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Clinical Trial Results:
A Phase II, randomized, double blind, parallel group,46 weeks dose-finding study of BI 456906 administered once weekly subcutaneously compared with placebo in patients with obesity or overweight

Summary
EudraCT number	2020-002479-37
Trial protocol	SE IE NL BE DE
Global end of trial date	07 Oct 2022

Results information
Results version number	v1(current)
This version publication date	22 Oct 2023
First version publication date	22 Oct 2023
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

1404-0036

ISRCTN number

US NCT number

NCT04667377

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

Scientific contact

Boehringer Ingelheim, Call Centre, 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

22 Nov 2022

Is this the analysis of the primary completion data?

Yes

Primary completion date

15 Sep 2022

Global end of trial reached?

Yes

Global end of trial date

07 Oct 2022

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, for further pivotal testing in Phase III studies.

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.

Background therapy

Evidence for comparator

Actual start date of recruitment

30 Mar 2021

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 44

Country: Number of subjects enrolled

Belgium: 8

Country: Number of subjects enrolled

Canada: 118

Country: Number of subjects enrolled

China: 14

Country: Number of subjects enrolled

Germany: 12

Country: Number of subjects enrolled

Netherlands: 29

Country: Number of subjects enrolled

New Zealand: 14

Country: Number of subjects enrolled

Poland: 23

Country: Number of subjects enrolled

Korea, Republic of: 25

Country: Number of subjects enrolled

Sweden: 40

Country: Number of subjects enrolled

United Kingdom: 10

Country: Number of subjects enrolled

United States: 183

Worldwide total number of subjects

520

EEA total number of subjects

112

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)

447

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

This was a randomised, double-blinded, parallel-design, placebo-controlled, multi-national, and multi-centre study with four different BI 456906 maintenance doses (ranging from 0.6 mg/week to 4.8 mg/week) in subjects with obesity or overweight (body mass index (BMI) >=27 kg/m2), and without diabetes mellitus.

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. (Trial) participants 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

Investigator, Carer, Assessor, Subject

Blinding implementation details

Subjects, investigators, central reviewers, and everyone involved in trial conduct or analysis, or with any other interest in this trial, remained blinded about the randomised treatment assignments until after the database lock. The data monitoring committee (DMC) was provided with unblinded data to allow them to fulfil their tasks as outlined in the DMC charter. An independent team, not otherwise involved in the conduct of the trial, provided the unblinded results to the DMC.

Are arms mutually exclusive

Yes

0.6 mg BI 456906 - planned maintenance treatment

Arm description

Subjects with obesity or overweight were administered a solution for injection of BI 456906, by a weekly subcutaneous injection of two syringes (0.5 mL filling volume per syringe) on the same injection day, of 0.3 mg on Week 1 and 2, and 0.6 mg on Week 3 to Week 20 (dose escalation phase, with fixed dose escalation from Week 1 to Week 10 and flexible dose escalation from Week 11 to Week 20). From Week 21 to Week 46 (maintenance dosing phase) subjects stayed on the dose of 0.6 mg BI 456906. Subject not tolerating the assigned dose escalation schedule due to gastrointestinal adverse events (AEs) had the option of dose adjustment during the flexible part of the dose escalation phase (Week 11 - 20) which could lead to a maintenance dose lower than the dose the subjects was randomised to.

Arm type

Experimental

Investigational medicinal product name

BI 456906

Investigational medicinal product code

Other name

Survodutide

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects with obesity or overweight were administered a solution for injection of BI 456906, by a weekly subcutaneous injection of two syringes (0.5 mL filling volume per syringe) on the same injection day, of 0.3 mg on Week 1 and 2, and 0.6 mg on Week 3 to Week 20 (dose escalation phase, with fixed dose escalation from Week 1 to Week 10 and flexible dose escalation from Week 11 to Week 20). From Week 21 to Week 46 (maintenance dosing phase) subjects stayed on the dose of 0.6 mg BI 456906. Subjects not tolerating the assigned dose escalation schedule due to gastrointestinal adverse events had the option of dose adjustment during the flexible part of the dose escalation phase (Week 11 - 20) which could lead to a maintenance dose lower than the dose the subject was randomised to.

2.4 mg BI 456906 - planned maintenance treatment

Arm description

Subjects with obesity or overweight were administered a solution for injection of BI 456906, by a weekly subcutaneous injection of two syringes (0.5 mL filling volume per syringe) on the same injection day, of 0.3 mg on Week 1 and Week 2, 0.6 mg on Week 3 and Week 4, 0.9 mg on Week 5 and Week 6, 1.2 mg on Week 7 to Week 10, 1.8 mg on Week 11 to Week 14 and 2.4 mg on Week 15 to Week 20 (dose escalation phase, with fixed dose escalation from Week 1 to Week 10 and flexible dose escalation from Week 11 to Week 20). From Week 21 to Week 46 (maintenance dosing phase) subjects stayed on the dose of 2.4 mg BI 456906. Subject not tolerating the assigned dose escalation schedule due to gastrointestinal adverse events had the option of dose adjustment during the flexible part of the dose escalation phase (Week 11 - 20) which could lead to a maintenance dose lower than the dose the subject was randomised to.

Arm type

Experimental

Investigational medicinal product name

BI 456906

Investigational medicinal product code

Other name

Survodutide

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subject with obesity or overweight were administered a solution for injection of BI 456906, by a weekly subcutaneous injection of two syringes (0.5 mL filling volume per syringe) on the same injection day, of 0.3 mg on Week 1 and Week 2, 0.6 mg on Week 3 and Week 4, 0.9 mg on Week 5 and Week 6, 1.2 mg on Week 7 to Week 10, 1.8 mg on Week 11 to Week 14 and 2.4 mg on Week 15 to Week 20 (dose escalation phase, with fixed dose escalation from Week 1 to Week 10 and flexible dose escalation from Week 11 to Week 20). From Week 21 to Week 46 (maintenance dosing phase) subjects stayed on the dose of 2.4 mg BI 456906. Subjects not tolerating the assigned dose escalation schedule due to gastrointestinal adverse events had the option of dose adjustment during the flexible part of the dose escalation phase (Week 11 - 20) which could lead to a maintenance dose lower than the dose the subject was randomised to.

3.6 mg BI 456906 - planned maintenance treatment

Arm description

Subjects with obesity or overweight were administered a solution for injection of BI 456906, by a weekly subcutaneous injection of two syringes (0.5 mL filling volume per syringe) on the same injection day, of 0.3 mg on Week 1 and Week 2, 0.6 mg on Week 3 and Week 4, 0.9 mg on Week 5 and Week 6, 1.2 mg on Week 7 to Week 10, 1.8 mg on Week 11 and Week 12, 2.4 mg on Week 13 and Week 14, 3.0 mg on Week 15 and Week 16, and 3.6 mg on Week 17 to Week 20 (dose escalation phase, with fixed dose escalation from Week 1 to Week 10 and flexible dose escalation from Week 11 to Week 20). From Week 21 to Week 46 (maintenance dosing phase) subjects stayed on the dose of 3.6 mg BI 456906. Subject not tolerating the assigned dose escalation schedule due to gastrointestinal adverse events had the option of dose adjustment during the flexible part of the dose escalation phase (Week 11 - 20) which could lead to a maintenance dose lower than the dose the subject was randomised to.

Arm type

Experimental

Investigational medicinal product name

BI 456906

Investigational medicinal product code

Other name

Survodutide

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects with obesity or overweight were administered a solution for injection of BI 456906, by a weekly subcutaneous injection of two syringes (0.5 mL filling volume per syringe) on the same injection day, of 0.3 mg on Week 1 and Week 2, 0.6 mg on Week 3 and Week 4, 0.9 mg on Week 5 and Week 6, 1.2 mg on Week 7 to Week 10, 1.8 mg on Week 11 and Week 12, 2.4 mg on Week 13 and Week 14, 3.0 mg on Week 15 and Week 16, and 3.6 mg on Week 17 to Week 20 (dose escalation phase, with fixed dose escalation from Week 1 to Week 10 and flexible dose escalation from Week 11 to Week 20). From Week 21 to Week 46 (maintenance dosing phase) subjects stayed on the dose of 3.6 mg BI 456906. Subject not tolerating the assigned dose escalation schedule due to gastrointestinal adverse events had the option of dose adjustment during the flexible part of the dose escalation phase (Week 11 - 20) which could lead to a maintenance dose lower than the dose the subject was randomised to.

4.8 mg BI 456906 - planned maintenance treatment

Arm description

Subjects with obesity or overweight were administered a solution for injection of BI 456906, by a weekly subcutaneous injection of two syringes (0.5 mL filling volume per syringe) on the same injection day, of 0.3 mg on Week 1 and Week 2, 0.6 mg on Week 3 and Week 4, 0.9 mg on Week 5 and Week 6, 1.2 mg on Week 7 and Week 8, 1.8 mg on Week 9 and Week 10, 2.4 mg on Week 11 and Week 12, 3.3 mg on Week 13 and Week 14, 4.2 mg on Week 15 and Week 16, and 4.8 mg on Week 17 to Week 20 (dose escalation phase, with fixed dose escalation from Week 1 to Week 10 and flexible dose escalation from Week 11 to Week 20). From Week 21 to Week 46 (maintenance dosing phase) subjects stayed on the dose of 4.8 mg BI 456906. Subject not tolerating the assigned dose escalation schedule due to gastrointestinal AEs had the option of dose adjustment during the flexible part of the dose escalation phase (Week 11 - 20) which could lead to a maintenance dose lower than the dose the subject was randomised to.

Arm type

Experimental

Investigational medicinal product name

BI 456906

Investigational medicinal product code

Other name

Survodutide

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects with obesity or overweight were administered a solution for injection of BI 456906, by a weekly subcutaneous injection of two syringes (0.5 mL filling volume per syringe) on the same injection day, of 0.3 mg on Week 1 and Week 2, 0.6 mg on Week 3 and Week 4, 0.9 mg on Week 5 and Week 6, 1.2 mg on Week 7 and Week 8, 1.8 mg on Week 9 and Week 10, 2.4 mg on Week 11 and Week 12, 3.3 mg on Week 13 and Week 14, 4.2 mg on Week 15 and Week 16, and 4.8 mg on Week 17 to Week 20 (dose escalation phase, with fixed dose escalation from Week 1 to Week 10 and flexible dose escalation from Week 11 to Week 20). From Week 21 to Week 46 (maintenance dosing phase) subjects stayed on the dose of 4.8 mg BI 456906. Subject not tolerating the assigned dose escalation schedule due to gastrointestinal AEs had the option of dose adjustment during the flexible part of the dose escalation phase (Week 11 - 20) which could lead to a maintenance dose lower than the dose the subject was randomised to.

Placebo

Arm description

Subjects with obesity or overweight were administered a solution for injection of Placebo, by a weekly subcutaneous injection of two syringes on the same injection day, for 46 weeks.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects with obesity or overweight were administered a solution for injection of Placebo, by a weekly subcutaneous injection of two syringes on the same injection day, for 46 weeks.

Number of subjects in period 1	0.6 mg BI 456906 - planned maintenance treatment	2.4 mg BI 456906 - planned maintenance treatment	3.6 mg BI 456906 - planned maintenance treatment	4.8 mg BI 456906 - planned maintenance treatment	Placebo
Started	78	78	77	77	77
Treated during dose escalation period	77	78	77	77	77
Completed	77	78	76	76	77
Not completed	1	0	1	1	0
No post-baseline efficacy data	-	-	1	1	-
Not treated	1	-	-	-	-

Period 2 title

Full analysis set (FAS)

Is this the baseline period?

Yes ^[1]

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer, Assessor

Blinding implementation details

Are arms mutually exclusive

Yes

0.6 mg BI 456906 - planned maintenance treatment

Arm description

Subjects with obesity or overweight were administered a solution for injection of BI 456906, by a weekly subcutaneous injection of two syringes (0.5 mL filling volume per syringe) on the same injection day, of 0.3 mg on Week 1 and 2, and 0.6 mg on Week 3 to Week 20 (dose escalation phase, with fixed dose escalation from Week 1 to Week 10 and flexible dose escalation from Week 11 to Week 20). From Week 21 to Week 46 (maintenance dosing phase) subjects stayed on the dose of 0.6 mg BI 456906. Subjects not tolerating the assigned dose escalation schedule due to gastrointestinal adverse events had the option of dose adjustment during the flexible part of the dose escalation phase (Week 11 - 20) which could lead to a maintenance dose lower than the dose the subject was randomised to.

Arm type

Experimental

Investigational medicinal product name

BI 456906

Investigational medicinal product code

Other name

Survodutide

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects with obesity or overweight were administered a solution for injection of BI 456906, by a weekly subcutaneous injection of two syringes (0.5 mL filling volume per syringe) on the same injection day, of 0.3 mg on Week 1 and 2, and 0.6 mg on Week 3 to Week 20 (dose escalation phase, with fixed dose escalation from Week 1 to Week 10 and flexible dose escalation from Week 11 to Week 20). From Week 21 to Week 46 (maintenance dosing phase) subjects stayed on the dose of 0.6 mg BI 456906. Subjects not tolerating the assigned dose escalation schedule due to gastrointestinal adverse events had the option of dose adjustment during the flexible part of the dose escalation phase (Week 11 - 20) which could lead to a maintenance dose lower than the dose the subject was randomised to.

2.4 mg BI 456906 - planned maintenance treatment

Arm description

Arm type

Experimental

Investigational medicinal product name

BI 456906

Investigational medicinal product code

Other name

Survodutide

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

3.6 mg BI 456906 - planned maintenance treatment

Arm description

Subjects with obesity or overweight were administered a solution for injection of BI 456906, by a weekly subcutaneous injection of two syringes (0.5 mL filling volume per syringe) on the same injection day, of 0.3 mg on Week 1 and Week 2, 0.6 mg on Week 3 and Week 4, 0.9 mg on Week 5 and Week 6, 1.2 mg on Week 7 to Week 10, 1.8 mg on Week 11 and Week 12, 2.4 mg on Week 13 and Week 14, 3.0 mg on Week 15 and Week 16, and 3.6 mg on Week 17 to Week 20 (dose escalation phase, with fixed dose escalation from Week 1 to Week 10 and flexible dose escalation from Week 11 to Week 20). From Week 21 to Week 46 (maintenance dosing phase) subjects stayed on the dose of 3.6 mg BI 456906. Subject not tolerating the assigned dose escalation schedule due to gastrointestinal adverse events had the option of dose adjustment during the flexible part of the dose escalation phase (Week 11 - 20) which could lead to a maintenance dose lower than the dose the subject was randomised to.

Arm type

Experimental

Investigational medicinal product name

BI 456906

Investigational medicinal product code

Other name

Survodutide

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects with obesity or overweight were administered a solution for injection of BI 456906, by a weekly subcutaneous injection of two syringes (0.5 mL filling volume per syringe) on the same injection day, of 0.3 mg on Week 1 and Week 2, 0.6 mg on Week 3 and Week 4, 0.9 mg on Week 5 and Week 6, 1.2 mg on Week 7 to Week 10, 1.8 mg on Week 11 and Week 12, 2.4 mg on Week 13 and Week 14, 3.0 mg on Week 15 and Week 16, and 3.6 mg on Week 17 to Week 20 (dose escalation phase, with fixed dose escalation from Week 1 to Week 10 and flexible dose escalation from Week 11 to Week 20). From Week 21 to Week 46 (maintenance dosing phase) subjects stayed on the dose of 3.6 mg BI 456906. Subject not tolerating the assigned dose escalation schedule due to gastrointestinal adverse events had the option of dose adjustment during the flexible part of the dose escalation phase (Week 11 - 20) which could lead to a maintenance dose lower than the dose the subject was randomised to.

4.8 mg BI 456906 - planned maintenance treatment

Arm description

Subjects with obesity or overweight were administered a solution for injection of BI 456906, by a weekly subcutaneous injection of two syringes (0.5 mL filling volume per syringe) on the same injection day, of 0.3 mg on Week 1 and Week 2, 0.6 mg on Week 3 and Week 4, 0.9 mg on Week 5 and Week 6, 1.2 mg on Week 7 and Week 8, 1.8 mg on Week 9 and Week 10, 2.4 mg on Week 11 and Week 12, 3.3 mg on Week 13 and Week 14, 4.2 mg on Week 15 and Week 16, and 4.8 mg on Week 17 to Week 20 (dose escalation phase, with fixed dose escalation from Week 1 to Week 10 and flexible dose escalation from Week 11 to Week 20). From Week 21 to Week 46 (maintenance dosing phase) subjects stayed on the dose of 4.8 mg BI 456906. Subject not tolerating the assigned dose escalation schedule due to gastrointestinal AEs had the option of dose adjustment during the flexible part of the dose escalation phase (Week 11 - 20) which could lead to a maintenance dose lower than the dose the subject was randomised to.

Arm type

Experimental

Investigational medicinal product name

BI 456906

Investigational medicinal product code

Other name

Survodutide

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects with obesity or overweight were administered a solution for injection of BI 456906, by a weekly subcutaneous injection of two syringes (0.5 mL filling volume per syringe) on the same injection day, of 0.3 mg on Week 1 and Week 2, 0.6 mg on Week 3 and Week 4, 0.9 mg on Week 5 and Week 6, 1.2 mg on Week 7 and Week 8, 1.8 mg on Week 9 and Week 10, 2.4 mg on Week 11 and Week 12, 3.3 mg on Week 13 and Week 14, 4.2 mg on Week 15 and Week 16, and 4.8 mg on Week 17 to Week 20 (dose escalation phase, with fixed dose escalation from Week 1 to Week 10 and flexible dose escalation from Week 11 to Week 20). From Week 21 to Week 46 (maintenance dosing phase) subjects stayed on the dose of 4.8 mg BI 456906. Subject not tolerating the assigned dose escalation schedule due to gastrointestinal AEs had the option of dose adjustment during the flexible part of the dose escalation phase (Week 11 - 20) which could lead to a maintenance dose lower than the dose the subject was randomised to.

Placebo

Arm description

Subjects with obesity or overweight were administered a solution for injection of Placebo, by a weekly subcutaneous injection of two syringes on the same injection day, for 46 weeks.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects with obesity or overweight were administered a solution for injection of Placebo, by a weekly subcutaneous injection of two syringes on the same injection day, for 46 weeks.

Notes
[1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
Justification: Period with number of subjects included in the full analysis set (FAS) is used as baseline period.

Number of subjects in period 2 ^[2]	0.6 mg BI 456906 - planned maintenance treatment	2.4 mg BI 456906 - planned maintenance treatment	3.6 mg BI 456906 - planned maintenance treatment	4.8 mg BI 456906 - planned maintenance treatment	Placebo
Started	77	78	76	76	77
Treated during maintenance period	55	60	59	55	57
Completed	47	45	48	47	46
Not completed	30	33	28	29	31
Adverse event, non-fatal	15	20	19	22	4
Lost to Follow-up	1	1	1	-	1
Perceived lack of efficacy	-	2	1	-	7
COVID-related	-	-	1	1	-
Burden of study procedures	3	3	1	1	5
Other not specified below	5	3	5	3	9
Change of residence	-	1	-	-	1
Missing	1	-	-	-	-
Protocol deviation	3	2	-	2	2
Withdrawal by subject	2	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: Worldwide 520 were enrolled, whereof 387 were actually randomised in the trial and 384 were included in the baseline period (FAS).

Baseline characteristics

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Reporting group title

0.6 mg BI 456906 - planned maintenance treatment

Reporting group description

Subjects with obesity or overweight were administered a solution for injection of BI 456906, by a weekly subcutaneous injection of two syringes (0.5 mL filling volume per syringe) on the same injection day, of 0.3 mg on Week 1 and 2, and 0.6 mg on Week 3 to Week 20 (dose escalation phase, with fixed dose escalation from Week 1 to Week 10 and flexible dose escalation from Week 11 to Week 20). From Week 21 to Week 46 (maintenance dosing phase) subjects stayed on the dose of 0.6 mg BI 456906. Subjects not tolerating the assigned dose escalation schedule due to gastrointestinal adverse events had the option of dose adjustment during the flexible part of the dose escalation phase (Week 11 - 20) which could lead to a maintenance dose lower than the dose the subject was randomised to.

Reporting group title

2.4 mg BI 456906 - planned maintenance treatment

Reporting group description

Reporting group title

3.6 mg BI 456906 - planned maintenance treatment

Reporting group description

Subjects with obesity or overweight were administered a solution for injection of BI 456906, by a weekly subcutaneous injection of two syringes (0.5 mL filling volume per syringe) on the same injection day, of 0.3 mg on Week 1 and Week 2, 0.6 mg on Week 3 and Week 4, 0.9 mg on Week 5 and Week 6, 1.2 mg on Week 7 to Week 10, 1.8 mg on Week 11 and Week 12, 2.4 mg on Week 13 and Week 14, 3.0 mg on Week 15 and Week 16, and 3.6 mg on Week 17 to Week 20 (dose escalation phase, with fixed dose escalation from Week 1 to Week 10 and flexible dose escalation from Week 11 to Week 20). From Week 21 to Week 46 (maintenance dosing phase) subjects stayed on the dose of 3.6 mg BI 456906. Subject not tolerating the assigned dose escalation schedule due to gastrointestinal adverse events had the option of dose adjustment during the flexible part of the dose escalation phase (Week 11 - 20) which could lead to a maintenance dose lower than the dose the subject was randomised to.

Reporting group title

4.8 mg BI 456906 - planned maintenance treatment

Reporting group description

Subjects with obesity or overweight were administered a solution for injection of BI 456906, by a weekly subcutaneous injection of two syringes (0.5 mL filling volume per syringe) on the same injection day, of 0.3 mg on Week 1 and Week 2, 0.6 mg on Week 3 and Week 4, 0.9 mg on Week 5 and Week 6, 1.2 mg on Week 7 and Week 8, 1.8 mg on Week 9 and Week 10, 2.4 mg on Week 11 and Week 12, 3.3 mg on Week 13 and Week 14, 4.2 mg on Week 15 and Week 16, and 4.8 mg on Week 17 to Week 20 (dose escalation phase, with fixed dose escalation from Week 1 to Week 10 and flexible dose escalation from Week 11 to Week 20). From Week 21 to Week 46 (maintenance dosing phase) subjects stayed on the dose of 4.8 mg BI 456906. Subject not tolerating the assigned dose escalation schedule due to gastrointestinal AEs had the option of dose adjustment during the flexible part of the dose escalation phase (Week 11 - 20) which could lead to a maintenance dose lower than the dose the subject was randomised to.

Reporting group title

Placebo

Reporting group description

Subjects with obesity or overweight were administered a solution for injection of Placebo, by a weekly subcutaneous injection of two syringes on the same injection day, for 46 weeks.

Reporting group values	0.6 mg BI 456906 - planned maintenance treatment	2.4 mg BI 456906 - planned maintenance treatment	3.6 mg BI 456906 - planned maintenance treatment	4.8 mg BI 456906 - planned maintenance treatment	Placebo	Total
Number of subjects	77	78	76	76	77	384
Age categorical
Full analysis set (FAS): All randomised patients who received at least one dose of trial medication and who had analysable data for at least one efficacy endpoint.
Units: Subjects
Adults (18-64 years)	67	68	68	66	66	335
Elderly (From 65-84 years)	10	10	8	10	11	49
Age Continuous
Full analysis set (FAS): All randomised patients who received at least one dose of trial medication and who had analysable data for at least one efficacy endpoint.
Units: years
arithmetic mean (standard deviation)	48.6 ± 12.6	49.0 ± 13.1	50.3 ± 11.8	47.6 ± 13.5	50.0 ± 13.5	-
Sex: Female, Male
Full analysis set (FAS): All randomised patients who received at least one dose of trial medication and who had analysable data for at least one efficacy endpoint.
Units: Participants
Female	51	54	51	53	53	262
Male	26	24	25	23	24	122
Race (NIH/OMB)
Full analysis set (FAS): All randomised patients who received at least one dose of trial medication and who had analysable data for at least one efficacy endpoint.
Units: Subjects
American Indian or Alaska Native	0	0	0	1	0	1
Asian	8	9	9	7	7	40
Native Hawaiian or Other Pacific Islander	0	0	0	1	1	2
Black or African American	10	8	3	8	8	37
White	59	60	63	59	60	301
More than one race	0	1	1	0	1	3
Unknown or Not Reported	0	0	0	0	0	0
Ethnicity (NIH/OMB)
Full analysis set (FAS): All randomised patients who received at least one dose of trial medication and who had analysable data for at least one efficacy endpoint.
Units: Subjects
Hispanic or Latino	3	1	2	6	5	17
Not Hispanic or Latino	74	77	74	70	72	367
Unknown or Not Reported	0	0	0	0	0	0
Body weight at baseline
Full analysis set (FAS): All randomised patients who received at least one dose of trial medication and who had analysable data for at least one efficacy endpoint.
Units: Kilogram (kg)
arithmetic mean (standard deviation)	106.98 ± 18.71	106.57 ± 22.97	104.68 ± 19.63	105.86 ± 17.39	104.32 ± 22.95	-

End points

Top of page

Reporting group title

0.6 mg BI 456906 - planned maintenance treatment

Reporting group description

Reporting group title

2.4 mg BI 456906 - planned maintenance treatment

Reporting group description

Subjects with obesity or overweight were administered a solution for injection of BI 456906, by a weekly subcutaneous injection of two syringes (0.5 mL filling volume per syringe) on the same injection day, of 0.3 mg on Week 1 and Week 2, 0.6 mg on Week 3 and Week 4, 0.9 mg on Week 5 and Week 6, 1.2 mg on Week 7 to Week 10, 1.8 mg on Week 11 to Week 14 and 2.4 mg on Week 15 to Week 20 (dose escalation phase, with fixed dose escalation from Week 1 to Week 10 and flexible dose escalation from Week 11 to Week 20). From Week 21 to Week 46 (maintenance dosing phase) subjects stayed on the dose of 2.4 mg BI 456906. Subject not tolerating the assigned dose escalation schedule due to gastrointestinal adverse events had the option of dose adjustment during the flexible part of the dose escalation phase (Week 11 - 20) which could lead to a maintenance dose lower than the dose the subject was randomised to.

Reporting group title

3.6 mg BI 456906 - planned maintenance treatment

Reporting group description

Subjects with obesity or overweight were administered a solution for injection of BI 456906, by a weekly subcutaneous injection of two syringes (0.5 mL filling volume per syringe) on the same injection day, of 0.3 mg on Week 1 and Week 2, 0.6 mg on Week 3 and Week 4, 0.9 mg on Week 5 and Week 6, 1.2 mg on Week 7 to Week 10, 1.8 mg on Week 11 and Week 12, 2.4 mg on Week 13 and Week 14, 3.0 mg on Week 15 and Week 16, and 3.6 mg on Week 17 to Week 20 (dose escalation phase, with fixed dose escalation from Week 1 to Week 10 and flexible dose escalation from Week 11 to Week 20). From Week 21 to Week 46 (maintenance dosing phase) subjects stayed on the dose of 3.6 mg BI 456906. Subject not tolerating the assigned dose escalation schedule due to gastrointestinal adverse events had the option of dose adjustment during the flexible part of the dose escalation phase (Week 11 - 20) which could lead to a maintenance dose lower than the dose the subject was randomised to.

Reporting group title

4.8 mg BI 456906 - planned maintenance treatment

Reporting group description

Subjects with obesity or overweight were administered a solution for injection of BI 456906, by a weekly subcutaneous injection of two syringes (0.5 mL filling volume per syringe) on the same injection day, of 0.3 mg on Week 1 and Week 2, 0.6 mg on Week 3 and Week 4, 0.9 mg on Week 5 and Week 6, 1.2 mg on Week 7 and Week 8, 1.8 mg on Week 9 and Week 10, 2.4 mg on Week 11 and Week 12, 3.3 mg on Week 13 and Week 14, 4.2 mg on Week 15 and Week 16, and 4.8 mg on Week 17 to Week 20 (dose escalation phase, with fixed dose escalation from Week 1 to Week 10 and flexible dose escalation from Week 11 to Week 20). From Week 21 to Week 46 (maintenance dosing phase) subjects stayed on the dose of 4.8 mg BI 456906. Subject not tolerating the assigned dose escalation schedule due to gastrointestinal AEs had the option of dose adjustment during the flexible part of the dose escalation phase (Week 11 - 20) which could lead to a maintenance dose lower than the dose the subject was randomised to.

Reporting group title

Placebo

Reporting group description

Subjects with obesity or overweight were administered a solution for injection of Placebo, by a weekly subcutaneous injection of two syringes on the same injection day, for 46 weeks.

Reporting group title

0.6 mg BI 456906 - planned maintenance treatment

Reporting group description

Subjects with obesity or overweight were administered a solution for injection of BI 456906, by a weekly subcutaneous injection of two syringes (0.5 mL filling volume per syringe) on the same injection day, of 0.3 mg on Week 1 and 2, and 0.6 mg on Week 3 to Week 20 (dose escalation phase, with fixed dose escalation from Week 1 to Week 10 and flexible dose escalation from Week 11 to Week 20). From Week 21 to Week 46 (maintenance dosing phase) subjects stayed on the dose of 0.6 mg BI 456906. Subjects not tolerating the assigned dose escalation schedule due to gastrointestinal adverse events had the option of dose adjustment during the flexible part of the dose escalation phase (Week 11 - 20) which could lead to a maintenance dose lower than the dose the subject was randomised to.

Reporting group title

2.4 mg BI 456906 - planned maintenance treatment

Reporting group description

Reporting group title

3.6 mg BI 456906 - planned maintenance treatment

Reporting group description

Subjects with obesity or overweight were administered a solution for injection of BI 456906, by a weekly subcutaneous injection of two syringes (0.5 mL filling volume per syringe) on the same injection day, of 0.3 mg on Week 1 and Week 2, 0.6 mg on Week 3 and Week 4, 0.9 mg on Week 5 and Week 6, 1.2 mg on Week 7 to Week 10, 1.8 mg on Week 11 and Week 12, 2.4 mg on Week 13 and Week 14, 3.0 mg on Week 15 and Week 16, and 3.6 mg on Week 17 to Week 20 (dose escalation phase, with fixed dose escalation from Week 1 to Week 10 and flexible dose escalation from Week 11 to Week 20). From Week 21 to Week 46 (maintenance dosing phase) subjects stayed on the dose of 3.6 mg BI 456906. Subject not tolerating the assigned dose escalation schedule due to gastrointestinal adverse events had the option of dose adjustment during the flexible part of the dose escalation phase (Week 11 - 20) which could lead to a maintenance dose lower than the dose the subject was randomised to.

Reporting group title

4.8 mg BI 456906 - planned maintenance treatment

Reporting group description

Subjects with obesity or overweight were administered a solution for injection of BI 456906, by a weekly subcutaneous injection of two syringes (0.5 mL filling volume per syringe) on the same injection day, of 0.3 mg on Week 1 and Week 2, 0.6 mg on Week 3 and Week 4, 0.9 mg on Week 5 and Week 6, 1.2 mg on Week 7 and Week 8, 1.8 mg on Week 9 and Week 10, 2.4 mg on Week 11 and Week 12, 3.3 mg on Week 13 and Week 14, 4.2 mg on Week 15 and Week 16, and 4.8 mg on Week 17 to Week 20 (dose escalation phase, with fixed dose escalation from Week 1 to Week 10 and flexible dose escalation from Week 11 to Week 20). From Week 21 to Week 46 (maintenance dosing phase) subjects stayed on the dose of 4.8 mg BI 456906. Subject not tolerating the assigned dose escalation schedule due to gastrointestinal AEs had the option of dose adjustment during the flexible part of the dose escalation phase (Week 11 - 20) which could lead to a maintenance dose lower than the dose the subject was randomised to.

Reporting group title

Placebo

Reporting group description

Subjects with obesity or overweight were administered a solution for injection of Placebo, by a weekly subcutaneous injection of two syringes on the same injection day, for 46 weeks.

Primary: Percentage change in body weight from baseline to Week 46

Top of page

End point title

Percentage change in body weight from baseline to Week 46

End point description

Percentage change in body weight from baseline to Week 46 was modeled using a mixed model for repeated measures (MMRM) with fixed effects for baseline body weight as a continuous linear covariate, and treatment, gender, visit, treatment by visit interaction and baseline by visit interaction as factors, using visit as repeated measures, an unstructured covariance matrix to model within subject measurements, adjusted mean (standard error) at Week 46 is reported. For analysis, all available post-baseline body weight measurements (on- and off-treatment) were used, except those for subjects who discontinued treatment early due to COVID-19. For these subjects only on-treatment values were used. That is, a hypothetical strategy was used for intercurrent event (ICE) "COVID-19 pandemic-related early treatment discontinuation", a treatment policy strategy for ICE "non-pandemic-related early treatment discontinuation". FAS, using planned maintenance treatment.

End point type

Primary

End point timeframe

Baseline, Week 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 28, 32, 36, 40, and 46.

End point values	0.6 mg BI 456906 - planned maintenance treatment	2.4 mg BI 456906 - planned maintenance treatment	3.6 mg BI 456906 - planned maintenance treatment	4.8 mg BI 456906 - planned maintenance treatment	Placebo
Number of subjects analysed	76	78	76	76	77
Units: Percentage change
least squares mean (standard error)	-6.19 ± 1.07	-12.51 ± 1.01	-13.22 ± 1.04	-14.94 ± 1.01	-2.82 ± 1.06

MCP-mod - Exponential model fit

Statistical analysis description

A flat vs. non-flat dose-response relationship across the 4 doses of BI 456906 and placebo was tested using the Multiple Comparison Procedure - Modelling (MCP-Mod) approach which evaluated simultaneously 5 different potential dose-response patterns (Linear, Exponential, Emax1, Emax2, Sigmoid Emax) while protecting the overall probability of type I error (one-sided alpha of 2.5%).

Comparison groups

0.6 mg BI 456906 - planned maintenance treatment v 2.4 mg BI 456906 - planned maintenance treatment v 3.6 mg BI 456906 - planned maintenance treatment v 4.8 mg BI 456906 - planned maintenance treatment v Placebo

Number of subjects included in analysis

383

Analysis specification

Pre-specified

Analysis type

other ^[1]

P-value

< 0.0001 ^[2]

Method

MCP-Mod - Exponential model fit

Confidence interval

Notes
[1] - Covariate adjusted fixed effect estimates of mean percentage change in body weight at Week 46 for each treatment group with associated covariance matrix were extracted from the MMRM (including fixed effects for baseline body weight as a continuous linear covariate, and treatment, gender, visit, treatment by visit interaction and baseline by visit interaction as factors) and used as input for the MCP-Mod. Model Assumption: 50% of maximum effect achieved at dose 3.6 mg.
[2] - P-value is adjusted for multiplicity.

MCP-mod - Linear model fit

Statistical analysis description

Comparison groups

Number of subjects included in analysis

383

Analysis specification

Pre-specified

Analysis type

other ^[3]

P-value

< 0.0001 ^[4]

Method

MCP-Mod - Linear model fit

Confidence interval

Notes
[3] - Covariate adjusted fixed effect estimates of mean percentage change in body weight at Week 46 for each treatment group with associated covariance matrix were extracted from the MMRM (including fixed effects for baseline body weight as a continuous linear covariate, and treatment, gender, visit, treatment by visit interaction and baseline by visit interaction as factors) and used as input for the MCP-Mod.
[4] - P-value is adjusted for multiplicity.

MMRM - 4.8 mg BI vs Placebo

Statistical analysis description

No formal hypotheses were tested. MMRM with fixed effects for baseline body weight as a continuous linear covariate, and treatment, gender, visit, treatment by visit interaction and baseline by visit interaction as factors, using visit as repeated measures and an unstructured covariance matrix to model within subject measurements.

Comparison groups

4.8 mg BI 456906 - planned maintenance treatment v Placebo

Number of subjects included in analysis

153

Analysis specification

Pre-specified

Analysis type

other ^[5]

P-value

< 0.0001 ^[6]

Method

Mixed models analysis

Parameter type

Difference of adjusted means

Point estimate

-12.12

Confidence interval

level

95%

sides

2-sided

lower limit

-15

upper limit

-9.24

Variability estimate

Standard error of the mean

Dispersion value

1.46

Notes
[5] - Kenward-Roger approximation was used to estimate the denominator degrees of freedom. Difference was calculated as BI 456906 - placebo.
[6] - P-value is considered nominal.

MMRM - 0.6 mg BI vs Placebo

Statistical analysis description

Comparison groups

0.6 mg BI 456906 - planned maintenance treatment v Placebo

Number of subjects included in analysis

153

Analysis specification

Pre-specified

Analysis type

other ^[7]

P-value

= 0.0257 ^[8]

Method

Mixed models analysis

Parameter type

Difference of adjusted means

Point estimate

-3.37

Confidence interval

level

95%

sides

2-sided

lower limit

-6.33

upper limit

-0.41

Variability estimate

Standard error of the mean

Dispersion value

1.5

Notes
[7] - Kenward-Roger approximation was used to estimate the denominator degrees of freedom. Difference was calculated as BI 456906 - placebo.
[8] - P-value is considered nominal.

MMRM - 2.4 mg BI vs Placebo

Statistical analysis description

Comparison groups

2.4 mg BI 456906 - planned maintenance treatment v Placebo

Number of subjects included in analysis

155

Analysis specification

Pre-specified

Analysis type

other ^[9]

P-value

< 0.0001 ^[10]

Method

Mixed models analysis

Parameter type

Difference of adjusted means

Point estimate

-9.69

Confidence interval

level

95%

sides

2-sided

lower limit

-12.57

upper limit

-6.81

Variability estimate

Standard error of the mean

Dispersion value

1.46

Notes
[9] - Kenward-Roger approximation was used to estimate the denominator degrees of freedom. Difference was calculated as BI 456906 - placebo.
[10] - P-value is considered nominal.

MMRM - 3.6 mg BI vs Placebo

Statistical analysis description

Comparison groups

3.6 mg BI 456906 - planned maintenance treatment v Placebo

Number of subjects included in analysis

153

Analysis specification

Pre-specified

Analysis type

other ^[11]

P-value

< 0.0001 ^[12]

Method

Mixed models analysis

Parameter type

Difference of adjusted means

Point estimate

-10.4

Confidence interval

level

95%

sides

2-sided

lower limit

-13.32

upper limit

-7.49

Variability estimate

Standard error of the mean

Dispersion value

1.48

Notes
[11] - Kenward-Roger approximation was used to estimate the denominator degrees of freedom. Difference was calculated as BI 456906 - placebo.
[12] - P-value is considered nominal.

MCP-mod - Emax2 model fit

Statistical analysis description

Comparison groups

Number of subjects included in analysis

383

Analysis specification

Pre-specified

Analysis type

other ^[13]

P-value

< 0.0001 ^[14]

Method

MCP-Mod - Emax2 model fit

Confidence interval

Notes
[13] - Covariate adjusted fixed effect estimates of mean percentage change in body weight at Week 46 for each treatment group with associated covariance matrix were extracted from the MMRM (including fixed effects for baseline body weight as a continuous linear covariate, and treatment, gender, visit, treatment by visit interaction and baseline by visit interaction as factors) and used as input for the MCP-Mod. Model Assumption: 70% of maximum effect achieved at dose 4.8 mg.
[14] - P-value is adjusted for multiplicity.

MCP-mod - Emax1 model fit

Statistical analysis description

Comparison groups

Number of subjects included in analysis

383

Analysis specification

Pre-specified

Analysis type

other ^[15]

P-value

< 0.0001 ^[16]

Method

MCP-Mod - Emax1 model fit

Confidence interval

Notes
[15] - Covariate adjusted fixed effect estimates of mean percentage change in body weight at Week 46 for each treatment group with associated covariance matrix were extracted from the MMRM (including fixed effects for baseline body weight as a continuous linear covariate, and treatment, gender, visit, treatment by visit interaction and baseline by visit interaction as factors) and used as input for the MCP-Mod. Model Assumption: 90% of maximum effect achieved at dose 4.8 mg.
[16] - P-value is adjusted for multiplicity.

MCP-mod - Sigmoid Emax model fit

Statistical analysis description

Multiple comparison procedure and Modeling (MCP-Mod) dose finding analysis to simultaneously evaluate different potential dose response patterns (Linear, Exponential, Emax1, Emax2, Sigmoid Emax), whilst protecting the overall probability of Type 1 error (one-sided, 2.5%) to identify the best-fitting model. Null hypothesis: There is a flat dose-response curve across the placebo and the BI 456906 dose groups with regard to the percentage change in body weight from baseline to Week 46.

Comparison groups

Number of subjects included in analysis

383

Analysis specification

Pre-specified

Analysis type

other ^[17]

P-value

< 0.0001 ^[18]

Method

MCP-Mod - Sigmoid Emax model fit

Confidence interval

Notes
[17] - Model Assumption: 50% of maximum effect achieved at dose 2.4 mg, 90% of maximum effect achieved at dose 4.8 mg.
[18] - P-value is adjusted for multiplicity.

Secondary: Weight loss of ≥ 5% of baseline weight at Week 46

Top of page

End point title

Weight loss of ≥ 5% of baseline weight at Week 46

End point description

Weight loss of greater than or equal to 5 percent (≥5%) of baseline weight at Week 46 (yes/no), reported as percentage of subjects who achieved a weight loss of ≥5% of baseline weight at Week 46. For analysis, all available post-baseline body weight measurements (on- and off-treatment) were used, except those for subjects who discontinued treatment early due to COVID-19. For these subjects only on-treatment values were used. Percentages were rounded to one decimal place. Full analysis set (all randomised subjects who received at least one dose of study treatment and who have analysable data for at least one efficacy endpoint) using planned maintenance treatment.

End point type

Secondary

End point timeframe

At baseline and at Week 46.

End point values	0.6 mg BI 456906 - planned maintenance treatment	2.4 mg BI 456906 - planned maintenance treatment	3.6 mg BI 456906 - planned maintenance treatment	4.8 mg BI 456906 - planned maintenance treatment	Placebo
Number of subjects analysed	56	58	61	64	54
Units: Percentage of subjects
number (not applicable)	60.7	81.0	82.0	82.8	25.9

Logistic regression - 0.6 mg BI vs Placebo

Statistical analysis description

Logistic regression after multiple imputation. Analysis based on all available post-baseline body weight measurements (on-treatment (first intake of study drug until 28 days after last intake of study drug) and off-treatment), except those for subjects who discontinued treatment early due to COVID-19. For these subjects only on-treatment values were used.

Comparison groups

0.6 mg BI 456906 - planned maintenance treatment v Placebo

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

other ^[19]

P-value

= 0.0015 ^[20]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

3.28

Confidence interval

level

95%

sides

2-sided

lower limit

1.57

upper limit

6.84

Notes
[19] - Missing body weight measurements were multiply imputed using MMRM with treatment, gender, baseline body weight as factors. “Percentage change in body weight from baseline to Week 46” and “Body weight loss ≥ 5% at Week 46 (yes/no)” were derived per subject in each of the 1000 imputed datasets. Each dataset was analysed by a logistic regression. Multiple estimates from multiple imputation runs were summarised using Rubin’s method. Odds ratio is calculated as BI 456906 / Placebo.
[20] - P-value is considered nominal.

Logistic regression - 4.8 mg BI vs Placebo

Statistical analysis description

Logistic regression after multiple imputation. Analysis based on all available post-baseline body weight measurements (on-treatment (first intake of study drug until 28 days after last intake of study drug) and off-treatment), except for participants who discontinued treatment early due to COVID, only the on-treatment post-baseline body weight measurements were used.

Comparison groups

4.8 mg BI 456906 - planned maintenance treatment v Placebo

Number of subjects included in analysis

118

Analysis specification

Pre-specified

Analysis type

other ^[21]

P-value

< 0.0001 ^[22]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

10.77

Confidence interval

level

95%

sides

2-sided

lower limit

4.77

upper limit

24.31

Notes
[21] - Missing body weight measurements were multiply imputed using MMRM with treatment, gender, baseline body weight as factors “Percentage change in body weight from baseline to Week 46” and “Body weight loss ≥ 5% at Week 46 (yes/no)” were derived per participant in each of the 1000 imputed datasets. Each dataset was analysed by a logistic regression. Multiple estimates from multiple imputation runs were summarised using Rubin’s method. Odds ratio is calculated as BI 456906 / Placebo.
[22] - P-value is considered nominal.

Logistic regression - 3.6 mg BI vs Placebo

Statistical analysis description

Comparison groups

3.6 mg BI 456906 - planned maintenance treatment v Placebo

Number of subjects included in analysis

115

Analysis specification

Pre-specified

Analysis type

other ^[23]

P-value

< 0.0001 ^[24]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

7.48

Confidence interval

level

95%

sides

2-sided

lower limit

3.41

upper limit

16.41

Notes
[23] - Missing body weight measurements were multiply imputed using MMRM with treatment, gender, baseline body weight as factors. “Percentage change in body weight from baseline to Week 46” and “Body weight loss ≥ 5% at Week 46 (yes/no)” were derived per subject in each of the 1000 imputed datasets. Each dataset was analysed by a logistic regression. Multiple estimates from multiple imputation runs were summarised using Rubin’s method. Odds ratio is calculated as BI 456906 / Placebo.
[24] - P-value is considered nominal.

Logistic regression - 2.4 mg BI vs Placebo

Statistical analysis description

Comparison groups

2.4 mg BI 456906 - planned maintenance treatment v Placebo

Number of subjects included in analysis

112

Analysis specification

Pre-specified

Analysis type

other ^[25]

P-value

< 0.0001 ^[26]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

8.83

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

19.46

Notes
[25] - Missing body weight measurements were multiply imputed using MMRM with treatment, gender, baseline body weight as factors. “Percentage change in body weight from baseline to Week 46” and “Body weight loss ≥ 5% at Week 46 (yes/no)” were derived per subject in each of the 1000 imputed datasets. Each dataset was analysed by a logistic regression. Multiple estimates from multiple imputation runs were summarised using Rubin’s method. Odds ratio is calculated as BI 456906 / Placebo.
[26] - P-value is considered nominal.

Secondary: Weight loss of ≥ 10% of baseline weight at Week 46

Top of page

End point title

Weight loss of ≥ 10% of baseline weight at Week 46

End point description

Weight loss of greater than or equal to 10 percent (≥10%) of baseline weight at Week 46 (yes/no), reported as percentage of subjects who achieved a weight loss of ≥10% of baseline weight at Week 46. For analysis, all available post-baseline body weight measurements (on- and off-treatment) were used, except those for subjects who discontinued treatment early due to COVID-19. For these subjects only on-treatment values were used. Percentages were rounded to one decimal place. Full analysis set (all randomised subjects who received at least one dose of study treatment and who have analysable data for at least one efficacy endpoint) using planned maintenance treatment.

End point type

Secondary

End point timeframe

At baseline and at Week 46.

End point values	0.6 mg BI 456906 - planned maintenance treatment	2.4 mg BI 456906 - planned maintenance treatment	3.6 mg BI 456906 - planned maintenance treatment	4.8 mg BI 456906 - planned maintenance treatment	Placebo
Number of subjects analysed	56	58	61	64	54
Units: Percentage of subjects
number (not applicable)	33.9	65.5	65.6	68.8	11.1

Logistic regression - 0.6 mg BI vs Placebo

Statistical analysis description

Comparison groups

0.6 mg BI 456906 - planned maintenance treatment v Placebo

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

other ^[27]

P-value

= 0.012 ^[28]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

3.22

Confidence interval

level

95%

sides

2-sided

lower limit

1.29

upper limit

8.02

Notes
[27] - Missing body weight measurements were multiply imputed using MMRM with treatment, gender, baseline body weight as factors. “Percentage change in body weight from baseline to Week 46” and “Body weight loss ≥ 10% at Week 46 (yes/no)” were derived per subject in each of the 1000 imputed datasets. Each dataset was analysed by a logistic regression. Multiple estimates from multiple imputation runs were summarised using Rubin’s method. Odds ratio is calculated as BI 456906 / Placebo.
[28] - P-value is considered nominal.

Logistic regression - 2.4 mg BI vs Placebo

Statistical analysis description

Comparison groups

2.4 mg BI 456906 - planned maintenance treatment v Placebo

Number of subjects included in analysis

112

Analysis specification

Pre-specified

Analysis type

other ^[29]

P-value

< 0.0001 ^[30]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

10.62

Confidence interval

level

95%

sides

2-sided

lower limit

4.36

upper limit

25.86

Notes
[29] - Missing body weight measurements were multiply imputed using MMRM with treatment, gender, baseline body weight as factors. “Percentage change in body weight from baseline to Week 46” and “Body weight loss ≥ 10% at Week 46 (yes/no)” were derived per subject in each of the 1000 imputed datasets. Each dataset was analysed by a logistic regression. Multiple estimates from multiple imputation runs were summarised using Rubin’s method. Odds ratio is calculated as BI 456906 / Placebo.
[30] - P-value is considered nominal.

Logistic regression - 3.6 mg BI vs Placebo

Statistical analysis description

Comparison groups

3.6 mg BI 456906 - planned maintenance treatment v Placebo

Number of subjects included in analysis

115

Analysis specification

Pre-specified

Analysis type

other ^[31]

P-value

< 0.0001 ^[32]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

9.78

Confidence interval

level

95%

sides

2-sided

lower limit

4.02

upper limit

23.79

Notes
[31] - Missing body weight measurements were multiply imputed using MMRM with treatment, gender, baseline body weight as factors. “Percentage change in body weight from baseline to Week 46” and “Body weight loss ≥ 10% at Week 46 (yes/no)” were derived per subject in each of the 1000 imputed datasets. Each dataset was analysed by a logistic regression. Multiple estimates from multiple imputation runs were summarised using Rubin’s method. Odds ratio is calculated as BI 456906 / Placebo.
[32] - P-value is considered nominal.

Logistic regression - 4.8 mg BI vs Placebo

Statistical analysis description

Comparison groups

4.8 mg BI 456906 - planned maintenance treatment v Placebo

Number of subjects included in analysis

118

Analysis specification

Pre-specified

Analysis type

other ^[33]

P-value

< 0.0001 ^[34]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

14.5

Confidence interval

level

95%

sides

2-sided

lower limit

5.91

upper limit

35.55

Notes
[33] - Missing body weight measurements were multiply imputed using MMRM with treatment, gender, baseline body weight as factors. “Percentage change in body weight from baseline to Week 46” and “Body weight loss ≥ 10% at Week 46 (yes/no)” were derived per subject in each of the 1000 imputed datasets. Each dataset was analysed by a logistic regression. Multiple estimates from multiple imputation runs were summarised using Rubin’s method. Odds ratio is calculated as BI 456906 / Placebo.
[34] - P-value is considered nominal.

Secondary: Weight loss of ≥ 15% of baseline weight at Week 46

Top of page

End point title

Weight loss of ≥ 15% of baseline weight at Week 46

End point description

Weight loss of greater than or equal to 15 percent (≥15%) of baseline weight at Week 46 (yes/no), reported as percentage of subjects who achieved a weight loss of ≥15% of baseline weight at Week 46. For analysis, all available post-baseline body weight measurements (on- and off-treatment) were used, except those for subjects who discontinued treatment early due to COVID-19. For these subjects only on-treatment values were used. Percentages were rounded to one decimal place. Full analysis set (all randomised subjects who received at least one dose of study treatment and who have analysable data for at least one efficacy endpoint) using planned maintenance treatment.

End point type

Secondary

End point timeframe

At baseline and at Week 46.

End point values	0.6 mg BI 456906 - planned maintenance treatment	2.4 mg BI 456906 - planned maintenance treatment	3.6 mg BI 456906 - planned maintenance treatment	4.8 mg BI 456906 - planned maintenance treatment	Placebo
Number of subjects analysed	56	58	61	64	54
Units: Percentage of subjects
number (not applicable)	12.5	37.9	45.9	54.7	5.6

Logistic regression - 0.6 mg BI vs Placebo

Statistical analysis description

Comparison groups

0.6 mg BI 456906 - planned maintenance treatment v Placebo

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

other ^[35]

P-value

= 0.2654 ^[36]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

2.13

Confidence interval

level

95%

sides

2-sided

lower limit

0.56

upper limit

8.02

Notes
[35] - Missing body weight measurements were multiply imputed using MMRM with treatment, gender, baseline body weight as factors. “Percentage change in body weight from baseline to Week 46” and “Body weight loss ≥ 15% at Week 46 (yes/no)” were derived per subject in each of the 1000 imputed datasets. Each dataset was analysed by a logistic regression. Multiple estimates from multiple imputation runs were summarised using Rubin’s method. Odds ratio is calculated as BI 456906 / Placebo.
[36] - P-value is considered nominal.

Logistic regression - 4.8 mg BI vs Placebo

Statistical analysis description

Comparison groups

4.8 mg BI 456906 - planned maintenance treatment v Placebo

Number of subjects included in analysis

118

Analysis specification

Pre-specified

Analysis type

other ^[37]

P-value

< 0.0001 ^[38]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

21.02

Confidence interval

level

95%

sides

2-sided

lower limit

6.47

upper limit

68.28

Notes
[37] - Missing body weight measurements were multiply imputed using MMRM with treatment, gender, baseline body weight as factors. “Percentage change in body weight from baseline to Week 46” and “Body weight loss ≥ 15% at Week 46 (yes/no)” were derived per subject in each of the 1000 imputed datasets. Each dataset was analysed by a logistic regression. Multiple estimates from multiple imputation runs were summarised using Rubin’s method. Odds ratio is calculated as BI 456906 / Placebo.
[38] - P-value is considered nominal.

Logistic regression - 3.6 mg BI vs Placebo

Statistical analysis description

Comparison groups

3.6 mg BI 456906 - planned maintenance treatment v Placebo

Number of subjects included in analysis

115

Analysis specification

Pre-specified

Analysis type

other ^[39]

P-value

< 0.0001 ^[40]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

11.79

Confidence interval

level

95%

sides

2-sided

lower limit

3.62

upper limit

38.36

Notes
[39] - Missing body weight measurements were multiply imputed using MMRM with treatment, gender, baseline body weight as factors. “Percentage change in body weight from baseline to Week 46” and “Body weight loss ≥ 15% at Week 46 (yes/no)” were derived per subject in each of the 1000 imputed datasets. Each dataset was analysed by a logistic regression. Multiple estimates from multiple imputation runs were summarised using Rubin’s method. Odds ratio is calculated as BI 456906 / Placebo.
[40] - P-value is considered nominal.

Logistic regression - 2.4 mg BI vs Placebo

Statistical analysis description

Comparison groups

2.4 mg BI 456906 - planned maintenance treatment v Placebo

Number of subjects included in analysis

112

Analysis specification

Pre-specified

Analysis type

other ^[41]

P-value

= 0.0002 ^[42]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

9.47

Confidence interval

level

95%

sides

2-sided

lower limit

2.89

upper limit

30.95

Notes
[41] - Missing body weight measurements were multiply imputed using MMRM with treatment, gender, baseline body weight as factors. “Percentage change in body weight from baseline to Week 46” and “Body weight loss ≥ 15% at Week 46 (yes/no)” were derived per subject in each of the 1000 imputed datasets. Each dataset was analysed by a logistic regression. Multiple estimates from multiple imputation runs were summarised using Rubin’s method. Odds ratio is calculated as BI 456906 / Placebo.
[42] - P-value is considered nominal.

Secondary: Absolute change in body weight from baseline to Week 46

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End point title

Absolute change in body weight from baseline to Week 46

End point description

Absolute change in body weight from baseline to Week 46 was modeled using a mixed model for repeated measures (MMRM) with fixed effects for baseline body weight as a continuous linear covariate, and treatment, gender, visit, treatment by visit interaction and baseline by visit interaction as factors, using visit (Week 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 28, 32, 36, 40, and 46) as repeated measures and an unstructured covariance matrix to model within subject measurements, adjusted mean (standard error) at Week 46 is reported. MMRM analysis was performed on the Full analysis set (FAS, all randomised participants who received at least one dose of study treatment and who have analysable data for at least one efficacy endpoint), using planned maintenance treatment (dose assigned at randomisation) and including only on-treatment data, regardless of whether early treatment discontinuation was COVID-19 related.

End point type

Secondary

End point timeframe

Baseline, Week 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 28, 32, 36, 40, and 46.

End point values	0.6 mg BI 456906 - planned maintenance treatment	2.4 mg BI 456906 - planned maintenance treatment	3.6 mg BI 456906 - planned maintenance treatment	4.8 mg BI 456906 - planned maintenance treatment	Placebo
Number of subjects analysed	75	78	76	76	76
Units: Kilogram (kg)
least squares mean (standard error)	-7.21 ± 1.06	-14.75 ± 1.03	-15.64 ± 1.04	-18.47 ± 1.04	-2.68 ± 1.04

MMRM - 0.6 mg BI vs Placebo

Statistical analysis description

Comparison groups

0.6 mg BI 456906 - planned maintenance treatment v Placebo

Number of subjects included in analysis

151

Analysis specification

Pre-specified

Analysis type

other ^[43]

P-value

= 0.0025 ^[44]

Method

Mixed models analysis

Parameter type

Difference of adjusted means

Point estimate

-4.53

Confidence interval

level

95%

sides

2-sided

lower limit

-7.44

upper limit

-1.61

Variability estimate

Standard error of the mean

Dispersion value

1.48

Notes
[43] - Kenward-Roger approximation was used to estimate the denominator degrees of freedom. Difference was calculated as BI 456906 - placebo.
[44] - P-value is considered nominal.

MMRM - 2.4 mg BI vs Placebo

Statistical analysis description

Comparison groups

2.4 mg BI 456906 - planned maintenance treatment v Placebo

Number of subjects included in analysis

154

Analysis specification

Pre-specified

Analysis type

other ^[45]

P-value

< 0.0001 ^[46]

Method

Mixed models analysis

Parameter type

Difference of adjusted means

Point estimate

-12.07

Confidence interval

level

95%

sides

2-sided

lower limit

-14.94

upper limit

-9.19

Variability estimate

Standard error of the mean

Dispersion value

1.46

Notes
[45] - Kenward-Roger approximation was used to estimate the denominator degrees of freedom. Difference was calculated as BI 456906 - placebo.
[46] - P-value is considered nominal.

MMRM - 3.6 mg BI vs Placebo

Statistical analysis description

Comparison groups

3.6 mg BI 456906 - planned maintenance treatment v Placebo

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

other ^[47]

P-value

< 0.0001 ^[48]

Method

Mixed models analysis

Parameter type

Difference of adjusted means

Point estimate

-12.96

Confidence interval

level

95%

sides

2-sided

lower limit

-15.85

upper limit

-10.07

Variability estimate

Standard error of the mean

Dispersion value

1.47

Notes
[47] - Kenward-Roger approximation was used to estimate the denominator degrees of freedom. Difference was calculated as BI 456906 - placebo.
[48] - P-value is considered nominal.

MMRM - 4.8 mg BI vs Placebo

Statistical analysis description

Comparison groups

4.8 mg BI 456906 - planned maintenance treatment v Placebo

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

other ^[49]

P-value

< 0.0001 ^[50]

Method

Mixed models analysis

Parameter type

Difference of adjusted means

Point estimate

-15.78

Confidence interval

level

95%

sides

2-sided

lower limit

-18.67

upper limit

-12.9

Variability estimate

Standard error of the mean

Dispersion value

1.47

Notes
[49] - Kenward-Roger approximation was used to estimate the denominator degrees of freedom. Difference was calculated as BI 456906 - placebo.
[50] - P-value is considered nominal.

Secondary: Absolute change in waist circumference from baseline to Week 46

Top of page

End point title

Absolute change in waist circumference from baseline to Week 46

End point description

Absolute change in waist circumference from baseline to Week 46 was modeled using a mixed model for repeated measures (MMRM) with fixed effects for baseline waist circumference as a continuous linear covariate, and treatment, gender, visit, treatment by visit interaction and baseline by visit interaction as factors, using visit (Week 6, 12, 18, 24, 32, 40, and 46) as repeated measures and an unstructured covariance matrix to model within subject measurements, adjusted mean (standard error) at Week 46 is reported. MMRM analysis was performed on the full analysis set (FAS, all randomised participants who received at least one dose of study treatment and who have analysable data for at least one efficacy endpoint), using planned maintenance treatment (dose assigned at randomisation) and including only on-treatment data, regardless of whether early treatment discontinuation was COVID-19 related.

End point type

Secondary

End point timeframe

Baseline, Week 6, 12, 18, 24, 32, 40, and 46.

End point values	0.6 mg BI 456906 - planned maintenance treatment	2.4 mg BI 456906 - planned maintenance treatment	3.6 mg BI 456906 - planned maintenance treatment	4.8 mg BI 456906 - planned maintenance treatment	Placebo
Number of subjects analysed	71	71	74	75	72
Units: Centimeter (cm)
least squares mean (standard error)	-8.32 ± 1.22	-14.99 ± 1.21	-14.96 ± 1.19	-16.01 ± 1.19	-3.96 ± 1.20

MMRM - 0.6 mg BI vs Placebo

Statistical analysis description

No formal hypotheses were tested. MMRM with fixed effects for baseline waist circumference as a continuous linear covariate, and treatment, gender, visit, treatment by visit interaction and baseline by visit interaction as factors, using visit as repeated measures and an unstructured covariance matrix to model within subject measurements.

Comparison groups

0.6 mg BI 456906 - planned maintenance treatment v Placebo

Number of subjects included in analysis

143

Analysis specification

Pre-specified

Analysis type

other ^[51]

P-value

= 0.0116 ^[52]

Method

Mixed models analysis

Parameter type

Difference of adjusted means

Point estimate

-4.36

Confidence interval

level

95%

sides

2-sided

lower limit

-7.74

upper limit

-0.98

Variability estimate

Standard error of the mean

Dispersion value

1.71

Notes
[51] - Kenward-Roger approximation was used to estimate the denominator degrees of freedom. Difference was calculated as BI 456906 - placebo.
[52] - P-value is considered nominal.

MMRM - 2.4 mg BI vs Placebo

Statistical analysis description

Comparison groups

2.4 mg BI 456906 - planned maintenance treatment v Placebo

Number of subjects included in analysis

143

Analysis specification

Pre-specified

Analysis type

other ^[53]

P-value

< 0.0001 ^[54]

Method

Mixed models analysis

Parameter type

Difference of adjusted means

Point estimate

-11.03

Confidence interval

level

95%

sides

2-sided

lower limit

-14.39

upper limit

-7.66

Variability estimate

Standard error of the mean

Dispersion value

1.71

Notes
[53] - Kenward-Roger approximation was used to estimate the denominator degrees of freedom. Difference was calculated as BI 456906 - placebo.
[54] - P-value is considered nominal

MMRM - 3.6 mg BI vs Placebo

Statistical analysis description

Comparison groups

3.6 mg BI 456906 - planned maintenance treatment v Placebo

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

other ^[55]

P-value

< 0.0001 ^[56]

Method

Mixed models analysis

Parameter type

Difference of adjusted means

Point estimate

-11

Confidence interval

level

95%

sides

2-sided

lower limit

-14.33

upper limit

-7.67

Variability estimate

Standard error of the mean

Dispersion value

1.69

Notes
[55] - Kenward-Roger approximation was used to estimate the denominator degrees of freedom. Difference was calculated as BI 456906 - placebo.
[56] - P-value is considered nominal.

MMRM - 4.8 mg BI vs Placebo

Statistical analysis description

Comparison groups

4.8 mg BI 456906 - planned maintenance treatment v Placebo

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

other ^[57]

P-value

< 0.0001 ^[58]

Method

Mixed models analysis

Parameter type

Difference of adjusted means

Point estimate

-12.05

Confidence interval

level

95%

sides

2-sided

lower limit

-15.39

upper limit

-8.71

Variability estimate

Standard error of the mean

Dispersion value

1.69

Notes
[57] - Kenward-Roger approximation was used to estimate the denominator degrees of freedom. Difference was calculated as BI 456906 - placebo.
[58] - P-value is considered nominal.

Secondary: Absolute change in systolic blood pressure from baseline to Week 46

Top of page

End point title

Absolute change in systolic blood pressure from baseline to Week 46

End point description

Absolute change in systolic blood pressure from baseline to Week 46 was modeled using a mixed model for repeated measures (MMRM) with fixed effects for baseline systolic blood pressure as a continuous linear covariate, and treatment, gender, visit, treatment by visit interaction and baseline by visit interaction as factors, using visit Week 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 28, 32, 36, 40, and 46) as repeated measures and an unstructured covariance matrix to model within subject measurements, adjusted mean (standard error) at Week 46 is reported. MMRM analysis was performed on the full analysis set (FAS, all randomised participants who received at least one dose of study treatment and who have analysable data for at least one efficacy endpoint), using planned maintenance treatment (dose assigned at randomisation) and including only on-treatment data, regardless of whether early treatment discontinuation was COVID-19 related.

End point type

Secondary

End point timeframe

Baseline, Week 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 28, 32, 36, 40, and 46.

End point values	0.6 mg BI 456906 - planned maintenance treatment	2.4 mg BI 456906 - planned maintenance treatment	3.6 mg BI 456906 - planned maintenance treatment	4.8 mg BI 456906 - planned maintenance treatment	Placebo
Number of subjects analysed	75	78	76	76	76
Units: Millimeter of mercury (mmHg)
least squares mean (standard error)	-6.19 ± 1.47	-8.08 ± 1.48	-8.66 ± 1.44	-8.62 ± 1.46	-2.46 ± 1.46

MMRM - 0.6 mg BI vs Placebo

Statistical analysis description

No formal hypotheses were tested. MMRM with fixed effects for baseline systolic blood pressure as a continuous linear covariate, and treatment, gender, visit, treatment by visit interaction and baseline by visit interaction as factors, using visit as repeated measures and an unstructured covariance matrix to model within subject measurements.

Comparison groups

0.6 mg BI 456906 - planned maintenance treatment v Placebo

Number of subjects included in analysis

151

Analysis specification

Pre-specified

Analysis type

other ^[59]

P-value

= 0.0733 ^[60]

Method

Mixed models analysis

Parameter type

Difference of adjusted means

Point estimate

-3.73

Confidence interval

level

95%

sides

2-sided

lower limit

-7.82

upper limit

0.35

Variability estimate

Standard error of the mean

Dispersion value

2.08

Notes
[59] - Kenward-Roger approximation was used to estimate the denominator degrees of freedom. Difference was calculated as BI 456906 - placebo.
[60] - P-value is considered nominal.

MMRM - 3.6 mg BI vs Placebo

Statistical analysis description

Comparison groups

3.6 mg BI 456906 - planned maintenance treatment v Placebo

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

other ^[61]

P-value

= 0.0027 ^[62]

Method

Mixed models analysis

Parameter type

Difference of adjusted means

Point estimate

-6.2

Confidence interval

level

95%

sides

2-sided

lower limit

-10.23

upper limit

-2.17

Variability estimate

Standard error of the mean

Dispersion value

2.05

Notes
[61] - Kenward-Roger approximation was used to estimate the denominator degrees of freedom. Difference was calculated as BI 456906 - placebo.
[62] - P-value is considered nominal.

MMRM - 4.8 mg BI vs Placebo

Statistical analysis description

Comparison groups

4.8 mg BI 456906 - planned maintenance treatment v Placebo

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

other ^[63]

P-value

= 0.0033 ^[64]

Method

Mixed models analysis

Parameter type

Difference of adjusted means

Point estimate

-6.16

Confidence interval

level

95%

sides

2-sided

lower limit

-10.25

upper limit

-2.06

Variability estimate

Standard error of the mean

Dispersion value

2.08

Notes
[63] - Kenward-Roger approximation was used to estimate the denominator degrees of freedom. Difference was calculated as BI 456906 - placebo.
[64] - P-value is considered nominal.

MMRM - 2.4 mg BI vs Placebo

Statistical analysis description

Comparison groups

2.4 mg BI 456906 - planned maintenance treatment v Placebo

Number of subjects included in analysis

154

Analysis specification

Pre-specified

Analysis type

other ^[65]

P-value

< 0.0072 ^[66]

Method

Mixed models analysis

Parameter type

Difference of adjusted means

Point estimate

-5.62

Confidence interval

level

95%

sides

2-sided

lower limit

-9.71

upper limit

1.53

Variability estimate

Standard error of the mean

Dispersion value

2.08

Notes
[65] - Kenward-Roger approximation was used to estimate the denominator degrees of freedom. Difference was calculated as BI 456906 - placebo.
[66] - P-value is considered nominal.

Secondary: Absolute change in diastolic blood pressure from baseline to Week 46

Top of page

End point title

Absolute change in diastolic blood pressure from baseline to Week 46

End point description

Absolute change in diastolic blood pressure from baseline to Week 46 was modeled using a mixed model for repeated measures (MMRM) with fixed effects for baseline diastolic blood pressure as a continuous linear covariate, and treatment, gender, visit, treatment by visit interaction and baseline by visit interaction as factors, using visit Week 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 28, 32, 36, 40, and 46) as repeated measures and an unstructured covariance matrix to model within subject measurements, adjusted mean (standard error) at Week 46 is reported. MMRM analysis was performed on the full analysis set (FAS, all randomised participants who received at least one dose of study treatment and who have analysable data for at least one efficacy endpoint), using planned maintenance treatment (dose assigned at randomisation) and including only on-treatment data, regardless of whether early treatment discontinuation was COVID-19 related.

End point type

Secondary

End point timeframe

Baseline, Week 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 28, 32, 36, 40, and 46.

End point values	0.6 mg BI 456906 - planned maintenance treatment	2.4 mg BI 456906 - planned maintenance treatment	3.6 mg BI 456906 - planned maintenance treatment	4.8 mg BI 456906 - planned maintenance treatment	Placebo
Number of subjects analysed	75	78	76	76	76
Units: Millimeter of mercury (mmHg)
least squares mean (standard error)	-3.31 ± 0.90	-4.36 ± 0.90	-4.31 ± 0.87	-4.80 ± 0.89	-1.87 ± 0.89

MMRM - 3.6 mg BI vs Placebo

Statistical analysis description

No formal hypotheses were tested. MMRM with fixed effects for baseline diastolic blood pressure as a continuous linear covariate, and treatment, gender, visit, treatment by visit interaction and baseline by visit interaction as factors, using visit as repeated measures and an unstructured covariance matrix to model within subject measurements.

Comparison groups

3.6 mg BI 456906 - planned maintenance treatment v Placebo

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

other ^[67]

P-value

= 0.0506 ^[68]

Method

Mixed models analysis

Parameter type

Difference of adjusted means

Point estimate

-2.44

Confidence interval

level

95%

sides

2-sided

lower limit

-4.9

upper limit

0.01

Variability estimate

Standard error of the mean

Dispersion value

1.24

Notes
[67] - Kenward-Roger approximation was used to estimate the denominator degrees of freedom. Difference was calculated as BI 456906 - placebo.
[68] - P-value is considered nominal.

MMRM - 2.4 mg BI vs Placebo

Statistical analysis description

Comparison groups

2.4 mg BI 456906 - planned maintenance treatment v Placebo

Number of subjects included in analysis

154

Analysis specification

Pre-specified

Analysis type

other ^[69]

P-value

= 0.0495 ^[70]

Method

Mixed models analysis

Parameter type

Difference of adjusted means

Point estimate

-2.49

Confidence interval

level

95%

sides

2-sided

lower limit

-4.97

upper limit

Variability estimate

Standard error of the mean

Dispersion value

1.26

Notes
[69] - Kenward-Roger approximation was used to estimate the denominator degrees of freedom. Difference was calculated as BI 456906 - placebo.
[70] - P-value is considered nominal.

MMRM - 0.6 mg BI vs Placebo

Statistical analysis description

Comparison groups

0.6 mg BI 456906 - planned maintenance treatment v Placebo

Number of subjects included in analysis

151

Analysis specification

Pre-specified

Analysis type

other ^[71]

P-value

= 0.2569 ^[72]

Method

Mixed models analysis

Parameter type

Difference of adjusted means

Point estimate

-1.44

Confidence interval

level

95%

sides

2-sided

lower limit

-3.92

upper limit

1.05

Variability estimate

Standard error of the mean

Dispersion value

1.26

Notes
[71] - Kenward-Roger approximation was used to estimate the denominator degrees of freedom. Difference was calculated as BI 456906 - placebo.
[72] - P-value is considered nominal.

MMRM - 4.8 mg BI vs Placebo

Statistical analysis description

Comparison groups

4.8 mg BI 456906 - planned maintenance treatment v Placebo

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

other ^[73]

P-value

= 0.0202 ^[74]

Method

Mixed models analysis

Parameter type

Difference of adjusted means

Point estimate

-2.93

Confidence interval

level

95%

sides

2-sided

lower limit

-5.4

upper limit

-0.46

Variability estimate

Standard error of the mean

Dispersion value

1.25

Notes
[73] - Kenward-Roger approximation was used to estimate the denominator degrees of freedom. Difference was calculated as BI 456906 - placebo.
[74] - P-value is considered nominal.

Adverse events

Top of page

Timeframe for reporting adverse events

From first drug administration until last drug administration, plus 28 days residual effect period (REP), up to 360 days.

Adverse event reporting additional description

Safety analysis was performed on the treated set (TS) according to actual maintenance treatment (defined as the actual dose subjects received during the dose maintenance phase, or as the next planned maintenance dose up from the last dose taken prior to treatment discontinuation).

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

25.0

Reporting group title

0.6 mg BI 456906 - actual maintenance treatment

Reporting group description

Subjects with obesity or overweight were administered a solution for injection of BI 456906, by a weekly subcutaneous injection of two syringes (0.5 mL filling volume per syringe) on the same injection day, of 0.3 mg on Week 1 and 2, and 0.6 mg on Week 3 to Week 20 (dose escalation phase, with fixed dose escalation from Week 1 to Week 10 and flexible dose escalation from Week 11 to Week 20). From Week 21 to Week 46 (maintenance dosing phase) subjects stayed on the dose of 0.6 mg BI 456906. Subjects not tolerating the assigned dose escalation schedule due to gastrointestinal adverse events had the option of dose adjustment during the flexible part of the dose escalation phase (Week 11 - 20) which could lead to a maintenance dose lower than the dose the subject was randomised to.

Reporting group title

2.4 mg BI 456906 - actual maintenance treatment

Reporting group description

Reporting group title

Placebo

Reporting group description

Subjects with obesity or overweight were administered a solution for injection of Placebo, by a weekly subcutaneous injection of two syringes on the same injection day, for 46 weeks.

Reporting group title

4.8 mg BI 456906 - actual maintenance treatment

Reporting group description

Subjects with obesity or overweight were administered a solution for injection of BI 456906, by a weekly subcutaneous injection of two syringes (0.5 mL filling volume per syringe) on the same injection day, of 0.3 mg on Week 1 and Week 2, 0.6 mg on Week 3 and Week 4, 0.9 mg on Week 5 and Week 6, 1.2 mg on Week 7 and Week 8, 1.8 mg on Week 9 and Week 10, 2.4 mg on Week 11 and Week 12, 3.3 mg on Week 13 and Week 14, 4.2 mg on Week 15 and Week 16, and 4.8 mg on Week 17 to Week 20 (dose escalation phase, with fixed dose escalation from Week 1 to Week 10 and flexible dose escalation from Week 11 to Week 20). From Week 21 to Week 46 (maintenance dosing phase) subjects stayed on the dose of 4.8 mg BI 456906. Subject not tolerating the assigned dose escalation schedule due to gastrointestinal AEs had the option of dose adjustment during the flexible part of the dose escalation phase (Week 11 - 20) which could lead to a maintenance dose lower than the dose the subject was randomised to.

Reporting group title

3.6 mg BI 456906 - actual maintenance treatment

Reporting group description

Subjects with obesity or overweight were administered a solution for injection of BI 456906, by a weekly subcutaneous injection of two syringes (0.5 mL filling volume per syringe) on the same injection day, of 0.3 mg on Week 1 and Week 2, 0.6 mg on Week 3 and Week 4, 0.9 mg on Week 5 and Week 6, 1.2 mg on Week 7 to Week 10, 1.8 mg on Week 11 and Week 12, 2.4 mg on Week 13 and Week 14, 3.0 mg on Week 15 and Week 16, and 3.6 mg on Week 17 to Week 20 (dose escalation phase, with fixed dose escalation from Week 1 to Week 10 and flexible dose escalation from Week 11 to Week 20). From Week 21 to Week 46 (maintenance dosing phase) subjects stayed on the dose of 3.6 mg BI 456906. Subject not tolerating the assigned dose escalation schedule due to gastrointestinal adverse events had the option of dose adjustment during the flexible part of the dose escalation phase (Week 11 - 20) which could lead to a maintenance dose lower than the dose the subject was randomised to.

Serious adverse events	0.6 mg BI 456906 - actual maintenance treatment	2.4 mg BI 456906 - actual maintenance treatment	Placebo	4.8 mg BI 456906 - actual maintenance treatment	3.6 mg BI 456906 - actual maintenance treatment
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 92 (2.17%)	3 / 92 (3.26%)	5 / 77 (6.49%)	4 / 54 (7.41%)	4 / 71 (5.63%)
number of deaths (all causes)	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Intraductal proliferative breast lesion
subjects affected / exposed	0 / 92 (0.00%)	0 / 92 (0.00%)	0 / 77 (0.00%)	0 / 54 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	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
Glioblastoma multiforme
subjects affected / exposed	0 / 92 (0.00%)	0 / 92 (0.00%)	0 / 77 (0.00%)	1 / 54 (1.85%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	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
Bowen's disease
subjects affected / exposed	1 / 92 (1.09%)	0 / 92 (0.00%)	0 / 77 (0.00%)	0 / 54 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	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
Malignant melanoma in situ
subjects affected / exposed	0 / 92 (0.00%)	1 / 92 (1.09%)	0 / 77 (0.00%)	0 / 54 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Incisional hernia
subjects affected / exposed	0 / 92 (0.00%)	0 / 92 (0.00%)	0 / 77 (0.00%)	0 / 54 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	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
Wrist fracture
subjects affected / exposed	0 / 92 (0.00%)	0 / 92 (0.00%)	0 / 77 (0.00%)	0 / 54 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	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
Ear and labyrinth disorders
Deafness
subjects affected / exposed	0 / 92 (0.00%)	1 / 92 (1.09%)	0 / 77 (0.00%)	0 / 54 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Vomiting
subjects affected / exposed	1 / 92 (1.09%)	0 / 92 (0.00%)	0 / 77 (0.00%)	0 / 54 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 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
Nausea
subjects affected / exposed	1 / 92 (1.09%)	0 / 92 (0.00%)	0 / 77 (0.00%)	0 / 54 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 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
Reproductive system and breast disorders
Uterine prolapse
subjects affected / exposed	0 / 92 (0.00%)	0 / 92 (0.00%)	0 / 77 (0.00%)	1 / 54 (1.85%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	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
Endometrial hyperplasia
subjects affected / exposed	0 / 92 (0.00%)	0 / 92 (0.00%)	1 / 77 (1.30%)	0 / 54 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	0 / 92 (0.00%)	0 / 92 (0.00%)	0 / 77 (0.00%)	1 / 54 (1.85%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	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
Cholelithiasis
subjects affected / exposed	0 / 92 (0.00%)	0 / 92 (0.00%)	0 / 77 (0.00%)	1 / 54 (1.85%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	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
Respiratory, thoracic and mediastinal disorders
Pulmonary congestion
subjects affected / exposed	0 / 92 (0.00%)	0 / 92 (0.00%)	1 / 77 (1.30%)	0 / 54 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Angioedema
subjects affected / exposed	0 / 92 (0.00%)	0 / 92 (0.00%)	0 / 77 (0.00%)	0 / 54 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	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
Renal and urinary disorders
Renal failure
subjects affected / exposed	1 / 92 (1.09%)	0 / 92 (0.00%)	0 / 77 (0.00%)	0 / 54 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 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
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion
subjects affected / exposed	0 / 92 (0.00%)	0 / 92 (0.00%)	1 / 77 (1.30%)	0 / 54 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Tooth abscess
subjects affected / exposed	0 / 92 (0.00%)	0 / 92 (0.00%)	1 / 77 (1.30%)	0 / 54 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	0 / 92 (0.00%)	0 / 92 (0.00%)	0 / 77 (0.00%)	1 / 54 (1.85%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	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
Cellulitis
subjects affected / exposed	0 / 92 (0.00%)	1 / 92 (1.09%)	0 / 77 (0.00%)	0 / 54 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
COVID-19 pneumonia
subjects affected / exposed	0 / 92 (0.00%)	0 / 92 (0.00%)	1 / 77 (1.30%)	0 / 54 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	1 / 92 (1.09%)	0 / 92 (0.00%)	0 / 77 (0.00%)	0 / 54 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 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

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

Non-serious adverse events	0.6 mg BI 456906 - actual maintenance treatment	2.4 mg BI 456906 - actual maintenance treatment	Placebo	4.8 mg BI 456906 - actual maintenance treatment	3.6 mg BI 456906 - actual maintenance treatment
Total subjects affected by non serious adverse events
subjects affected / exposed	70 / 92 (76.09%)	79 / 92 (85.87%)	48 / 77 (62.34%)	46 / 54 (85.19%)	64 / 71 (90.14%)
Nervous system disorders
Headache
subjects affected / exposed	8 / 92 (8.70%)	7 / 92 (7.61%)	6 / 77 (7.79%)	5 / 54 (9.26%)	10 / 71 (14.08%)
occurrences all number	9	8	11	12	13
Dizziness
subjects affected / exposed	1 / 92 (1.09%)	8 / 92 (8.70%)	2 / 77 (2.60%)	4 / 54 (7.41%)	10 / 71 (14.08%)
occurrences all number	1	10	3	4	10
General disorders and administration site conditions
Fatigue
subjects affected / exposed	6 / 92 (6.52%)	5 / 92 (5.43%)	6 / 77 (7.79%)	5 / 54 (9.26%)	13 / 71 (18.31%)
occurrences all number	6	5	6	5	19
Injection site bruising
subjects affected / exposed	3 / 92 (3.26%)	3 / 92 (3.26%)	4 / 77 (5.19%)	3 / 54 (5.56%)	2 / 71 (2.82%)
occurrences all number	3	5	5	6	3
Gastrointestinal disorders
Abdominal pain upper
subjects affected / exposed	3 / 92 (3.26%)	5 / 92 (5.43%)	1 / 77 (1.30%)	2 / 54 (3.70%)	8 / 71 (11.27%)
occurrences all number	4	8	1	2	13
Abdominal pain
subjects affected / exposed	4 / 92 (4.35%)	10 / 92 (10.87%)	1 / 77 (1.30%)	3 / 54 (5.56%)	5 / 71 (7.04%)
occurrences all number	6	12	1	3	7
Abdominal distension
subjects affected / exposed	4 / 92 (4.35%)	4 / 92 (4.35%)	3 / 77 (3.90%)	3 / 54 (5.56%)	7 / 71 (9.86%)
occurrences all number	4	6	3	6	7
Eructation
subjects affected / exposed	4 / 92 (4.35%)	6 / 92 (6.52%)	0 / 77 (0.00%)	2 / 54 (3.70%)	5 / 71 (7.04%)
occurrences all number	5	6	0	4	5
Gastrooesophageal reflux disease
subjects affected / exposed	2 / 92 (2.17%)	7 / 92 (7.61%)	3 / 77 (3.90%)	5 / 54 (9.26%)	10 / 71 (14.08%)
occurrences all number	2	8	3	5	13
Haemorrhoids
subjects affected / exposed	0 / 92 (0.00%)	0 / 92 (0.00%)	1 / 77 (1.30%)	3 / 54 (5.56%)	1 / 71 (1.41%)
occurrences all number	0	0	1	3	1
Dyspepsia
subjects affected / exposed	7 / 92 (7.61%)	9 / 92 (9.78%)	3 / 77 (3.90%)	7 / 54 (12.96%)	8 / 71 (11.27%)
occurrences all number	9	11	3	16	15
Nausea
subjects affected / exposed	36 / 92 (39.13%)	60 / 92 (65.22%)	15 / 77 (19.48%)	32 / 54 (59.26%)	45 / 71 (63.38%)
occurrences all number	116	163	21	98	157
Constipation
subjects affected / exposed	11 / 92 (11.96%)	19 / 92 (20.65%)	4 / 77 (5.19%)	13 / 54 (24.07%)	22 / 71 (30.99%)
occurrences all number	12	19	6	18	25
Diarrhoea
subjects affected / exposed	22 / 92 (23.91%)	21 / 92 (22.83%)	8 / 77 (10.39%)	9 / 54 (16.67%)	17 / 71 (23.94%)
occurrences all number	31	25	10	18	52
Vomiting
subjects affected / exposed	13 / 92 (14.13%)	28 / 92 (30.43%)	4 / 77 (5.19%)	13 / 54 (24.07%)	28 / 71 (39.44%)
occurrences all number	23	56	4	28	64
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	2 / 92 (2.17%)	2 / 92 (2.17%)	2 / 77 (2.60%)	0 / 54 (0.00%)	4 / 71 (5.63%)
occurrences all number	2	2	2	0	4
Psychiatric disorders
Insomnia
subjects affected / exposed	3 / 92 (3.26%)	5 / 92 (5.43%)	1 / 77 (1.30%)	1 / 54 (1.85%)	1 / 71 (1.41%)
occurrences all number	3	5	1	1	1
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	7 / 92 (7.61%)	2 / 92 (2.17%)	3 / 77 (3.90%)	2 / 54 (3.70%)	4 / 71 (5.63%)
occurrences all number	8	2	5	3	10
Arthralgia
subjects affected / exposed	10 / 92 (10.87%)	3 / 92 (3.26%)	5 / 77 (6.49%)	2 / 54 (3.70%)	8 / 71 (11.27%)
occurrences all number	11	4	7	2	9
Infections and infestations
Urinary tract infection
subjects affected / exposed	4 / 92 (4.35%)	2 / 92 (2.17%)	2 / 77 (2.60%)	2 / 54 (3.70%)	6 / 71 (8.45%)
occurrences all number	4	3	2	2	11
Upper respiratory tract infection
subjects affected / exposed	2 / 92 (2.17%)	1 / 92 (1.09%)	3 / 77 (3.90%)	4 / 54 (7.41%)	5 / 71 (7.04%)
occurrences all number	2	1	3	5	6
Nasopharyngitis
subjects affected / exposed	8 / 92 (8.70%)	5 / 92 (5.43%)	7 / 77 (9.09%)	3 / 54 (5.56%)	6 / 71 (8.45%)
occurrences all number	14	5	8	3	10
COVID-19
subjects affected / exposed	18 / 92 (19.57%)	11 / 92 (11.96%)	17 / 77 (22.08%)	7 / 54 (12.96%)	17 / 71 (23.94%)
occurrences all number	19	13	19	7	17
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	11 / 92 (11.96%)	10 / 92 (10.87%)	1 / 77 (1.30%)	3 / 54 (5.56%)	16 / 71 (22.54%)
occurrences all number	15	12	1	17	18

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Were there any global substantial amendments to the protocol? Yes

24 Sep 2021

Global amendment 1: Exclusion criteria were revised: Time period of stability in body weight was changed from past 3 to past 12 weeks; List of endocrinologic disorders leading to obesity was revised to include hypogonadism and growth hormone deficiency as exclusion criteria and to allow well-controlled hypothyroidism and polycystic ovarian disease; Prior surgery of the Gastrointestinal (GI) tract that could interfere with body weight was further explained; Q wave and T wave (QT)/ corrected QT interval (QTc) prolongation-related criterion was simplified; Squamous cell carcinoma added. Flow Chart was revised: Specifying that a pregnancy test is urinary; Electrocardiogram (ECG) added to visits 14,16,17,19; Insulin and C-peptide were added to efficacy parameters of fasting sample (also added to safety lab parameters); Footnote 17 was expanded to explain the procedures regarding E-diary and counselling at Visit 19 for patients who had discontinued the treatment. Inclusion criteria were revised: Reference added to criterion 5 for explanation. Criteria for discontinuation of trial treatment were revised: Criteria added: patients that require hospitalization due to drug-related gastrointestinal adverse event assessed by investigator; Exception added to which patients should stay in the trial after treatment discontinuation to exclude Glucagon-Like-Peptide 1 Receptor Agonist (GLP-1 RA) treated patients.

24 Sep 2021

Global amendment 1 (continued): Drug assignment and administration was revised due to authority request: Patients who cannot tolerate the study drug during Weeks 1 to 10 and Weeks 21 to 46 should be discontinued from the treatment. Restrictions regarding concomitant treatment were revised: Medications known to significantly prolong the QT or QTc interval administered for a period of >2 weeks was added. Assessment of safety was revised due to authority request: Clarification was added to encourage investigators to repeat imaging and laboratory testing in case of abnormal findings. ECG description was expanded due to authority request: Regarding the review of the ECG results by investigator; Regarding repetition of ECG recording in case of abnormalities. Explanation of process regarding cross referencing adverse events (AEs) list against Always Serious List was added due to authority request. Doses expressed in conventional units (mmol/L or nmol/L) were added to values of calcitonin, fasting serum triglyceride, fasting plasma glucose, 2-hour oral glucose tolerance test (OGTT). Clarification on who should complete PHQ-9 and C-SSRS questionnaires was added. Clarification on time points for diet/exercise counselling was added. Clarification of safety lab analysis handling if central lab cannot provide analysis due to COVID-19 restrictions. Instructions for trial drug administration were revised: To allow exceptions for visits schedule; To allow exceptions for pre-defined combination of syringes. Blood pressure measurement procedure was revised.

16 Feb 2022

Global amendment 2: Description of an interim analysis to be performed during the trial for sponsor planning purposes was added.

29 Apr 2022

Global amendment 3: It was added that discontinuation of trial treatment due to COVID-19 infection and a possibility to recommence the study treatment after skipping two consecutive doses is up to investigator’s discretion. It was added the randomisation codes will be provided during the trial to bioanalytics to exclude samples from placebo patients from the analysis of antidrug antibodies. Removal of description of Per Protocol Set and of reference to Per Protocol Set in primary endpoint analysis. Removal of the statement that important protocol deviations may lead to an exclusion from the analysis.

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, double blind, parallel group,46 weeks dose-finding study of BI 456906 administered once weekly subcutaneously compared with placebo in patients with obesity or overweight

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage change in body weight from baseline to Week 46

Primary: Percentage change in body weight from baseline to Week 46

Secondary: Weight loss of ≥ 5% of baseline weight at Week 46

Secondary: Weight loss of ≥ 5% of baseline weight at Week 46

Secondary: Weight loss of ≥ 10% of baseline weight at Week 46

Secondary: Weight loss of ≥ 10% of baseline weight at Week 46

Secondary: Weight loss of ≥ 15% of baseline weight at Week 46

Secondary: Weight loss of ≥ 15% of baseline weight at Week 46

Secondary: Absolute change in body weight from baseline to Week 46

Secondary: Absolute change in body weight from baseline to Week 46

Secondary: Absolute change in waist circumference from baseline to Week 46

Secondary: Absolute change in waist circumference from baseline to Week 46

Secondary: Absolute change in systolic blood pressure from baseline to Week 46

Secondary: Absolute change in systolic blood pressure from baseline to Week 46

Secondary: Absolute change in diastolic blood pressure from baseline to Week 46

Secondary: Absolute change in diastolic blood pressure from baseline to Week 46

Adverse events

Adverse events

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Substantial protocol amendments (globally)

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Outside EU/EEA

Clinical trials

Clinical Trial Results: A Phase II, randomized, double blind, parallel group,46 weeks dose-finding study of BI 456906 administered once weekly subcutaneously compared with placebo in patients with obesity or overweight

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage change in body weight from baseline to Week 46

Primary: Percentage change in body weight from baseline to Week 46

Secondary: Weight loss of ≥ 5% of baseline weight at Week 46

Secondary: Weight loss of ≥ 5% of baseline weight at Week 46

Secondary: Weight loss of ≥ 10% of baseline weight at Week 46

Secondary: Weight loss of ≥ 10% of baseline weight at Week 46

Secondary: Weight loss of ≥ 15% of baseline weight at Week 46

Secondary: Weight loss of ≥ 15% of baseline weight at Week 46

Secondary: Absolute change in body weight from baseline to Week 46

Secondary: Absolute change in body weight from baseline to Week 46

Secondary: Absolute change in waist circumference from baseline to Week 46

Secondary: Absolute change in waist circumference from baseline to Week 46

Secondary: Absolute change in systolic blood pressure from baseline to Week 46

Secondary: Absolute change in systolic blood pressure from baseline to Week 46

Secondary: Absolute change in diastolic blood pressure from baseline to Week 46

Secondary: Absolute change in diastolic blood pressure from baseline to Week 46

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase II, randomized, double blind, parallel group,46 weeks dose-finding study of BI 456906 administered once weekly subcutaneously compared with placebo in patients with obesity or overweight