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Clinical Trial Results:
A Phase II, randomized, parallel group, dose-finding study of subcutaneously administered BI 456906 for 16 weeks, compared with placebo and open-label semaglutide in patients with type 2 diabetes mellitus

Summary
EudraCT number	2019-002390-60
Trial protocol	ES DE HU CZ GB IT
Global end of trial date	05 Nov 2021

Results information
Results version number	v1(current)
This version publication date	15 Dec 2022
First version publication date	15 Dec 2022
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

1404-0002

ISRCTN number

US NCT number

NCT04153929

WHO universal trial number (UTN)

Sponsor organisation name

Boehringer Ingelheim

Sponsor organisation address

Binger Strasse 173, Ingelheim am Rhein, Germany, 55216

Public contact

Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 18002430127, clintriage.rdg@boehringer-ingelheim.com

Scientific contact

Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 18002430127, clintriage.rdg@boehringer-ingelheim.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

06 Dec 2021

Is this the analysis of the primary completion data?

Yes

Primary completion date

08 Oct 2021

Global end of trial reached?

Yes

Global end of trial date

05 Nov 2021

Was the trial ended prematurely?

Main objective of the trial

The primary objective was to demonstrate proof of clinical concept (PoCC) with respect to a non-flat dose response curve and to define a suitable dose escalation scheme and dose range for BI 456906 regarding safety, tolerability, and efficacy.

Protection of trial subjects

Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct. Rescue medication was allowed for all subjects as required.

Background therapy

Evidence for comparator

Actual start date of recruitment

09 Jun 2020

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 36

Country: Number of subjects enrolled

Austria: 9

Country: Number of subjects enrolled

Canada: 71

Country: Number of subjects enrolled

Czechia: 23

Country: Number of subjects enrolled

Germany: 15

Country: Number of subjects enrolled

Hungary: 70

Country: Number of subjects enrolled

Korea, Republic of: 27

Country: Number of subjects enrolled

New Zealand: 28

Country: Number of subjects enrolled

Poland: 55

Country: Number of subjects enrolled

Spain: 29

Country: Number of subjects enrolled

Taiwan: 13

Country: Number of subjects enrolled

United Kingdom: 25

Country: Number of subjects enrolled

United States: 268

Worldwide total number of subjects

669

EEA total number of subjects

201

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

498

From 65 to 84 years

171

85 years and over

Subject disposition

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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.

Screening 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.

Period 1 title

Randomised

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Carer, Data analyst, Assessor

Blinding implementation details

The trial had 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 remained blinded with regard to the randomized treatment assignments until after database lock. The semaglutide group was open label.

Are arms mutually exclusive

Yes

Placebo

Arm description

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.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

BI 456906 0.3 mg

Arm description

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.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

BI 456906 0.9 mg

Arm description

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

BI 456906 1.8 mg

Arm description

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

BI 456906 2.7 mg

Arm description

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

BI 456906 1.2 twice weekly (2.4) mg

Arm description

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).

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

BI 456906 1.8 twice weekly (3.6) mg

Arm description

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).

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Semaglutide

Arm description

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 1	Placebo	BI 456906 0.3 mg	BI 456906 0.9 mg	BI 456906 1.8 mg	BI 456906 2.7 mg	BI 456906 1.2 twice weekly (2.4) mg	BI 456906 1.8 twice weekly (3.6) mg	Semaglutide
Started	60	50	50	52	50	51	50	50
Completed	59	50	50	52	50	51	49	50
Not completed	1	0	0	0	0	0	1	0
No treated	1	-	-	-	-	-	1	-

Period 2 title

Treated

Is this the baseline period?

Yes ^[1]

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Carer, Data analyst, Assessor

Blinding implementation details

Are arms mutually exclusive

Yes

Placebo

Arm description

Arm type

Placebo

Investigational medicinal product name

Matching placebo to BI 456906 (isotonic sodium chloride solution)

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Patients with type 2 diabetes mellitus were administered solution for subcutaneous injection of placebo matched to BI 456906 once weekly for 16 weeks or twice weekly for 16 weeks.

BI 456906 0.3 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

BI 456906

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Patients with type 2 diabetes mellitus were administered once weekly subcutaneously a solution for injection of BI 456906 of 0.3 milligram (mg) on Week 1-Week 16.

BI 456906 0.9 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

BI 456906

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Patients with type 2 diabetes mellitus 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.

BI 456906 1.8 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

BI 456906

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Patients with type 2 diabetes mellitus 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.

BI 456906 2.7 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

BI 456906

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Patients with type 2 diabetes mellitus 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.

BI 456906 1.2 twice weekly (2.4) mg

Arm description

Arm type

Experimental

Investigational medicinal product name

BI 456906

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Patients with type 2 diabetes mellitus 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).

BI 456906 1.8 twice weekly (3.6) mg

Arm description

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).

Arm type

Experimental

Investigational medicinal product name

BI 456906

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Patients with type 2 diabetes mellitus 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).

Semaglutide

Arm description

Arm type

Active comparator

Investigational medicinal product name

Semaglutide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Patients with type 2 diabetes mellitus 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.

Notes
[1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
Justification: Period 1 are the randomised subjects, period 2 the treated, baseline characteristics are reported for the treated subjects.

Number of subjects in period 2 ^[2]	Placebo	BI 456906 0.3 mg	BI 456906 0.9 mg	BI 456906 1.8 mg	BI 456906 2.7 mg	BI 456906 1.2 twice weekly (2.4) mg	BI 456906 1.8 twice weekly (3.6) mg	Semaglutide
Started	59	50	50	52	50	51	49	50
Completed	49	41	45	36	33	45	37	45
Not completed	10	9	5	16	17	6	12	5
Consent withdrawn by subject	3	1	-	3	1	-	1	-
Adverse event, non-fatal	3	5	5	11	15	4	8	2
Lost to follow-up	2	1	-	1	1	-	-	-
Other than listed	2	2	-	1	-	2	2	1
Protocol deviation	-	-	-	-	-	-	1	2

Notes
[2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: In total 669 subjects were enrolled in this trial. From these 669 subjects only 413 subjects were randomised.

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Reporting group title

BI 456906 0.3 mg

Reporting group description

Reporting group title

BI 456906 0.9 mg

Reporting group description

Reporting group title

BI 456906 1.8 mg

Reporting group description

Reporting group title

BI 456906 2.7 mg

Reporting group description

Reporting group title

BI 456906 1.2 twice weekly (2.4) mg

Reporting group description

Reporting group title

BI 456906 1.8 twice weekly (3.6) mg

Reporting group description

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).

Reporting group title

Semaglutide

Reporting group description

Reporting group values	Placebo	BI 456906 0.3 mg	BI 456906 0.9 mg	BI 456906 1.8 mg	BI 456906 2.7 mg	BI 456906 1.2 twice weekly (2.4) mg	BI 456906 1.8 twice weekly (3.6) mg	Semaglutide	Total
Number of subjects	59	50	50	52	50	51	49	50	411
Age categorical
Treated set (TS): TS included all patients who were randomized and received at least one dose of study drug.
Units: Participants
In utero	0	0	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0	0	0
Adults (18-64 years)	44	40	38	39	35	39	36	38	309
From 65-84 years	15	10	12	13	15	12	13	12	102
85 years and over	0	0	0	0	0	0	0	0	0
Age Continuous
Treated set (TS): TS included all patients who were randomized and received at least one dose of study drug.
Units: years
arithmetic mean (standard deviation)	57.5 ( 10.5 )	56.1 ( 10.2 )	58.2 ( 9.6 )	55.3 ( 10.3 )	59.6 ( 8.5 )	58.3 ( 8.8 )	57.7 ( 9.4 )	55.8 ( 10.5 )	-
Sex: Female, Male
Treated set (TS): TS included all patients who were randomized and received at least one dose of study drug.
Units: Participants
Female	28	24	22	25	17	24	22	16	178
Male	31	26	28	27	33	27	27	34	233
Race (NIH/OMB)
Treated set (TS): TS included all patients who were randomized and received at least one dose of study drug.
Units: Subjects
American Indian or Alaska Native	0	1	0	0	0	0	1	0	2
Asian	8	4	5	8	4	5	3	5	42
Native Hawaiian or Other Pacific Islander	1	0	0	0	0	0	0	0	1
Black or African American	3	3	1	2	2	4	3	2	20
White	47	42	44	42	43	41	42	43	344
More than one race	0	0	0	0	0	0	0	0	0
Unknown or Not Reported	0	0	0	0	1	1	0	0	2
Ethnicity (NIH/OMB)
Treated set (TS): TS included all patients who were randomized and received at least one dose of study drug.
Units: Subjects
Hispanic or Latino	15	11	8	12	12	10	9	14	91
Not Hispanic or Latino	44	39	42	40	38	41	40	36	320
Unknown or Not Reported	0	0	0	0	0	0	0	0	0
Glycosylated hemoglobin A1c (HbA1c) measured in percentage units [%]
Glycosylated hemoglobin A1c (HbA1c) measured in percentage units [%] at baseline is presented. Treated set (TS): TS included all patients who were randomized and received at least one dose of study drug.
Units: percentage of HbA1c
arithmetic mean (standard deviation)	8.15 ( 0.85 )	8.09 ( 0.76 )	7.89 ( 0.80 )	8.14 ( 0.86 )	8.18 ( 0.97 )	8.11 ( 0.94 )	7.97 ( 0.71 )	8.03 ( 0.82 )	-

End points

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Reporting group title

Placebo

Reporting group description

Reporting group title

BI 456906 0.3 mg

Reporting group description

Reporting group title

BI 456906 0.9 mg

Reporting group description

Reporting group title

BI 456906 1.8 mg

Reporting group description

Reporting group title

BI 456906 2.7 mg

Reporting group description

Reporting group title

BI 456906 1.2 twice weekly (2.4) mg

Reporting group description

Reporting group title

BI 456906 1.8 twice weekly (3.6) mg

Reporting group description

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).

Reporting group title

Semaglutide

Reporting group description

Reporting group title

Placebo

Reporting group description

Reporting group title

BI 456906 0.3 mg

Reporting group description

Reporting group title

BI 456906 0.9 mg

Reporting group description

Reporting group title

BI 456906 1.8 mg

Reporting group description

Reporting group title

BI 456906 2.7 mg

Reporting group description

Reporting group title

BI 456906 1.2 twice weekly (2.4) mg

Reporting group description

Reporting group title

BI 456906 1.8 twice weekly (3.6) mg

Reporting group description

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).

Reporting group title

Semaglutide

Reporting group description

Primary: Absolute change in HbA1c from baseline to 16 weeks

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End point title

Absolute change in HbA1c from baseline to 16 weeks

End point description

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. 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.

End point type

Primary

End point timeframe

At baseline and at Week 17 (16 weeks after treatment start).

End point values	Placebo	BI 456906 0.3 mg	BI 456906 0.9 mg	BI 456906 1.8 mg	BI 456906 2.7 mg	BI 456906 1.2 twice weekly (2.4) mg	BI 456906 1.8 twice weekly (3.6) mg	Semaglutide
Number of subjects analysed	49	41	46	36	33	44	36	45
Units: percentage (%) of HbA1c
arithmetic mean (standard deviation)	-0.23 ( 0.81 )	-0.91 ( 0.71 )	-1.37 ( 0.93 )	-1.79 ( 0.92 )	-1.67 ( 0.78 )	-1.68 ( 0.90 )	-1.79 ( 0.76 )	-1.50 ( 0.84 )

Statistical Analysis 1

Statistical analysis description

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.

Comparison groups

Placebo v BI 456906 0.3 mg v BI 456906 0.9 mg v BI 456906 1.8 mg v BI 456906 2.7 mg v BI 456906 1.2 twice weekly (2.4) mg v BI 456906 1.8 twice weekly (3.6) mg

Number of subjects included in analysis

285

Analysis specification

Pre-specified

Analysis type

other ^[1]

P-value

< 0.0001

Method

MCP-Mod linear model fit

Confidence interval

Notes
[1] - Mixed Model Repeated Measures (MMRM) estimates were used as input for the MCP-Mod. 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. Model assumption: The maximum effect is achieved at 3.6 mg dose.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo v BI 456906 0.3 mg v BI 456906 0.9 mg v BI 456906 1.8 mg v BI 456906 2.7 mg v BI 456906 1.2 twice weekly (2.4) mg v BI 456906 1.8 twice weekly (3.6) mg

Number of subjects included in analysis

285

Analysis specification

Pre-specified

Analysis type

other ^[2]

P-value

< 0.0001

Method

MCP-Mod Exponential model fit

Confidence interval

Notes
[2] - Mixed Model Repeated Measures (MMRM) estimates were used as input for the MCP-Mod. 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. Model assumption: 90% of the maximum effect is achieved at 3.6 mg dose.

Statistical Analysis 3

Statistical analysis description

Comparison groups

Placebo v BI 456906 0.3 mg v BI 456906 0.9 mg v BI 456906 1.8 mg v BI 456906 2.7 mg v BI 456906 1.2 twice weekly (2.4) mg v BI 456906 1.8 twice weekly (3.6) mg

Number of subjects included in analysis

285

Analysis specification

Pre-specified

Analysis type

other ^[3]

P-value

< 0.0001

Method

MCP-Mod Emax 1 model fit

Confidence interval

Notes
[3] - Mixed Model Repeated Measures (MMRM) estimates were used as input for the MCP-Mod. 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. Model assumption: 90% of the maximum effect is achieved at 3.6 mg dose.

Statistical Analysis 5

Statistical analysis description

Comparison groups

Placebo v BI 456906 0.3 mg v BI 456906 0.9 mg v BI 456906 1.8 mg v BI 456906 2.7 mg v BI 456906 1.2 twice weekly (2.4) mg v BI 456906 1.8 twice weekly (3.6) mg

Number of subjects included in analysis

285

Analysis specification

Pre-specified

Analysis type

other ^[4]

P-value

< 0.0001

Method

MCP-Mod Sigmoid Emax model fit

Confidence interval

Notes
[4] - Mixed Model Repeated Measures (MMRM) estimates were used as input for the MCP-Mod. 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. Model assumption: 50% of the maximum effect is achieved at 1.8 mg and 90% of the maximum effect is achieved at 3.6 mg dose.

Statistical Analysis 4

Statistical analysis description

Comparison groups

Placebo v BI 456906 0.3 mg v BI 456906 0.9 mg v BI 456906 1.8 mg v BI 456906 2.7 mg v BI 456906 1.2 twice weekly (2.4) mg v BI 456906 1.8 twice weekly (3.6) mg

Number of subjects included in analysis

285

Analysis specification

Pre-specified

Analysis type

other ^[5]

P-value

< 0.0001

Method

MCP-Mod Emax 2 model fit

Confidence interval

Notes
[5] - Mixed Model Repeated Measures (MMRM) estimates were used as input for the MCP-Mod. 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. Model assumption: 70% of the maximum effect is achieved at 3.6 mg dose.

Statistical Analysis 6

Statistical analysis description

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.

Comparison groups

Placebo v BI 456906 0.3 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[6]

P-value

< 0.0001 ^[7]

Method

Mixed Model for Repeated Measures

Parameter type

Difference of adjusted means

Point estimate

-0.76

Confidence interval

level

95%

sides

2-sided

lower limit

-1.06

upper limit

-0.46

Notes
[6] - No formal hypotheses were tested. Kenward-Roger was used to estimate denominator degrees of freedom. Difference was calculated as BI 456906 0.3 mg - Placebo at Week 17.
[7] - P-value is considered nominal.

Statistical Analysis 7

Statistical analysis description

Comparison groups

Placebo v BI 456906 0.9 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[8]

P-value

< 0.0001 ^[9]

Method

Mixed Model for Repeated Measures

Parameter type

Difference of adjusted means

Point estimate

-1.31

Confidence interval

level

95%

sides

2-sided

lower limit

-1.6

upper limit

-1.01

Notes
[8] - No formal hypotheses were tested. Kenward-Roger was used to estimate denominator degrees of freedom. Difference was calculated as BI 456906 0.9 mg - Placebo at Week 17.
[9] - P-value is considered nominal.

Statistical Analysis 8

Statistical analysis description

Comparison groups

Placebo v BI 456906 1.8 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[10]

P-value

< 0.0001 ^[11]

Method

Mixed Model for Repeated Measures

Parameter type

Difference of adjusted means

Point estimate

-1.56

Confidence interval

level

95%

sides

2-sided

lower limit

-1.87

upper limit

-1.26

Notes
[10] - No formal hypotheses were tested. Kenward-Roger was used to estimate denominator degrees of freedom. Difference was calculated as BI 456906 1.8 mg - Placebo at Week 17.
[11] - P-value is considered nominal.

Statistical Analysis 9

Statistical analysis description

Comparison groups

Placebo v BI 456906 2.7 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[12]

P-value

< 0.0001 ^[13]

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

Difference of adjusted means

Point estimate

-1.41

Confidence interval

level

95%

sides

2-sided

lower limit

-1.72

upper limit

-1.1

Notes
[12] - No formal hypotheses were tested. Kenward-Roger was used to estimate denominator degrees of freedom. Difference was calculated as BI 456906 2.7 mg - Placebo at Week 17.
[13] - P-value is considered nominal.

Statistical Analysis 10

Statistical analysis description

Comparison groups

Placebo v BI 456906 1.2 twice weekly (2.4) mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[14]

P-value

< 0.0001 ^[15]

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

Difference of adjusted means

Point estimate

-1.49

Confidence interval

level

95%

sides

2-sided

lower limit

-1.78

upper limit

-1.19

Notes
[14] - No formal hypotheses were tested. Kenward-Roger was used to estimate denominator degrees of freedom. Difference was calculated as BI 456906 1.2 twice weekly (2.4) mg - Placebo at Week 17.
[15] - P-value is considered nominal.

Statistical Analysis 11

Statistical analysis description

Comparison groups

Placebo v BI 456906 1.8 twice weekly (3.6) mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[16]

P-value

< 0.0001 ^[17]

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

Difference of adjusted means

Point estimate

-1.53

Confidence interval

level

95%

sides

2-sided

lower limit

-1.84

upper limit

-1.22

Notes
[16] - No formal hypotheses were tested. Kenward-Roger was used to estimate denominator degrees of freedom. Difference was calculated as BI 456906 1.8 twice weekly (3.6) mg - Placebo at Week 17.
[17] - P-value is considered nominal.

Secondary: Key secondary endpoint: The relative change in body weight from baseline to 16 weeks

Top of page

End point title

Key secondary endpoint: The relative change in body weight from baseline to 16 weeks

End point description

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. 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.

End point type

Secondary

End point timeframe

At baseline and at Week 17 (16 weeks after treatment start ).

End point values	Placebo	BI 456906 0.3 mg	BI 456906 0.9 mg	BI 456906 1.8 mg	BI 456906 2.7 mg	BI 456906 1.2 twice weekly (2.4) mg	BI 456906 1.8 twice weekly (3.6) mg	Semaglutide
Number of subjects analysed	49	41	46	36	33	44	37	45
Units: percentage of body weight change
arithmetic mean (standard deviation)	-1.20 ( 3.52 )	-1.86 ( 2.91 )	-4.43 ( 3.92 )	-6.63 ( 5.13 )	-6.68 ( 4.05 )	-7.16 ( 6.06 )	-8.95 ( 5.33 )	-5.40 ( 4.33 )

Statistical Analysis 12

Statistical analysis description

Comparison groups

Placebo v BI 456906 0.3 mg v BI 456906 0.9 mg v BI 456906 1.8 mg v BI 456906 2.7 mg v BI 456906 1.2 twice weekly (2.4) mg v BI 456906 1.8 twice weekly (3.6) mg

Number of subjects included in analysis

286

Analysis specification

Pre-specified

Analysis type

other ^[18]

P-value

< 0.0001

Method

MCP-Mod linear model fit

Confidence interval

Notes
[18] - Mixed Model Repeated Measures (MMRM) estimates were used as input for the MCP-Mod. 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. Model assumption: The maximum effect is achieved at 3.6 mg dose.

Statistical Analysis 13

Statistical analysis description

Comparison groups

Placebo v BI 456906 0.3 mg v BI 456906 0.9 mg v BI 456906 1.8 mg v BI 456906 2.7 mg v BI 456906 1.2 twice weekly (2.4) mg v BI 456906 1.8 twice weekly (3.6) mg

Number of subjects included in analysis

286

Analysis specification

Pre-specified

Analysis type

other ^[19]

P-value

< 0.0001

Method

MCP-Mod exponential model fit

Confidence interval

Notes
[19] - Mixed Model Repeated Measures (MMRM) estimates were used as input for the MCP-Mod. 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. Model assumption: 90% of the maximum effect is achieved at 3.6 mg dose.

Statistical Analysis 14

Statistical analysis description

Comparison groups

Placebo v BI 456906 0.3 mg v BI 456906 0.9 mg v BI 456906 1.8 mg v BI 456906 2.7 mg v BI 456906 1.2 twice weekly (2.4) mg v BI 456906 1.8 twice weekly (3.6) mg

Number of subjects included in analysis

286

Analysis specification

Pre-specified

Analysis type

other ^[20]

P-value

< 0.0001

Method

MCP-Mod Emax 1 model fit

Confidence interval

Notes
[20] - Mixed Model Repeated Measures (MMRM) estimates were used as input for the MCP-Mod. 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. Model assumption: 90% of the maximum effect is achieved at 3.6 mg dose.

Statistical Analysis 15

Statistical analysis description

Comparison groups

Placebo v BI 456906 0.3 mg v BI 456906 0.9 mg v BI 456906 1.8 mg v BI 456906 2.7 mg v BI 456906 1.2 twice weekly (2.4) mg v BI 456906 1.8 twice weekly (3.6) mg

Number of subjects included in analysis

286

Analysis specification

Pre-specified

Analysis type

other ^[21]

P-value

< 0.0001

Method

MCP-Mod Emax 2 model fit

Confidence interval

Notes
[21] - Mixed Model Repeated Measures (MMRM) estimates were used as input for the MCP-Mod. 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. Model assumption: 70% of the maximum effect is achieved at 3.6 mg dose.

Statistical Analysis 16

Statistical analysis description

Comparison groups

Placebo v BI 456906 0.3 mg v BI 456906 0.9 mg v BI 456906 1.8 mg v BI 456906 2.7 mg v BI 456906 1.2 twice weekly (2.4) mg v BI 456906 1.8 twice weekly (3.6) mg

Number of subjects included in analysis

286

Analysis specification

Pre-specified

Analysis type

other ^[22]

P-value

< 0.0001

Method

MCP-Mod Sigmoid Emax model fit

Confidence interval

Notes
[22] - Mixed Model Repeated Measures (MMRM) estimates were used as input for the MCP-Mod. 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. Model assumption: 50% of the maximum effect is achieved at 1.8 mg and 90% of the maximum effect is achieved at 3.6 mg dose.

Statistical Analysis 17

Statistical analysis description

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.

Comparison groups

Placebo v BI 456906 0.3 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[23]

P-value

= 0.2228 ^[24]

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

Difference of adjusted means

Point estimate

-1.11

Confidence interval

level

95%

sides

2-sided

lower limit

-2.9

upper limit

0.68

Notes
[23] - No formal hypotheses were tested. Kenward-Roger was used to estimate denominator degrees of freedom. Difference was calculated as BI 456906 0.3 mg- Placebo at Week 17.
[24] - P-value is considered nominal.

Statistical Analysis 18

Statistical analysis description

Comparison groups

Placebo v BI 456906 0.9 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[25]

P-value

< 0.0001 ^[26]

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

Difference of adjusted means

Point estimate

-3.79

Confidence interval

level

95%

sides

2-sided

lower limit

-5.56

upper limit

-2.01

Notes
[25] - No formal hypotheses were tested. Kenward-Roger was used to estimate denominator degrees of freedom. Difference was calculated as BI 456906 0.9 mg- Placebo at Week 17.
[26] - P-value is considered nominal.

Statistical Analysis 19

Statistical analysis description

Comparison groups

Placebo v BI 456906 1.8 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[27]

P-value

< 0.0001 ^[28]

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

Difference of adjusted means

Point estimate

-5.61

Confidence interval

level

95%

sides

2-sided

lower limit

-7.41

upper limit

-3.81

Notes
[27] - No formal hypotheses were tested. Kenward-Roger was used to estimate denominator degrees of freedom. Difference was calculated as BI 456906 1.8 mg- Placebo at Week 17.
[28] - P-value is considered nominal.

Statistical Analysis 20

Statistical analysis description

Comparison groups

Placebo v BI 456906 2.7 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[29]

P-value

< 0.0001 ^[30]

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

Difference of adjusted means

Point estimate

-6.25

Confidence interval

level

95%

sides

2-sided

lower limit

-8.12

upper limit

-4.38

Notes
[29] - No formal hypotheses were tested. Kenward-Roger was used to estimate denominator degrees of freedom. Difference was calculated as BI 456906 2.7 mg - Placebo at Week 17.
[30] - P-value is considered nominal.

Statistical Analysis 21

Statistical analysis description

Comparison groups

Placebo v BI 456906 1.2 twice weekly (2.4) mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[31]

P-value

< 0.0001 ^[32]

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

Difference of adjusted means

Point estimate

-6.25

Confidence interval

level

95%

sides

2-sided

lower limit

-8.02

upper limit

-4.47

Notes
[31] - No formal hypotheses were tested. Kenward-Roger was used to estimate denominator degrees of freedom. Difference was calculated as BI 456906 1.2 twice weekly (2.4) mg - Placebo at Week 17.
[32] - P-value is considered nominal.

Statistical Analysis 22

Statistical analysis description

Comparison groups

Placebo v BI 456906 1.8 twice weekly (3.6) mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[33]

P-value

< 0.0001 ^[34]

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

Difference of adjusted means

Point estimate

-7.68

Confidence interval

level

95%

sides

2-sided

lower limit

-9.52

upper limit

-5.83

Notes
[33] - No formal hypotheses were tested. Kenward-Roger was used to estimate denominator degrees of freedom. Difference was calculated as BI 456906 1.8 twice weekly (3.6) mg - Placebo at Week 17.
[34] - P-value is considered nominal.

Secondary: The absolute change in body weight from baseline to 16 weeks

Top of page

End point title

The absolute change in body weight from baseline to 16 weeks

End point description

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. 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.

End point type

Secondary

End point timeframe

At baseline and at Week 17 (16 weeks after treatment start).

End point values	Placebo	BI 456906 0.3 mg	BI 456906 0.9 mg	BI 456906 1.8 mg	BI 456906 2.7 mg	BI 456906 1.2 twice weekly (2.4) mg	BI 456906 1.8 twice weekly (3.6) mg	Semaglutide
Number of subjects analysed	49	41	46	36	33	44	37	45
Units: kilogram (kg)
arithmetic mean (standard deviation)	-1.28 ( 3.05 )	-1.90 ( 3.12 )	-4.41 ( 4.07 )	-6.31 ( 4.53 )	-6.88 ( 4.41 )	-6.75 ( 6.10 )	-8.88 ( 4.93 )	-5.18 ( 4.52 )

Statistical Analysis 23

Statistical analysis description

Comparison groups

Placebo v BI 456906 0.3 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[35]

P-value

= 0.4439 ^[36]

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

Difference of adjusted means

Point estimate

-0.66

Confidence interval

level

95%

sides

2-sided

lower limit

-2.34

upper limit

1.03

Notes
[35] - No formal hypotheses were tested. Kenward-Roger was used to estimate denominator degrees of freedom. Difference was calculated as BI 456906 0.3 mg - Placebo at Week 17.
[36] - P-value is considered nominal.

Statistical Analysis 25

Statistical analysis description

Comparison groups

Placebo v BI 456906 1.8 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[37]

P-value

< 0.0001 ^[38]

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

Difference of adjusted means

Point estimate

-4.93

Confidence interval

level

95%

sides

2-sided

lower limit

-6.62

upper limit

-3.23

Notes
[37] - No formal hypotheses were tested. Kenward-Roger was used to estimate denominator degrees of freedom. Difference was calculated as BI 456906 1.8 mg - Placebo at Week 17.
[38] - P-value is considered nominal

Statistical Analysis 24

Statistical analysis description

Comparison groups

Placebo v BI 456906 0.9 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[39]

P-value

= 0.0001 ^[40]

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

Difference of adjusted means

Point estimate

-3.28

Confidence interval

level

95%

sides

2-sided

lower limit

-4.95

upper limit

-1.61

Notes
[39] - No formal hypotheses were tested. Kenward-Roger was used to estimate denominator degrees of freedom. Difference was calculated as BI 456906 0.9 mg - Placebo at Week 17.
[40] - P-value is considered nominal.

Statistical Analysis 26

Statistical analysis description

Comparison groups

Placebo v BI 456906 2.7 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[41]

P-value

< 0.0001 ^[42]

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

Difference of adjusted means

Point estimate

-5.76

Confidence interval

level

95%

sides

2-sided

lower limit

-7.53

upper limit

-4

Notes
[41] - No formal hypotheses were tested. Kenward-Roger was used to estimate denominator degrees of freedom. Difference was calculated as BI 456906 2.7 mg - Placebo at Week 17.
[42] - P-value is considered nominal.

Statistical Analysis 27

Statistical analysis description

Comparison groups

Placebo v BI 456906 1.2 twice weekly (2.4) mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[43]

P-value

< 0.0001 ^[44]

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

Difference of adjusted means

Point estimate

-5.44

Confidence interval

level

95%

sides

2-sided

lower limit

-7.11

upper limit

-3.77

Notes
[43] - No formal hypotheses were tested. Kenward-Roger was used to estimate denominator degrees of freedom. Difference was calculated as BI 456906 1.2 twice weekly (2.4) mg - Placebo at Week 17.
[44] - P-value is considered nominal.

Statistical Analysis 28

Statistical analysis description

Comparison groups

Placebo v BI 456906 1.8 twice weekly (3.6) mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[45]

P-value

< 0.0001 ^[46]

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

Difference of adjusted means

Point estimate

-7.05

Confidence interval

level

95%

sides

2-sided

lower limit

-8.79

upper limit

-5.31

Notes
[45] - No formal hypotheses were tested. Kenward-Roger was used to estimate denominator degrees of freedom. Difference was calculated as BI 456906 1.8 twice weekly (3.6) mg - Placebo at Week 17.
[46] - P-value is considered nominal.

Statistical Analysis 29

Statistical analysis description

Comparison groups

Placebo v Semaglutide

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[47]

P-value

< 0.0001 ^[48]

Method

Mixed Model Repeated Measures (MMRM)

Parameter type

Difference of adjusted means

Point estimate

-3.85

Confidence interval

level

95%

sides

2-sided

lower limit

-5.52

upper limit

-2.18

Notes
[47] - No formal hypotheses were tested. Kenward-Roger was used to estimate denominator degrees of freedom. Difference was calculated as Semaglutide - Placebo at Week 17.
[48] - P-value is considered nominal.

Secondary: The absolute change in waist circumference from baseline to 16 weeks

Top of page

End point title

The absolute change in waist circumference from baseline to 16 weeks

End point description

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. 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.

End point type

Secondary

End point timeframe

At baseline and at Week 17 (16 weeks after treatment start).

End point values	Placebo	BI 456906 0.3 mg	BI 456906 0.9 mg	BI 456906 1.8 mg	BI 456906 2.7 mg	BI 456906 1.2 twice weekly (2.4) mg	BI 456906 1.8 twice weekly (3.6) mg	Semaglutide
Number of subjects analysed	49	43	47	39	35	45	36	46
Units: centimeter
arithmetic mean (standard deviation)	-1.95 ( 9.08 )	-2.73 ( 10.49 )	-1.80 ( 10.55 )	-3.63 ( 10.94 )	-7.47 ( 12.24 )	-4.61 ( 9.73 )	-12.89 ( 25.50 )	-3.63 ( 5.05 )

Statistical Analysis 30

Statistical analysis description

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.

Comparison groups

Placebo v BI 456906 0.3 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[49]

P-value

= 0.7708 ^[50]

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

Difference of adjusted means

Point estimate

-0.62

Confidence interval

level

95%

sides

2-sided

lower limit

-4.82

upper limit

3.57

Notes
[49] - No formal hypotheses were tested. Kenward-Roger was used to estimate denominator degrees of freedom. Difference was calculated as BI 456906 0.3 mg - Placebo at Week 17.
[50] - P-value is considered nominal.

Statistical Analysis 31

Statistical analysis description

Comparison groups

Placebo v BI 456906 0.9 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[51]

P-value

= 0.7462 ^[52]

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

Difference of adjusted means

Point estimate

0.68

Confidence interval

level

95%

sides

2-sided

lower limit

-3.44

upper limit

4.79

Notes
[51] - No formal hypotheses were tested. Kenward-Roger was used to estimate denominator degrees of freedom. Difference was calculated as BI 456906 0.9 mg - Placebo at Week 17.
[52] - P-value is considered nominal.

Statistical Analysis 32

Statistical analysis description

Comparison groups

Placebo v BI 456906 1.8 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[53]

P-value

= 0.1302 ^[54]

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

Difference of adjusted means

Point estimate

-3.32

Confidence interval

level

95%

sides

2-sided

lower limit

-7.62

upper limit

0.98

Notes
[53] - No formal hypotheses were tested. Kenward-Roger was used to estimate denominator degrees of freedom. Difference was calculated as BI 456906 1.8 mg - Placebo at Week 17.
[54] - P-value is considered nominal.

Statistical Analysis 33

Statistical analysis description

Comparison groups

Placebo v BI 456906 2.7 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[55]

P-value

= 0.0414 ^[56]

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

Difference of adjusted means

Point estimate

-4.61

Confidence interval

level

95%

sides

2-sided

lower limit

-9.03

upper limit

-0.18

Notes
[55] - No formal hypotheses were tested. Kenward-Roger was used to estimate denominator degrees of freedom. Difference was calculated as BI 456906 2.7 mg- Placebo at Week 17.
[56] - P-value is considered nominal.

Statistical Analysis 34

Statistical analysis description

Comparison groups

Placebo v BI 456906 1.2 twice weekly (2.4) mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[57]

P-value

= 0.2273 ^[58]

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

Difference of adjusted means

Point estimate

-2.55

Confidence interval

level

95%

sides

2-sided

lower limit

-6.71

upper limit

1.6

Notes
[57] - No formal hypotheses were tested. Kenward-Roger was used to estimate denominator degrees of freedom. Difference was calculated as BI 456906 1.2 twice weekly (2.4) mg - Placebo at Week 17.
[58] - P-value is considered nominal.

Statistical Analysis 35

Statistical analysis description

Comparison groups

Placebo v BI 456906 1.8 twice weekly (3.6) mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[59]

P-value

= 0.0002 ^[60]

Method

Mixed Model for Repeated Measures (MMRM)

Parameter type

Difference of adjusted means

Point estimate

-8.4

Confidence interval

level

95%

sides

2-sided

lower limit

-12.81

upper limit

-3.98

Notes
[59] - No formal hypotheses were tested. Kenward-Roger was used to estimate denominator degrees of freedom. Difference was calculated as BI 456906 1.8 twice weekly (3.6) mg - Placebo at Week 17.
[60] - P-value is considered nominal.

Statistical Analysis 36

Statistical analysis description

Comparison groups

Placebo v Semaglutide

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[61]

P-value

= 0.1967 ^[62]

Method

Mixed Model Repeated Measures (MMRM)

Parameter type

Difference of adjusted means

Point estimate

-2.72

Confidence interval

level

95%

sides

2-sided

lower limit

-6.86

upper limit

1.42

Notes
[61] - No formal hypotheses were tested. Kenward-Roger was used to estimate denominator degrees of freedom. Difference was calculated as Semaglutide - Placebo at Week 17.
[62] - P-value is considered nominal.

Secondary: Percentage of patients with 5 % or greater body weight loss from baseline to 16 weeks

Top of page

End point title

Percentage of patients with 5 % or greater body weight loss from baseline to 16 weeks

End point description

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. 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.

End point type

Secondary

End point timeframe

At baseline and at Week 17 (16 weeks after treatment start).

End point values	Placebo	BI 456906 0.3 mg	BI 456906 0.9 mg	BI 456906 1.8 mg	BI 456906 2.7 mg	BI 456906 1.2 twice weekly (2.4) mg	BI 456906 1.8 twice weekly (3.6) mg	Semaglutide
Number of subjects analysed	59	50	50	52	50	51	49	50
Units: percentage of patients
number (not applicable)	6.8	8.0	38.0	42.3	46.0	56.9	57.1	38.0

Statistical Analysis 37

Statistical analysis description

Method: Logistic regression model for body weight loss with treatment as fixed effect.

Comparison groups

Placebo v BI 456906 0.3 mg

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

other ^[63]

Method

Parameter type

Odds ratio (OR)

Point estimate

1.22

Confidence interval

level

95%

sides

2-sided

lower limit

0.28

upper limit

5.2

Notes
[63] - Odds Ratio was calculated as BI 456906 / Placebo.

Statistical Analysis 38

Statistical analysis description

Method: Logistic regression model for body weight loss with treatment as fixed effect.

Comparison groups

Placebo v BI 456906 0.9 mg

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

other ^[64]

Method

Parameter type

Odds ratio (OR)

Point estimate

7.92

Confidence interval

level

95%

sides

2-sided

lower limit

2.43

upper limit

25.74

Notes
[64] - Odds Ratio was calculated as BI 456906 / Placebo.

Statistical Analysis 39

Statistical analysis description

Method: Logistic regression model for body weight loss with treatment as fixed effect.

Comparison groups

Placebo v BI 456906 1.8 mg

Number of subjects included in analysis

111

Analysis specification

Pre-specified

Analysis type

other ^[65]

Method

Parameter type

Odds ratio (OR)

Point estimate

17.68

Confidence interval

level

95%

sides

2-sided

lower limit

5.21

upper limit

60.03

Notes
[65] - Odds Ratio was calculated as BI 456906 / Placebo.

Statistical Analysis 40

Statistical analysis description

Method: Logistic regression model for body weight loss with treatment as fixed effect.

Comparison groups

Placebo v BI 456906 2.7 mg

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

other ^[66]

Method

Parameter type

Odds ratio (OR)

Point estimate

25.87

Confidence interval

level

95%

sides

2-sided

lower limit

7.31

upper limit

91.55

Notes
[66] - Odds Ratio was calculated as BI 456906 / Placebo.

Statistical Analysis 41

Statistical analysis description

Method: Logistic regression model for body weight loss with treatment as fixed effect.

Comparison groups

Placebo v BI 456906 1.2 twice weekly (2.4) mg

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

other ^[67]

Method

Parameter type

Odds ratio (OR)

Point estimate

21.75

Confidence interval

level

95%

sides

2-sided

lower limit

6.57

upper limit

72.04

Notes
[67] - Odds Ratio was calculated as BI 456906 / Placebo.

Statistical Analysis 42

Statistical analysis description

Method: Logistic regression model for body weight loss with treatment as fixed effect.

Comparison groups

Placebo v BI 456906 1.8 twice weekly (3.6) mg

Number of subjects included in analysis

108

Analysis specification

Pre-specified

Analysis type

^[68]

Method

Parameter type

Odds ratio (OR)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

9.84

upper limit

124.47

Notes
[68] - Odds Ratio was calculated as BI 456906 / Placebo.

Statistical Analysis 43

Statistical analysis description

Method: Logistic regression model for body weight loss with treatment as fixed effect.

Comparison groups

Placebo v Semaglutide

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

other ^[69]

Method

Parameter type

Odds ratio (OR)

Point estimate

8.22

Confidence interval

level

95%

sides

2-sided

lower limit

2.52

upper limit

26.79

Notes
[69] - Odds Ratio was calculated as Semaglutide / Placebo.

Secondary: Percentage of patients with 10% or greater body weight loss from baseline to 16 weeks

Top of page

End point title

Percentage of patients with 10% or greater body weight loss from baseline to 16 weeks

End point description

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. 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.

End point type

Secondary

End point timeframe

At baseline and at Week 17 (16 weeks after treatment start).

End point values	Placebo	BI 456906 0.3 mg	BI 456906 0.9 mg	BI 456906 1.8 mg	BI 456906 2.7 mg	BI 456906 1.2 twice weekly (2.4) mg	BI 456906 1.8 twice weekly (3.6) mg	Semaglutide
Number of subjects analysed	59	50	50	52	50	51	49	50
Units: percentage of patients
number (not applicable)	0.0	2.0	6.0	13.5	16.0	25.5	34.7	16.0

Statistical Analysis 44

Statistical analysis description

Method: Logistic regression model using Firth’s bias-reducing penalized maximum likelihood estimation for body weight loss with treatment as fixed effect.

Comparison groups

Placebo v BI 456906 0.3 mg

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

other ^[70]

Method

Parameter type

Odds ratio (OR)

Point estimate

3.67

Confidence interval

level

95%

sides

2-sided

lower limit

0.14

upper limit

95.73

Notes
[70] - Odds Ratio was calculated as BI 456906 / Placebo.

Statistical Analysis 45

Statistical analysis description

Method: Logistic regression model using Firth’s bias-reducing penalized maximum likelihood estimation for body weight loss with treatment as fixed effect.

Comparison groups

Placebo v BI 456906 0.9 mg

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

other ^[71]

Method

Parameter type

Odds ratio (OR)

Point estimate

7.97

Confidence interval

level

95%

sides

2-sided

lower limit

0.39

upper limit

163.56

Notes
[71] - Odds Ratio was calculated as BI 456906 / Placebo.

Statistical Analysis 46

Statistical analysis description

Method: Logistic regression model using Firth’s bias-reducing penalized maximum likelihood estimation for body weight loss with treatment as fixed effect.

Comparison groups

Placebo v BI 456906 1.8 mg

Number of subjects included in analysis

111

Analysis specification

Pre-specified

Analysis type

other ^[72]

Method

Parameter type

Odds ratio (OR)

Point estimate

25.17

Confidence interval

level

95%

sides

2-sided

lower limit

1.35

upper limit

471.09

Notes
[72] - Odds Ratio was calculated as BI 456906 / Placebo.

Statistical Analysis 47

Statistical analysis description

Method: Logistic regression model using Firth’s bias-reducing penalized maximum likelihood estimation for body weight loss with treatment as fixed effect.

Comparison groups

Placebo v BI 456906 2.7 mg

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

other ^[73]

Method

Parameter type

Odds ratio (OR)

Point estimate

33.01

Confidence interval

level

95%

sides

2-sided

lower limit

1.78

upper limit

613.51

Notes
[73] - Odds Ratio was calculated as BI 456906 / Placebo.

Statistical Analysis 48

Statistical analysis description

Method: Logistic regression model using Firth’s bias-reducing penalized maximum likelihood estimation for body weight loss with treatment as fixed effect.

Comparison groups

Placebo v BI 456906 1.2 twice weekly (2.4) mg

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

other ^[74]

Method

Parameter type

Odds ratio (OR)

Point estimate

42.44

Confidence interval

level

95%

sides

2-sided

lower limit

2.37

upper limit

761.44

Notes
[74] - Odds Ratio was calculated as BI 456906 / Placebo.

Statistical Analysis 49

Statistical analysis description

Method: Logistic regression model using Firth’s bias-reducing penalized maximum likelihood estimation for body weight loss with treatment as fixed effect.

Comparison groups

Placebo v BI 456906 1.8 twice weekly (3.6) mg

Number of subjects included in analysis

108

Analysis specification

Pre-specified

Analysis type

other ^[75]

Method

Parameter type

Odds ratio (OR)

Point estimate

84.53

Confidence interval

level

95%

sides

2-sided

lower limit

4.71

upper limit

999

Notes
[75] - Odds Ratio was calculated as BI 456906 / Placebo.

Statistical Analysis 50

Statistical analysis description

Method: Logistic regression model using Firth’s bias-reducing penalized maximum likelihood estimation for body weight loss with treatment as fixed effect.

Comparison groups

Placebo v Semaglutide

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

other ^[76]

Method

Parameter type

Odds ratio (OR)

Point estimate

22.44

Confidence interval

level

95%

sides

2-sided

lower limit

1.22

upper limit

413.33

Notes
[76] - Odds Ratio was calculated as Semaglutide / Placebo.

Adverse events

Top of page

Timeframe for reporting adverse events

From first intake of any trial drug until last intake of any trial drug (planned: 16 weeks) + residual effect period (BI 456906: 28 days, Semaglutide: 35 days), up to 159 days.

Adverse event reporting additional description

Treated set (TS): This patient set included all patients who were randomized and received at least one dose of study drug.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24.1

Reporting group title

Placebo

Reporting group description

Reporting group title

BI 456906 0.3 mg

Reporting group description

Reporting group title

BI 456906 2.7 mg

Reporting group description

Reporting group title

BI 456906 1.2 twice weekly (2.4) mg

Reporting group description

Reporting group title

BI 456906 1.8 twice weekly (3.6) mg

Reporting group description

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).

Reporting group title

Semaglutide

Reporting group description

Reporting group title

BI 456906 0.9 mg

Reporting group description

Reporting group title

BI 456906 1.8 mg

Reporting group description

Serious adverse events	Placebo	BI 456906 0.3 mg	BI 456906 2.7 mg	BI 456906 1.2 twice weekly (2.4) mg	BI 456906 1.8 twice weekly (3.6) mg	Semaglutide	BI 456906 0.9 mg	BI 456906 1.8 mg
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 59 (5.08%)	1 / 50 (2.00%)	2 / 50 (4.00%)	1 / 51 (1.96%)	0 / 49 (0.00%)	0 / 50 (0.00%)	4 / 50 (8.00%)	3 / 52 (5.77%)
number of deaths (all causes)	0	0	0	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0	0	0
Vascular disorders
Hypotension
subjects affected / exposed	1 / 59 (1.69%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
IIIrd nerve paralysis
subjects affected / exposed	0 / 59 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Paraparesis
subjects affected / exposed	0 / 59 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Autoimmune disorder
subjects affected / exposed	0 / 59 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	1 / 50 (2.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 59 (0.00%)	1 / 50 (2.00%)	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 59 (0.00%)	0 / 50 (0.00%)	1 / 50 (2.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	1 / 59 (1.69%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Irritable bowel syndrome
subjects affected / exposed	0 / 59 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	1 / 50 (2.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mouth ulceration
subjects affected / exposed	0 / 59 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	1 / 50 (2.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 59 (0.00%)	1 / 50 (2.00%)	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	1 / 59 (1.69%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pharyngeal ulceration
subjects affected / exposed	0 / 59 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	1 / 50 (2.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 59 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	1 / 51 (1.96%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	0 / 59 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	1 / 51 (1.96%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Cellulitis
subjects affected / exposed	0 / 59 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	2 / 50 (4.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Viraemia
subjects affected / exposed	0 / 59 (0.00%)	0 / 50 (0.00%)	1 / 50 (2.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 59 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Placebo	BI 456906 0.3 mg	BI 456906 2.7 mg	BI 456906 1.2 twice weekly (2.4) mg	BI 456906 1.8 twice weekly (3.6) mg	Semaglutide	BI 456906 0.9 mg	BI 456906 1.8 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	18 / 59 (30.51%)	27 / 50 (54.00%)	33 / 50 (66.00%)	33 / 51 (64.71%)	37 / 49 (75.51%)	20 / 50 (40.00%)	30 / 50 (60.00%)	40 / 52 (76.92%)
Investigations
Lipase increased
subjects affected / exposed	0 / 59 (0.00%)	2 / 50 (4.00%)	2 / 50 (4.00%)	1 / 51 (1.96%)	0 / 49 (0.00%)	3 / 50 (6.00%)	4 / 50 (8.00%)	1 / 52 (1.92%)
occurrences all number	0	2	2	2	0	4	4	1
Weight decreased
subjects affected / exposed	0 / 59 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	6 / 51 (11.76%)	4 / 49 (8.16%)	1 / 50 (2.00%)	1 / 50 (2.00%)	2 / 52 (3.85%)
occurrences all number	0	0	0	6	4	1	1	2
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 59 (0.00%)	1 / 50 (2.00%)	1 / 50 (2.00%)	1 / 51 (1.96%)	3 / 49 (6.12%)	1 / 50 (2.00%)	4 / 50 (8.00%)	0 / 52 (0.00%)
occurrences all number	0	1	2	1	5	1	4	0
Headache
subjects affected / exposed	4 / 59 (6.78%)	4 / 50 (8.00%)	1 / 50 (2.00%)	3 / 51 (5.88%)	5 / 49 (10.20%)	0 / 50 (0.00%)	5 / 50 (10.00%)	4 / 52 (7.69%)
occurrences all number	6	9	1	3	5	0	5	7
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 59 (0.00%)	1 / 50 (2.00%)	1 / 50 (2.00%)	1 / 51 (1.96%)	2 / 49 (4.08%)	0 / 50 (0.00%)	2 / 50 (4.00%)	3 / 52 (5.77%)
occurrences all number	0	1	1	1	3	0	2	3
Fatigue
subjects affected / exposed	0 / 59 (0.00%)	3 / 50 (6.00%)	2 / 50 (4.00%)	4 / 51 (7.84%)	5 / 49 (10.20%)	1 / 50 (2.00%)	1 / 50 (2.00%)	3 / 52 (5.77%)
occurrences all number	0	4	3	5	6	1	1	3
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	2 / 59 (3.39%)	3 / 50 (6.00%)	6 / 50 (12.00%)	2 / 51 (3.92%)	4 / 49 (8.16%)	1 / 50 (2.00%)	1 / 50 (2.00%)	1 / 52 (1.92%)
occurrences all number	5	3	9	2	5	1	2	1
Abdominal discomfort
subjects affected / exposed	0 / 59 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	1 / 51 (1.96%)	2 / 49 (4.08%)	0 / 50 (0.00%)	0 / 50 (0.00%)	4 / 52 (7.69%)
occurrences all number	0	0	0	1	2	0	0	4
Abdominal pain upper
subjects affected / exposed	1 / 59 (1.69%)	3 / 50 (6.00%)	1 / 50 (2.00%)	5 / 51 (9.80%)	2 / 49 (4.08%)	1 / 50 (2.00%)	1 / 50 (2.00%)	1 / 52 (1.92%)
occurrences all number	1	3	1	5	2	1	1	1
Constipation
subjects affected / exposed	0 / 59 (0.00%)	3 / 50 (6.00%)	7 / 50 (14.00%)	8 / 51 (15.69%)	5 / 49 (10.20%)	3 / 50 (6.00%)	2 / 50 (4.00%)	7 / 52 (13.46%)
occurrences all number	0	3	10	9	7	3	2	8
Diarrhoea
subjects affected / exposed	7 / 59 (11.86%)	12 / 50 (24.00%)	7 / 50 (14.00%)	8 / 51 (15.69%)	11 / 49 (22.45%)	5 / 50 (10.00%)	8 / 50 (16.00%)	9 / 52 (17.31%)
occurrences all number	24	17	8	11	36	8	10	25
Dyspepsia
subjects affected / exposed	0 / 59 (0.00%)	4 / 50 (8.00%)	4 / 50 (8.00%)	4 / 51 (7.84%)	7 / 49 (14.29%)	1 / 50 (2.00%)	3 / 50 (6.00%)	5 / 52 (9.62%)
occurrences all number	0	6	13	4	7	1	4	9
Eructation
subjects affected / exposed	0 / 59 (0.00%)	2 / 50 (4.00%)	3 / 50 (6.00%)	1 / 51 (1.96%)	1 / 49 (2.04%)	2 / 50 (4.00%)	2 / 50 (4.00%)	3 / 52 (5.77%)
occurrences all number	0	2	6	1	1	2	3	3
Flatulence
subjects affected / exposed	1 / 59 (1.69%)	2 / 50 (4.00%)	1 / 50 (2.00%)	4 / 51 (7.84%)	1 / 49 (2.04%)	0 / 50 (0.00%)	3 / 50 (6.00%)	2 / 52 (3.85%)
occurrences all number	1	2	2	4	1	0	4	2
Nausea
subjects affected / exposed	5 / 59 (8.47%)	10 / 50 (20.00%)	23 / 50 (46.00%)	14 / 51 (27.45%)	23 / 49 (46.94%)	6 / 50 (12.00%)	14 / 50 (28.00%)	25 / 52 (48.08%)
occurrences all number	5	19	46	21	33	14	20	49
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 59 (0.00%)	1 / 50 (2.00%)	2 / 50 (4.00%)	2 / 51 (3.92%)	1 / 49 (2.04%)	2 / 50 (4.00%)	3 / 50 (6.00%)	4 / 52 (7.69%)
occurrences all number	0	1	2	3	1	2	3	4
Vomiting
subjects affected / exposed	3 / 59 (5.08%)	7 / 50 (14.00%)	13 / 50 (26.00%)	6 / 51 (11.76%)	11 / 49 (22.45%)	2 / 50 (4.00%)	9 / 50 (18.00%)	12 / 52 (23.08%)
occurrences all number	5	11	21	11	16	2	14	18
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 59 (1.69%)	2 / 50 (4.00%)	2 / 50 (4.00%)	1 / 51 (1.96%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	3 / 52 (5.77%)
occurrences all number	1	2	2	1	0	0	0	3
Infections and infestations
Nasopharyngitis
subjects affected / exposed	3 / 59 (5.08%)	0 / 50 (0.00%)	1 / 50 (2.00%)	0 / 51 (0.00%)	1 / 49 (2.04%)	0 / 50 (0.00%)	2 / 50 (4.00%)	1 / 52 (1.92%)
occurrences all number	3	0	1	0	1	0	4	1
Urinary tract infection
subjects affected / exposed	1 / 59 (1.69%)	0 / 50 (0.00%)	2 / 50 (4.00%)	1 / 51 (1.96%)	1 / 49 (2.04%)	1 / 50 (2.00%)	1 / 50 (2.00%)	4 / 52 (7.69%)
occurrences all number	1	0	2	1	1	1	1	4
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	2 / 59 (3.39%)	6 / 50 (12.00%)	11 / 50 (22.00%)	9 / 51 (17.65%)	15 / 49 (30.61%)	3 / 50 (6.00%)	7 / 50 (14.00%)	6 / 52 (11.54%)
occurrences all number	3	6	12	9	15	3	7	10
Hypoglycaemia
subjects affected / exposed	2 / 59 (3.39%)	1 / 50 (2.00%)	2 / 50 (4.00%)	0 / 51 (0.00%)	3 / 49 (6.12%)	4 / 50 (8.00%)	1 / 50 (2.00%)	3 / 52 (5.77%)
occurrences all number	6	1	2	0	3	18	1	13

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Were there any global substantial amendments to the protocol? Yes

28 Sep 2020

Amendment 1 Part 1: Measures taken due to the Coronavirus disease 2019 (COVID-19) pandemic were added: Trial medication could be sent to patient’s home when physical visits were not possible due to the COVID-19 pandemic. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) tests to be done locally. A clinic visit could be performed remotely when physical visits were not possible due to the COVID-19 pandemic. All COVID-19 related deviations were to be documented and their implications were taken into consideration for the analysis of data. Criteria for discontinuation of trial treatment were revised: Sustained symptomatic hypotension or hypertension was defined. “ QT interval corrected for heart rate using the method of Fridericia (QTcF) change from baseline” changed from 30 ms to 60 ms. Baseline was clarified as at randomization. Trial treatment was to be terminated and patient discontinued if patient had symptoms of SARS-CoV-2 infection or diagnosed with COVID-19, patients could resume treatment if the results were negative.

28 Sep 2020

Amendment 1 Part 2: Instructions for trial drug administration were revised: Injection time “over at least 15 seconds” changed to “over 5 to 10 seconds”. Instructions for medication administration from vials revised: If the volume exceeds 1.0 mL, the dose may be divided into two syringes and will be injected into two different injection sites on the same side of the abdomen. The next dose should be administered on the alternate side of the abdomen. Added the following: The placebo solution for BI 456906 is filled either into a vial or a syringe, and their composition is identical. The vials are used from weeks 1 to 6, and the pre- filled syringes are used from weeks 7 to 16. Procedures for monitoring of hyperglycemic and hypoglycemic events were revised: Guidance for self-monitoring of blood glucose revised. Patient should also contact the site when FBG was below 70 mg/dL (3.9 mmol/L). Hypoglycemic events classified using standard definitions as levels 1, 2, and 3. Criteria for treatment of hyperglycemia were added: Hypoglycemic events should be treated and additional glucose monitoring should be implemented per investigator discretion and medical judgement. Investigator should make a determination if a hyperglycemic or a hypoglycemic event should be reported as an adverse events (AE).

28 Sep 2020

Amendment 1 Part 3: Clarification on restrictions: Dietary supplements that potentially induce change in body weight were not permitted. Over-the-counter and prescribed weight loss products were not permitted. Assessment of skin rashes was added at request from Health Authority. More flexibility was added to let patients use their own glucometer if it was their preference. Patients did not need to return the glucometers at the end of the study, to avoid dispensing the used glucometer to another patient due to COVID-19. Analytical method for semaglutide was revised as follows: semaglutide plasma concentrations was determined by a fit-for-purpose validated liquid chromatography-tandem mass spectrometer (LC-MS/MS) assay using extended acceptance criteria of 20% (25% at lower limit of quantification (LLOQ)).

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
A Phase II, randomized, parallel group, dose-finding study of subcutaneously administered BI 456906 for 16 weeks, compared with placebo and open-label semaglutide in patients with type 2 diabetes mellitus

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Absolute change in HbA1c from baseline to 16 weeks

Primary: Absolute change in HbA1c from baseline to 16 weeks

Secondary: Key secondary endpoint: The relative change in body weight from baseline to 16 weeks

Secondary: Key secondary endpoint: The relative change in body weight from baseline to 16 weeks

Secondary: The absolute change in body weight from baseline to 16 weeks

Secondary: The absolute change in body weight from baseline to 16 weeks

Secondary: The absolute change in waist circumference from baseline to 16 weeks

Secondary: The absolute change in waist circumference from baseline to 16 weeks

Secondary: Percentage of patients with 5 % or greater body weight loss from baseline to 16 weeks

Secondary: Percentage of patients with 5 % or greater body weight loss from baseline to 16 weeks

Secondary: Percentage of patients with 10% or greater body weight loss from baseline to 16 weeks

Secondary: Percentage of patients with 10% or greater body weight loss from baseline to 16 weeks

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Outside EU/EEA

Clinical trials

Clinical Trial Results: A Phase II, randomized, parallel group, dose-finding study of subcutaneously administered BI 456906 for 16 weeks, compared with placebo and open-label semaglutide in patients with type 2 diabetes mellitus

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Absolute change in HbA1c from baseline to 16 weeks

Primary: Absolute change in HbA1c from baseline to 16 weeks

Secondary: Key secondary endpoint: The relative change in body weight from baseline to 16 weeks

Secondary: Key secondary endpoint: The relative change in body weight from baseline to 16 weeks

Secondary: The absolute change in body weight from baseline to 16 weeks

Secondary: The absolute change in body weight from baseline to 16 weeks

Secondary: The absolute change in waist circumference from baseline to 16 weeks

Secondary: The absolute change in waist circumference from baseline to 16 weeks

Secondary: Percentage of patients with 5 % or greater body weight loss from baseline to 16 weeks

Secondary: Percentage of patients with 5 % or greater body weight loss from baseline to 16 weeks

Secondary: Percentage of patients with 10% or greater body weight loss from baseline to 16 weeks

Secondary: Percentage of patients with 10% or greater body weight loss from baseline to 16 weeks

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase II, randomized, parallel group, dose-finding study of subcutaneously administered BI 456906 for 16 weeks, compared with placebo and open-label semaglutide in patients with type 2 diabetes mellitus