Diabetes Mellitus, Type 2
Conditions
Brief summary
This study is open to adults with type 2 diabetes who take metformin but still have too high blood sugar. The purpose of the study is to find the best dose of BI 456906 that reduces blood sugar. The study also looks at whether BI 456906 helps the participants lose weight. Participants are in the study for about 23 weeks. During this time, most participants visit the study site about 13 times. Some participants visit the study site about 20 times. At the start of the study, the participants are put into 7 groups. The participants in groups 1 to 6 get injections under the skin once or twice every week. Some participants get different doses of BI 456906 and other participants get placebo. Placebo injections look like the BI 456906 injections, but contain no medicine. Participants in group 7 get semaglutide injections every week. Semaglutide is another medicine for adults with type 2 diabetes. During the study, the doctors regularly take blood samples from the participants and measure their body weight. The changes in blood sugar levels and body weight are compared between the groups. The doctors also check the general health of the participants.
Interventions
DRUGBI 456906
Solution for Injection
DRUGPlacebo
Solution for Injection
DRUGSemaglutide
Solution for Injection
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
The trial has a double blind design within each dose group. Patients, investigators and everyone involved in trial conduct or analysis or with any other interest in this trial will remain blinded with regard to the randomized treatment assignments until after database lock. The semaglutide group is open label.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Signed and dated written informed consent in accordance with International conference on harmonization - Good clinical practice (ICH GCP) and local legislation. * Male and female patients 18 years to 75 years (both inclusive) of age on the day of signing informed consent. * Diagnosis of Type 2 diabetes mellitus (T2DM) at least 6 months prior to informed consent. * Glycosylated hemoglobin A1c (HbA1c) 7.0%-10.0% (both inclusive) at screening. * Treatment with a stable dose of metformin ≥ 1000mg/day for at least 3 months prior to screening. * Body mass index (BMI) 25 kg/m2-50 kg/m2 (both inclusive) at screening. * Women of childbearing potential must be ready and able to use highly effective methods of birth control.
Exclusion criteria
* Patients with type 1 diabetes. * Exposure to semaglutide, or other Glucagon-like-peptide 1 receptor (GLP-1R) agonists (including combination products) within 3 months prior to screening, or any previous exposure to BI 456906. * Any additional oral anti-hyperglycemic medication beyond metformin within 3 months prior to screening. * Use of insulin for glycemic control within 12 months prior to screening. * Resting Heart Rate \>100 bpm or blood pressure ≥160/95 mmHg at screening. * A marked baseline prolongation of QT/QTc (Fridericia) interval or any other clinically significant Electrocardiogram (ECG) finding at screening. * Body weight change of +/- 5% or more in the past 3 months or on anti-obesity therapies at any time during the 6 months prior to screening. * Continuous oral pharmacotherapy to treat any clinical condition during the Trial. Following medications are allowed: * metformin, anti-hypertensives (any medication known to cause heart block or bradycardia such as beta-blockers, verapamil and diltiazem are excluded unless used to treat heart rate control or hypertension), * Hormone replacement therapy including thyroid hormone, lipid lowering, proton pump inhibitors, H2 blockers for Gastric esophageal reflux disease (GERD), analgesics, * sleep medications * antihistamines * selective Alpha receptor blocker for benign prostatic hyperplasia Patients must be on a stable dose for at least 3 months Prior to Screening * Any suicidal behavior in the past 2 years, any suicidal ideation of type 4 or 5 in the Columbia-suicide severity rating scale (C-SSRS) in the past 3 months at screening. * Chronic or relevant acute infections. * Women who are pregnant, nursing, or who plan to become pregnant while in the trial. * Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change in HbA1c From Baseline to 16 Weeks | At baseline and at Week 17 (16 weeks after treatment start). | Absolute change in glycosylated hemoglobin A1c (HbA1c) from baseline to 16 weeks after treatment start is presented. The measurements for this outcome were performed at baseline and at Week 17. Absolute change from baseline in HbA1c to 16 weeks after treatment start was calculated by subtracting the baseline HbA1c value from the HbA1c value at Week 17. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Key Secondary Endpoint: The Relative Change in Body Weight From Baseline to 16 Weeks | At baseline and at Week 17 (16 weeks after treatment start ). | The relative change in body weight from baseline to 16 weeks after treatment start is presented. The measurements for this outcome were performed at baseline and at Week 17. The relative change in body weight from baseline to 16 weeks after treatment start was calculated as (body weight at Week 17 - body weight at baseline/body weight at baseline) \* 100. |
| The Absolute Change in Body Weight From Baseline to 16 Weeks | At baseline and at Week 17 (16 weeks after treatment start). | The absolute change in body weight from baseline to 16 weeks after treatment start is presented. Measurements for this outcome were performed at baseline and at Week 17. The absolute change in body weight from baseline to 16 weeks after treatment start was calculated as: body weight at Week 17- body weight at baseline. |
| The Absolute Change in Waist Circumference From Baseline to 16 Weeks | At baseline and at Week 17 (16 weeks after treatment start). | The absolute change in waist circumference from baseline to 16 weeks after treatment start is presented. Measurements for this outcome were performed at baseline and at Week 17. The absolute change in waist circumference from baseline to 16 weeks after treatment start was calculated as: waist circumference at Week 17- waist circumference at baseline. |
| Percentage of Patients With 5 % or Greater Body Weight Loss From Baseline to 16 Weeks | At baseline and at Week 17 (16 weeks after treatment start). | The percentage of patients with 5 percent (%) or greater body weight loss from baseline to 16 weeks after treatment start is presented. Measurements for this outcome were performed at baseline and at Week 17. |
| Percentage of Patients With 10% or Greater Body Weight Loss From Baseline to 16 Weeks | At baseline and at Week 17 (16 weeks after treatment start). | The percentage of patients with 10 % or greater body weight loss from baseline to 16 weeks after treatment start is presented. Measurements for this outcome were performed at baseline and at Week 17. |
Countries
Australia, Austria, Canada, Czechia, Germany, Hungary, New Zealand, Poland, Puerto Rico, South Korea, Spain, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
This was a randomized, multicenter placebo and active comparator controlled, double-blind within dose groups, parallel-group, 16-week trial in patients with type 2 diabetes mellitus (T2DM). An open-label arm (semaglutide) was included as benchmark to compare response curves and support assumptions for Phase III design.
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.
Participants by arm
| Arm | Count |
|---|---|
| Placebo This arm comprises all placebo treated patients, regardless of the dose group in which they were treated. Patients with type 2 diabetes mellitus with insufficient glycaemic control despite diet, exercise and metformin treatment were administered solution for subcutaneous injection of placebo matched to BI 456906 once weekly for 16 weeks or twice weekly for 16 weeks. | 59 |
| BI 456906 0.3 mg Patients with type 2 diabetes mellitus with insufficient glycaemic control despite diet, exercise and metformin treatment were administered once weekly subcutaneously a solution for injection of BI 456906 of 0.3 milligram (mg) on Week 1-Week 16. | 50 |
| BI 456906 0.9 mg Patients with type 2 diabetes mellitus with insufficient glycaemic control despite diet, exercise and metformin treatment were administered once weekly subcutaneously a solution for injection of BI 456906 of 0.3 milligram (mg) on Week 1 and Week 2, 0.6 mg on Week 3 and Week 4, 0.9 mg on Week 5-Week 16. | 50 |
| BI 456906 1.8 mg Patients with type 2 diabetes mellitus with insufficient glycaemic control despite diet, exercise and metformin treatment were administered once weekly subcutaneously a solution for injection of BI 456906 of 0.3 milligram (mg) on Week 1, 0.6 mg on Week 2, 0.9 mg on Week 3, 1.2 mg on Week 4, 1.5 mg on Week 5, and 1.8 mg on Week 6- Week 16. | 52 |
| BI 456906 2.7 mg Patients with type 2 diabetes mellitus with insufficient glycaemic control despite diet, exercise and metformin treatment were administered once weekly subcutaneously a solution for injection of BI 456906 of 0.6 milligram (mg) on Week 1 and Week 2, 1.2 mg on Week 3 and Week 4, 1.8 mg on Week 5, 2.4 mg on Week 6, 2.7 mg on Week 7- Week 16. | 50 |
| BI 456906 1.2 Twice Weekly (2.4) mg Patients with type 2 diabetes mellitus with insufficient glycaemic control despite diet, exercise and metformin treatment were administered twice weekly subcutaneously a solution for injection of BI 456906 of 0.3 milligram (mg) on Week 1 and Week 2 (total weekly dose=0.6 mg), 0.6 mg on Week 3 and Week 4 (total weekly dose=1.2 mg), 0.9 mg on Week 5 and Week 6 (total weekly dose=1.8 mg), 1.2 mg on Week 7- Week 16 (total weekly dose 2.4 mg). | 51 |
| BI 456906 1.8 Twice Weekly (3.6) mg Patients with type 2 diabetes mellitus with insufficient glycaemic control despite diet, exercise and metformin treatment were administered twice weekly subcutaneously a solution for injection of BI 456906 of 0.3 milligram (mg) on Week 1 (total weekly dose=0.6 mg), 0.6 mg on Week 2 (total weekly dose=1.2 mg), 0.9 mg on Week 3 (total weekly dose=1.8 mg), 1.2 mg on Week 4 (total weekly dose 2.4 mg), 1.5 mg on Week 5 and on Week 6 (total weekly dose 3 mg), 1.8 mg on Week 7 -Week 16 (total weekly dose =3.6 mg). | 49 |
| Semaglutide Patients with type 2 diabetes mellitus with insufficient glycaemic control despite diet, exercise and metformin treatment were administered once weekly subcutaneously a solution for injection of Semaglutide of 0.25 milligram (mg) on Week 1-Week 4, 0.5 mg on Week 5-Week 8, 1.0 mg on Week 9-Week 16. | 50 |
| Total | 411 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 5 | 5 | 11 | 15 | 4 | 8 | 2 |
| Overall Study | Lost to Follow-up | 2 | 1 | 0 | 1 | 1 | 0 | 0 | 0 |
| Overall Study | Not treated | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Other than listed | 2 | 2 | 0 | 1 | 0 | 2 | 2 | 1 |
| Overall Study | Protocol Violation | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 2 |
| Overall Study | Withdrawal by Subject | 3 | 1 | 0 | 3 | 1 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Semaglutide | BI 456906 1.8 Twice Weekly (3.6) mg | BI 456906 1.2 Twice Weekly (2.4) mg | BI 456906 2.7 mg | BI 456906 1.8 mg | BI 456906 0.9 mg | BI 456906 0.3 mg | Placebo | Total |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 55.8 Years STANDARD_DEVIATION 10.5 | 57.7 Years STANDARD_DEVIATION 9.4 | 58.3 Years STANDARD_DEVIATION 8.8 | 59.6 Years STANDARD_DEVIATION 8.5 | 55.3 Years STANDARD_DEVIATION 10.3 | 58.2 Years STANDARD_DEVIATION 9.6 | 56.1 Years STANDARD_DEVIATION 10.2 | 57.5 Years STANDARD_DEVIATION 10.5 | 57.3 Years STANDARD_DEVIATION 9.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 14 Participants | 9 Participants | 10 Participants | 12 Participants | 12 Participants | 8 Participants | 11 Participants | 15 Participants | 91 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 36 Participants | 40 Participants | 41 Participants | 38 Participants | 40 Participants | 42 Participants | 39 Participants | 44 Participants | 320 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Glycosylated hemoglobin A1c (HbA1c) measured in percentage units [%] | 8.03 percentage of HbA1c STANDARD_DEVIATION 0.82 | 7.97 percentage of HbA1c STANDARD_DEVIATION 0.71 | 8.11 percentage of HbA1c STANDARD_DEVIATION 0.94 | 8.18 percentage of HbA1c STANDARD_DEVIATION 0.97 | 8.14 percentage of HbA1c STANDARD_DEVIATION 0.86 | 7.89 percentage of HbA1c STANDARD_DEVIATION 0.8 | 8.09 percentage of HbA1c STANDARD_DEVIATION 0.76 | 8.15 percentage of HbA1c STANDARD_DEVIATION 0.85 | 8.07 percentage of HbA1c STANDARD_DEVIATION 0.84 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 3 Participants | 5 Participants | 4 Participants | 8 Participants | 5 Participants | 4 Participants | 8 Participants | 42 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 3 Participants | 4 Participants | 2 Participants | 2 Participants | 1 Participants | 3 Participants | 3 Participants | 20 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 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 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 43 Participants | 42 Participants | 41 Participants | 43 Participants | 42 Participants | 44 Participants | 42 Participants | 47 Participants | 344 Participants |
| Sex: Female, Male Female | 16 Participants | 22 Participants | 24 Participants | 17 Participants | 25 Participants | 22 Participants | 24 Participants | 28 Participants | 178 Participants |
| Sex: Female, Male Male | 34 Participants | 27 Participants | 27 Participants | 33 Participants | 27 Participants | 28 Participants | 26 Participants | 31 Participants | 233 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 59 | 0 / 50 | 0 / 50 | 0 / 52 | 0 / 50 | 0 / 51 | 0 / 49 | 0 / 50 |
| other Total, other adverse events | 18 / 59 | 27 / 50 | 30 / 50 | 40 / 52 | 33 / 50 | 33 / 51 | 37 / 49 | 20 / 50 |
| serious Total, serious adverse events | 3 / 59 | 1 / 50 | 4 / 50 | 3 / 52 | 2 / 50 | 1 / 51 | 0 / 49 | 0 / 50 |
Outcome results
Primary
Absolute Change in HbA1c From Baseline to 16 Weeks
Absolute change in glycosylated hemoglobin A1c (HbA1c) from baseline to 16 weeks after treatment start is presented. The measurements for this outcome were performed at baseline and at Week 17. Absolute change from baseline in HbA1c to 16 weeks after treatment start was calculated by subtracting the baseline HbA1c value from the HbA1c value at Week 17.
Time frame: At baseline and at Week 17 (16 weeks after treatment start).
Population: Full Analysis Set (FAS): This patient set included all patients who were randomized and received at least one dose of study drug and who had analysable data for at least one efficacy endpoint. Only patients with non-missing results are reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change in HbA1c From Baseline to 16 Weeks | -0.23 percentage (%) of HbA1c | Standard Deviation 0.81 |
| BI 456906 0.3 mg | Absolute Change in HbA1c From Baseline to 16 Weeks | -0.91 percentage (%) of HbA1c | Standard Deviation 0.71 |
| BI 456906 0.9 mg | Absolute Change in HbA1c From Baseline to 16 Weeks | -1.37 percentage (%) of HbA1c | Standard Deviation 0.93 |
| BI 456906 1.8 mg | Absolute Change in HbA1c From Baseline to 16 Weeks | -1.79 percentage (%) of HbA1c | Standard Deviation 0.92 |
| BI 456906 2.7 mg | Absolute Change in HbA1c From Baseline to 16 Weeks | -1.67 percentage (%) of HbA1c | Standard Deviation 0.78 |
| BI 456906 1.2 Twice Weekly (2.4) mg | Absolute Change in HbA1c From Baseline to 16 Weeks | -1.68 percentage (%) of HbA1c | Standard Deviation 0.9 |
| BI 456906 1.8 Twice Weekly (3.6) mg | Absolute Change in HbA1c From Baseline to 16 Weeks | -1.79 percentage (%) of HbA1c | Standard Deviation 0.76 |
| Semaglutide | Absolute Change in HbA1c From Baseline to 16 Weeks | -1.50 percentage (%) of HbA1c | Standard Deviation 0.84 |
Comparison: A flat vs. non-flat dose-response relationship across the 6 doses of BI 456906 and placebo was tested using the Multiple Comparison Procedure - Modelling (MCP-Mod) approach which evaluated simultaneously 5 different plausible dose-response patterns (linear, exponential, Emax 1, Emax 2 and Sigmoid Emax) while protecting the overall probability of type I error (one-sided alpha of 0.025). For the twice weekly dosing schemes the total dose per week was considered for the MCP-Mod analysis.p-value: <0.0001MCP-Mod linear model fit
Comparison: A flat vs. non-flat dose-response relationship across the 6 doses of BI 456906 and placebo was tested using the Multiple Comparison Procedure - Modelling (MCP-Mod) approach which evaluated simultaneously 5 different plausible dose-response patterns (linear, exponential, Emax 1, Emax 2 and Sigmoid Emax) while protecting the overall probability of type I error (one-sided alpha of 0.025). For the twice weekly dosing schemes the total dose per week was considered for the MCP-Mod analysis.p-value: <0.0001MCP-Mod Exponential model fit
Comparison: A flat vs. non-flat dose-response relationship across the 6 doses of BI 456906 and placebo was tested using the Multiple Comparison Procedure - Modelling (MCP-Mod) approach which evaluated simultaneously 5 different plausible dose-response patterns (linear, exponential, Emax 1, Emax 2 and Sigmoid Emax) while protecting the overall probability of type I error (one-sided alpha of 0.025). For the twice weekly dosing schemes the total dose per week was considered for the MCP-Mod analysis.p-value: <0.0001MCP-Mod Emax 1 model fit
Comparison: A flat vs. non-flat dose-response relationship across the 6 doses of BI 456906 and placebo was tested using the Multiple Comparison Procedure - Modelling (MCP-Mod) approach which evaluated simultaneously 5 different plausible dose-response patterns (linear, exponential, Emax 1, Emax 2 and Sigmoid Emax) while protecting the overall probability of type I error (one-sided alpha of 0.025). For the twice weekly dosing schemes the total dose per week was considered for the MCP-Mod analysis.p-value: <0.0001MCP-Mod Emax 2 model fit
Comparison: A flat vs. non-flat dose-response relationship across the 6 doses of BI 456906 and placebo was tested using the Multiple Comparison Procedure - Modelling (MCP-Mod) approach which evaluated simultaneously 5 different plausible dose-response patterns (linear, exponential, Emax 1, Emax 2 and Sigmoid Emax) while protecting the overall probability of type I error (one-sided alpha of 0.025). For the twice weekly dosing schemes the total dose per week was considered for the MCP-Mod analysis.p-value: <0.0001MCP-Mod Sigmoid Emax model fit
Comparison: Mixed Model Repeated Measures (MMRM) with fixed, categorical factors of treatment at each visit, and continuous factors of baseline at each visit, using visit (Week 5, 8, 12, 16 and 17) as repeated measures, subject as random effect, unstructured covariance matrix to model within subject measurements.p-value: <0.000195% CI: [-1.06, -0.46]Mixed Model for Repeated Measures
Comparison: Mixed Model Repeated Measures (MMRM) with fixed, categorical factors of treatment at each visit, and continuous factors of baseline at each visit, using visit (Week 5, 8, 12, 16 and 17) as repeated measures, subject as random effect, unstructured covariance matrix to model within subject measurements.p-value: <0.000195% CI: [-1.6, -1.01]Mixed Model for Repeated Measures
Comparison: Mixed Model Repeated Measures (MMRM) with fixed, categorical factors of treatment at each visit, and continuous factors of baseline at each visit, using visit (Week 5, 8, 12, 16 and 17) as repeated measures, subject as random effect, unstructured covariance matrix to model within subject measurements.p-value: <0.000195% CI: [-1.87, -1.26]Mixed Model for Repeated Measures
Comparison: Mixed Model Repeated Measures (MMRM) with fixed, categorical factors of treatment at each visit, and continuous factors of baseline at each visit, using visit (Week 5, 8, 12, 16 and 17) as repeated measures, subject as random effect, unstructured covariance matrix to model within subject measurements.p-value: <0.000195% CI: [-1.72, -1.1]Mixed Model for Repeated Measures (MMRM)
Comparison: Mixed Model Repeated Measures (MMRM) with fixed, categorical factors of treatment at each visit, and continuous factors of baseline at each visit, using visit (Week 5, 8, 12, 16 and 17) as repeated measures, subject as random effect, unstructured covariance matrix to model within subject measurements.p-value: <0.000195% CI: [-1.78, -1.19]Mixed Model for Repeated Measures (MMRM)
Comparison: Mixed Model Repeated Measures (MMRM) with fixed, categorical factors of treatment at each visit, and continuous factors of baseline at each visit, using visit (Week 5, 8, 12, 16 and 17) as repeated measures, subject as random effect, unstructured covariance matrix to model within subject measurements.p-value: <0.000195% CI: [-1.84, -1.22]Mixed Model for Repeated Measures (MMRM)
Secondary
Key Secondary Endpoint: The Relative Change in Body Weight From Baseline to 16 Weeks
The relative change in body weight from baseline to 16 weeks after treatment start is presented. The measurements for this outcome were performed at baseline and at Week 17. The relative change in body weight from baseline to 16 weeks after treatment start was calculated as (body weight at Week 17 - body weight at baseline/body weight at baseline) \* 100.
Time frame: At baseline and at Week 17 (16 weeks after treatment start ).
Population: Full Analysis Set (FAS): This patient set included all patients who were randomized and received at least one dose of study drug and who had analysable data for at least one efficacy endpoint. Only patients with non-missing results are reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Key Secondary Endpoint: The Relative Change in Body Weight From Baseline to 16 Weeks | -1.20 percentage of body weight change | Standard Deviation 3.52 |
| BI 456906 0.3 mg | Key Secondary Endpoint: The Relative Change in Body Weight From Baseline to 16 Weeks | -1.86 percentage of body weight change | Standard Deviation 2.91 |
| BI 456906 0.9 mg | Key Secondary Endpoint: The Relative Change in Body Weight From Baseline to 16 Weeks | -4.43 percentage of body weight change | Standard Deviation 3.92 |
| BI 456906 1.8 mg | Key Secondary Endpoint: The Relative Change in Body Weight From Baseline to 16 Weeks | -6.63 percentage of body weight change | Standard Deviation 5.13 |
| BI 456906 2.7 mg | Key Secondary Endpoint: The Relative Change in Body Weight From Baseline to 16 Weeks | -6.68 percentage of body weight change | Standard Deviation 4.05 |
| BI 456906 1.2 Twice Weekly (2.4) mg | Key Secondary Endpoint: The Relative Change in Body Weight From Baseline to 16 Weeks | -7.16 percentage of body weight change | Standard Deviation 6.06 |
| BI 456906 1.8 Twice Weekly (3.6) mg | Key Secondary Endpoint: The Relative Change in Body Weight From Baseline to 16 Weeks | -8.95 percentage of body weight change | Standard Deviation 5.33 |
| Semaglutide | Key Secondary Endpoint: The Relative Change in Body Weight From Baseline to 16 Weeks | -5.40 percentage of body weight change | Standard Deviation 4.33 |
Comparison: A flat vs. non-flat dose-response relationship across the 6 doses of BI 456906 and placebo was tested using the Multiple Comparison Procedure - Modelling (MCP-Mod) approach which evaluated simultaneously 5 different plausible dose-response patterns (linear, exponential, Emax 1, Emax 2 and Sigmoid Emax) while protecting the overall probability of type I error (one-sided alpha of 0.025). For the twice weekly dosing schemes the total dose per week was considered for the MCP-Mod analysis.p-value: <0.0001MCP-Mod linear model fit
Comparison: A flat vs. non-flat dose-response relationship across the 6 doses of BI 456906 and placebo was tested using the Multiple Comparison Procedure - Modelling (MCP-Mod) approach which evaluated simultaneously 5 different plausible dose-response patterns (linear, exponential, Emax 1, Emax 2 and Sigmoid Emax) while protecting the overall probability of type I error (one-sided alpha of 0.025). For the twice weekly dosing schemes the total dose per week was considered for the MCP-Mod analysis.p-value: <0.0001MCP-Mod exponential model fit
Comparison: A flat vs. non-flat dose-response relationship across the 6 doses of BI 456906 and placebo was tested using the Multiple Comparison Procedure - Modelling (MCP-Mod) approach which evaluated simultaneously 5 different plausible dose-response patterns (linear, exponential, Emax 1, Emax 2 and Sigmoid Emax) while protecting the overall probability of type I error (one-sided alpha of 0.025). For the twice weekly dosing schemes the total dose per week was considered for the MCP-Mod analysis.p-value: <0.0001MCP-Mod Emax 1 model fit
Comparison: A flat vs. non-flat dose-response relationship across the 6 doses of BI 456906 and placebo was tested using the Multiple Comparison Procedure - Modelling (MCP-Mod) approach which evaluated simultaneously 5 different plausible dose-response patterns (linear, exponential, Emax 1, Emax 2 and Sigmoid Emax) while protecting the overall probability of type I error (one-sided alpha of 0.025). For the twice weekly dosing schemes the total dose per week was considered for the MCP-Mod analysis.p-value: <0.0001MCP-Mod Emax 2 model fit
Comparison: A flat vs. non-flat dose-response relationship across the 6 doses of BI 456906 and placebo was tested using the Multiple Comparison Procedure - Modelling (MCP-Mod) approach which evaluated simultaneously 5 different plausible dose-response patterns (linear, exponential, Emax 1, Emax 2 and Sigmoid Emax) while protecting the overall probability of type I error (one-sided alpha of 0.025). For the twice weekly dosing schemes the total dose per week was considered for the MCP-Mod analysis.p-value: <0.0001MCP-Mod Sigmoid Emax model fit
Comparison: Mixed Model Repeated Measures (MMRM) with fixed, categorical factors of treatment at each visit, and continuous factors of baseline at each visit, using visit (Week 2, 3, 4, 5, 6, 7, 8, 12, 16 and 17 ) as repeated measures, subject as random effect, unstructured covariance matrix to model within subject measurements.p-value: 0.222895% CI: [-2.9, 0.68]Mixed Model for Repeated Measures (MMRM)
Comparison: Mixed Model Repeated Measures (MMRM) with fixed, categorical factors of treatment at each visit, and continuous factors of baseline at each visit, using visit (Week 2, 3, 4, 5, 6, 7, 8, 12, 16 and 17 ) as repeated measures, subject as random effect, unstructured covariance matrix to model within subject measurements.p-value: <0.000195% CI: [-5.56, -2.01]Mixed Model for Repeated Measures (MMRM)
Comparison: Mixed Model Repeated Measures (MMRM) with fixed, categorical factors of treatment at each visit, and continuous factors of baseline at each visit, using visit (Week 2, 3, 4, 5, 6, 7, 8, 12, 16 and 17 ) as repeated measures, subject as random effect, unstructured covariance matrix to model within subject measurements.p-value: <0.000195% CI: [-7.41, -3.81]Mixed Model for Repeated Measures (MMRM)
Comparison: Mixed Model Repeated Measures (MMRM) with fixed, categorical factors of treatment at each visit, and continuous factors of baseline at each visit, using visit (Week 2, 3, 4, 5, 6, 7, 8, 12, 16 and 17 ) as repeated measures, subject as random effect, unstructured covariance matrix to model within subject measurements.p-value: <0.000195% CI: [-8.12, -4.38]Mixed Model for Repeated Measures (MMRM)
Comparison: Mixed Model Repeated Measures (MMRM) with fixed, categorical factors of treatment at each visit, and continuous factors of baseline at each visit, using visit (Week 2, 3, 4, 5, 6, 7, 8, 12, 16 and 17 ) as repeated measures, subject as random effect, unstructured covariance matrix to model within subject measurements.p-value: <0.000195% CI: [-8.02, -4.47]Mixed Model for Repeated Measures (MMRM)
Comparison: Mixed Model Repeated Measures (MMRM) with fixed, categorical factors of treatment at each visit, and continuous factors of baseline at each visit, using visit (Week 2, 3, 4, 5, 6, 7, 8, 12, 16 and 17 ) as repeated measures, subject as random effect, unstructured covariance matrix to model within subject measurements.p-value: <0.000195% CI: [-9.52, -5.83]Mixed Model for Repeated Measures (MMRM)
Secondary
Percentage of Patients With 10% or Greater Body Weight Loss From Baseline to 16 Weeks
The percentage of patients with 10 % or greater body weight loss from baseline to 16 weeks after treatment start is presented. Measurements for this outcome were performed at baseline and at Week 17.
Time frame: At baseline and at Week 17 (16 weeks after treatment start).
Population: Full Analysis Set (FAS): This patient set included all patients who were randomized and received at least one dose of study drug and who had analysable data for at least one efficacy endpoint. Only patients with non-missing results are reported.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Patients With 10% or Greater Body Weight Loss From Baseline to 16 Weeks | 0.0 percentage of patients |
| BI 456906 0.3 mg | Percentage of Patients With 10% or Greater Body Weight Loss From Baseline to 16 Weeks | 2.0 percentage of patients |
| BI 456906 0.9 mg | Percentage of Patients With 10% or Greater Body Weight Loss From Baseline to 16 Weeks | 6.0 percentage of patients |
| BI 456906 1.8 mg | Percentage of Patients With 10% or Greater Body Weight Loss From Baseline to 16 Weeks | 13.5 percentage of patients |
| BI 456906 2.7 mg | Percentage of Patients With 10% or Greater Body Weight Loss From Baseline to 16 Weeks | 16.0 percentage of patients |
| BI 456906 1.2 Twice Weekly (2.4) mg | Percentage of Patients With 10% or Greater Body Weight Loss From Baseline to 16 Weeks | 25.5 percentage of patients |
| BI 456906 1.8 Twice Weekly (3.6) mg | Percentage of Patients With 10% or Greater Body Weight Loss From Baseline to 16 Weeks | 34.7 percentage of patients |
| Semaglutide | Percentage of Patients With 10% or Greater Body Weight Loss From Baseline to 16 Weeks | 16.0 percentage of patients |
Comparison: Method: Logistic regression model using Firth's bias-reducing penalized maximum likelihood estimation for body weight loss with treatment as fixed effect.95% CI: [0.14, 95.73]
Comparison: Method: Logistic regression model using Firth's bias-reducing penalized maximum likelihood estimation for body weight loss with treatment as fixed effect.95% CI: [0.39, 163.56]
Comparison: Method: Logistic regression model using Firth's bias-reducing penalized maximum likelihood estimation for body weight loss with treatment as fixed effect.95% CI: [1.35, 471.09]
Comparison: Method: Logistic regression model using Firth's bias-reducing penalized maximum likelihood estimation for body weight loss with treatment as fixed effect.95% CI: [1.78, 613.51]
Comparison: Method: Logistic regression model using Firth's bias-reducing penalized maximum likelihood estimation for body weight loss with treatment as fixed effect.95% CI: [2.37, 761.44]
Comparison: Method: Logistic regression model using Firth's bias-reducing penalized maximum likelihood estimation for body weight loss with treatment as fixed effect.95% CI: [4.71, 999]
Comparison: Method: Logistic regression model using Firth's bias-reducing penalized maximum likelihood estimation for body weight loss with treatment as fixed effect.95% CI: [1.22, 413.33]
Secondary
Percentage of Patients With 5 % or Greater Body Weight Loss From Baseline to 16 Weeks
The percentage of patients with 5 percent (%) or greater body weight loss from baseline to 16 weeks after treatment start is presented. Measurements for this outcome were performed at baseline and at Week 17.
Time frame: At baseline and at Week 17 (16 weeks after treatment start).
Population: Full Analysis Set (FAS): This patient set included all patients who were randomized and received at least one dose of study drug and who had analysable data for at least one efficacy endpoint. Only patients with non-missing results are reported.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Patients With 5 % or Greater Body Weight Loss From Baseline to 16 Weeks | 6.8 percentage of patients |
| BI 456906 0.3 mg | Percentage of Patients With 5 % or Greater Body Weight Loss From Baseline to 16 Weeks | 8.0 percentage of patients |
| BI 456906 0.9 mg | Percentage of Patients With 5 % or Greater Body Weight Loss From Baseline to 16 Weeks | 38.0 percentage of patients |
| BI 456906 1.8 mg | Percentage of Patients With 5 % or Greater Body Weight Loss From Baseline to 16 Weeks | 42.3 percentage of patients |
| BI 456906 2.7 mg | Percentage of Patients With 5 % or Greater Body Weight Loss From Baseline to 16 Weeks | 46.0 percentage of patients |
| BI 456906 1.2 Twice Weekly (2.4) mg | Percentage of Patients With 5 % or Greater Body Weight Loss From Baseline to 16 Weeks | 56.9 percentage of patients |
| BI 456906 1.8 Twice Weekly (3.6) mg | Percentage of Patients With 5 % or Greater Body Weight Loss From Baseline to 16 Weeks | 57.1 percentage of patients |
| Semaglutide | Percentage of Patients With 5 % or Greater Body Weight Loss From Baseline to 16 Weeks | 38.0 percentage of patients |
Comparison: Method: Logistic regression model for body weight loss with treatment as fixed effect.95% CI: [0.28, 5.2]
Comparison: Method: Logistic regression model for body weight loss with treatment as fixed effect.95% CI: [2.43, 25.74]
Comparison: Method: Logistic regression model for body weight loss with treatment as fixed effect.95% CI: [5.21, 60.03]
Comparison: Method: Logistic regression model for body weight loss with treatment as fixed effect.95% CI: [7.31, 91.55]
Comparison: Method: Logistic regression model for body weight loss with treatment as fixed effect.95% CI: [6.57, 72.04]
Comparison: Method: Logistic regression model for body weight loss with treatment as fixed effect.95% CI: [9.84, 124.47]
Comparison: Method: Logistic regression model for body weight loss with treatment as fixed effect.95% CI: [2.52, 26.79]
Secondary
The Absolute Change in Body Weight From Baseline to 16 Weeks
The absolute change in body weight from baseline to 16 weeks after treatment start is presented. Measurements for this outcome were performed at baseline and at Week 17. The absolute change in body weight from baseline to 16 weeks after treatment start was calculated as: body weight at Week 17- body weight at baseline.
Time frame: At baseline and at Week 17 (16 weeks after treatment start).
Population: Full Analysis Set (FAS): This patient set included all patients who were randomized and received at least one dose of study drug and who had analysable data for at least one efficacy endpoint. Only patients with non-missing results are reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | The Absolute Change in Body Weight From Baseline to 16 Weeks | -1.28 kilogram (kg) | Standard Deviation 3.05 |
| BI 456906 0.3 mg | The Absolute Change in Body Weight From Baseline to 16 Weeks | -1.90 kilogram (kg) | Standard Deviation 3.12 |
| BI 456906 0.9 mg | The Absolute Change in Body Weight From Baseline to 16 Weeks | -4.41 kilogram (kg) | Standard Deviation 4.07 |
| BI 456906 1.8 mg | The Absolute Change in Body Weight From Baseline to 16 Weeks | -6.31 kilogram (kg) | Standard Deviation 4.53 |
| BI 456906 2.7 mg | The Absolute Change in Body Weight From Baseline to 16 Weeks | -6.88 kilogram (kg) | Standard Deviation 4.41 |
| BI 456906 1.2 Twice Weekly (2.4) mg | The Absolute Change in Body Weight From Baseline to 16 Weeks | -6.75 kilogram (kg) | Standard Deviation 6.1 |
| BI 456906 1.8 Twice Weekly (3.6) mg | The Absolute Change in Body Weight From Baseline to 16 Weeks | -8.88 kilogram (kg) | Standard Deviation 4.93 |
| Semaglutide | The Absolute Change in Body Weight From Baseline to 16 Weeks | -5.18 kilogram (kg) | Standard Deviation 4.52 |
Comparison: Mixed Model Repeated Measures (MMRM) with fixed, categorical factors of treatment at each visit, and continuous factors of baseline at each visit, using visit (Week 2, 3, 4, 5, 6, 7, 8, 12, 16 and 17 ) as repeated measures, subject as random effect, unstructured covariance matrix to model within subject measurements.p-value: 0.443995% CI: [-2.34, 1.03]Mixed Model for Repeated Measures (MMRM)
Comparison: Mixed Model Repeated Measures (MMRM) with fixed, categorical factors of treatment at each visit, and continuous factors of baseline at each visit, using visit (Week 2, 3, 4, 5, 6, 7, 8, 12, 16 and 17 ) as repeated measures, subject as random effect, unstructured covariance matrix to model within subject measurements.p-value: 0.000195% CI: [-4.95, -1.61]Mixed Model for Repeated Measures (MMRM)
Comparison: Mixed Model Repeated Measures (MMRM) with fixed, categorical factors of treatment at each visit, and continuous factors of baseline at each visit, using visit (Week 2, 3, 4, 5, 6, 7, 8, 12, 16 and 17 ) as repeated measures, subject as random effect, unstructured covariance matrix to model within subject measurements.p-value: <0.000195% CI: [-6.62, -3.23]Mixed Model for Repeated Measures (MMRM)
Comparison: Mixed Model Repeated Measures (MMRM) with fixed, categorical factors of treatment at each visit, and continuous factors of baseline at each visit, using visit (Week 2, 3, 4, 5, 6, 7, 8, 12, 16 and 17 ) as repeated measures, subject as random effect, unstructured covariance matrix to model within subject measurements.p-value: <0.000195% CI: [-7.53, -4]Mixed Model for Repeated Measures (MMRM)
Comparison: Mixed Model Repeated Measures (MMRM) with fixed, categorical factors of treatment at each visit, and continuous factors of baseline at each visit, using visit (Week 2, 3, 4, 5, 6, 7, 8, 12, 16 and 17 ) as repeated measures, subject as random effect, unstructured covariance matrix to model within subject measurements.p-value: <0.000195% CI: [-7.11, -3.77]Mixed Model for Repeated Measures (MMRM)
Comparison: Mixed Model Repeated Measures (MMRM) with fixed, categorical factors of treatment at each visit, and continuous factors of baseline at each visit, using visit (Week 2, 3, 4, 5, 6, 7, 8, 12, 16 and 17 ) as repeated measures, subject as random effect, unstructured covariance matrix to model within subject measurements.p-value: <0.000195% CI: [-8.79, -5.31]Mixed Model for Repeated Measures (MMRM)
Comparison: Mixed Model Repeated Measures (MMRM) with fixed, categorical factors of treatment at each visit, and continuous factors of baseline at each visit, using visit (Week 2, 3, 4, 5, 6, 7, 8, 12, 16 and 17 ) as repeated measures, subject as random effect, unstructured covariance matrix to model within subject measurements.p-value: <0.000195% CI: [-5.52, -2.18]Mixed Model Repeated Measures (MMRM)
Secondary
The Absolute Change in Waist Circumference From Baseline to 16 Weeks
The absolute change in waist circumference from baseline to 16 weeks after treatment start is presented. Measurements for this outcome were performed at baseline and at Week 17. The absolute change in waist circumference from baseline to 16 weeks after treatment start was calculated as: waist circumference at Week 17- waist circumference at baseline.
Time frame: At baseline and at Week 17 (16 weeks after treatment start).
Population: Full Analysis Set (FAS): This patient set included all patients who were randomized and received at least one dose of study drug and who had analysable data for at least one efficacy endpoint. Only patients with non-missing results are reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | The Absolute Change in Waist Circumference From Baseline to 16 Weeks | -1.95 centimeter | Standard Deviation 9.08 |
| BI 456906 0.3 mg | The Absolute Change in Waist Circumference From Baseline to 16 Weeks | -2.73 centimeter | Standard Deviation 10.49 |
| BI 456906 0.9 mg | The Absolute Change in Waist Circumference From Baseline to 16 Weeks | -1.80 centimeter | Standard Deviation 10.55 |
| BI 456906 1.8 mg | The Absolute Change in Waist Circumference From Baseline to 16 Weeks | -3.63 centimeter | Standard Deviation 10.94 |
| BI 456906 2.7 mg | The Absolute Change in Waist Circumference From Baseline to 16 Weeks | -7.47 centimeter | Standard Deviation 12.24 |
| BI 456906 1.2 Twice Weekly (2.4) mg | The Absolute Change in Waist Circumference From Baseline to 16 Weeks | -4.61 centimeter | Standard Deviation 9.73 |
| BI 456906 1.8 Twice Weekly (3.6) mg | The Absolute Change in Waist Circumference From Baseline to 16 Weeks | -12.89 centimeter | Standard Deviation 25.5 |
| Semaglutide | The Absolute Change in Waist Circumference From Baseline to 16 Weeks | -3.63 centimeter | Standard Deviation 5.05 |
Comparison: Mixed Model Repeated Measures (MMRM) with fixed, categorical factors of treatment at each visit, and continuous factors of baseline at each visit, using visit (Week 6 and 17 ) as repeated measures, subject as random effect, unstructured covariance matrix to model within subject measurements.p-value: 0.770895% CI: [-4.82, 3.57]Mixed Model for Repeated Measures (MMRM)
Comparison: Mixed Model Repeated Measures (MMRM) with fixed, categorical factors of treatment at each visit, and continuous factors of baseline at each visit, using visit (Week 6 and 17 ) as repeated measures, subject as random effect, unstructured covariance matrix to model within subject measurements.p-value: 0.746295% CI: [-3.44, 4.79]Mixed Model for Repeated Measures (MMRM)
Comparison: Mixed Model Repeated Measures (MMRM) with fixed, categorical factors of treatment at each visit, and continuous factors of baseline at each visit, using visit (Week 6 and 17 ) as repeated measures, subject as random effect, unstructured covariance matrix to model within subject measurements.p-value: 0.130295% CI: [-7.62, 0.98]Mixed Model for Repeated Measures (MMRM)
Comparison: Mixed Model Repeated Measures (MMRM) with fixed, categorical factors of treatment at each visit, and continuous factors of baseline at each visit, using visit (Week 6 and 17 ) as repeated measures, subject as random effect, unstructured covariance matrix to model within subject measurements.p-value: 0.041495% CI: [-9.03, -0.18]Mixed Model for Repeated Measures (MMRM)
Comparison: Mixed Model Repeated Measures (MMRM) with fixed, categorical factors of treatment at each visit, and continuous factors of baseline at each visit, using visit (Week 6 and 17 ) as repeated measures, subject as random effect, unstructured covariance matrix to model within subject measurements.p-value: 0.227395% CI: [-6.71, 1.6]Mixed Model for Repeated Measures (MMRM)
Comparison: Mixed Model Repeated Measures (MMRM) with fixed, categorical factors of treatment at each visit, and continuous factors of baseline at each visit, using visit (Week 6 and 17 ) as repeated measures, subject as random effect, unstructured covariance matrix to model within subject measurements.p-value: 0.000295% CI: [-12.81, -3.98]Mixed Model for Repeated Measures (MMRM)
Comparison: Mixed Model Repeated Measures (MMRM) with fixed, categorical factors of treatment at each visit, and continuous factors of baseline at each visit, using visit (Week 6 and 17 ) as repeated measures, subject as random effect, unstructured covariance matrix to model within subject measurements.p-value: 0.196795% CI: [-6.86, 1.42]Mixed Model Repeated Measures (MMRM)