued due to Coronavirus disease 2019 (COVID-19). Only subjects with available data at baseline and week 12 were included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BI 3006337 50 mg | Relative Percentage Change in Liver Steatosis From Baseline After 12 Weeks of Treatment | -13.01 Percent change | Standard Deviation 21.92 |
| BI 3006337 100 mg | Relative Percentage Change in Liver Steatosis From Baseline After 12 Weeks of Treatment | -16.59 Percent change | Standard Deviation 40.28 |
| BI 3006337 150 mg | Relative Percentage Change in Liver Steatosis From Baseline After 12 Weeks of Treatment | -39.21 Percent change | Standard Deviation 14.73 |
| Placebo | Relative Percentage Change in Liver Steatosis From Baseline After 12 Weeks of Treatment | 6.13 Percent change | Standard Deviation 35.24 |
Secondary
Time From Dosing to the Maximum Measured Concentration of BI 3006337 in Serum at Steady State (Tmax,ss) After the Last Dose in Week 12
Time from dosing to the maximum measured concentration of BI 3006337 in serum at steady state (tmax,ss) after the last dose in Week 12 is reported.
Time frame: 0 hours (prior to drug administration) and 3, 7, 11, 15, 23, 27, 31, 35, 39, 47, 72, 168 hours after drug administration in week 12
Population: Pharmacokinetic parameter analysis set (PKS): This set includes all trial participants in the treated set (TS) who provide at least one primary or secondary PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BI 3006337 50 mg | Time From Dosing to the Maximum Measured Concentration of BI 3006337 in Serum at Steady State (Tmax,ss) After the Last Dose in Week 12 | 13 Hour |
| BI 3006337 100 mg | Time From Dosing to the Maximum Measured Concentration of BI 3006337 in Serum at Steady State (Tmax,ss) After the Last Dose in Week 12 | 15 Hour |
| BI 3006337 150 mg | Time From Dosing to the Maximum Measured Concentration of BI 3006337 in Serum at Steady State (Tmax,ss) After the Last Dose in Week 12 | 27 Hour |