Clinical trial NCT04153929
Conditions: Diabetes Mellitus, Type 2
Sponsor: Boehringer Ingelheim
Start date: 2020-04-30; Completion date: 2021-11-04
Enrollment: 413 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is open to adults with type 2 diabetes who take metformin but still have too high blood sugar. The purpose of the study is to find the best dose of BI 456906 that reduces blood sugar. The study also looks at whether BI 456906 helps the participants lose weight.

Participants are in the study for about 23 weeks. During this time, most participants visit the study site about 13 times. Some participants visit the study site about 20 times. At the start of the study, the participants are put into 7 groups. The participants in groups 1 to 6 get injections under the skin once or twice every week. Some participants get different doses of BI 456906 and other participants get placebo. Placebo injections look like the BI 456906 injections, but contain no medicine. Participants in group 7 get semaglutide injections every week. Semaglutide is another medicine for adults with type 2 diabetes.

During the study, the doctors regularly take blood samples from the participants and measure their body weight. The changes in blood sugar levels and body weight are compared between the groups. The doctors also check the general health of the participants.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None arm 6: None arm 7: None arm 8: None
Interventions: intervention 1: BI 456906 intervention 2: Placebo intervention 3: Semaglutide
Intervention descriptions: intervention 1: Solution for Injection intervention 2: Solution for Injection intervention 3: Solution for Injection

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (16.0) / Saved on: 30 Aug 2018
Clinical Trial Protocol
TITLE PAGE
Document Number:
c26686857-02
EudraCT No.
2019-002390-60
BI Trial No.
1404-0002
BI Investigational
Medicinal Product(s)
BI 456906
Title
A Phase II, randomized, parallel group, dose-finding study of 
subcutaneously administered BI 456906 for 16 weeks, compared 
with placebo and open-label semaglutide in patients with type 2
diabetes mellitus.
Lay Title
A study to test whether different doses of BI 456906 are effective 
in treating adults with type 2 diabetes.
Clinical Phase
Phase II
Clinical Trial Leader
Phone:
Fax: 
Coordinating 
Investigator
Phone:
Fax: 
Status
Final Protocol (revised protocol based on global amendment 1)
Version and Date
Version: 2
Date: 28 September 2020
Page 1 of 87
Proprietary confidential information.
2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim 
Protocol date
28 August 2019
Revision date
28 Sep 2020
BI trial number
1404-0002
Title of trial
A Phase II, randomized, parallel group, dose-finding study of 
subcutaneously administered BI 456906 for 16 weeks, compared 
with placebo and open-label semaglutide in patients with type 2 
diabetes mellitus.
Coordinating 
Investigator
Phone: 
Fax: 
Trial site(s)
Multicenter trial conducted in approximately 14 countries
Clinical phase
II
Trial rationale
The trial is designed to evaluate safety, tolerability, PK and PD of 
BI 456906 in male and female patients with type 2 diabetes mellitus 
(T2DM) using multiple escalation schemes and doses, and will 
support dose selection for phase 3 clinical development of 
BI 456906.
Trial objective
The primary objective is to demonstrate proof of clinical concept 
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 3 studies.
Trial endpoints
Primary endpoint:
1. Absolute change in HbA1c from baseline to 16 weeks.
Secondary endpoints:
1. The relative body weight change from baseline to 16 weeks
(key secondary endpoint).
2. The absolute body weight change from baseline to 16 
weeks.
3. The absolute change in waist circumference from baseline to 
16 weeks.
4. The percentage of patients with 5% or greater body weight 
loss from baseline to 16 weeks.
5. The percentage of patients with 10% or greater body weight 
loss from baseline to 16 weeks.
Trial design
Randomized, double blind within dose groups, parallel, placebo and 
active comparator controlled trial
Total number of patients
randomized
Approximately 410


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Number of patients on 
each treatment
60 patients in each of the six BI 456906/placebo dose groups
50 patients in the semaglutide group
Diagnosis
Type 2 diabetes mellitus
Main inclusion- and 
exclusion criteria
Inclusion criteria:
1. Signed and dated written informed consent in accordance 
with ICH GCP and local legislation.
2. Male and female patients 18 years to 75 years (both 
inclusive) of age on the day of signing informed consent.
3. Diagnosis of T2DM at least 6 months prior to informed 
consent.
4. HbA1c 7.0%-10.0% (both inclusive) at screening.
5. Treatment with a stable dose of metformin ≥ 1000mg/day
for at least 3 months prior to screening.
6. Body mass index (BMI) 25 kg/m2-50 kg/m2 (both inclusive) 
at screening.
7. Women of childbearing potential must be ready and able to 
use highly effective methods of birth control.
Exclusion criteria:
1. Patients with type 1 diabetes.
2. Exposure to semaglutide, or other GLP-1R agonists
(including combination products) within 3 months prior to 
screening, or any previous exposure to BI 456906.
3. Any additional oral anti-hyperglycemic medication beyond 
metformin within 3 months prior to screening. 
4. Use of insulin for glycemic control within 12 months prior 
to screening.
5. Resting Heart Rate >100 bpm or blood pressure ≥160/95 
mm Hg at screening.
6. A marked prolongation of QT/QTc (Fridericia) interval or 
any other clinically significant ECG finding at screening.
7. Body weight change of +/- 5% or more in the past 3 months
or on anti-obesity therapies at any time during the 6 months 
prior to screening.
8. Continuous oral pharmacotherapy to treat any clinical 
condition during the trial. Following medications are 
allowed:

metformin

anti-hypertensives*

hormone replacement therapy including thyroid 
hormone

lipid lowering

proton pump inhibitors

H2 blockers for GERD

analgesics 

sleep medications

antihistamines


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
selective alpha receptor blocker for benign prostatic 
hyperplasia
Patients must be on a stable dose for at least 3 months prior 
to screening.
*Any medications known to cause heart block or 
bradycardia such as beta-blockers, verapamil and diltiazem 
are excluded unless used to treat heart rate control or 
hypertension. 
9. Any suicidal behavior in the past 2 years, any suicidal 
ideation of type 4 or 5 in the C-SSRS in the past 3 months at 
screening.
10. Chronic or relevant acute infections.
11. Women who are pregnant, nursing, or who plan to become 
pregnant while in the trial. 
Test products
BI 456906 or matching placebo
dose
Multiple doses
mode of 
administration
Subcutaneous injection
Comparator product
Semaglutide
dose
Multiple doses
mode of
administration
Subcutaneous injection
Duration of treatment
16 weeks
Statistical methods
For the primary analysis, the analyses for dose-finding will be 
performed using multiple comparison and modelling techniques
(MCPMod) whereby several possible dose response models
(patterns) will be evaluated, while keeping full control of the type I 
error at 2.5%, one-sided to identify the best-fitting model or subset 
of models.  To account for the repeated nature of the data and the 
covariates in the model, mixed model repeated measures (MMRM)
analysis will be carried out and covariate adjusted fixed effect 
estimates of average response for each dose group and the 
covariance matrix will be extracted from the fit and used for 
MCPMod analysis.  The analysis will be repeated for the relative 
body weight change from baseline to 16 weeks. Descriptive 
statistics will be presented for primary and secondary endpoints.


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FLOW CHART
Trial Period
Screening
Treatment Period
Follow-
up29
Visit1
13
2
3
4
5
6
7
8
94
105
116
127
(EOT)
13
Days
-14 days
1
8
15
22
29
36
43
50
78
106
113
141
Study Week2
- 2 weeks
Week 
1
Week 
2
Week 
3
Week 
4
Week 
5
Week 
6
Week 
7
Week 
8
Week 
12
Week 
16
Week 
17
Week 
21
Time window for visits
N/A
± 1
day
± 1
day
±1
day
± 1
day
± 1
day
± 1
day
± 1
day
± 2
days
± 2
days
± 2
days
+ 4
days
Informed consent8
X
Demographics
X
Medical history
X
Inclusion/Exclusion
X
X
Physical examination
X
X
X
X
Pregnancy testing9
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Body Weight10
X
X
X
X
X
X
X
X
X
X
X
X
X
Waist circumference11
X
X
X
X
Laboratory tests (safety labs)12
X
X
X
X
X
X
X
X
HbA1c
X
X
X
X
X
X
X
X
12-lead ECG13
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomization
X
Medication kit allocation (IRT)14
X
X
X
X
X
X
X
X
X
X
Study drug administration15
X
X
X
X
X
X
X
X
X
X
s.c., injection training16
X
X
X
Check injection site reactions
X
X
X
X
X
X
X
X
X
X
X
X
Blood sampling for PK17
X
X
X
X
X
X
X
X
X
X
X
X


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FLOW CHART (cont.)
Trial Period
Screening
Treatment Period
Follow-
up29
Visit1
13
2
3
4
5
6
7
8
94
105
116
127
(EOT)
13
Days
-14 days
1
8
15
22
29
36
43
50
78
106
113
141
Week2
- 2 weeks
Week 
1
Week 
2
Week 
3
Week 
4
Week
5
Week 
6
Week
7
Week 
8
Week 
12
Week 
16
Week 
17
Week 
21
Time window for visits
N/A
± 1
day
± 1
day
±1
day
± 1
day
± 1
day
± 1
day
± 1
day
± 2
days
± 2
days
± 2
days
+ 4
days
Blood sampling for ADA/NAb18
X
X
X
X
X
X
X
Blood sampling, biomarkers19, 20
X
X
X
X
X
X
Blood sampling for 
pharmacogenomics
(pre-specified)21
X
Blood sampling for biobanking22
(unspecified, optional)
X
X
Diet/exercise counseling30
X
X
X
X
X
X
X
X
Dispense patient diary (IMP-self 
administration)
X
X
X23
Dispense SMBG patient diary & 
review24
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense blood glucose 
monitor24
X
   
AEs/SAEs/AESIs
X
X
X
X
X
X
X
X
X
X
X
X
X
C-SSRS27
X
X
X
X
X
X
X
X
X
X
X
X
X
Medication compliance check28
X
X
X
X
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
Completion of participation
X


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Footnotes for Flow Chart
1.
In dose groups 5 and 6 (twice weekly dosing), every 2nd dose (of a particular week) taken by the patient at a clinic visit, will be recorded in eCRF under 
visit 2A, 3A, 4A, 5A, 6A, 7A, and 8A.  Any AEs or changes in concomitant medications, and self monitoring of blood glucose (SMBG) diary will be 
checked when patient comes to the clinic for the 2nd dose.
2.
Study week indicates start of the week.
3.
Screening visit can be less than 14 days from the randomization.   Before randomization, investigator should ensure that all safety lab results and central 
ECG reading are available, and all required medical records are available to ensure that patient has met all the inclusion criteria and does not meet any of 
the exclusion criteria.
4.
All patients will self administer the injections (twice a week for dose groups 5 and 6) at home between visits 9 and 10 (Day 57, Day 64, and Day 
71). Patients will have the option to visit the clinic on the specified days (±1 day), if they want the injection to be administered by qualified staff 
at the clinic.  Patients will maintain a diary (dispensed at the site) to record date, time, and site of injection.  Patients should also make note of 
any injection site reactions in the diary.
5.
All patients will self administer the injections (twice a week for dose groups 5 and 6) at home between visits 10 and 11 (Day 85, Day 92, and 
Day 99). Patients will have the option to visit the clinic on the specified days (±1 day), if they want the injection to be administered by qualified
staff at theclinic.  Patients will maintain a diary (dispensed at the site) to record date, time, and site of injection.  Patients should also make note 
of any injection site reactions in the diary.
6.
In dose groups 5 and 6 (twice a week dosing), patients will self administer the second dose of the injections at home between visits 11 and 12 
(Day 109 or Day 110). Patients will have the option to visit the clinic on the specified day (±1 day), if they want the injection to be administered 
by qualified staff at theclinic.  Patients will maintain a diary (dispensed at the site) to record date, time, and site of injection.  Patients should 
also make note of any injection site reactions in the diary.
7.
Patients in dose groups 5 and 6 (twice weekly dosing) will also have the end of treatment (EOT) visit scheduled on Day 113 as in other dose groups.  If 
patients discontinue from the trial during the treatment period, they should complete the EOT visit, and complete trial procedures associated with EOT visit 
before entering the follow-up period.
8.
Patient must be informed and written informed consent obtained prior to starting any screeningprocedures.
9.
Serum pregnancy test at screening visit (test performed at central lab), and urine pregnancy test in the clinic for other visits.  Please see additional 
guidelines in section 6.1.
10. Body mass index will be calculated automatically.  For weight measurement, follow guidelines in section 5.1.2.
11. For waist circumference measurement, follow guidelines in section 5.1.2.
12. Fasting is not required at visits when safety labs are drawn (including screening visit).  However, some of these visits will coincide with visits when 
samples for biomarker analysis are collected or PRO questionnaires are administered when fasting is required (see footnote 20).


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13. ECG should be recorded in triplicate (i.e. three single ECGs recorded within 180 seconds) at the screening visit.  ECGs should be recorded before blood 
samples are taken.  ECG recording may be repeated by investigator for medical or quality reasons. For ECG measurements, follow guidelines in section 
5.2.4.
14. At visits 9, 10, and 11, IRT will assign medication kits for use at home until the next scheduled clinic visit.  For example, at visit 9, kits assigned will 
include the medication to be administered in the clinic for visit 9 and all the medication needed for the patient for use at home until visit 10.  IRT will 
assign semaglutide kits only at visits 2, 6, 9, and 10.
15. Patients randomized to dose groups 5 and 6 will be dosed twice a week.  The first dose of each week will be administered on the days shown in the Flow 
Chart, and all visit procedures for that day will be completed as indicated in the Flow Chart.  The 2nd dose of each week will be administered 3 or 4 days 
after the 1st dose of each week.  Patient will visit the clinic for the 2nd injection except between visits 9 and 10, between visits 10 and 11, and between visits 
11 and 12.
16. Patients should be trained on how to self administer the medication provided as pre-filled syringes.  If the patient is not willing to self administer the 
injections, the patient should be given the option to visit the clinic and have the medication administered by the qualified site staff.  Training at visit 
11 is only for patients in dose groups 5 and 6 (twice weekly dosing).
17. Pre-dose PK samples (except Visits 12 and 13). PK samples will not be collected on dosing days between visits 9 and 10, between visits 10 and 11, and 
between visits 11 and 12.  PK samples will not be collected when patients in dose groups 5 and 6 (twice a week dosing) come to the clinic for their 2nd
dose (see footnote 1).
18. Blood sample for anti-drug antibody (ADA) analysis and NAbs (see section 5.4).  Blood samples for ADA analysis and NAbs will not be taken from 
patients in dose group 7 (semaglutide, open-label).
19. Blood samples for the exploratory biomarkers. The first biomarker sample at randomization visit should be taken before the administration of study 
drug as this will serve as the baseline.
20. Patients should be instructed to come in the fasting state after at least 10 hours without regular food intake, at the visits biomarker samples are drawn, or
at the visits when PRO questionnaires are completed.  On days when fasting is required, patients should plan on taking their metformin dose (if 
applicable) after the blood draws and PRO questionnaires are completed.
21. Sample for pre-specified pharmacogenomics testing.  This sample is collected from all patients participating in the study.
22. Blood samples for biobanking.  Samples collected at visit 2 and end of treatment.  Samples collected for biobanking at end of treatment will include 
only two samples (1 x 4 ml K2-EDTA tube and 1 x 4 ml serum tube). Sample for DNA banking will not be collected at the end of treatment visit.  This 
testing is optional for the patients, and the samples are collected only if the patient has signed a separate consent form (see section 5.6).
23. Only for patients in dose groups 5 and 6 (twice a week dosing).
24. All patients will be provided with SMBG monitoring device for use at home during the study.  Patients may also use their own device for self 
monitoring of blood glucose. Patients will enter measurements from the blood glucose monitor in a patient diary.  Site staff will review the diary at each 
clinic visit.
25.
 
 


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27. C-SSRS, Columbia-Suicide Severity Rating Scale.  Questionnaires will be provided in the ISF.  The C-SSRS will be administered at the screening visit using 
the “baseline/screening” version.  After the screening visit, the assessment “since last visit” will be performed at clinic visits.
28. Medication compliance (study drug administration in the clinic and at home) should be monitored throughout the treatment period to ensure the required 
compliance criteria are met (section  4.3).
29. Visit 13, Follow-up visit is the End of Study visit.
30. Diet and exercise counseling should be performed per local guidelines.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................5
TABLE OF CONTENTS ......................................................................................................10
ABBREVIATIONS................................................................................................................14
1.
INTRODUCTION...............................................................................................16
1.1
MEDICAL BACKGROUND.............................................................................16
1.2
DRUG PROFILE................................................................................................17
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................20
1.4
BENEFIT - RISK ASSESSMENT.....................................................................20
1.4.1
Benefits.................................................................................................................20
1.4.2
Risks .....................................................................................................................21
1.4.3
Discussion.............................................................................................................22
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................23
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........23
2.1.1
Main objectives....................................................................................................23
2.1.2
Primary endpoint................................................................................................23
2.1.3
Secondary endpoints...........................................................................................23
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................25
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................25
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS.........................................................................................26
3.3
SELECTION OF TRIAL POPULATION .......................................................26
3.3.1
Main diagnosis for trial entry ............................................................................26
3.3.2
Inclusion criteria .................................................................................................27
3.3.3
Exclusion criteria ................................................................................................27
3.3.4
Withdrawal of patients from treatment or assessments..................................30
3.3.4.1
Discontinuation of trial treatment .........................................................................31
3.3.4.2
Withdrawal of consent to trial participation .........................................................32
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................32
4.
TREATMENTS...................................................................................................33
4.1
INVESTIGATIONAL TREATMENTS ...........................................................33
4.1.2
Selection of doses in the trial and dose modifications......................................35
4.1.3
Method of assigning patients to treatment groups...........................................36
4.1.4
Drug assignment and administration of doses for each patient......................37


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4.1.5
Blinding and procedures for unblinding...........................................................39
4.1.5.1
Blinding.................................................................................................................39
4.1.5.2
Unblinding and breaking the code ........................................................................39
4.1.6
Packaging, labelling, and re-supply...................................................................40
4.1.7
Storage conditions...............................................................................................40
4.1.8
Drug accountability.............................................................................................40
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................41
4.2.1
Other treatments and emergency procedures..................................................41
4.2.2
Restrictions ..........................................................................................................42
4.2.2.1
Restrictions regarding concomitant treatment ......................................................42
4.2.2.2
Restrictions on diet and life style..........................................................................43
4.2.2.3
Contraception requirements..................................................................................43
4.3
TREATMENT COMPLIANCE........................................................................43
5.
ASSESSMENTS..................................................................................................45
5.1
ASSESSMENT OF EFFICACY........................................................................45
5.1.1
HbA1c...................................................................................................................45
5.1.2
Weight and waist circumference .......................................................................45
5.2
ASSESSMENT OF SAFETY.............................................................................46
5.2.1
Vital signs.............................................................................................................46
5.2.2
Physical examination ..........................................................................................46
5.2.3
Safety laboratory parameters ............................................................................46
5.2.4
Electrocardiogram ..............................................................................................48
5.2.5
Other safety parameters.....................................................................................49
5.2.5.1
Suicidal risk assessment and reporting.............................................................49
5.2.5.2
Self monitoring of blood glucose........................................................................50
5.2.6
Assessment of adverse events.............................................................................51
5.2.6.1
Definitions of adverse events................................................................................51
5.2.6.2
Adverse event collection and reporting ................................................................55
 
5.4
IMMUNOGENICITY ........................................................................................57
5.4.1
Timing of immunogenicity measures ................................................................57
5.5
ASSESSMENT OF BIOMARKERS.................................................................58


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5.8
APPROPRIATENESS OF MEASUREMENTS..............................................60
6.
INVESTIGATIONAL PLAN.............................................................................62
6.1
VISIT SCHEDULE.............................................................................................62
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................63
6.2.1
Screening and run-in period ..............................................................................63
6.2.2
Treatment period ................................................................................................64
6.2.3
Follow-up period and trial completion..............................................................65
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................66
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................66
7.2
PLANNED ANALYSES.....................................................................................66
7.2.1
General considerations .......................................................................................66
7.2.2
Primary endpoint analyses.................................................................................66
7.2.3
Secondary endpoint analyses .............................................................................68
7.2.5
Safety analyses.....................................................................................................71
7.2.6
Other Analyses ....................................................................................................71
7.2.7
Interim Analyses .................................................................................................71
7.3
HANDLING OF MISSING DATA ...................................................................72
7.4
RANDOMIZATION...........................................................................................72
7.5
PATIENTS DETERMINATION OF SAMPLE SIZE ....................................72
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........73
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................73
8.2
DATA QUALITY ASSURANCE ......................................................................74
8.3
RECORDS...........................................................................................................74
8.3.1
Source documents ...............................................................................................74
8.3.2
Direct access to source data and documents.....................................................75
8.3.3
Storage period of records ...................................................................................75
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................76
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........76
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................76
8.6
TRIAL MILESTONES.......................................................................................76
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................77
9.
REFERENCES....................................................................................................79
9.1
PUBLISHED REFERENCES............................................................................79
9.2
UNPUBLISHED REFERENCES......................................................................80
10.
APPENDICES.....................................................................................................81
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................82


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11.1
GLOBAL AMENDMENT 1 ..............................................................................82


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ABBREVIATIONS
ADA
Anti-drug antibody
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area under the curve
BI
Boehringer Ingelheim
BMI
Body mass index
BPM
Beats per minute
CCS
Canadian cardiovascular society
CK
Creatine kinase
Cmax
Maximum (or peak) serum concentration
COVID-19
Corona virus disease 2019
CRA
Clinical research associate
CRO
Contract research organization
C-SSRS
Columbia-suicide severity rating scale
CTR
Clinical trial report
DDPi
Dipeptidyl peptidase inhibitor
DILI
Drug-induced liver injury
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eDC
Electronic data capture
eCRF
Electronic case report form
EDTA
Ethylenediaminetetraacetic acid
eGFR
Estimated glomerular filtration rate
ELF
Enhanced liver fibrosis
EOT
End of treatment
EU
European Union
EudraCT
European clinical trials database
FBG
Fasting blood glucose
FDA
Food and Drug Administration
FGF-21
Fibroblast growth factor 21
GCGR
Glucagon receptor
GCP
Good clinical practice
GERD
Gastric esophageal reflux disease
GI
Gastrointestinal
GLP-1R
Glucagon-like-peptide 1 receptor
Hb
Hemoglobin
HbA1c
Glycosylated hemoglobin A1c
HDL
High density lipoprotein
HIV/AIDS
Human immunodeficiency virus/acquired immune deficiency
syndrome


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ICH
International conference on harmonization
IEC
Independent ethics committee
IFU
Instructions for use
IRB
Institutional review board
IRT
Interactive response technology
ISF
Investigator site file
LDL
Low density lipoprotein
LPLT
Last patient last treatment
MCPMod
Multiple comparison and modelling techniques
MMRM
Mixed model repeated measures
MRD
Multiple rising dose
NAb 
Neutralizing antibody 
NTI
Narrow therapeutic index
NYHA
New York health association
PD
Pharmacodynamics
PK
Pharmacokinetics
PK/PD
Pharmacokinetics/Pharmacodynamics
PoCC
Proof of clinical concept
PRO
Patient reported outcome
Qw
Quantum Well (once a week)
QT
Time between start of the Q-wave and end of the T-wave     
in an electrocardiogram
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate using the method of
Fridericia
s.c.
Subcutaneous
SAE
Serious adverse event
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SD
Standard deviation
SGLT-2i
Sodium-glucose cotransporter-2 inhibitors
SMBG
Self monitoring of blood glucose
SMC
Safety monitoring committee
SOP
Standard operating procedure
SUSARs
Suspected unexpected serious adverse reactions
SU
Sulfonylureas
T2DM
Type 2 diabetes mellitus
 
TSAP
Trial statistical analysis plan
ULN
Upper limit normal
WBC
White blood cells
WOCBP
Women of child-bearing potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Type 2 diabetes mellitus (T2DM) is a highly prevalent disease affecting 30.3 million 
Americans, or 9.4% of the US population in 2015.  According to the American Diabetes 
Association, about 1.5 million Americans are newly diagnosed with type 2 diabetes every 
year.
T2DM is associated with a variety of medical conditions, including all components of the 
metabolic syndrome, obesity, cardiovascular, pulmonary, gastrointestinal (GI), endocrine, 
musculo-skeletal as well as psychosocial diseases.  Although some of these conditions can be 
treated by currently available medications, others including obesity are very difficult to treat 
and pose a significant challenge to caregivers. T2DM is also an important health condition 
for the aging population, as approximately one-quarter of people over the age of 65 years 
have T2DM and one-half of older adults have prediabetes. Patients with T2DM have higher 
rates of premature death, functional disability, and coexisting illnesses.
The first treatment for T2DM is often dietary intervention, physical activity, and weight loss. 
Most of the time these measures are not enough to bring blood glucose levels and body 
weight down to the normal range.  The next step is taking a medicine that lowers blood 
glucose levels. Recommended first line therapy is metformin, followed by other oral anti-
hyperglycemic medication or injectable medication such as glucagon-like-peptide 1 receptor 
agonist or insulin.
The proportion of patients with T2DM who achieve recommended glycosylated hemoglobin 
A1c (HbA1c), blood pressure, and low density lipoprotein (LDL) cholesterol levels has 
increased in recent years.  Nevertheless, a 2013 report found that 33–49% of patients still did 
not meet general targets for glycemic, blood pressure, or cholesterol control, and only 14% 
met targets for all three measures while also avoiding smoking. Therefore, T2DM still poses 
a significant clinical and economic burden to individuals and society. After adjusting for 
inflation, economic costs of T2DM increased by 26% from 2012 to 2017. This is attributed to 
the increased prevalence of T2DM and the increased cost for care per person with T2DM
(P19-01871).
There is strong and consistent evidence that obesity management is beneficial in the 
treatment of type 2 diabetes.  In patients with type 2 diabetes who have obesity/overweight, 
modest and sustained weight loss has been shown to improve glycemic control and to reduce 
the need for glucose-lowering medications.
BI 456906 is a dual glucagon-like-peptide 1 receptor (GLP-1R) and glucagon receptor 
(GCGR) agonist that is being evaluated for the indications of glycemic control in T2DM and 
chronic weight management in obesity/overweight. GLP-1R agonism achieves glucose 
lowering by inducing glucose-dependent insulin-secretion acting at the pancreatic β-cell.  In 
addition, GLP-1R agonists lower body weight by the inhibition of food intake and also by 
delaying gastric emptying and intestinal transit. GCGR agonism is expected to reduce body 


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weight by increasing energy expenditure, and might positively affect lipid metabolism 
resulting in lowering of plasma and liver triglycerides and plasma cholesterol.
In patients with T2DM and obesity/overweight, dual agonism at the GLP-1R and GCGR is 
anticipated to result in lower HbA1c and body weight (c14085752-06) that is expected to be 
of greater magnitude than compared to GLP-1R agonism alone.
1.2
DRUG PROFILE
Mode of action
s 
 
Semaglutide is a GLP-1R agonist indicated as an adjunct to diet and exercise to improve 
glycemic control in adults with T2DM. Semaglutide has demonstrated improved glycemic 
control and body weight loss. The most common adverse reactions, reported in ≥5% of 
patients treated with semaglutide are: nausea, vomiting, diarrhea, abdominal pain and 
constipation.  BI 456906 and semaglutide are considered as investigational medicinal product 
in this trial.


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For a more detailed description of the profile, please refer to the current Investigator’s 
Brochure for BI 456906, and the Summary of Product Characteristics (SmPC) or US Package 
Insert for semaglutide.
1.3
RATIONALE FOR PERFORMING THE TRIAL
BI 456906 is a dual GLP-1R and GCGR agonist being evaluated in the indications of
glycemic control in T2DM and chronic weight management in obesity/overweight.
This study is a 16-week phase 2 study to examine up to 6 dose levels of BI 456906 
administered once or twice weekly compared to placebo and open-label semaglutide in 
patients with T2DM who are inadequately controlled with diet and exercise and stable doses
of metformin. 
It is designed to evaluate safety, tolerability, PK and PD of BI 456906 in male and female 
patients with T2DM using multiple escalation schemes and doses, and will support dose 
selection for phase 3 clinical development of BI 456906.
1.4
BENEFIT - RISK ASSESSMENT
More information on the benefits, risks, and known AEs will be presented in the 
Investigator’s Brochure. The US prescribing information for semaglutide will be provided 
which gives more information on the known and expected benefits and risks of semaglutide.
1.4.1
Benefits
In the proposed patient population with T2DM, improvements in hyperglycemia and body 
weight are anticipated. The expected benefit for the selected patient population is improved 
glycemic control and body weight loss, and an improvement of the associated metabolic risk 
factors and patient reported outcomes.


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In addition, participation in the study is of major importance to the development of a new 
subcutaneous (s.c.) once-weekly medication, which might improve the future therapy in 
patients with T2DM and obesity/overweight.
1.4.2
Risks
The risk for patients caused by the study procedures and the risks related to the exposure to 
the study drug are reasonably low and do not outweigh the potential benefits. The expected 
side effects are known to be dose dependent, easy to monitor and manageable in clinical 
trials. 
Among the expected and well known side effects for GLP1-R agonist based therapies are: 

Gastrointestinal disorders

Metabolism and nutrition disorders

Cardiac disorders

Administration site conditions
These side effects can be reduced by careful dose escalation, are known to be dose 
dependent, are easy to monitor and manageable in clinical trials. 
In this study, the following safety measures will be applied in order to minimize the risk for 
trial patients:

An extensive safety laboratory will be performed.

Patients with severe hypoglycemia within 6 months prior to screening, or a history of 
hypoglycemia unawareness or poor recognition of hypoglycemic symptoms are 
excluded from the trial.

Self monitoring of blood glucose (SMBG) devices will be provided to patients 
(section 5.2.5.2). Patients can also use their own device.

Rescue medication in case of hyperglycemia can be initiated during the treatment 
period of the trial (section 4.2.1).

Patients in the placebo group will remain on standard of care that includes metformin 
therapy, and diet and exercise counseling.

There are no risks expected by stopping the study drug during the course of the trial.

Electrocardiogram (ECG) monitoring will be performed at screening, randomization 
and within predefined intervals during the trial, and criteria for heart rate, QT 
prolongation and cardiac conduction disorders are defined.

Dose adjustment in the highest weekly dose group and the highest twice weekly 
dosing group is allowed (section 4.1.2)

During the study, patients will be under medical observation and thoroughly 
monitored for both expected and unexpected AEs including administration and 
evaluation of the Columbia-Suicide Severity Rating Scale (C-SSRS).

Pediatric patients are excluded from the trial.

Females of childbearing potential who are pregnant, breast-feeding or intend to 
become pregnant or are not using an adequate contraceptive method throughout the 
trial including the 4-week follow-up period are excluded from the trial 
(section 4.2.2.3)


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Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure patients´ 
safety.
The mechanism of action of BI 456906, and available preclinical and clinical data for 
BI 456906 are not indicating an increased risk of infections. Based on the pharmacological 
mechanism of BI 456906, the review of the non-clinical and clinical data available so far for 
this compound, and considering the clinical and post-marketing data available from the 
GLP-1 receptor agonists available on the market, there is no indication that BI 456906 could 
increase the risk of severe viral infections. 
Patient participation in this trial will be consistent with local public health guidance and
regulations.  Patients with symptoms of SARS-CoV-2 infection will be excluded from 
participation in the trial.  During participation in the study, if a patient is diagnosed with 
COVID-19, or is suspected to have SARS-CoV-2 infection when diagnostic testing is not 
available, trial treatment will be terminated and the patient will be discontinued from the 
study. 
If local regulations require a SARS-Cov-2 test for patients to participate in the trial, the site 
investigator may order a polymerase chain reaction (PCR) test or another test to diagnose 
acute infection that will be performed locally at screening. Patients who test positive will be 
informed about the test result and they will not be eligible to participate in the trial in 
accordance to exclusion criterion 27 in the protocol.
A safety monitoring committee (SMC) will be established, comprising of trial investigators, 
members of the BI trial team, and trial independent members. The SMC will review blinded 
safety data at regular intervals (section 8.7).
1.4.3
Discussion
BI 456906 was well tolerated in safety pharmacology and toxicology studies and the main 
effects seen reflected the intended pharmacology of the compound. 
 
In a multiple rising dose trial with weekly dose escalation up to 3.0 mg q.w., BI 456906 
did not reveal relevant safety signals although drug-related gastrointestinal and cardiac side 
effects were reported. All side effects were expected in nature such as nausea, dyspepsia, 
decreased appetite, heart rate increase and conduction disorders and are in line with other
GLP-1 R agonist based therapies. Most of the reported AEs were mild or moderate in 
intensity. Severe AEs diarrhea (2) and vomiting (1) were reported for 3 out of 67 patients 
treated with BI 456906. No deaths, SAEs, protocol-specified AESIs, or other significant AEs
were reported in this trial to date.
The expected benefit for the selected patient population is improved glycemic control and 
body weight loss, and an improvement of the associated metabolic risk factors and patient 
reported outcomes.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective of the trial is to demonstrate a dose-relationship of BI 456906 on HbA1c 
(absolute change) from baseline to 16 weeks relative to placebo in patients with T2DM.  
Secondary objectives are to assess the effect of BI 456906 on change in body weight. An 
open-label comparator (semaglutide) will allow for comparison of the effects against a pure 
GLP-1R agonist.
This trial is 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 this purpose, a multiple comparison procedure 
with modelling techniques (MCPMod) approach is considered.
2.1.2
Primary endpoint

Absolute change in HbA1c from baseline to 16 weeks.
2.1.3
Secondary endpoints
1. The relative body weight change from baseline to 16 weeks (key secondary endpoint).
2. The absolute body weight change from baseline to 16 weeks.
3. The absolute change in waist circumference from baseline to 16 weeks.
4. The percentage of patients with 5% or greater body weight loss from baseline to
16 weeks.
5. The percentage of patients with 10% or greater body weight loss from baseline to
16 weeks.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This trial is a multicenter, randomized, double-blinded within dose groups, parallel, 
placebo-controlled clinical trial with dose-escalation schemes in patients with T2DM.  
In addition, an open-label GLP-1R (semaglutide) group will be included as benchmark to 
compare response curves and support assumptions for phase 3 design. A schematic 
illustration of the dose escalation scheme is presented in Figure 3.1: 1. The different 
treatment arms and the doses are also presented in Table 4.1.4: 1.
Figure 3.1: 1 Dose escalation scheme
Additional exploratory endpoints will include changes in liver biomarkers, lipid profiles, 
anti-drug antibody measurements, as well as patient reported outcome measures. 


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The results of this dose-finding study will serve as PoCC in patients with T2DM, and will 
provide the basis for decision making to proceed to the next phase based on safety,
tolerability, and also efficacy including HbA1c and body weight. In addition, the dose 
escalation scheme identified in this trial is expected to be extrapolated to associated 
indications such as chronic weight management. Due to the fact that GLP-1R agonist based 
therapies are associated with gastrointestinal side effects like nausea and vomiting, all doses 
above 0.6 mg will be reached through dose escalation.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS
This trial is designed to evaluate safety, tolerability, PK and PD of BI 456906 in
male and female patients with T2DM using multiple escalation schemes and doses, and will 
support dose selection for phase 3 clinical development of BI 456906. To compare the effect 
on glycemic control and body weight reduction to established GLP-1R agonists, an 
open label active comparator (semaglutide) was chosen. Semaglutide currently represents the
most efficacious GLP-1R agonist with once-weekly posology and is approved in the 
indication for glycemic control in patients with T2DM. To optimize for the well known 
gastrointestinal side effects with GLP-1 based therapies, especially at the beginning of 
treatment, 6 dose escalation schemes with different dose escalation phases were selected to 
define the most favorable dose escalation in terms of tolerability and PD for phase 3 trials.
3.3
SELECTION OF TRIAL POPULATION
It is planned to screen 615 patients and randomize 410 patients with type 2 diabetes in this 
clinical trial. Enrollment will be competitive and patients will be enrolled in approximately 
80 study sites in multiple countries. Additional study sites may be added for patient 
recruitment, or initiated sites may be closed for lack of enrollment. Although the trial is 
targeting glycemic control as its primary endpoint, many patients with elevated body mass 
index (BMI) are expected to enter the trial, which will benefit in the assessment of weight 
loss criteria as secondary endpoints.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the investigator site file at the investigational site irrespective of whether or not 
they have been treated with investigational drug. If a patient is enrolled in error (does not 
meet all inclusion criteria or meets one or more exclusion criteria on the day of enrollment), 
the sponsor should be contacted immediately by the investigator to determine whether the 
patient may continue in the trial. If both agree that it is medically appropriate to continue, the 
investigator must obtain documented approval from the sponsor to allow the wrongly 
enrolled patient to continue in the trial.
3.3.1
Main diagnosis for trial entry
Patients with T2DM who have insufficient glycemic control despite diet, exercise and 
metformin treatment.


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Please refer to section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the inclusion and exclusion criteria.
3.3.2
Inclusion criteria
1. Signed and dated written informed consent in accordance with ICH GCP and local 
legislation prior to admission to the trial.
2. Male and female patients 18 years to 75 years (both inclusive) of age on the day of 
signing informed consent.
3. Diagnosis of T2DM at least 6 months prior to informed consent.
4. HbA1c 7.0%-10.0% (both inclusive) at screening.
5. Treatment with a stable dose of metformin ≥ 1000mg/day (either immediate release or 
extended release) for at least 3 months prior to screening.
6. BMI 25 kg/m2-50 kg/m2 (both inclusive) at screening.
7. Women of childbearing potential (WOCBP)1 must be ready and able to use highly 
effective methods of birth control per ICH M3 (R2) that result in a low failure rate of 
less than 1% per year when used consistently and correctly. A list of contraception 
methods meeting these criteria is provided in the patient information and in section 
4.2.2.3.
3.3.3
Exclusion criteria
1. Patients with type 1 diabetes.
2. Exposure to semaglutide, or other GLP-1R agonists (including combination products) 
within 3 months prior to screening, or any previous exposure to BI 456906, or history 
of relevant allergy or hypersensitivity (including allergy, intolerability or lack of 
efficacy to study drug or drugs that belong to the GLP-1R agonist class).
3. Any additional oral anti-hypergylcemic medication beyond metformin (e.g. SUs, 
DDPi, SGLT-2i, GLP-1s, a-glucosidase inhibitors, meglitinides) within the 3 months 
prior to screening.
4. Use of insulin for glycemic control within 12 months prior to screening.  Short-term
(up to 14 days) use of insulin for acute conditions (e.g. hospitalization and/or surgery) 
is allowed. 
5. More than one episode of ketoacidosis or hyperosmolar state requiring hospitalization 
within 6 months prior to screening.
6. More than one episode of severe hypoglycemia, defined as the occurrence of 
neuroglycopenic symptoms requiring the assistance of another person for recovery in 
the 6 months prior to screening, or any history of hypoglycemia unawareness or poor 
recognition of hypoglycemic symptoms in the 6 months prior to screening.
7. Resting Heart Rate >100 beats per minute (bpm) or blood pressure ≥160/95 mm Hg at 
screening, or renal artery stenosis or evidence of labile blood pressure including 
                                                
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Tubal ligation is NOT a method of permanent sterilization.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.


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symptomatic hypotension, or history of relevant orthostatic hypotension, fainting 
spells, or blackouts.
8. A marked prolongation of QT/QTc (Fridericia) interval that are greater than 450 
ms at the screening or at the randomization visit) or any other abnormal or clinically 
significant ECG finding at screening (e.g., type 2 second-degree AV block 
(Type Mobitz II) or third-degree AV block).
9. Heart rhythm disturbances (e.g., bradycardia with baseline HR < 50 bpm (in the 
absence of medications that lower the heart rate), supraventricular tachycardia or 
tachyarrhythmia (e.g. atrial fibrillation, atrial flutter, or ventricular 
tachycardia), considered by the investigator indicative of relevant cardiac disease or 
with abnormalities that may interfere with the interpretation of changes in ECG 
intervals at screening. Family history of long QT-syndrome, use of prescription or 
over-the-counter medications known to significantly prolong the QT or QTc interval 
at screening. 
10. Any of the following conditions or procedures within the last 6 months prior to 
screening: myocardial infarction, unstable angina, clinically relevant coronary artery 
disease (e.g. CCS grading of Angina pectoris grade III and IV), coronary artery 
bypass graft, urgent percutaneous coronary intervention (diagnostic angiograms and 
elective coronary interventions are permitted), transient ischaemic attack, 
cerebrovascular accident (stroke) or decompensated congestive heart failure.
11. History or currently diagnosed with congestive heart failure, New York Health 
Association (NYHA) class III-IV. History of symptomatic ventricular tachycardia, or 
history of type 2 second degree AV block (Type Mobitz II) or third degree AV block.
12. Body weight change of +/- 5% or more in the past 3 months or on anti-obesity 
therapies at any time during the 6 months prior to screening (including all kinds of 
medication and weight loss surgery, aggressive diet regimen, etc.).
13. Ongoing oral pharmacotherapy treatments or within 3 months prior to screening. 
Examples of excluded medications: 

anti-hyperglycaemic agents (except metformin)

anti-depressants 

central nervous system stimulants 

anti-psychotics

anticonvulsants (except gabapentin)

diuretics (except thiazides)

systemic corticosteroids 

antithrombotics (except low dose aspirin)
14. Major surgery (according to the investigator’s assessment) performed within 
12 weeks prior to randomization or planned within 6 months after screening, e.g., hip 
replacement.
15. Prior surgery of the GI tract (including minimally invasive/endoscopic bariatric 
devices, bariatric surgery) that could interfere with body weight except appendectomy, 
simple hernia repair, and simple cholecystectomy.
16. Known significant autonomic neuropathy as evidenced by urinary retention, resting 
tachycardia, orthostatic hypotension, diabetic diarrhoea, diagnosis of gastroparesis, or 
clinically significant gastric emptying abnormalities. 


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17. Acute proliferative diabetic retinopathy or expected medical intervention/surgery 
during the trial.
18. History of chronic or acute pancreatitis or elevation of serum lipase/amylase 
> 2x upper limit normal (ULN), or serum triglyceride levels of > 500 mg/dl at 
screening.  Doses for lipid lowering medication must be stable for 3 months prior to 
screening.
19. Estimated glomerular filtration rate (eGFR) of <45 mL/min/1∙73 m2, or a level of 
serum creatinine or eGFR that would contraindicate the use of metformin.
20. Have calcitonin ≥20 pg/mL at screening.
21. Have symptoms of liver disease, chronic or acute hepatitis, or serum levels of alanine 
aminotransferase (ALT), aspartate aminotransferase (AST) above 2.5 x ULN at 
screening.
22. Personal or family history of medullary thyroid carcinoma or history of multiple 
endocrine neoplasia syndrome type 2, acromegalie, morbus cushing or 
pheochromocytoma, manifest hypo- or hyperthyroidism at screening.
23. Continuous oral pharmacotherapy to treat any clinical condition during the trial.  
Following medications are allowed:

metformin

anti-hypertensives*

hormone replacement therapy including thyroid hormone

lipid lowering

proton pump inhibitors

H2 blockers for GERD

analgesics 

sleep medications

antihistamines

selective alpha receptor blocker for benign prostatic hyperplasia
Patients must be on a stable dose of continuous oral pharmacotherapy for at 
least 3 months prior to screening.
*Any medications known to cause heart block or bradycardia such as beta-
blockers, verapamil and diltiazem are excluded unless used to treat heart rate 
control or hypertension. 
24. Use of drugs with narrow therapeutic index (NTI), except levothyroxine (see 
exclusion criteria 23). A list of NTI drugs can be found under the link 
https://www.drugbank.ca/categories/DBCAT003972. The list of NTI drugs will be 
provided in the investigator site file (ISF).
25. Diseases of the central nervous system (including but not limited to any kind of 
seizures or stroke), and other relevant neurological or psychiatric disorders.
26. Any suicidal behavior in the past 2 years, any suicidal ideation of type 4 or 5 in the 
C-SSRS in the past 3 months at screening.
27. Chronic or relevant acute infections (including but not limited to respiratory tract 
infections, urinary tract infection, bladder infection, diabetic foot syndrome, 


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enterocolitis, abscess, tuberculosis, meningitis, influenza, Epstein-Barr virus, 
HIV/AIDS, and hepatitis B or C).
28. A history of atopy (severe or multiple allergic manifestations) or clinically significant 
multiple or severe drug allergies, or intolerance to topical corticosteroids, or severe 
post treatment hypersensitivity reactions (including, but not limited to, erythema 
multiforme major, linear immunoglobulin A dermatosis, toxic epidermal necrolysis, 
anaphylaxis, angioedema, or exfoliative dermatitis).
29. History of organ transplant (corneal transplants [keratoplasty] is allowed).
30. Participation in another trial where an investigational drug has been administered 
within 60 days or 5 half-lives (whichever is longer), or involving an investigational 
device within 30 days prior to planned administration of study drug, or current 
participation in another trial involving administration of an investigational drug or 
device, or receiving other investigational treatments.
31. Alcohol, drug or confectionary liquorice abuse within the 3 months prior to screening
that would interfere with trial participation or any ongoing condition leading to a 
decreased compliance to study procedures or study drug intake in the investigator’s 
opinion.
32. Any documented active or suspected malignancy or history of malignancy within 
5 years prior to screening, except appropriately treated basal cell carcinoma of the 
skin.
33. Blood donation of 450 ml or more within 3 months prior to screening visit or any 
blood donation within the prior month.
34. Blood transfusion or severe blood loss within 3 months prior to screening, or have 
known haemoglobinopathy, haemolytic anemia, sickle cell anemia, or have a
hemoglobin (Hb) value <11 g/dl (males) and <10 g/dl (females), or any other 
condition known to interfere with HbA1c methodology.
35. Women who are pregnant, nursing, or who plan to become pregnant while in the trial. 
36. Patients who must or wish to continue the intake of restricted medications or any drug 
considered likely to interfere with the safe conduct of the trial.
37. Patients not expected to comply with the protocol requirements or not expected to 
complete the trial as scheduled (e.g. chronic alcohol or drug abuse or any other 
condition that, in the investigator’s opinion, makes the patient an unreliable trial 
participant).
38. Previous enrollment in this trial, except under the re-screening criteria for this study 
(section 6.2.1).
39. Patient had confirmed active infection with SARS-CoV-2 within the past 3 months
from screening.
3.3.4
Withdrawal of patients from treatment or assessments
Patients may discontinue trial treatment or withdraw consent to trial participation as a whole
(“withdrawal of consent”) with very different implications; please see section 3.3.4.1 and 
3.3.4.2 below. Every effort should be made to keep the patients in the trial. Measures to 
control the withdrawal rate include careful patient selection, appropriate explanation of the 
trial requirements and procedures prior to trial enrollment, as well as the explanation of the 
consequences of withdrawal. Patients should be made aware of potential anticipated GI 
symptoms during the trial, and investigator should provide guidance on how to avoid or 


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overcome them.  The decision to discontinue trial treatment or withdraw consent to trial
participation and the reason must be documented in the patient files and electronic case report 
form (eCRF).  If applicable, consider the requirements for AE collection reporting (please see 
sections 5.2.6.2.1 and 5.2.6.2.2).
3.3.4.1
Discontinuation of trial treatment
An individual patient will discontinue trial treatment if:

The patient wants to discontinue trial treatment, without the need to justify the decision.

An AE or clinically significant laboratory change or abnormality occurred that the 
investigator judges to warrant discontinuation of trial treatment. 

Sustained symptomatic hypotension or hypertension: For hypotension, episode of 
symptoms (such as light-headedness or dizziness) associated with a systolic blood 
pressure <100 mm Hg for > 60 minutes or for hypertension, episode of symptoms such as 
headaches, shortness of breath or nosebleeds associated with a systolic blood pressure > 
160 mm Hg in at least three consecutive measurements, each at least 30 minutes apart.

Clinically relevant changes in ECG (QTcF prolongation >500 ms or an increase of 60 ms 
versus baseline (randomization), or Type Mobitz II, or third-degree AV block), or any 
symptomatic AV block, newly developed atrial fibrillation, or atrial flutter that require 
medical intervention.

Sinus tachycardia (HR >120/min in two consecutive assessments 5 minutes apart) and/or
tachyarrhythmia (HR >110/min) or cardiac conditions requiring medical intervention.

Ventricular tachycardia in ECG or syncope.

Clinically relevant coronary artery disease (e.g. CCS grading of Angina pectoris grade III 
and IV or congestive heart failure, NYHA class III-IV).

The patient shows an elevation of AST and/or ALT ≥3-fold ULN combined with an 
elevation of total bilirubin ≥2-fold ULN (measured in the same blood sample) and/or 
needs to be followed up according to the ‘DILI checklist’ provided in the ISF.

The patient is diagnosed with COVID-19, or is suspected to have SARS-CoV-2 infection 
when diagnostic testing is not available (see section 5.2.3), trial treatment will be 
terminated and the patient will be discontinued from the study.  Positive test should be 
reported as an AE, and reason for premature withdrawal should be recorded as “other 
AE”.  If the patient tests negative, trial treatment will be resumed and the interruption of 
trial medication should be documented in the medication compliance page.

The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future.

The patient needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment for more than two weeks.  This includes agents 
that have been demonstrated to lower blood glucose and body weight (and includes 
rescue therapy). 

Change in dose of metformin for more than 2 consecutive weeks during the trial which 
includes the screening and treatment periods (change to an equivalent dose strength but 
with different release formulation is allowed).

Out of compliance with study drug (missing doses), please see section 4.3.


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
The patient can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events, other diseases, or pregnancy).
If the trial treatment is discontinued, the patient should remain in the trial to complete the 
EOT visit (visit 12) and follow-up period, and given his/her agreement, will undergo the 
procedures for the EOT and follow-up visit (visit 13) as outlined in the Flow Chart and 
section 6.2.3.
3.3.4.2
Withdrawal of consent to trial participation
Patients may withdraw their consent to trial participation at any time without the need to 
justify the decision.  If a patient wants to withdraw consent, the investigator should be 
involved in the discussion with the patient and explain the difference between trial treatment 
discontinuation and withdrawal of consent to trial participation, as well as explain the options 
for continued follow-up after trial treatment discontinuation, please see section 3.3.4.1 above.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial
site at any time for the following reasons:
1. Failure to meet expected enrollment goals overall or at a particular trial site.
2. Emergence of any efficacy/safety information invalidating the earlier positive 
benefit-risk-assessment that could significantly affect the continuation of the trial.
3. Sponsor decides to discontinue further development of the investigational product.
4. Deviations from GCP, the trial protocol, or the contract impairing the appropriate conduct 
of the trial.
The investigator or the trial site will be reimbursed for reasonable expenses incurred in case 
of trial termination (except in case of the fourth reason).


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4.
TREATMENTS


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4.1.2
Selection of doses in the trial and dose modifications
Doses from 0.3 mg to 3.6 mg were selected for weekly or twice-weekly dosing based on the 
following considerations: 
Safety and tolerability of BI 456906 was evaluated in healthy subjects and patients with 
obesity/overweight up to 16 weeks for doses up to 3.15 mg/week (daily dosing) and up to 4.8 
mg /week (weekly dosing), ie exceeding the highest dose planned for 1404-0002. The results 
indicate that the most common GI side effects could be mitigated by a more gradual increase 
in exposure.
The lowest dose of 0.3 mg in this trial was selected to support modelling of exposure-
response (MCPMod dose-response and population PK/PD modelling) and is predicted to 
achieve sub-therapeutic PD response comparable to placebo.
 
The selection of different dose levels and uptitration schemes to be investigated will support a 
robust dose-exposure-response analysis of multiple safety and efficacy measures to support 
selection of a suitable dose regimen for BI 456906.  This will allow for optimizing 


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benefit/risk (especially towards tolerability for GI side effects) for further clinical 
development.
Dose adjustment will be allowed for patients assigned only to the two highest dose groups
(dose groups 4 and 6, Table 4.1.4: 1). In dose groups 4 and 6, if a patient does not tolerate 
the target titrated dose at the end week 6 (visit 8) due to moderate to severe nausea and/or 
vomiting in the previous two weeks, and the investigator does not believe that the patient will 
tolerate the pre-planned dose with further increasing exposure, dose adjustment is allowed.
In dose group 4, the weekly target dose may be reduced to 1.8 mg at the beginning of week 7
 
 
 
If in the opinion of the investigator the patient does not tolerate the reduced dose in dose 
groups 4 and 6, patient will be discontinued from treatment, and the patient will complete the 
end of treatment visit, and the follow-up period.  Dose adjustment is allowed only at the end 
of week 6 (visit 7), and only in dose groups 4 and 6.  The actual dose received by the patient 
(weekly or twice weekly) should be recorded in the eCRF.
4.1.3
Method of assigning patients to treatment groups
After the assessment of all inclusion and exclusion criteria, each eligible patient will be 
randomized to one of the dose groups (dose groups 1 to 6 or semaglutide).  Within dose 
groups 1 to 6, patients will be randomized to active or placebo in a 5:1 ratio.  Semaglutide 
group (dose group 7) will be open label without placebo.  In each of the dose groups from 
1 to 6, a total of 60 patients will be randomized (50 active and 10 placebo).  A total of 
50 patients will be randomized to dose group 7, the open label semaglutide group.
For patients discontinued during the treatment period (does not include follow-up period), 
additional patients may be added. In each dose group, additional patients may be added after 
5 patients discontinue from the trial (starting with the 6th discontinued patient in that 
particular dose group). The number of patients added in each dose group should not exceed 
12 patients in dose groups 1 to 6, or 10 patients in dose group 7, which is 20% of the total 
planned randomized in each dose group. Patients in the screening period may be allowed to 
continue and be randomized in the study even if the maximum limit is reached in each dose 
group.  For dose groups 1 to 6, added patients will be randomized using Interactive Response 
Technology (IRT).  It is not guaranteed that the added patient will be assigned to the same 
treatment as the discontinued patient.
Randomization will be performed using the IRT at visit 2.  Randomization is not stratified in 
this trial.  Note that the medication kit number is different from the patient number (patient 


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number is generated during the screening visit via the IRT System, and medication kit 
numbers will be assigned via IRT).
4.1.4
Drug assignment and administration of doses for each patient
Table 4.1.4: 1 shows the dose groups and the dose escalation scheme within each dose group.
Table 4.1.4: 1
Dose escalation scheme*
Treatment
group
Weekly/twice weekly dosing in (mg)
Week 1
Week 2
Week 3
Week 4
Week 5
Week 6
Weeks 7-16
Dose group 1 
0.3
0.3
0.3
0.3
0.3
0.3
0.3
Dose group 2
0.3
0.3
0.6
0.6
0.9
0.9
0.9
Dose group 3
0.3
0.6
0.9
1.2
1.5
1.8
1.8
Dose group 4
0.6
0.6
1.2
1.2
1.8
2.4
2.7
Dose group 5
twice 
weekly**
0.3 (0.6)
0.3 (0.6)
0.6 (1.2)
0.6 (1.2)
0.9 (1.8)
0.9 (1.8)
1.2 (2.4)
Dose group 6
twice 
weekly**
0.3 (0.6)
0.6 (1.2)
0.9 (1.8)
1.2 (2.4)
1.5 (3.0)
1.5 (3.0)
1.8 (3.6)
Dose group 7 
Semaglutide
0.25
0.25
0.25
0.25
0.5
0.5
0.5/1.0§
*Patients in dose groups 1 to 6 will receive BI 456906 or placebo (blinded within dose 
groups).  All patients in the semaglutide group will receive semaglutide (open label).
**Weekly dose in parenthesis.
§Semaglutide dosing: 0.5 mg at Weeks 7 and 8; 1 mg at Weeks 9 to 16.
 
 
 
 
 
 
 
 


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COVID-19 pandemic: contingency plan:
During the COVID-19 pandemic, physical visits to the sites may need to be restricted to 
ensure patient safety.  Based on a thorough assessment of the benefits and risks, the 
investigator may still decide to continue the trial treatment, and trial medication may be 
shipped to the patient’s home if acceptable according to local law and regulations.  The 
decision to ship trial medication to the patient’s home will be made by the sponsor in 
consultation with the site investigator.  Vials containing BI 456906 or matching placebo 
cannot be shipped to the patient’s home as they are not suitable for self administration.  Only 
pre-filled syringes and semaglutide pens can be shipped.


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4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
The trial has a double blind design within each dose group (dose groups 1 to 6).  Patients, 
investigators and everyone involved in trial conduct or analysis or with any other interest in 
this trial will remain blinded with regard to the randomized treatment assignments until after 
database lock.  The semaglutide group (dose group 7) is open label.
Patients in dose groups 1 to 6 will receive medication from vials that contain active or 
placebo from weeks 1 to 6, and this randomized treatment assignment will remain blinded.  
The volume which should be administered at each visit will be known to the study site staff 
who administers the injection.  Therefore the blinding will be maintained within each dose 
group, but not across dose groups.
For weeks 7 to 16, patients in dose groups 1 to 6 will receive medication from pre-filled 
syringes (0.5 mL fill volume) that contain active medication or placebo.  Each patient will
receive 2 injections (active/active, or active/placebo, or placebo/placebo) once a week
(dose groups 1 to 4) or twice a week (dose group 5 and 6) for 10 weeks.
The particular dose group (1 to 6) to which the patient was randomized should not be made 
available to the patient.  Patient will know if they are randomized to the open label 
semaglutide group, or to one of the two twice weekly dosing groups (5 and 6).  Patients 
assigned to the open label semaglutide group will receive single-patient-use pens from which 
the respective dose for each week is administered.
The access to the randomization code will be kept restricted until its release for final analysis.
The randomization codes will be provided to bioanalytics group during the course of the trial
to allow for the exclusion from the analyses samples from placebo patients.  Bioanalytics will 
not disclose the randomization code or the results of their measurements until the trial is
unblinded after database lock. The randomization codes may be provided to the unblinded 
team if a decision was made to conduct interim analysis (Section 7.2.7).
4.1.5.2
Unblinding and breaking the code
Emergency unblinding will be available to the investigator via IRT.  It must be used only in
an emergency situation when the identity of the study drug must be known to the investigator
in order to provide appropriate medical treatment or otherwise assure safety of trial
participants.  The reason for unblinding must be documented in the source documents and/or 
appropriate eCRF page.  If the patient is unblinded by the investigator, patient will have to be 
discontinued from the trial.  Discontinued patients will complete the EOT and follow-up 
visits.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from BI’s Pharmacovigilance group to 
access the randomization code for individual patients during trial conduct.  The access to the 
code will only be given to authorized pharmacovigilance representatives for processing in the 
pharmacovigilance database system and not be shared further.


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4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI or a designated contract 
research organization (CRO).  They will be packaged and labelled in accordance with the 
principles of Good Manufacturing Practice.  Re-supply to the sites will be managed via the
IRT system, which will also monitor expiry dates of supplies available at the sites.
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
Drug supplies will be kept at the site in their original packaging and in a secure limited access 
storage area according to the recommended storage conditions on the medication label.  
A temperature log must be maintained at the study site for documentation.  If the storage 
conditions are found to be outside the specified range, the procedure described in the ISF has 
to be followed and a Clinical Research Associate (CRA), as provided in the list of contacts
should be contacted immediately.
Pre-filled syringes dispensed to patients at specific visits (Flow Chart) should be transported 
in insulated bags with cooling gel packs (or other similar cooling methods) from the site to 
the home.  Patient should store the medication at home according to the recommended 
storage conditions on the medication label.  Patients will not maintain a temperature log.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered by the sponsor
when the following requirements are fulfilled:

Approval of the clinical trial protocol by the Institutional Review Board (IRB) / ethics 
committee,

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site,

Approval/notification of the regulatory authority, e.g. competent authority,

Availability of the curriculum vitae of the Principal Investigator,

Availability of a signed and dated clinical trial protocol,

Availability of the proof of a medical license for the Principal Investigator,

Availability of Food and Drug Administration (FDA) Form 1572 (if applicable).
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be sent to other investigators or clinics.  Patients should be instructed to return all 
unused investigational medication (carton with the pre-filled syringes or single-patient-use 
pens), and the empty cartons from used medication, at the next clinic visit.  The sharps 
container (dispensed to the patient) where the used pre-filled syringes or the single-patient-
use pens are stored should be returned to the clinic when it is full or at the end of treatment 
visit.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each patient, and the return to the sponsor or warehouse / 


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drug distribution center or alternative disposal of unused products. If applicable, the sponsor 
or warehouse / drug distribution center will maintain records of the disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational medicinal product and trial
patients. The investigator or designee will maintain records that document adequately that the 
patients were provided the doses specified by the Clinical Trial Protocol and reconcile all 
investigational medicinal products received from the sponsor. At the time of return to the 
sponsor and/or appointed CRO, the investigator or designee must verify that all unused or 
partially used drug supplies have been returned by the clinical trial patient and that no 
remaining supplies are in the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
Rescue medication, for the treatment of hyperglycemia, can be initiated in patients that meet 
the following criteria: 

The patient is fully compliant with assigned therapeutic regimen, and 

Either of the following measurements for fasting blood glucose (FBG) occurs in the 
absence of any acute condition that is known to raise blood glucose levels:
o
During the first 6 weeks post-randomization: FBG above 270 mg/dl (15 
mmol/L) or
o
During weeks 7 to 16 post-randomization: FBG above 
240 mg/dl (13.3 mmol/L).
Patients will receive a self monitoring blood glucose device or they can use their own device 
to measure FBG levels.  All patients will receive a paper diary to record the measurements
(section 5.2.5.2).

Randomized treatment period: weekly blood glucose measurements in a fasted state 
(fasting for at least 10 hours).

Follow-up period: at least one blood glucose measurement in a fasted state (fasting for 
at least 10 hours).

At any time patient is symptomatic,  i.e. experiences signs/symptoms of hyper- or 
hypoglycemia

Patient should contact the site any time FBG is above 240 mg/dl (>13.3 mmol/L) or 
below 70 mg/dl (3.9 mmol/L)
Hypoglycemic Events: 
Hypoglycemic Events will be recorded in the eCRF using the definitions below (R18-1820):
Level 1
A glucose alert value of 70 mg/dL (3.9 mmol/L) or less
Level 2
A glucose level of 54 mg/dL (3.0 mmol/L) is sufficiently low to 
indicate serious, clinically important hypoglycemia


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Level 3
Severe hypoglycemia, as defined by the American Diabetes 
Association, denotes severe cognitive impairment requiring external 
assistance for recovery
Hypoglycemic events should be treated and additional glucose monitoring should be 
implemented per investigator discretion and medical judgement.  
Investigator should make a determination if a hyperglycemic or a hypoglycemic event should 
be reported as an AE.
A fasting plasma glucose sample and a HbA1c sample should be taken before initiation of 
rescue therapy and sent to the central laboratory for analysis.  The HbA1c sample is not 
required if the test was performed by the central laboratory within the last 4 weeks.
Rescue medication can be used from when treatment is initiated until the end of the 
treatment. The choice of rescue medication and its dosage will be left to the discretion of the 
investigator, depending upon existing concomitant medications.  Regardless of the choice 
made, rescue medication should be taken in accordance with the local prescribing 
information of that respective medication, taking into account potential contraindications.
If, in the investigator’s clinical opinion, no further effect from the rescue medication is 
anticipated and the patient’s hyperglycaemia cannot be controlled, study medication should 
be permanently discontinued, and the patient should be discontinued from the trial.  If 
continuous additional anti-hyperglycemic medication is instituted, study medication should 
be permanently discontinued, and the patient should be discontinued from the trial.  If a 
decision is made to discontinue the patient from the trial, patient should complete the end of 
treatment visit and complete the follow-up period.
Any rescue medication or any change in dose (i.e. reduction/increase) of antidiabetic 
medication (including background therapy) will be recorded in the source documents and on 
the appropriate pages of the eCRF.
Rescue medication will not be provided as part of the clinical trial supplies, unless required 
by local laws and regulations.
There are no special emergency procedures to be followed in this trial.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Patients should continue to take the same dose of metformin that they were on at the time of 
randomization in the trial.  Investigator may reduce the dose if hypoglycemic episodes are 
observed.  However, the metformin dose should be at least 1000 mg/day.  If there is change 
in the formulation (e.g. immediate release to extended release), the investigator should 
determine the comparable dose.


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4.2.2.2
Restrictions on diet and life style
Patients participating in the trial should refrain from donating blood during the entire duration 
of the trial which includes the follow-up period.
Patients will receive dietary and exercise counseling for management of T2DM, at clinic 
visits specified in the Flow Chart.
Dietary supplements that potentially induce change in body weight, over-the-counter or 
prescribed weight loss products, and products including St. John's wort (Hypericum 
perforatum) are not permitted starting 4 days before first drug administration until the end of 
trial. 
Excessive physical activity and manual labor outside usual amount should be avoided from 
randomization until the end of trial.
4.2.2.3
Contraception requirements
WOCBP (for the definition please refer to section 3.3.2) and their male sexual partner able to 
father a child must use two medically approved methods of birth control throughout the trial,
and for a period of at least 5 weeks after last study drug intake, one male barrier method or 
male vasectomy, and one highly effective non-barrier method.  Oral contraceptives are not 
permitted in female participants of the study.
Men (partner of a trial participant) must be vasectomised with documented absence of sperm 
or use a condom if their sexual partner is a WOCBP.  Contraception is not required for males 
participating in the study.
WOCBP (trial participant or partner of a trial participant) must use a highly effective method 
of birth control per ICH M3 (R2) that results in a low failure rate of less than 1% per year 
when used consistently and correctly if their sexual partner is a man able to father a child.

Combined (estrogen and progestogen containing) hormonal birth control that prevents 
ovulation (intravaginal, transdermal).

Progestogen-only hormonal birth control that prevents ovulation (injectable, implantable).

Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS).

Bilateral tubal occlusion
Or
Patients must abstain from male-female sex. This is defined as being in line with the 
preferred and usual lifestyle of the patient.  Periodic abstinence e.g. calendar, ovulation, 
symptothermal, post-ovulation methods; declaration of abstinence for the duration of 
exposure to study drug; and withdrawal are not acceptable.
4.3
TREATMENT COMPLIANCE
Patients should be encouraged to be fully compliant with the medication dosing schedule.  
Patients should be compliant on clinic visits within the protocol allowed time window.  


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Patients should be compliant on the dosing schedule when they self administer the study drug
at home with pre-filled syringes or single-patient-use-pen.
If a dose is missed on the planned dosing day, patients should take the planned dose within 
2 days for weekly dosing groups (1 to 4, and 7) or within 1 day for twice a week dosing 
groups (5 and 6).  If more time has elapsed since the missed dose, then patients should wait to 
take the next planned dose.  
A minimum of 5 days between weekly doses and a minimum of 2 days between twice weekly 
doses is required.  A 24-hour period is considered as one day.
In dose groups 1 to 4, and 7 (weekly dosing), patients are considered out of compliance, and 
should be discontinued from the trial if they miss 2 of the first 6 planned doses (first 6 weeks 
of dosing) or miss more than 2 doses during weeks 7 to 16.  In dose groups 1 to 4, and 7, the 
total missed doses during the trial cannot exceed 4 doses.
In dose groups 5 and 6 (twice a week dosing), patients are considered out of compliance, and 
should be discontinued from the trial if they miss 4 doses of the first 12 planned doses (first 6 
weeks of dosing) or miss 4 doses during weeks 7 to 16.  In dose groups 5 and 6, the total 
missed doses during the trial cannot exceed 8 doses.
Discontinued patients due to noncompliance should stop taking study drug, complete EOT 
visit (visit 12), and also complete the follow up visit (visit 13) 5 weeks after the last dose.
At visits 9 and 10, pre-filled syringes (BI 456906 or matching placebo) or single-patient-use-
pens (semaglutide) are dispensed to the patients in all dose groups to self administer the 
injections for the 3 weeks before the next clinic visit.  At visit 11, pre-filled syringes are 
dispensed to patients in dose groups 5 and 6 (twice a week dosing) for the last dose to be 
taken after visit 11.  Date, time, and site of injection will be recorded by the patients in a 
diary that will be dispensed at visits 9, 10, and 11.  Patients should bring the diary to the 
clinic at the following visit.  A copy of the paper diary will be placed in the ISF.
Patients should be instructed to return all unused investigational medication (carton with the 
pre-filled syringes or single-patient-use pens), and the empty cartons from the used 
medication at the next clinic visit.  Compliance will be determined by the study site staff.


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
The primary endpoint is the absolute change in HbA1c from baseline to 16 weeks.  
Throughout the protocol, the term “baseline” refers to the last observation prior to 
administration of the first dose of the study drug. 
Secondary endpoints are directed towards assessment of body weight changes, and the 
endpoints are as follows:
1. The relative body weight change from baseline to 16 weeks (key secondary endpoint).
2. The absolute body weight change from baseline to 16 weeks.
3. The absolute change in waist circumference from baseline to 16 weeks.
4. The percentage of patients with 5% or greater body weight loss from baseline to 16 
weeks.
5. The percentage of patients with 10% or greater body weight loss from baseline to 16 
weeks.
5.1.1
HbA1c
Blood samples will be taken from patients for the determination of HbA1c at the central
laboratory.  Further details about sample collection, handling, shipment, and assay procedures 
can be found in the central laboratory manual.
5.1.2
Weight and waist circumference
Weight measurements should always be done on the same scales for one patient whenever 
possible.  Mechanical and digital scales are acceptable. In order to get comparable body 
weight values, shoes, coats/jackets, and any headgear should be taken off, and pockets should 
be emptied of heavy objects (i.e. keys, coins etc.).  Headgear worn for religious reasons are 
acceptable, but this should be worn for all weight measurements in the trial.  Patient should 
empty the bladder before weight is measured.
Waist circumference should be determined by measuring the midpoint between the lowest rib 
and the iliac crest.  The measuring tape should be made of a material that is not easily 
stretched.  The tape should be placed perpendicular to the long axis of the body and 
horizontal to the floor and applied with sufficient tension to conform to the measurement 
surface.  Waist circumference measurements should be made around a patient’s bare midriff, 
after the patient exhales while standing without shoes and with both feet touching the ground 
and arms hanging freely.


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5.2
ASSESSMENT OF SAFETY
5.2.1
Vital signs
Vital signs will be evaluated at the time points specified in the Flow Chart, prior to blood 
sampling.  This includes systolic and diastolic blood pressure, pulse rate (electronically or by 
palpation count for 1 minute) in a seated position without crossed legs after 5 minutes of rest, 
respiratory rate, and temperature.  The results must be included in the source documents 
available at the site.
5.2.2
Physical examination
A complete physical examination will be performed at the time points specified in the Flow 
Chart.  The physical examination should be conducted according to the local medical 
practice.  It should include at a minimum general appearance, neck, lungs, cardiovascular 
system, abdomen, extremities, and skin including visual check for skin rashes.  Skin rashes 
will be recorded in the eCRF as an AE.
Measurement of height and body weight will be performed at the time points specified in the 
Flow Chart.  The results must be included in the source documents available at the site. 
5.2.3
Safety laboratory parameters
Safety laboratory parameters to be assessed are listed in Table 5.2.3: 1.  For the sampling
time points please see the Flow Chart.
All analyses will be performed by a central laboratory, and the respective reference ranges 
will be provided in the ISF. Instructions regarding sample collection, sample handling/ 
processing and sample shipping are provided in the laboratory manual. 
The central laboratory will send reports to the investigator.  It is the responsibility of the 
investigator to evaluate the laboratory reports.  Clinically relevant abnormal findings as 
judged by the investigator will be reported as AEs (please refer to section 5.2.6).
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (section 5.2.6.1 and the DILI Checklist is provided in the electronic data capture 
(eDC) system. The amount of blood taken from the patient concerned will be increased due to 
this additional sampling.
The central laboratory will transfer the data to the sponsor periodically.


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Table 5.2.3: 1
Safety laboratory parameters
Category
Test name
Haematology
Haematocrit
Hemoglobin
Reticulocyte Count (reflex test if Hb outside normal range)
Red Blood Cells (RBC) / Erythrocytes
WBC / Leukocytes
Platelet Count / Thrombocytes
Differential Automatic (relative and absolute count): 
Neutrophils, Eosinophils, Basophils, Monocytes,  Lymphocytes
Clinical chemistry
Albumin 
Alkaline phosphatase
Amylase
ALT (alanine aminotransaminase, SGPT)
AST (aspartate aminotransaminase, SGOT) 
Bicarbonate
Bilirubin total, fractionated if increased 
Calcium 
Chloride 
Creatinine 
Creatine kinase (CK)
CK-MB, troponin (reflex tests if CK is elevated)
-GT (gamma-glutamyl transferase)
Glucose (plasma, not fasted)
Lactate dehydrogenase (LDH)
Lipase
Magnesium 
Phosphate 
Potassium
Protein total 
Sodium
Urea (blood urea nitrogen, BUN)
Uric acid
Thyroid stimulating hormone (TSH)
Calcitonin*
eGFR*
C-Reactive Protein*
Infectious serology
Hepatitis B surface antigen*
Hepatitis C antibodies*
HIV-1/2 combination*
Lipids
Cholesterol (total)
HDL cholesterol 
LDL cholesterol (including VLDL)
Triglycerides


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Table 5.2.3: 1
Safety laboratory parameters: (cont.)
Category
Test name
Urinalysis 
Semi quantitative
Nitrite
Protein
Ketone
Urine pH
Leukocyte esterase (for WBC)
Blood (erythrocytes)
Quantitative**
Albumin
Creatinine
Urine drug screen*
Cannabis
Cocaine
Benzodiazepine
Amphetamines
Barbiturates
Methadone
Opiates
Other
SARS-CoV-2 testing (when applicable, see Section 3.3.4.1) will 
be performed locally.  Samples must not be shipped to central lab
for testing.
*Measured only at the screening visit.
**Albumin/creatinine ratio in spot urine will be calculated at the central lab.
5.2.4
Electrocardiogram
A 12-lead ECG should be collected at the time points specified in the Flow Chart.  ECG will 
be recorded in triplicate at the screening visit (i.e. three single ECGs recorded within 180 
seconds).
Centralized ECG services will be provided by an external vendor for all clinic visits 
(including unscheduled visits). Standardized equipment and an ECG machine quick guide 
will be provided by the vendor.
ECGs should be collected according to the study-specific recommendations, using the 
standardized equipment provided by the vendor.  ECGs may be repeated for quality or safety 
reasons.  Patients should be supine for approximately 5-10 minutes before ECG collection.  
Patients should remain supine, but awake, during the ECG collection process. 
ECG recordings will be transmitted electronically to a vendor for central reading.  The ECG 
recordings will be centrally evaluated and rated as normal, abnormal, or unable to evaluate, 
and the results will be sent to the study site.  The site investigator should review the report.  If 
the ECG is rated as abnormal, the site investigator will have to determine if the abnormal 


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findings are clinically significant.  The site investigator will have the responsibility to follow
up with the patient if there are any clinically significant findings in the ECG report.
After the screening visit, the investigator must review the ECG results from central reading to 
ensure patient has met all the entry criteria for the study.  The QTcF value at the screening 
visit is the average of the three recordings.  Any pre-existing conditions should be recorded as 
baseline conditions.  ECG recorded at the randomization visit should be evaluated by the 
investigator before the patient receives the first dose.  If abnormalities are observed by the 
investigator in the ECG reading at randomization visit, the investigator may wait until the 
results from central reading are available, and the randomization visit may be rescheduled.
After the patient is randomized, if a clinically significant increase in the QTcF interval from 
baseline or any other clinically significant quantitative or qualitative change from baseline is 
identified, the investigator will assess the symptoms (e.g., palpitations, near syncope, and 
syncope) and decide if the patient will continue in the trial.  The investigator must also ensure 
that patient does not meet any of the stopping criteria, such as tachycardia, arrhythmia or 
conduction disorders (Section 3.3.4.1).  Any new findings or deterioration of previous 
findings observed during the trial will be recorded as AEs or SAEs, and should be followed 
up and/or treated as medically appropriate per local standards.
Although the ECGs are transmitted to the vendor for central reading, the investigator has the 
responsibility to complete an initial review as soon as the ECG recordings are obtained at the 
clinic visit.  At any time during the trial, the investigator may decide to place a hold on 
further dosing of the patient if there is an indication of any abnormalities in the ECG, and 
would prefer to wait until the results from the central reading are available.
All ECGs that are read in the central location will be stored in the vendor’s database, and will 
be transmitted to the sponsor periodically.
5.2.5
Other safety parameters
5.2.5.1
Suicidal risk assessment and reporting
There has been no suicidal risk identified for BI 456906 in clinical data obtained to date.  
However, evaluation of suicidal behavior and ideation is important in clinical development 
and the Columbia-Suicide Severity Rating Scale, C-SSRS, will be used to prospectively
assess suicidal behaviour and ideation (R12-4395).
The C-SSRS is an investigator-rated interview, developed by clinical experts in cooperation 
with the FDA, assessing both suicidal behavior and suicidal ideation.  It does not give a 
global score, but provides some categorical and some severity information specifically for 
behavior and ideation.
The C-SSRS interview may be administered by any type of physician, psychologist, clinical 
social worker, mental health counselor, nurse, or research coordinator with C-SSRS training.  
It has a typical duration of five minutes, and causes only a low burden on patients.  At a 
minimum, the interview consists of 2 screening questions related to suicidal ideation and 4 
related to suicidal behavior, and may be expanded to up to 17 items in case of positive 
responses.


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The C-SSRS has been widely used in large multinational clinical trials.  The C-SSRS will be 
administered at the screening visit (using the “baseline/screening” version) with the aim to 
exclude subjects with a life time history of suicidal ideation and behavior.  After the baseline 
visit, the assessment “since last visit” will be performed at clinic visits as specified in the 
Flow Chart.  The investigator is to review positive and negative reports for plausibility and 
clinical relevance.  Doubtful reports may be repeated or reports may be validated by a 
consulting psychiatrist. If there is a positive report of suicidal behavior or suicidal ideation 
type 4 or 5 after start of trial, the investigator is to immediately interview the patient during 
the clinic visit, and advise the patient to consult with a psychiatrist.  If the positive report is 
confirmed, appropriate actions for the patient’s safety must be initiated.  Treatment with 
study drug should be stopped and patient should be discontinued from the trial.  Additionally, 
all C-SSRS reports of suicidal ideation type 4 or 5 and all reports of suicidal behavior must 
be reported as separate SAEs by the investigator.  For ‘Self-injurious behavior, no suicidal 
intent’ (Type 11) standard AE / SAE reporting rules are to be applied. For each negative 
report (suicidal ideation type 1, 2 or 3) after start of the trial, the investigator is to decide 
based on clinical judgment whether it represents an AE as defined in the protocol, and if it is 
considered an AE then it must be reported accordingly.
5.2.5.2
Self monitoring of blood glucose
All patients will be provided an electronic blood glucose monitoring device and supplies for 
use at home during the trial for self-measurement of blood glucose. Patients may also use 
their own device for SMBG monitoring. The SMBG device is dispensed to the patient at the 
screening visit (visit 1).  Instructions on the proper use of the SMBG equipment will be 
provided to the patient by the site staff.  A paper diary will be dispensed along with the 
device, and the patient will enter the blood glucose measurements done at home in the diary.
SMBG should be performed regularly.  Recommendations are as follows:

Randomized treatment period: weekly blood glucose measurements in a fasted state 
(fasting for at least 10 hours).

Follow-up period: at least one blood glucose measurement in a fasted state (fasting for 
at least 10 hours).

At any time patient is symptomatic,  i.e. experiences signs/symptoms of hyper- or 
hypoglycemia.


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The patient will be informed to watch for these signs and symptoms, to test their blood sugar 
if they experience them, and to enter data from the SMBG device to a patient paper diary.  
Blood glucose measurements recorded in the patient diary (other than the seven-point 
measurements) are not entered in eCRFs unless it is related to an AE or SAE.
Throughout the trial, the patient should bring the paper diary to every clinic visit.  Study site 
staff should review the diary at each visit and follow-up if necessary. Site staff should 
provide additional instructions or training to the patient if needed.
Refer to section 4.2.1 for information on handling of hyperglycemia and hypoglycemia 
events.
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of adverse events 
5.2.6.1.1
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the eCRF and BI SAE form (if 
applicable):
Worsening of the underlying disease or of other pre-existing conditions 
Changes in vital signs, ECG, and physical examination and laboratory test results, if 
they are judged clinically relevant by the investigator.
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the eCRF only.
5.2.6.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE, which fulfils at least one of the 
following criteria:
-
results in death,
-
is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe,
-
requires inpatient hospitalization or prolongation of existing hospitalization
-
results in persistent or significant disability or incapacity,
-
is a congenital anomaly / birth defect,
-
is deemed serious for any other reason if it is an important medical event when based 
on appropriate medical judgement which may jeopardise the patient and may require 


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medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse. 
5.2.6.1.3
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.
The latest list of “Always Serious AEs” can be found in the eDC system. A copy of the latest 
list of “Always Serious AEs” will be provided upon request. These events should always be 
reported as SAEs as described above.
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as 
described in 5.2.6.2, subsections “AE Collection” and “AE reporting to sponsor and 
timelines”.
5.2.6.1.4
Adverse events of special interest
AESIs relates to any specific AE that has been identified at the project level as being of 
particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. 
AESIs need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAEs, please see section 5.2.6.2.2.
The following are considered as AESIs:

Pancreatitis

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters:

an elevation of AST and/or ALT ≥3 fold ULN combined with an elevation of total 
bilirubin ≥2 fold ULN measured in the same blood draw sample, or

aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided in eDC.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analyzed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.


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5.2.6.1.5
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are generally tolerated.
Moderate:
Sufficient discomfort to cause interference with usual activity.
Severe:
Incapacitating or causing inability to work or to perform usual activities.
As GI and cardiac AEs have been shown to be associated with pharmacological doses of 
GLP-1R agonists and glucagon, the intensity of such AEs are defined as follows for this 
clinical trial:
Nausea
Mild: 
Queasy sensation and/or the urge to vomit without decreased oral fluid or 
caloric intake 
Moderate: 
Queasy sensation and/or urge to vomit with decreased oral intake, but able to 
maintain adequate fluid and caloric intake without dehydration or malnutrition; 
may require pharmacologic intervention
Severe: 
Queasy sensation and/or urge to vomit with prolonged inadequate oral fluid or 
caloric intake; severe or medically significant but not immediately 
life-threatening; requiring i.v. fluids or is resistant to anti-nausea treatment, 
hospitalization (different from trial site) indicated
Vomiting
Mild: 
Less than 3 episodes in 24 hours (individual episodes separated by at least 
30 min)
Moderate: 
3 to 5 episodes in 24 hours (individual episodes separated by at least 30 min); 
may require pharmacologic intervention
Severe:
Six or more episodes in 24 hours (individual episodes separated by at least 30 
min); severe or medically significant but not immediately life-threatening; 
requiring i.v. fluids, or is resistant to antiemetic treatment, hospitalization 
(different from trial site) indicated
Diarrhea
Mild: 
Increase of <3 stools in 24 hours over baseline
Moderate: 
Increase of 3 to 5 stools in 24 hours over baseline; may require pharmacologic 
intervention
Severe: 
Increase of ≥6 stools in 24 hours over baseline; severe or medically significant 
but not immediately life-threatening; requiring i.v. fluids, or is resistant to 
anti-diarrheal treatment, hospitalization (different from trial site) indicated
Mobitz (type) I atrioventricular block
Mild: 
Asymptomatic, intervention not indicated
Moderate: 
Symptomatic, medical intervention indicated
Severe: 
Symptomatic and incompletely controlled medically or controlled with device 
(e.g., pacemaker)
Mobitz (type) II atrioventricular block
Mild: 
Asymptomatic, intervention not indicated
Moderate: 
Symptomatic, medical intervention indicated


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Severe: 
Symptomatic and incompletely controlled medically or controlled with device 
(e.g., pacemaker)
Sinus tachycardia
Mild: 
Asymptomatic, intervention not indicated
Moderate: 
Symptomatic, non-urgent medical intervention indicated
Severe: 
Urgent medical intervention indicated
Electrocardiogram QT corrected interval prolonged
Mild: 
QTcF increase from baseline of more than 30s and QTcF 450-480 ms
Moderate: 
QTcF increase from baseline of more than 30s and QTcF 481-500 ms
Severe: 
QTcF increase from baseline of more than 60s and QTcF >= 501 ms on at least 
two separate ECGs
5.2.6.1.6
Causal relationship of AEs
Medical judgement should be used to determine whether there is a reasonable possibility of a 
causal relationship between the AE and the given study treatment, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug.

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced.

No medically sound alternative aetiologies that could explain the event 
(e.g. pre-existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned).

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.


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
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the study drug treatment continues or remains 
unchanged.
5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate eCRF(s) by the 
investigator:
•
From signing the informed consent onwards until the individual patient’s end of trial: all 
AEs (serious and non-serious) and all AESIs.
•
After the individual patient’s end of trial: the investigator does not need to actively 
monitor the patient for new AEs but should only report any occurrence of cancer and trial 
treatment related SAEs and trial treatment related AESIs of which the investigator may 
become aware of by any means of communication (e.g. phone call). Those AEs should be 
reported on the BI SAE form (see 5.2.6.2.2), but not on the eCRF.
5.2.6.2.2
AE reporting to the sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form immediately (within 24 hours ) to the sponsor’s 
unique entry point (country specific reporting process will be provided in the ISF). The same 
timeline applies if follow-up information becomes available. In specific occasions, the 
investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and send the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.  All (S)AEs, including those persisting after individual patient’s end of trial
must be followed up until they have resolved, have been assessed as “chronic” or “stable”, 
or no further information can be obtained.
5.2.6.2.3
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken study drug, the investigator must report any drug exposure during 
pregnancy in a trial participant immediately (within 24 hours) by means of Part A of the 
Pregnancy Monitoring Form to the sponsor’s unique entry point.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).


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The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must also be completed.


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5.4
IMMUNOGENICITY
5.4.1
Timing of immunogenicity measures
Blood samples from patients will be obtained from patients receiving BI 456906 or placebo 
for the determination of ADA and neutralizing antibody (NAb) at the time points detailed in 
Flow Chart.  Blood samples will not be taken from patients in the semaglutide group (dose 
group 7) for ADA and NAb assessments. 
 
 
 


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5.5
ASSESSMENT OF BIOMARKERS
Several exploratory biomarkers will be determined as indirect response to study drug 
administration. Samples will be collected for biomarker analysis as shown in the Flow Chart.  


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5.8
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor patients’ safety and to determine pharmacokinetic and 
pharmacodynamic parameters in an appropriate way. The scheduled measurements will allow 
monitoring of changes in vital signs, standard laboratory values, and ECG parameters that 


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might occur as a result of administration of study drug. The safety assessments are standard, 
are accepted for evaluation of safety and tolerability of an s.c. administered drug, and are 
widely used in clinical trials.
 
 
 


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
The trial consists of a screening period, treatment period, and a follow-up period.  Following 
the 2-week screening period, patients will be randomized (visit 2) to one of the dose groups 
(dose groups 1 to 6 or semaglutide).  During the treatment period, there will be a dose
escalation period (for dose groups 2 to 7) followed by a dose maintenance period.  The
treatment period is followed by a 4-week follow-up period.
Patients should make all efforts to complete the trial which includes the 4-week follow-up 
period.  Investigators should encourage treatment compliance, and adherence to the protocol 
procedures.  All patients should adhere to the visit schedule as specified in the Flow Chart.  
Any deviations from the planned visit schedule should be documented.
In exceptional cases, if standard clinic visits at the trial sites are impossible or in situations 
where an individual patient is unable or unwilling to attend a clinic visit due to COVID-19 
related safety risks, the investigator must assess the risk-benefit for the individual patient and 
may decide to perform a visit remotely if this is in the best interests of the patient and if 
agreed with the sponsor. 
All COVID-19 related deviations from the original schedule of visits and procedures will be 
documented and the implications considered for the analysis of the trial data.
If any visit after randomization is rescheduled, subsequent visits should follow the original 
visit date.
At all clinic visits blood pressure should be measured, and ECG recorded before blood 
samples are taken.
Diet and exercise counseling will be provided to patients by a dietician or a trained staff 
member at the study site at visits specified in the Flow Chart.  Patients should be reminded at 
every clinic visit to follow the recommended diet and exercise regimen.  
Pregnancy tests
All women of child bearing potential will undergo serum pregnancy test at the screening visit 
(visit 1).  Patients who test positive for the serum pregnancy test will be excluded from the 
trial.  Urine pregnancy tests will be done at all visits in the clinic starting from visit 2.  There 
will not be a pregnancy test when patients in dose groups 5 and 6 (twice a week dosing) come 
to the clinic for their second dose of each week.  If the urine pregnancy test is positive, a 
serum pregnancy test will be done to confirm pregnancy.  If the serum pregnancy test is 
positive, study drug will be discontinued and patient will be discontinued from the trial.  If
serum pregnancy is negative, patient may continue in the trial.  If the urine pregnancy test is 


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positive at the randomization visit (visit 2), the patient must not be randomized into the trial 
unless the serum pregnancy test is negative.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening and run-in period
Screening (visit 1)
No trial procedures should be performed until the patient has consented to take part in the 
trial.  If the patient is willing to provide a blood sample for unspecified pharmacogenomics
and biomarker testing (biobanking), a separate consent must be obtained.  Each patient will 
be assigned a unique patient number and enrollment will be recorded in eCRF.
Once the patient has consented, the patient is considered to be enrolled in the trial. The 
patient should be recorded on the enrollment log and be registered in the IRT.
Baseline conditions, medical history, and eligibility criteria will be assessed at visit 1.  
Concomitant therapy and AE (if any) will be recorded.  At the conclusion of visit 1, patients 
should receive instructions on procedures to be followed during the screening period.
If the patient has met all the eligibility criteria, randomization visit (visit 2) will be scheduled.
Screening period may be extended by two weeks for administrative reasons after consultation 
with the Clinical Trial Manager.  Total screening period should not exceed 4 weeks 
(informed consent to randomization) unless written approval is obtained from the Clinical 
Trial Leader.
If screening period is extended for more than two weeks, the investigator should review the 
laboratory reports from the screening visit (visit 1), and make a determination if any labs 
specified in the protocol must be repeated before the randomization visit.  If deemed 
necessary, test samples should be drawn and sent to the central laboratory.  
Discontinuation during the screening period
If patients discontinue from the trial during the screening period, no additional clinic visits 
are required, and they will be marked as screen failures.  Patient will be registered as a screen 
failure in IRT.
Rescreening and retesting
A patient may be rescreened once with approval from the Clinical Trial Manager.  Patients 
who met all the inclusion criteria but were screen failed due to acute medical conditions that 
have since been resolved or those who were screen failed for administrative reasons (e.g., 
extended travel, life events) will be good candidates for re-screening.


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If the investigator believes that an ineligible lab test result is the result of an error or 
extenuating circumstance, then that lab test can be retested once without the patient having to
be rescreened.  Patients who do not meet to HbA1c inclusion criteria cannot be retested or 
rescreened.
6.2.2
Treatment period
Patients who meet all the protocol criteria will be randomized at visit 2.  After randomization, 
patients will start the treatment period which includes a dose escalation phase, followed by 
the dose maintenance phase as shown in Figure 3.1: 1.
Procedures to be completed at each clinic visit can be found in the Flow Chart.
At visits specified in the Flow Chart, patients should be instructed to come in the fasting state
after at least 10 hours without food intake.  Water intake is allowed. Fasting is required when 
patients attend visits when samples for biomarkers are collected or when PRO questionnaires 
are administered.
 
 
At each clinic visit, patients should be advised to follow the recommended diet and exercise 
plan.  Diet and exercise counseling sessions are held at visits indicated in the Flow Chart.  All 
clinic visits during the treatment period should preferably be on the same day of the week.  
On days when fasting is required, the clinic visit should ideally be scheduled in the mornings, 
if this is convenient for the patient.
Unscheduled visits may be arranged if necessary.  Procedures completed during an
unscheduled visit will depend on the circumstances under which the visit was scheduled, and 
at the discretion of the investigator.
After completion of the treatment period, patients will have the End of Treatment visit 
(visit 12).  All patients will then enter the 4-week follow-up period, and complete the 
observation period with the follow-up visit (visit 13).
Discontinuation during the treatment period
If patients discontinue from the trial during the treatment period (dose escalation phase or 
maintenance phase), they should complete the End of Treatment visit (visit 12), and a
follow up visit (corresponding to visit 13) will be scheduled 5 weeks after the last dose of 
study drug.  Every effort should be made to complete all the procedures at the EOT and 
follow-up visits.


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6.2.3
Follow-up period and trial completion
The four-week follow-up period extends from visit 12 until visit 13.  Visit 13 will be 5 weeks 
after the last dose (visit 11) which is the residual effect period in this trial.  Procedures to be 
completed at the follow-up visit can be found in the Flow Chart.  The sequence of visit 
procedures will be the same as in the treatment period.  The last clinic visit will be visit 13, 
the end of the study visit and this will mark the end of observation period, and the patient has 
completed the trial.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
The primary trial objective includes demonstration of PoCC with respect to a non-flat dose 
response curve, characterization of the dose-response relationship within the therapeutic 
range, and selection of the dose range for phase III development. For this purpose, the 
primary analysis uses methodology for dose finding employing MCPMod.
7.1
NULL AND ALTERNATIVE HYPOTHESES
The null hypothesis is that there is a flat dose response curve comparing the placebo and the 
BI 456906 dose groups. The alternative hypothesis is that there is a non-flat dose response 
curve indicating a benefit of BI 456906 over Placebo. 
The MCPMod procedure allows for simultaneous evaluation of different potential dose 
response patterns, whilst protecting the overall probability of type I error (one sided α of 
2.5%). The pre-specified models and their parameters used for this test are outlined in 
Section 7.2.2.
7.2
PLANNED ANALYSES
7.2.1
General considerations
For the dose-finding all randomized patients with at least 1 post-baseline measurement 
according to the treatment the patients were assigned will be included in the primary analysis. 
More details and all other analysis sets will be specified in the TSAP.
7.2.2
Primary endpoint analyses
The analyses for PoCC and dose-finding will be performed using MCPMod [R10-1424]
whereby several possible dose response models (patterns) will be evaluated, while keeping 
full control of the type I error at 2.5%, one-sided) to identify the best-fitting model or subset 
of models. 
To account for the repeated nature of the data and the covariates in the model, mixed model 
repeated measurements (MMRM) analysis will be carried out and covariate adjusted fixed 
effect estimates of average response for each dose group and the covariance matrix will be 
extracted from the fit and used for MCPMod analysis.  For the twice weekly dosing schemes
the total dose per week will be considered for the MCPMod analysis.
For this analysis a restricted maximum likelihood (REML) based approach using MMRM 
comparing the change from baseline of HbA1c at different timepoints of treatment.
The analysis will include the fixed, categorical effects of treatment and the fixed continuous 
effects of baseline at each visit.  Visit will be treated as the repeated measure with an 
unstructured covariance structure used to model the within patient measurements.


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The statistical model will be as follows:
 = 	
 +  + eij
 ~ (,).

response variable at visit j receiving treatment k for subject i


the baseline measurement of subject i, i=1,2,..,
	
coefficient of baseline effect at visit j

coefficient of treatment k at visit j, j=1,…,Z and k = 1, ..,Y ,
e
the random error associated with the jth visit of the ith subject. Errors are independent between 
subjects

an unstructured covariance matrix
The Kenward-Roger approximation will be used to estimate denominator degrees of freedom 
and adjust standard errors. The treatment comparison to placebo will be the contrast between 
treatments at the different visits and will be presented with 95% confidence intervals. The 
primary comparison will be performed at the visit of the primary interest.
For the PoCC testing and for the sample size calculation, the basic shape of each of the 
models to be tested must be pre-defined. Following models will be considered for this 
analysis 

The following model assumptions and resulting graphs (Figure 7.2.2: 1) have been 
selected to cover both plausible and a diverse range of dose response patterns. 
o
Linear: the maximum effect is achieved at 3.6 mg dose
o
Exponential: 90% of the maximum effect is achieved at 3.6 mg dose
o
Emax1: 90% of the maximum effect is achieved at 3.6 mg dose
o
Emax2: 70% of the maximum effect is achieved at 3.6 mg dose
o
SigEmax: 50% of the maximum effect is achieved at 1.8 mg and 90% of the 
maximum effect is achieved at 3.6 mg dose


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Figure 7.2.2: 1
Shape of the considered dose response patterns for the MCPMod 
analysis.
PoCC is established if at least one model is statistically significant, rejecting the null 
hypothesis of a flat dose response relationship over HbA1c jointly for each of the candidate 
dose response models with a contrast test controlled for the family–wise type I error rate at 
one sided α = 2.5%. 
For the open label arm, descriptive statistics for the respective endpoint will be presented.
7.2.3
Secondary endpoint analyses
For the key secondary endpoint body weight, analyses similar to the primary analysis of 
HbA1c will be performed.  
The absolute and relative body weight change as well as change in waist circumference will 
be assessed using an MMRM analysis as for the primary endpoint analysis. The estimates of 
average response to 16 weeks for each dose group will be presented.


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7.2.5
Safety analyses
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities
(MedDRA). Standard BI summary tables and listings will be produced. All adverse events 
with an onset between start of treatment and end of the REP, a period of 5 weeks after the last 
dose of study drug, will be assigned to the on-treatment period for evaluation.
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events, i.e. all adverse events occurring between start of treatment and end of the 
REP. Adverse events that start before first drug intake and deteriorate under treatment will 
also be considered as ‘treatment-emergent’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the MedDRA 
at database lock.
Laboratory data will be analyzed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be summarized. 
Treatment groups will be compared descriptively with regard to distribution parameters as 
well as with regard to frequency and percentage of patients with abnormal values or clinically 
relevant abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.
 
The PRO endpoints analyses are of exploratory nature and details will be provided in the 
TSAP.
7.2.7
Interim Analyses
Interim analyses may be performed during the conduct of this trial.  A limited number of the 
sponsor staff will be unblinded for the conduct of the interim analysis.  Investigators, study 
site staff, trial team, and patients will remain blinded.  If a decision is made to perform an 
interim analysis, more details will be specified in the interim analysis logistics plan.  The data 
from interim analysis may allow planning future trials and reporting key results but will not 
include MCPMod analyses.


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7.3
HANDLING OF MISSING DATA
For the primary endpoint the MMRM will be used to handle missing values. The imputation 
rules for secondary and further endpoints will be specified in the TSAP.
7.4
RANDOMIZATION
BI will arrange for the randomization and the packaging and labelling of study drug. The 
randomization list(s) will be generated using a validated system, which involves a pseudo-
random number generator so that the resulting treatment will be both reproducible and non-
predictable. The block size will be documented in the CTR Access to the codes will be 
controlled and documented (sections 4.1.3 and 4.1.5)
7.5
PATIENTS DETERMINATION OF SAMPLE SIZE
The sample size calculation is based on an assumed maximum effect size of BI 456906 vs. 
placebo of 0.5% change in HbA1c for the primary endpoint, as well as on the pre-specified 
models listed in section 5.1.2. The maximum effect size is assumed to be 0.5% with the 
standard deviation (SD) 1% (R17-4311).
For the contrast test (one-sided 2.5% alpha level), a sample size of 45 evaluable patients is 
needed in order to reach 94% average power for the assumed effect size of 0.6%. The powers 
for each model shape under different assumptions (different effect size and sample size) are 
summarized in the table below.
Table 7.5: 1
Power of MCPMod for each candidate set model and min, max, 
average power.
Model
Assumption 1
Max effect = 
0.6%, SD=1%, 
n=45
Assumption 2
Max effect = 0.6%, 
SD=1%, n=40
Assumption 3
Max effect = 
0.5%, SD=1%, 
n=45
Assumption 4
Max effect = 
0.5%, SD=1%, 
n=40
Linear
93.7%
91.7%
84.0%
76.2%
Exponential
91.6%
90.7%
81.8%
77.4%
Emax 1
93.5%
91.7%
81.7%
78.3%
Emax 2
95.7%
93.6%
88.1%
81.8%
Sigmoid Emax
98.9%
97.0%
92.3%
89.6%
Min
91.6%
90.7%
81.7%
76.2%
Max
98.9%
97.0%
92.3%
89.6%
The calculations for the PoCC step have been performed using Dose Finding R-package 
(R15-2001) with 1000 repetitions.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice, relevant BI SOPs, the EU directive 2001/20/EC / EU regulation 536/2014
and other relevant regulations.  Investigators and site staff must adhere to these principles. 
Deviation from the protocol, the principles of ICH GCP or applicable regulations will be 
treated as “protocol deviation”.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial patients against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor
with regard to publication of the results of this trial are described in the investigator contract. 
As a rule, no trial results should be published prior to finalisation of the Clinical Trial Report.
The certificate of insurance cover is made available to the investigator and the patients, and is
stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective IRB / Independent Ethics Committee (IEC) and competent 
authority, according to national and international regulations.  The same applies for the 
implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient according to ICH-GCP and to the regulatory and legal requirements of the 
participating country.  Each signature must be personally dated by each signatory and the 
informed consent and any additional patient-information form retained by the investigator as 
part of the trial records.  A signed copy of the informed consent and any additional patient
information must be given to each patient.
The patient must be given sufficient time to consider participation in the trial.  The 
investigator or delegate obtains written consent of the patient’s own free will with the 
informed consent form after confirming that the patient understands the contents.  The 
investigator or 
 delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.


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Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.  The consent and re-consenting 
process should be properly documented in the source documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management.  It is initiated by the assessment 
of critical data and processes for trial participant protection and reliability of the results as 
well as identification and assessment of associated risks.  An Integrated Quality and Risk 
Management Plan (IQRMP) documents the rationale and strategies for risk management
during trial conduct including monitoring approaches, vendor management and other 
processes focusing on areas of greatest risk.  Continuous risk review and assessment may 
lead to adjustments in trial conduct, trial design, or monitoring approaches.
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities.  The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
Electronic CRFs for individual patients will be provided by the sponsor.  See section 4.1.5.2
for rules about emergency code breaks.  For drug accountability, refer to section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient.  Source data as well as reported 
data should follow the “ALCOA principles” and be attributable, legible, contemporaneous, 
original and accurate.  Changes to the data should be traceable (audit trail).  Data reported on 
the eCRF must be consistent with the source data or the discrepancies must be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests.  In this case the investigator must make three documented attempts to 
retrieve previous medical records.   If this fails, a verbal feedback from the patient which is 
documented in their medical records at the study site, would be acceptable.
During the site visit the sponsor’s CRA or auditor must be granted access to the original 
patient file (please see section 8.3.2).  The investigator must ensure that all patient identifiers 
(e.g. patient’s name, initials, address, phone number, social security number) have properly 
been removed or redacted from any copy of the patients’ source documents before sending 
them to the sponsor.
If the patient is not compliant with the protocol, any corrective action (e.g. re-training) must 
be documented in the patient file.


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For the eCRF, data must be derived from source documents, for example:

Patient identification: gender, year of birth (in accordance with local laws and 
regulations)

Patient participation in the trial (substance, trial number, patient number, date patient was 
informed)

Dates of patient’s visits, including dispensing of study drug

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

Adverse events and outcome events (onset date (mandatory), and end date (if available))

Serious adverse events (onset date (mandatory), and end date (if available))

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)

Completion of patient’s participation in the trial (end date; in case of premature 
discontinuation document the reason for it).

Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria.  The absence of 
records (either medical records, or testing conducted specific for a protocol) to support 
inclusion/exclusion criteria does not make the patient eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The sponsor will monitor the conduct of the trial by regular on-site monitoring visits and 
in-house data quality review.  The frequency of site monitoring will be determined by 
assessing all characteristics of the trial, including its nature, objective, methodology and the 
degree of any deviations of the intervention from normal clinical practice.
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the eCRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all eCRFs and informed consents. The accuracy of the data 
will be verified by direct comparison with the source documents described in section 8.3.1.
The sponsor will also monitor compliance with the protocol and GCP.
8.3.3
Storage period of records
Trial sites:
The trial sites must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.


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8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements. 
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 7 and 12 of the WHO GCP 
handbook.
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the following exceptions: Personalized treatment 
data may be given to the patient’s personal physician or to other appropriate medical 
personnel responsible for the patient’s welfare.  Data generated at the site as a result of the 
trial need to be available for inspection on request by the participating physicians, the 
sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection, biobanking and 
future use of biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the separate biobanking informed 
consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials

An appropriate sample and data management system, including audit trail for clinical 
data and samples to identify and destroy such samples according to ICF is in place

A fit for purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data

Samples and/or data may be transferred to third parties and other countries as 
specified in the biobanking ICF
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial
(“Last Patient Completed”).  The “Last Patient Last Treatment” (LPLT) date is defined as 
the date on which the last patient in the whole trial is administered the last dose of trial 
treatment (as scheduled per protocol or prematurely).  Individual investigators will be 
notified of SUSARs occurring with the trial medication until 30 days after LPLT at their site.


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Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.  
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
A Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this trial. Tasks and responsibilities are defined in a contract. 
A safety monitoring committee (SMC) composed of participating investigators, members of 
the BI trial team and trial independent members will be established to review individual and 
aggregated safety data at regular intervals to determine the safety profile, and recommend
appropriateness of further enrollment.  A separate SMC charter will define SMC membership 
and SMC roles and responsibilities.  The SMC will operate under the principles specified in 
the charter, and the primary objective is to ensure and protect the safety and well being of the 
patients participating in the trial.
An independent data monitoring committee will not be established to monitor this trial.
Relevant documentation on the participating Principal Investigators (e.g. their curricula vitae)
will be filed in the ISF.  The investigators will have access to the BI clinical trial portal 
(Clinergize) which will serve as a temporary location to access sponsor provided documents 
before and during the trial.
BI has appointed a Clinical Trial Leader, responsible for coordinating all required activities, 
in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,


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-
ensure appropriate training and information of Clinical Trial Managers (CT 
Managers), CRAs, and investigators of participating countries.
The organization of the trial in the participating countries will be performed by the respective 
local or regional BI-organization, in accordance with applicable regulations and BI SOPs, or 
by a CRO with which the responsibilities and tasks will have been agreed and a written 
contract filed before initiation of the clinical trial.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organize, manage, and evaluate the trial are defined 
according to BI SOPs.  A list of responsible persons and relevant local information can be 
found in the ISF.
A central laboratory service, a centralized ECG service, and an IRT vendor will be used in 
this trial.  Details will be provided in the central laboratory manual, quick guide for ECG, and 
quick reference documents for IRT


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
P19-01871
American Diabetes Association Standards of Medical Care in Diabetes 
– 2019 abridged for primary care providers. Clin Diabetes 37 (1), 11 -
34 (2019)
R10-1424
Pinheiro J, Bornkamp B, Bretz F Design and analysis of dose-finding 
studies combining multiple comparisons and modeling procedures. J 
Biopharm Stat 16 (5), 639 - 656 (2006)
R12-4395
Guidance for industry: suicidal ideation and behavior: prospective
assessment of occurrence in clinical trials (draft guidance, August
2012).   http:// www. fda. gov/ downloads/ Drugs/ Guidance
RegulatoryInformation/ Guidances/UCM22 5130.pdf (access date: 5 
October 2012); 2012.
R15-2001
Bornkamp B, Pinheiro J, Bretz F Package 'DoseFinding' 
(February 19, 2015). 
http://cran.r-project.org/web/packages/DoseFinding/DoseFinding.pdf
(access date: 28 April 2015); Comprehensive R Archive Network 
(2015) 
R17-4311
Nauck MA, Petrie JR, Sesti G, Mannucci E, Courreges JP, Lindegaard 
ML, et al, Study 1821 Investigators A phase 2, randomized, dose-
finding study of the novel once-weekly human GLP-1 analog, 
semaglutide, compared with placebo and open-label liraglutide in 
patients with type 2 diabetes. Diabetes Care 39 (2), 231 - 241 (2016)
R18-1820
International Hypoglycaemia Study Group. Glucose concentrations of
less than 3.0 mmol/L (54 mg/dL) should be reported in dlinical
trials: a joint position statement of the American Diabetes
Association and the European Association for the Study of Diabetes.
Diabetes Care 2017;40:155-157.
R19-1407
Saxenda (liraglutide [rDNA origin] injection), solution for 
subcutaneous use (Novo Nordisk) (U.S. prescribing information, 
revised: 12/2014).
https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206321Ori
g1s000lbl.pdf (access date: 17 April 2019) (2014)


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9.2
UNPUBLISHED REFERENCES
c14085752-06
Investigator’s Brochure: BI 456906, Version 6.0; Indication 1404.P01, 
1404.P02, 1404.P03
c21168858-05
A phase I, blinded within dose groups, multiple dose, placebo-
controlled study to assess the safety, tolerability, pharmacokinetics and 
pharmacodynamics of different titration schemes of BI 456906 in 
patients with obesity and overweight. Clinical Trial Protocol 1404-
0003 (17 May 2019).
c28750666
Explorative safety analysis for all dose groups. 1404-0003 trial. 08 Jul 
2019
n00254908-01
Prediction of BI 456906 Pharmacokinetics and Therapeutic Dose in 
Human. Clinical Trial Report 1404-0001 (07 Mar 2017).
n00264884 
.: BI 456906: Assessment of CYP suppression 
potential in primary human hepatocytes using the basic model F0.5
according to EMA guidance.


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10.
APPENDICES
Not applicable


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
28 September 2020
EudraCT number
EU number
2019-002390-60
BI Trial number
1404-0002
BI Investigational Medicinal 
Product(s)
BI 456906
Title of protocol
A Phase II, randomized, parallel group, dose-
finding study of subcutaneously administered BI 
456906 for 16 weeks, compared with placebo and 
open-label semaglutide in patients with type 2 
diabetes mellitus.
Global Amendment due to urgent safety reasons
Global Amendment
Section to be changed
Flow Chart
Description of change
1. Check injection site reactions added to Visit 2
2. Footnote #30 added to indicate diet and 
exercise counselling should be performed per 
local guidelines.
3. Footnote #9: clarified that serum pregnancy test 
is performed at central lab for the screening 
visit.
4. Footnote #14: deleted “More details can be 
found in the IRT user manual”.
5. Footnote #17: Clarified PK samples drawn at 
Visits 12 and 13 are not pre-dose samples as 
there is no dosing scheduled for these visits.
Rationale for change
Corrections and clarifications.
Section to be changed
Section 1.2
Description of change
Additional safety data from Part B of the MRD 
study added.
Rationale for change
Part B of the MRD trial was completed.
Sections to be changed
Sections 1.4.2, 4.1.4, 5.2.3, and 6.1
Description of change
1. Section 1.4.2: addition to the risk section 
indicating that BI 456906 does not increase the 
risk of severe viral infections. Guidance is 
provided if local regulations require SARS-
CoV-2 testing for study entry.
2. Section 4.1.4: Circumstances under which trial 
medication can be sent to patient’s home when 
physical visits are not possible due to the 
COVID-19 pandemic.
3. Section 5.2.3: SARS-CoV-2 tests will be done 


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locally.
4. Section 6.1: Circumstances under which a 
clinic visit can be performed remotely when 
physical visits are not possible due to the 
COVID-19 pandemic.  All COVID-19 related 
deviations will be documented and the 
implications considered for the analysis of data.
Rationale for change
Measures taken due to the COVID-19 pandemic.
Sections to be changed
Sections 3.3.2, 3.3.3, and synopsis
Description of change
The following changes were made to the 
inclusion/exclusion criteria:
1. Inclusion #4: added “at screening”
2. Inclusion #7: deleted “men able to father a 
child”: male trial participants do not require 
contraception.
3. Exclusion #7: “supine” position removed, and  
deleted “or a change in antihypertensive 
medication 30 days prior to screening”.
4. Exclusion #8: revisions include QTcF interval
changed from 470 ms in males and 490 ms in 
females to 450ms in both males and females.
Deleted “an increase of 30 ms versus 
screening”.
5. Exclusion #9: added “supraventricular 
tachycardia” and “(e.g. atrial fibrillation, atrial 
flutter) to description of heart rhythm 
disturbances.  Deleted “with baseline HR 
>100/min”.
6. Exclusion #12: +/- 5% changed to “+/- 5% or 
more”. 6 months prior to randomization 
changed to 6 months prior to screening.
7. Exclusion #13: anticonvulsants (except 
gabapentin), systemic corticosteroids, and 
antithrombotics (except low dose aspirin) 
added to the excluded medications list.  
Diuretics are still excluded except thiazides.
Deleted “potentially induce a change in body 
weight”. Criteria for thyroid replacement 
therapy moved to exclusion #23.
8. Exclusion #23: sleep medications, 
antihistamines, selective alpha receptor blocker 
for benign prostatic hyperplasia, and hormone 
replacement therapy including thyroid hormone  
are allowed.  Inhaled respiratory medications 
are still allowed.  Added “any medications 
known to cause heart block or bradycardia such 
as beta-blockers, verapamil and diltiazem are


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excluded unless used to treat heart rate control 
or hypertension”.
9. Exclusion #24: levothyroxine is allowed.
10. Exclusion #39: new exclusion criteria, patients 
with confirmed SARS-CoV-2 infection in the 3 
months prior to screening cannot be included.
Rationale for change
Most changes are based on feedback from Health 
Authorities. New criteria added and a few
clarifications.
Sections to be changed
Sections 3.3.4.1 and 1.4.2
Description of change
1. Sustained symptomatic hypotension or 
hypertension is defined.
2. QTcF change from baseline changed from 30 
ms to 60 ms. Clarified baseline is 
randomization.
3. Trial treatment will be terminated and patient 
will be discontinued if patient has symptoms of 
SARS-CoV-2 infection or diagnosed with 
COVID-19.  Patients can resume treatment if 
the results are negative.
Rationale for change
Changes 1 and 2 are based on feedback from 
Health Authorities.  Change 3 is an added criterion 
for discontinuation.
Section to be changed
Section 4.1.2
Description of change
First part of 2nd paragraph was revised as follows:
Safety and tolerability of BI 456906 was evaluated 
in healthy subjects and patients with 
obesity/overweight up to 16 weeks for doses up to 
3.15 mg/week (daily dosing) and up to 4.8 mg 
/week (weekly dosing), i.e. exceeding the highest 
dose planned for 1404-0002.
Rationale for change
Additional rationale for doses selected in the high 
dose groups in this trial.
Section to be changed
Section 4.1.4
Description of change
1. …..injected into the skin fold “over at least 15 
seconds” changed to “over 5 to 10 seconds”.
2. Instructions for medication administration from 
vials revised as follows: If the volume exceeds 
1.0 mL, the dose may be divided into two 
syringes and will be injected into two different 
injection sites on the same side of the abdomen. 
The next dose should be administered on the 
alternate side of the abdomen.
3. Added the following: The placebo solution for 
BI 456906 is filled either into a vial or a 
syringe, and their composition is identical.  The 
vials are used from week 1 to 6, and the pre-


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filled syringes are used from week 7 to 16.
Rationale for change
Further clarification provided on the site of 
medication administration.
Clarified that the placebo for BI 456906 is the 
same in the vials and pre-filled syringes.
Section to be changed
Section 4.2.1
Description of change
1. Criteria for initiating treatment for 
hyperglycemia changed.
2. Guidance for self monitoring of blood glucose 
revised.
3. Patient should also contact the site when FBG 
is below 70 mg/dl (3.9 mmol/L).
4. Hypoglycemic events classified using standard 
definitions as Levels 1, 2, and 3.
5. Added the following: Hypoglycemic events 
should be treated and additional glucose 
monitoring should be implemented per 
investigator discretion and medical judgement.  
Investigator should make a determination if a 
hyperglycemic or a hypoglycemic event should 
be reported as an AE.
Rationale for change
Procedures to follow in the monitoring of 
hyperglycemic and hypoglycemic events have been 
revised.
Section to be changed
Section 4.2.2.2
Description of change
1. Dietary supplements that potentially induce 
change in body weight are not permitted. 
Over-the-counter and prescribed weight loss 
products are not permitted.
Rationale for change
Clarification on restrictions.
Section to be changed
Sections 4.2.2.3, 3.3.2, 5.2.6.2.3, and synopsis, 
Description of change
Contraception is not required for male participants 
in the trial. Revisions have been made to align with 
this change.
Rationale for change
Reproductive and developmental toxicity studies 
show that male and female fertility was unaffected.  
BI 45906 is not genotoxic or teratogenic.
Section to be changed
Sections 5.2.1, 5.2.2, and flowchart
Description of change
1. Section 5.2.1: Respiratory rate and temperature 
added to vital signs.
2. Flow chart and section 5.2.2: Assessment of 
skin rashes added to physical examination.  
Skin rashes will be recorded in the CRF as an 
AE.
Rationale for change
Assessment of skin rashes was a request from 
Health Authority. 


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Respiratory rate and temperature added in the 
evaluation of vital signs.
Section to be changed
Section 5.2.3
Description of change
Added in Table 5.2.3: 1: C-Reactive Protein test at 
screening visit only.
Rationale for change
Additional safety parameter added.
Sections to be changed
Section 5.2.4 and flowchart
Description of change
1. Footnote #13 in flowchart and Section 5.2.4: 
added “three single ECGs recorded within 180 
seconds”.
2. Section 5.2.4: added “The QTcF value at the 
screening visit is the average of the three 
recordings”. Replaced user manual with ECG 
machine quick guide. QT/QTc replaced with 
QTcF.
Rationale for change
Provided time window for the three ECGs at 
screening visit.  Clarified the baseline QTc value, 
and corrected the name of the ECG user guide.
Clarified QTc measurements.
Section to be changed
Section 5.2.5.1
Description of change
Added the following, “There has been no suicidal 
risk identified for BI 456906 in clinical data 
obtained to date.  However, evaluation of suicidal 
behavior and ideation is important in clinical 
development and the Columbia-Suicide Severity 
Rating Scale, C-SSRS, will be used to 
prospectively assess suicidal behaviour and 
ideation (R12-4395).”
Rationale for change
Added rationale for using the C-SSRS in this trial.
Section to be changed
Sections 5.2.5.2, 1.4.2, 4.2.1, and flowchart
Description of change
Patients may also use their own device for SMBG 
monitoring”.
Section 5.2.5.2: Guidance for self monitoring of 
blood glucose revised. Patients need not return the 
glucometers at the end of the study.
Rationale for change
Added more flexibility for patients to let them use 
their own glucometer if it is their preference.
Did not want to dispense the used glucometer to 
another patient due to COVID-19.
Section to be changed
Section 5.2.6.1.5
Description of change
Electrocardiogram QT corrected interval 
prolonged: QTc changed to QTcF.  In the severe 
category, increase from baseline changed from 30 
ms to 60 ms.
Rationale for change
QTc formula clarified, severe category revised.
Section to be changed


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Description of change
Rationale for change
Section to be changed
Sections 9.1 and 9.2
Description of change
Section 9.1: added two references: R18-1820 and 
R12-4395.
Section 9.2: reference for Investigator’s Brochure 
updated.
Rationale for change
Added references to support changes in the 
amendment.
Sections to be changed
Protocol, synopsis, Abbreviations, Sections 3.3, 
5.2.6.2.2, and 8.7
Description of change
1. Protocol version and date changed.
2. Abbreviations: COVID-19, SARS-CoV-2, 
QTcF added. QTcB deleted.
3. Section 3.3: number of sites increased from 70 
to 80.
4. Section 3.3, exclusion #36: “see section 
4.2.2.1” deleted (was an error).
5. Section 5.2.6.2.2: AE reporting process 
changed.
6. Section 8.7: IRT user manual and ECG user 
manual changed to IRT quick reference 
document and ECG quick guide respectively. 
The name of the documents are corrected.
7. Typos in the protocol corrected.
Rationale for change
Administrative changes
Section to be changed
Flow chart, Sections 4.3, and 6.2.3
Description of change
1. Flow chart: a) footnote #20, added guidance on 
metformin dosing on days fasting is required.
2. Section 4.3: Added “A 24-hour period is 
considered one day”.
3. Flow chart and Section 6.2.3: Last clinic visit is 
also the “end of study visit”
Rationale for change
Clarifications


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c26686857
2.0
clinical-trial-protocol-version-2
A Phase II, randomized, parallel group, dose-finding study of subcutaneously
administered BI 456906 for 16 weeks, compared with placebo and open-label
semaglutide in patients with type 2 diabetes mellitus.
Author-Trial Clinical
Pharmacokineticist
28 Sep 2020 15:40 CEST
Author-Clinical Trial Leader
28 Sep 2020 15:48 CEST
Approval-Translational Medicine
Expert
28 Sep 2020 15:49 CEST
Approval-Team Member Medicine
28 Sep 2020 16:13 CEST
Approval-
 Medicine
28 Sep 2020 17:43 CEST
Author-Trial Statistician
28 Sep 2020 17:59 CEST
Verification-Paper Signature
Completion
28 Sep 2020 18:46 CEST


Boehringer Ingelheim 
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SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c35576269-02
BI Trial No.:
1404-0002
Title:
A Phase II, randomized, parallel group, dose-finding study of
subcutaneously administered BI 456906 for 16 weeks, compared
with placebo and open-label semaglutide in patients with type 2
diabetes mellitus. 
Revised protocol #1 (c26686857-02)
Investigational
Product:
BI 456906
Responsible trial 
statisticians:
Phone: 
Date of statistical 
analysis plan:
26 NOV 2021 SIGNED
Version:
2.0
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reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................5
2.
LIST OF ABBREVIATIONS ..............................................................................6
3.
INTRODUCTION.................................................................................................9
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY....................10
5.
ENDPOINTS .......................................................................................................11
5.1
PRIMARY ENDPOINT .....................................................................................11
5.2
SECONDARY ENDPOINTS.............................................................................11
5.2.1
Key secondary endpoints...........................................................................11
5.2.2
Secondary endpoints..................................................................................11
5.4
OTHER VARIABLES........................................................................................12
5.4.1
Safety Endpoints ........................................................................................12
5.4.2
Demographic and other baseline characteristics ....................................13
5.4.3
Rescue Treatment ......................................................................................14
5.4.4
Treatment compliance and treatment exposure .....................................14
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................16
6.1
TREATMENTS...................................................................................................16
6.2
IMPORTANT PROTOCOL DEVIATIONS ...................................................18
6.3
PATIENT SETS ANALYSED...........................................................................19
6.5
POOLING OF CENTRES .................................................................................22
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................22
6.6.1
Withdrawals ...............................................................................................22
6.6.2
Efficacy data...............................................................................................23
6.6.3
Safety data ..................................................................................................24


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6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................25
7.
PLANNED ANALYSIS......................................................................................30
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........31
7.2
CONCOMITANT DISEASE AND MEDICATION........................................32
7.3
TREATMENT COMPLIANCE........................................................................33
7.4
PRIMARY ENDPOINT .....................................................................................33
7.5
SECONDARY ENDPOINTS.............................................................................36
7.5.1
Key secondary endpoint ............................................................................36
7.5.2
Secondary endpoints..................................................................................36
7.7
EXTENT OF EXPOSURE.................................................................................39
7.8
SAFETY ANALYSIS..........................................................................................39
7.8.1
Adverse events............................................................................................39
7.8.2
Laboratory data .........................................................................................41
7.8.3
Vital signs....................................................................................................42
7.8.4
ECG.............................................................................................................42
7.8.7
Other ...........................................................................................................44
7.9
ANALYSIS OF COVID-19 IMPACT...............................................................44
8.
REFERENCES....................................................................................................46


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10.
HISTORY TABLE..............................................................................................58


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LIST OF TABLES
Table 6.1: 1 
Flow chart of analysis phases ...........................................................................16
Table 6.1: 2 
Treatment groups..............................................................................................17
Table 6.3: 1
Patient sets analysed .........................................................................................21
Table 6.7: 1
Time windows for assignment of measurements to visits for statistical 
analyses for the following variables: Efficacy measurements that are 
measured at every visit and vital signs measurements .....................................27
Table 6.7: 2
Time windows for assignment of HbA1c, safety lab measurements and 
visits for statistical analyses........................................................28
Table 6.7: 3
Time windows for assignment of waist circumference to visits for statistical 
analyses.............................................................................................................28
Table 7.1: 1
Categories for summary of continuous variables .............................................32
Table 7.4: 2
Contrast coefficients.........................................................................................34
Table 10: 1
History table .....................................................................................................58


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADA
Anti-drug antibodies
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
ATC3
Anatomical-Therapeutic-Chemical classification level 3
BI
Boehringer Ingelheim
BLQ
Below the lower limit of quantification
BMI
Body mass index
BRI
Best response imputation
CARE
Clinical data analysis and reporting environment
CI
Confidence interval
COVID-19
Corona virus disease 2019
CRF
Case report form
C-SSRS
Columbia-Suicide Severity Rating Scale
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Arithmetic coefficient of variation
DBL
Database lock
DG
Dose group
DILI
Drug Induced Liver Injury
DMC
Data Monitoring Committee
ECDF
Empirical cumulative distribution functions
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic Data Capture
eGFR
estimated Glomerular Filtration Rate 
EMA
European Medicines Agency
EoT
End of treatment
ES
Enrolled set
EudraCT
European union drug regulating authorities clinical trials


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Term
Definition / description
FAS
Full analysis set
F/U
Follow-up
gCV
Geometric coefficient of variation
gMean
Geometric mean
HbA1c
Glycosylated hemoglobin A1c
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
iPD
Important protocol deviation
IRT
Interactive response technology
kg
Kilogram
LG
Logistic regression
LLOQ
Lower limit of quantification
LOQ
Limit of quantification
MAR
Missing at random
MCMC
Markov Chain Monte Carlo
MCP-Mod
Multiple Comparison Procedures and Modeling
MedDRA
Medical Dictionary for Regulatory Activities
MI
Multiple imputation
MMRM
Mixed Model Repeated Measures
MQRM
Medical quality review meeting
NA
Not available
Nabs
Neutralizing antibody
NRI
No response imputation
PD
Pharmacodynamic(s), protocol deviation
PG
Pharmacogenomic(s)
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic parameter set
PPS
Per protocol set
PRO
Patient Reported Outcome
PT
Preferred Term
Q1
1st quartile
Q3
3rd quartile


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Term
Definition / description
RAGe
Report appendix generator
REML
Restricted maximum likelihood
REP
Residual effect period
RPM
Report planning meeting
RS
Randomized set
SAE
Serious adverse event
SAF
Safety analysis set
SAP
Statistical analysis plan
SEM
Standard error of measurement
SD
Standard deviation
SDL
Subject data listing
SI
Système international d’unités
SMBG
Self-monitoring of blood glucose
SOC
System Organ Class
SS
Screened set
TFEQ-
R18V2
Three-Factor Eating Questionnaire revised version
TMF
Trial Master File
TS
Treated set
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal range
ULOQ
Upper limit of quantification
VAS
Visual analogue scale


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3.
INTRODUCTION
As per ICH E9 (11), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analyses described in the Clinical Trial Protocol 
(CTP) and its amendments, and to include detailed procedures for executing the statistical 
analysis of the primary and secondary variables and other data.
This TSAP assumes familiarity with the CTP, including Protocol Amendments. In particular, 
the TSAP is based on the planned analysis specification as written in CTP Section 7 
“Statistical Methods and Determination of Sample Size”. Therefore, TSAP readers may 
consult the CTP for more background information on the study, e.g., on study objectives, 
study design and population, treatments, definition of measurements and variables, planning 
of sample size, and randomization.
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by
), and a number 
of SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices).
Pharmacokinetics (PK) parameters will be calculated using Phoenix WinNonlinTM software
(version 8.1 or higher). R version 3.6.1 (or higher) with “DoseFinding” package (21) will be 
used for analysis based on Multiple Comparison Procedures and Modeling (MCP-Mod).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
Adaptations
All analyses stated in the CTP (latest version) will be performed as planned with the 
following adaptations:

In the CTP, the residual effect period (REP) of BI 456906 is 28 days, and the REP of 
semaglutide is approximately 5 weeks. However, for the definition of the analysis 
phases, a REP of 28 days is assumed for all treatment arms.

Overall compliance will not be calculated. Incompliances will be captured as protocol 
deviations.
Clarifications
According to the design of the trial the timeframe specified in the protocol as “to 16 weeks” 
refers to “at 16 weeks after treatment start” which means measurements planned for week 17 
(Study/Planned Day 113). I.e., change from baseline to “end of week 16” will be investigated.
For the analysis “week 17” and “Study/Planned Day 113” will be used for primary 
comparison to baseline.


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5.
ENDPOINTS
According to the design of the trial the timeframe specified in the protocol as “to 16 weeks” 
refers to measurements “at 16 weeks after treatment start” which is planned for week 17 
(Study/Planned Day 113). I.e., change from baseline to “end of week 16” will be investigated.
For consistence reasons the names of endpoints will stay as defined in the CTP. For the 
analysis “week 17” and “Study/Planned Day 113” will be used.
5.1
PRIMARY ENDPOINT
Absolute change in HbA1c from baseline to week 16 is the primary endpoint of efficacy in 
this trial.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
Relative body weight change from baseline to week 16 is the key secondary endpoint.
The endpoint will be reported in percentage.
5.2.2
Secondary endpoints
Secondary endpoints are defined as described below:

The absolute body weight change from baseline to week 16.

The absolute change in waist circumference from baseline to week 16.

The percentage of patients with 5% or greater body weight loss from baseline to week
16.

The percentage of patients with 10% or greater body weight loss from baseline to 
week 16.


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5.4
OTHER VARIABLES
5.4.1
Safety Endpoints
Safety will be assessed based on:

Adverse events

Safety laboratory values
o
Tests are listed in CTP Table 5.2.3:1.
o
Lab tests will be performed at the central laboratory service provider. Clinically 
relevant abnormal findings as judged by the investigator will be reported as AEs.

Vital signs, including
o
temperature
o
pulse rate
o
systolic blood pressure
o
diastolic blood pressure
o
respiratory rate

Columbia-Suicide Severity Rating Scale (C-SSRS)

12-lead ECG endpoints (centrally evaluated)
For the definition of baseline (Section 6.7) and a summary of time points scheduled 
for ECG recording and central evaluation please refer to CTP.
Quantitative ECG endpoints:
The following quantitative ECG endpoints will be determined for the ECG variables 
QTcF, HR, QT, PR, QRS, RR and QTcB, derived as described in additional Section 
9.6.3:

absolute values (per time point)

Time-matched changes from baseline (per time point)


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
Time-matched percent changes from baseline (per time point; for HR, PR, QRS)

Placebo-corrected changes from baseline (per time point)
Categorical ECG endpoints
The following categorical ECG endpoints will be determined based on the quantitative 
ECG endpoints:

New onset (meaning that this or a higher category was not present any time at 
baseline) of maximum QTcF interval > 450 to 480 msec, > 480 to 500 msec, or > 
500 msec on treatment.
For assignment of a particular subject to one of the above categories, all time 
points on-treatment (refer to Table 6.7: 1) will be considered. 

Maximum change from baseline of QT ≤ 60 msec, or > 60 msec on treatment

Maximum change from baseline of QTcF ≤ 30 msec, > 30 to ≤ 60 msec, or 
> 60 msec on treatment
The occurrence of any of the following will be considered as ‘notable findings’:

New onset (not present any time at baseline) of uncorrected QT interval > 
500 msec at any time on treatment

New onset of QTcF interval > 500 msec at any time on treatment

Change from baseline of QTcF > 60 msec at any time on treatment

Percent change from baseline of HR ≥ 25%, when corresponding on-treatment 
value of HR is > 100 beats/min, or percent change from baseline of HR - 25%, 
when corresponding on-treatment value of HR is < 50 beats/min, at any time on 
treatment

Percent change from baseline of PR ≥ 25%, when corresponding on-treatment 
value of PR interval is > 200 msec, at any time on treatment 

Percent change from baseline of QRS ≥ 10%, when corresponding on-treatment 
value of QRS duration is > 110 msec, at any time on treatment
For a detailed description of ‘new onset’, refer to Appendix Section 9.6.3
Findings from the morphological analyses of the ECGs will be determined and categorized 
based on SDTM terminology. For a detailed description of aggregation rules, refer to 
Appendix Section 9.6.3.
5.4.2
Demographic and other baseline characteristics
Standard demographic data and baseline characteristics are used as recorded in the eCRF.
These include sex, weight, height, BMI, race, ethnicity, age, site region.
BMI will be calculated as weight [kg] / height [m]2 (based on the last available weight 
measurement prior to the first dose of BI 456906). 


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Age [years] will be determined as the difference between year of birth and year of informed 
consent.
5.4.3
Rescue Treatment
Rescue medication will not be summarized separately, other as part of the concomitant 
medication summaries.
5.4.4
Treatment compliance and treatment exposure
The total duration of exposure will be calculated as the date of last administration of any trial 
treatment minus the date of first administration of any trial treatment + 1 day.
Additionally, the total duration of exposure (in weeks) will be categorized (non-disjunctively) 
as follows:

≥6 weeks

≥8 weeks

≥10 weeks

≥12 weeks

≥ 14 weeks

≥ 15 weeks

≥ 16 weeks


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For more details of study information on the treatment to be administered, assignment to 
treatment, and selection of dose, refer to Section 4 of the CTP.
The following study phases are defined:
Table 6.1: 1
Flow chart of analysis phases
Study analysis 
phase
Description
Start (included)
End (excluded)
Screening phase
Screening
Earlier of:
1) Date of informed consent
2) first screening procedure
1) Date/time of start of the first 
administration of the study drug
or
Dose escalation 
phase
Treatment 
phase 
Date/time of start of the first 
administration of the study 
drug (if applicable)
1) Date/time of dose administration in 
visit 8; or
2) if patient early discontinued study 
treatment before the first maintenance 
dose:
Earlier of:
2.1) Date of last administration of the 
study drug + 28 days +1 day at 0:00 
a.m.
2.2) Latest of:
2.2.1) Date of follow-up visit (Visit 13)
+1 day at 0:00 a.m.
2.2.2) End date on trial termination 
page +1 day at 0:00 a.m.
Maintenance 
phase
Date/time of dose 
administration in visit 8 (if 
applicable)
Earlier of:
1) Date of last administration of the 
study drug + 28 days +1 day at 0:00 
a.m.
2) Latest of:
2.1) Date of follow-up visit (Visit 13)
+1 day at 0:00 a.m.
2.2) End date on trial termination page 
+1 day at 0:00 a.m.
Follow-up1 phase 
(if applicable)
Off-
treatment 
phase (if 
applicable)
Date of last administration of 
the study drug + 28 days +1 
day at 0:00 a.m.
Latest of:
1) Date of follow-up visit (Visit 13);
2) End date on trial termination page 
+1 day at 0:00 a.m.
Dates are defined individually per patient. If more than one date is associated with a specific visit, measurements associated 
with a specific date are assigned to a study analysis phase according to the rules specified in the table. An analysis phase 
will not extend beyond the start date of the following phase.
1 The off-treatment phase (i.e., Follow-up phase) only exists if the trial completion date is after the date of last administration
+ 28 days + 1 day at 0:00 a.m.
 


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For patients who failed screening: adverse events recorded between the date of informed 
consent and the latest of date of screening visit +14 days at 0:00 am or the end date on trial 
termination page + 1 day at 0:00 am will be presented in a separate listing.
Missing dose administration times will be imputed with 12:00 am.
Treatment groups for the analysis of dose groups 1-7 will be labelled and sorted as follows:
Table 6.1: 2
Treatment groups
Treatment group*
Planned treatment
Placebo
Patients receiving placebo in dose group (DG) 1-6
BI 0.3 mg
Patients of DG 1 receiving active treatment
BI 0.9 mg
Patients of DG 2 receiving active treatment
BI 1.8 mg
Patients of DG 3 receiving active treatment 
BI 2.7 mg
Patients of DG 4 receiving active treatment 
BI 1.2 biw (2.4) mg
Patients of DG 5 receiving active treatment
BI 1.8 biw (3.6) mg
Patients of DG 6 receiving active treatment 
Semaglutide
Patients of DG 7
* Weekly dose in parenthesis


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6.2
IMPORTANT PROTOCOL DEVIATIONS
Data discrepancies and deviations from the CTP will be identified for all patients in the 
database (i.e., randomized patients). Consistency check listings (for identification of 
violations of time windows) and a list of protocol deviations will be provided to be discussed 
at the MQRM/RPM/DBLM. At this meeting, it will be decided whether a discrepant data 
value can be used in analyses or whether it must be queried in the clinical database. Each 
protocol deviation must be assessed to determine whether it is an important Protocol 
Deviation (iPD) and whether it is COVID-19 related. For definition of iPDs, and for the 
process of identification of these, refer to the BI reference document “Identify and Manage 
Important Protocol Deviations (iPD)” (2).
If any iPDs are identified, they are to be summarised into categories and will be captured 
in the MQRM/RPM/DBLM minutes. Handling of iPDs in analysis is included in the DV 
domain specifications (3) and stored within the TMF in EDMS. 
Not all iPDs will lead to exclusion from analysis sets. IPDs leading to exclusion from analysis 
sets are indicated as such in the DV domain specification sheet.
IPDs will be summarized and listed for the randomized set.


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6.3
PATIENT SETS ANALYSED
The following analysis sets will be defined for this trial:
Screened set (SS)
This patient set includes all patients screened in the trial and who signed informed consent. It 
will be used for display of patient disposition.
Randomized set (RS)
This patient set includes all screened patients who were randomized in the trial, regardless of 
whether any study drug was taken. Treatment assignment will be as randomized. 
Treated set (TS)
This patient set includes all patients who were randomized and received at least one dose of 
study drug. 
It will be the main analysis set for presentation of safety data. For treatment assignment see 
Table 6.1:2 and section Handling of Treatment Misallocations in Analysis Sets.
Full Analysis Set (FAS)
This patient set includes all patients who were randomized and received at least one dose of 
study drug and who have analysable data for at least one efficacy endpoint. 
Treatment assignment will be as randomized. This is the main analysis set for presentation of 
efficacy data.
Per-Protocol Set (PPS)
This patient set includes all patients in the FAS set who adhered to the CTP without any iPDs 
which are flagged for exclusion from the PPS in the DV domain specification. 
The PPS will be used for sensitivity analysis on the primary efficacy endpoint.
Pharmacokinetic parameter set (PKS)
This patient set includes all patients in the TS who provide at least one evaluable observation 
for the BI 456906 or semaglutide concentration, which was not flagged for exclusion. 
For treatment assignment see Table 6.1:2 and section Handling of Treatment Misallocations 
in Analysis Sets.
Handling of Treatment Misallocations in Analysis Sets
If a patient is randomized but took incorrect treatment during the study, then:
-
For efficacy analyses according to FAS and PPS, they will be reported under their 
randomized treatment groups. 
-
For PK analyses misallocations will be reviewed case by case.
-
For safety analyses using the TS:


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•
For DG 1-6 randomized to BI 456906: 
- As a patient is planned to receive multiple dose administrations of BI 456906, 
patients will be reported under their randomized treatment group for safety analysis 
in case that the patient receives only a few doses of the incorrect medication at only 
some dosing occasions. That is because the overall safety profile is expected to be 
driven by the amount of BI 456906 received in totality over the entire treatment 
duration. 
In case a patient receives an incorrect dose in a considerable amount of dosing 
occasions and deviates from the protocol (no pre-planned dose adjustment of DG 4 
or 6), the patient will be assigned to the respective or a lower dose group (in case no 
planned dose group with the respective dose exists). 
- Patients in DG 4 or 6 with pre-planned dose adjustment will be reported under their 
randomized treatment group for safety analysis.
•
For DG 1-6 randomized to placebo: If a patient is planned to receive placebo but 
receives at least one dose of the BI 456906 or semaglutide, then the patient will be 
assigned to BI 456906 0.3 mg (the lowest dose group of BI 456906 planned in the 
trial) or semaglutide treatment group, respectively. If the patient receives BI 456906 
at a considerable amount of dosing occasions, the patient will be assigned to the 
respective dose group of BI 456906.
•
For DG 7 (semaglutide): As a patient is planned to receive multiple dose 
administrations of semaglutide, patients will be reported under their randomized 
treatment group for safety analysis in case that the patient receives only a few doses 
of the incorrect medication at only some dosing occasions. That is because the 
overall safety profile is expected to be driven by the amount of semaglutide received 
in totality over the entire treatment duration. 
All treatment data for patients falling into the above categories will be reviewed shortly after 
DBL by the trial team. Any differences between the randomized treatment and the treatment 
used for safety analyses will be documented in the decision log.
Overview of Patient Sets used for analyses
Table 6.3: 1 illustrates the data sets which are to be used for each category class of endpoints, 
and the approaches used with regard to missing data. For explanation of the different methods 
of handling missing data, cf. Section 6.6.


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Table 6.3: 1
Patient sets analysed
Class of endpoint
Patient set
SS
RS
TS
FAS
PPS
PKS
Disposition
x
Compliance and exposure
x
iPD
x
Demographic/baseline 
characteristics
x
x
x
Concomitant disease and 
medication
x
Primary efficacy endpoint
MMRM+MCPMod,
MI+MMRM+
MCPMod 1, 
MMRM2,
descriptive
MMRM+MCPMod,
MI+MMRM+
MCPMod 1, 
descriptive
Key secondary efficacy 
endpoint 
MMRM+MCPMod,
MI+MMRM+
MCPMod 1, 
MMRM2,
descriptive
Secondary efficacy 
endpoints (Continuous)
MMRM,
descriptive
Secondary efficacy 
endpoints (Binary)
LG,
descriptive
Further safety parameters
x
1 sensitivity analysis
2 subgroup analysis
3 selected endpoints
LG = Logistic regression, “MMRM” and “MI+MMRM” represent analyses involving imputed data, cf. Section 6.6.2.


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6.5
POOLING OF CENTRES
There is no plan to perform statistical analysis by centers. All centers will be pooled.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Section 7.3 of the CTP and the following subsections describe the handling of missing data.
If not stated elsewise, the original results approach is used.
6.6.1
Withdrawals
The reasons for withdrawal from treatment will be reported as indicated on the eCRF.


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6.6.2
Efficacy data
Based on the different reasons for patients’ data missing for different endpoints, various 
approaches will be used to assess the impact of missing data on the efficacy endpoints of this 
trial, depending upon the type of the endpoint (cf. Table 6.3: 1). Approaches to be applied are 
described below.
Continuous efficacy endpoints
MMRM
For efficacy endpoints which are continuous in nature, the use of a restricted maximum 
likelihood (REML)-based mixed model repeated measures (MMRM) approach as the primary 
method, if applicable, will ensure that missing data are handled implicitly, via a missing at 
random (MAR) assumption, by the statistical model. 


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Binary efficacy endpoints
For all binary endpoints (i.e., endpoints that are either 1 (patient responded) or 0 (patient did 
not respond)), the main analysis will not be imputed.
, the following 
two imputation approaches will apply:

No Response Imputation (NRI):
-
If there are on-treatment data at the last planned visit before the visit with a missing 
outcome, then impute as success only if the visit also represents a success (independent of 
whether the preceding and following observations were selected for analysis based on 
time windows described in Section 6.7);
-
Otherwise, impute as a failure to achieve a response 

Best response imputation (BRI): 
-
Impute all missing values based on the best response observed for the patient at visits 
prior to withdrawal/occurrence of missing data (independent of whether the observations 
were selected for analysis based on time windows described in Section 6.7). If there is no 
non-missing data available (including baseline), then the missing value will be imputed as 
a failure.
6.6.3
Safety data
With respect to safety evaluations, it is not planned to impute missing values. Instead, for 
safety data all original data will be used.
The estimated glomerular filtration rate (eGFR) will be calculated according to Section 9.1.2
and will be tabulated separately as an exploratory safety biomarker.
The only exceptions where imputation might be necessary for safety evaluation are:
-
Missing or incomplete AE dates are imputed according to BI standards (4).
-
Lab data below the lower Limit of Quantification (LOQ) will be imputed according to BI 
standards (8). Values below lower LOQ will be imputed by 0.5 * lower LOQ. This means, if 
the value is given as ‘< x’, the imputed value will be 0.5*x. Values above upper LOQ will be 
imputed by the numeric value of the upper LOQ plus one rounding unit. This means, if the 
value is given as ‘>xx.x’ then the imputed value will be equal to xx.x + 0.1.
Partial start and stop dates for AEs and concomitant medications will be imputed to enable 
subsequent calculation (but not for display) by the following “worst case" approach:

A completely missing adverse event or concomitant medication start date will be 
assumed to mean present at screening.

If the day of the start date is missing the start date is set to first day of the month.

If the day and month of the start date are missing then the start date is set to 1st
January of the year.


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
In the case of AE start dates (only), if the stated imputation would make the AE 
become pre-treatment when this was not known from the incomplete date, it will be 
assumed instead that the AE started on the first day of treatment.

Missing start and stop times will not be imputed.
All other cases need to be assessed by the trial team on an individual basis, using the above 
points as guidance.
If the date of first administration of study medication is completely missing but the patient 
was known to have been randomized and treated, it will be assumed equal to the date of 
randomization. If only the month and year are available for the date of first administration of 
study medication, the date of randomization will be used if they are in the same month. If 
randomization was in the month prior to first drug administration, the first day of the month 
of first administration will be assumed.
ECG
If single cardiac cycles of an ECG are missing, the arithmetic mean for this single ECG will 
be computed with the reduced (1, 2 or 3) number of cardiac cycles.
If replicate ECG recordings of the centrally evaluated triplicate ECG recorded at Screening
are missing, the arithmetic means per time point will be computed with the reduced number 
(1 or 2) of recordings.
For the classification of the on-treatment QTc/QT intervals into ‘no new onset’ / ‘new onset’ 
categories, the handling of missing value is described in Appendix Section 9.6.
 
 
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Measurements reported with date and time and taken prior to start of administration of trial 
treatment will be considered pre-treatment values. Measurements reported with a date only 
(and no time) and taken on the day of first administration of trial treatment will be considered 
pre-treatment values if not stated otherwise.
Baseline, unless otherwise specified, is defined as the last measurement collected prior to the 
start of administration of the trial treatment.


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If the pre-treatment single ECG recording taken on the day of first administration of trial 
treatment is missing (or assessed as not evaluable, respectively) or recorded after drug
administration, the mean of the triplicate ECG recorded at Screening will be used as baseline 
value instead.
Measurements taken after start of administration of trial treatment will be considered either 
on- or off-treatment values based on the definition in Section 6.1, and will be assigned to 
visits for statistical analysis, if applicable, as defined below.
AE with missing onset time and occurring on the same day as the first treatment dose, the AE 
will be assigned to the “on treatment”. 
Analysis of AE data, and concomitant medication or non-drug therapies will not be based on 
visits. Frequency tables for these data will be using on-treatment data and categorized based 
on their occurring/starting dates (see Table 6.1: 1). Therefore, no assignment to time windows 
will be necessary for such data.
All other safety, efficacy and biomarker measurements will be assigned to visits based on 
extended time windows around the planned visit dates, defined relative to the day of first trial 
treatment (which is scheduled for Visit V2). These extended time windows are defined in 
Table 6.7: 1, Table 6.7: 2 and Table 6.7: 3. For all variables with a sparse sampling schedule 
that does not match the schedules in Table 6.7: 1, Table 6.7: 2 or Table 6.7: 3, the following 
rules apply:
-
For the extended time window of the baseline visit, start is not defined. It ends on Day 1. 
The subsequent extended time window starts on Day 2 (or on Day 1 after start of 
treatment, if measurement times are collected).
-
Start and end of the extended time windows will be equidistant from the planned visit day 
and the last and following planned visit day, respectively.
-
The end of the extended time window of the EoT visit is the end of the on-treatment 
phase as defined in Table 6.1: 1.
The derivation of the last value, minimum value and maximum value of laboratory and vital 
signs data will consider all on-treatment values (whether or not selected in any time window; 
see Table 6.1: 1 for definition of the on-treatment period) within the period of interest; these 
will be derived for analysis of laboratory and vital signs data.


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Table 6.7: 1
Time windows for assignment of measurements to visits for statistical analyses
for the following variables: Efficacy measurements that are measured at every visit and vital 
signs measurements 
Visit 
number
/ name
Study/ 
Planned 
day
Time window (Days)
Visit label
Window 
(per 
CTP)
Start
(per CTP)
End
(per CTP)
Start 
(extended)
End 
(extended)
V1
Screening
- 14 to 1 
Days
All pre-baseline 
measurements
V2
Baseline
Day 1
1 A
1
NA A
1 B
V3
Week 2
Day 8
+/- 1
7
9
1 B
11
V4
Week 3
Day 15
+/- 1
14
16
12
18
V5
Week 4
Day 22
+/- 1
21
23
19
25
V6
Week 5
Day 29
+/- 1
28
30
26
32
V7
Week 6
Day 36
+/- 1
35
37
33
39
V8
Week 7
Day 43
+/- 1
42
44
40
46
V9
Week 8
Day 50
+/- 1
49
51
47
64
V10
Week 12
Day 78
+/- 2
76
80
65
92
V11
Week 16
Day 106
+/- 2
104
108
93
109
V12
Week 17
(EoT)
Day 113
+/- 2
111
115
110
End of on-
treatment 
phaseC
V13
Follow-up
Day 141
+ 4  
141
145
Begin of 
follow.up 
phaseC
End of 
follow-up 
phaseC
Days are counted relative to the day of first treatment, which is defined as Day 1.
A In case of invalid or missing baseline measurement at Day 1, the last pre-treatment measurement will be used 
as baseline.
B Note that measurements made at Day 1 and assigned to the on-treatment period (because mistakenly made after 
start of trial treatment) via assessment on date and time (i.e., safety laboratory) will not be assigned as baseline.
C as defined in Table 6.1: 1
                       


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Table 6.7: 2
Time windows for assignment of HbA1c, safety lab measurements 
 
 to visits for statistical analyses
Visit 
number
/ name
Study / 
Planned 
day
Time window (Days)
Visit label
Window 
(per 
CTP)
Start
(per CTP)
End
(per CTP)
Start 
(extended)
End 
(extended)
V1
Screening
- 14 to 1 
Days
All pre-baseline 
measurements
V2
Baseline 
Day 1
1 A
1
NA A
1 B
V6
Week 5
Day 29
+/- 1
28
30
1 B
39
V9
Week 8
Day 50
+/- 1
49
51
40
64
V10
Week 12
Day 78
+/- 2
76
80
65
92
V11
Week 16
Day 106
+/- 2
104
108
93
109
V12
Week 17
(EoT)
Day 113
+/- 2
111
115
110
End of on-
treatment 
phaseC
V13
Follow-up
Day 141
+ 4  
141
145
Begin of 
follow.up 
phaseC
End of 
follow-up 
phaseC
Days are counted relative to the day of first treatment, which is defined as Day 1.
A In case of invalid or missing baseline measurement at Day 1, the last pre-treatment measurement will be used 
as baseline.
B Note that measurements made at Day 1 and assigned to the on-treatment period (because mistakenly made after 
start of trial treatment) via assessment on date and time (i.e., safety laboratory) will not be assigned as baseline, 
except for HbA1c, where measurements done at the date of start of trial treatment will be assigned to the 
baseline window as well.
C as defined in Table 6.1: 1
Table 6.7: 3
Time windows for assignment of waist circumference to visits for statistical 
analyses
Visit 
number
/ name
Study / 
Planned 
day
Time window (Days)
Visit label
Window 
(per 
CTP)
Start
(per CTP)
End
(per CTP)
Start 
(extended)
End 
(extended)
V1
Screening
- 14 to 1 
Days
All pre-baseline 
measurements
V2
Baseline 
Day 1
1 A
1
NA A
1B
V7
Week 6
Day 36
+/- 1
35
37
1 B
74
V12
Week 17
(EoT)
Day 113
+/- 2
111
115
75
End of on-
treatment 
phaseC
V13
Follow-up
Day 141
+ 4  
141
145
Begin of 
follow.up 
phaseC
End of 
follow-up 
phaseC
Days are counted relative to the day of first treatment, which is defined as Day 1.
A In case of invalid or missing baseline measurement at Day 1, the last pre-treatment measurement will be used 
as baseline.
B Note that measurements made at Day 1 and assigned to the on-treatment period (because mistakenly made after 
start of trial treatment) via assessment on date and time (i.e., safety laboratory) will not be assigned as baseline.
C as defined in Table 6.1: 1


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Repeated and unscheduled efficacy, safety and biomarker measurements will be handled 
similarly to scheduled measurements and will also be assigned to a time window depending 
upon the date/time of measurement. Only one observation per time window will be selected 
for statistical analysis at a particular visit.
Descriptive statistics of on-treatment laboratory data (except HbA1c) will be calculated by 
visit based on the following rules:

If pre-treatment, then use the last value 

If on treatment, then use the worst repeat (defined for each parameter as being the 
most critical direction for the patient) value depending on the position of the first lab 
value relative to the mean of the reference range. That means if the first value is below 
the mean of the reference range, then use the minimum value. If the first lab value is 
above the mean of the reference range, then use the maximum value. 
For the descriptive statistics of ECG intervals by visit, time windows according to 
Table 6.7: 1 will be used. Scheduled visits take precedent over unscheduled visits. The 
measurement closest to the plan target day is used. If there are two observations which have 
the same difference in days to the planned day (but are not on the same day), the later value 
will be selected. The derivation of the maximum value of an ECG interval (or worst case of
the morphological assessment, if applicable) will consider all on-treatment values (whether or 
not selected in any time window; see Table 6.1: 1 Table 6.1: 1 for definition of the on-
treatment period) within the period of interest.
For all other measurements especially HbA1c, the value which is closest to the protocol 
planned visit day will be selected. If there are two observations which have the same 
difference in days to the planned day (but are not on the same day), the later value will be 
selected. If there are two observations on the same day, the worst value will be selected.


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7.
PLANNED ANALYSIS
The format of the listings and tables will follow the BI guideline "Standards for Reporting of 
Clinical Trials and Project Summaries" (10)
 
The individual values of all patients will be listed, including those collected during the off-
treatment period. Listings will generally be sorted by treatment, country, centre number, 
patient number and visit (if visit is applicable in the respective listing). AE listings will be 
sorted by treatment group (see Section 7.8.1 below for details).
The following standard descriptive statistical parameters will be displayed in summary tables 
of continuous variables:
N:
number of non-missing observations
Mean:
arithmetic mean
SD:
standard deviation
Min:
minimum
Q1: 
lower quartile
Median:
median
Q3: 
upper quartile
Max:
maximum
For PK analyte concentrations, the following descriptive statistics will additionally be 
 
Statistical parameters will be displayed to a defined number of decimal places as specified in 
the BI guideline "Standards for Reporting of Clinical Trials and Project Summaries" (10). 
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment. Percentages will be rounded to one decimal place. The category missing 
will be displayed if and only if there actually are missing values. Percentages will be based on 
all patients in the respective patient set whether they have non-missing values or not if there is 
no other particular specification.
Note that for the analysis of all data in this trial, the primary approach is to report only those 
data that fall within the on-treatment period.
Disposition of the patient population participating in the trial will be summarised on SS by 
presentation of the frequency of patients screened, randomized, treated, who completed all 
doses of treatment as planned, who completed visit 11, who completed the study, who 


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prematurely discontinued study treatment, by reason, and who withdrew from the trial before 
study completion, by reason. Disposition will also be summarized and listed by country.
Patients who were re-screened (with a new patient number) will be counted only once in the 
screened set, and not be summarized as screening failures. Re-screened patients will be 
identified from IRT reports.
The frequency of patients with iPDs will be presented for the RS by treatment. The iPDs will 
be listed per patient indicating whether or not the iPD led to exclusion from patient sets 
analyzed. 
The frequency of patients in each of the different analysis sets will also be presented by 
treatment.
 
 
 
 
 
 
 
 
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the CTR.
Descriptive statistics will be presented by treatment for demographic parameters and baseline 
characteristics, based on the TS, FAS, and PPS respectively. 
For the continuous variables described below, categories are defined in Table 7.1: 1. These 
variables will be presented according to the number and percentage of patients in each 
category.


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Table 7.1: 1
Categories for summary of continuous variables
Variable
Categories
Age
< 50 years
≥50 to < 65 years
≥65 to < 75 years
≥ 75 years
< 65 years
≥ 65 years
Weight
< 70 kg
≥70 to < 80 kg
≥80 to < 90 kg
≥90 kg
BMI
< 30 kg/m2
≥30 to < 35 kg/m2
≥ 35 kg/m2
Time since first diagnosis
< 1 year
≥1 to < 5 years
≥5 to < 10 years
≥10 years
HbA1c
< 7.0%
≥7.0 to < 8.0%
≥8.0 to < 9.0%
≥9.0 to ≤10.0%
> 10.0%
<8.0%
≥ 8.0%
7.2
CONCOMITANT DISEASE AND MEDICATION
Only descriptive statistics are planned for this section of the report. Analyses of concomitant 
diseases and medication will be based on the TS.
Concomitant diseases (i.e., baseline conditions) and concomitant non-drug therapies will be 
coded according to the most recent version of MedDRA. Concomitant medications will be 
coded according to the most recent version of the World Health Organisation – Drug 
Dictionary.
Concomitant diseases which are present at start of the study will be descriptively summarized 
by treatment. 
A medication/non-drug therapy will be considered concomitant to treatment, if

it is ongoing at the start of trial treatment or

it starts within the on-treatment period (see Section 6.1 for a definition of study analysis 
phases).
A medication/non-drug therapy will be considered as prior medication/non-drug therapy, if 
the end date of the medication/therapy is at any time prior to the start of trial treatment.


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Concomitant medication use will be summarized by treatment with frequency and percentage 
of patients by ATC3 class and preferred name. Summaries will be presented for concomitant 
medication starting any time during the on-treatment period or are still ongoing at treatment 
start (cf. Section 6.1).
Concomitant use of non-drug therapies will be summarized with frequency and percentage. 
Summaries will be presented for concomitant non-drug therapies starting any time during the 
on-treatment period or are still ongoing at treatment start (cf. Section 6.1).
7.3
TREATMENT COMPLIANCE
Incorrect dosing will be documented in the respective iPDs.
7.4
PRIMARY ENDPOINT
The primary treatment comparison will be performed as if all patients took randomized 
treatment for the duration of the trial.
The Multiple Comparison Procedures and Modeling (MCP-Mod) approach (11, 12) is 
implemented in two main steps: (1) trial design stage; (2) trial analysis stage. The procedures 
for the trial design stage, including the selection of candidate models covering a suitable range 
of dose-response shapes and sample size and power calculations, are provided in the CTP 
Section 7.2.2 and 7.5. The procedures for the trial analysis stage are specified below.
For the primary endpoint analysis, first, a mixed effect model for repeated measurements 
(MMRM) is calculated to estimate the treatment effect in each dose group and the 
corresponding covariance matrix. Using the MCP-Mod approach, these estimates are then 
further used to (1) test for a non-flat dose response curve and (2) to identify suitable dose-
response shapes out of a selection of candidate models. The final model will then be 
calculated by averaging over all significant model shapes. 
The primary analysis of primary endpoint will be based on the FAS, excluding patients 
randomized to semaglutide. For the twice weekly dosing schemes the total dose per week will 
be considered for the MCP-Mod analysis. Consequently, the doses which are included are 0, 
0.3, 0.9, 1.8, 2.4, 2.7, and 3.6 mg of BI 456906.
MMRM analysis
The change from baseline of HbA1c at Weeks 5, 8, 12, 16 and 17 will be evaluated using a 
restricted maximum likelihood (REML) based MMRM approach accounting for the following 
sources of variation: ‘baseline’ as a continuous covariate, ‘visit’ and ‘treatment’, and the 
interactions ‘visit*treatment’ and ‘visit*baseline’ as categorical fixed effect. Visit will be 
treated as the repeated measure with an unstructured covariance matrix used to model the 
within patient measurements. To estimate denominator degrees of freedom the Kenward-
Roger approximation will be used. The statistical model can be found in the CTP, Section 
7.2.2.


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In the event of model non-convergence, the methods described in Section 9.3 will be utilized 
to resolve this.
SAS code for MMRM:
The following SAS code will be used to calculate the MMRM.
PROC MIXED DATA=alldat cl method=reml; 
  CLASS visit(ref=’Week 17’) trt(ref=’Placebo’) subject; 
  MODEL cfb_HbA1c = trt visit visit*trt base base*visit / ddfm=kr s CL; 
  REPEATED visit / subject= subject type=un r rcorr; 
  LSMEANS visit*trt / pdiff=all om cl alpha=0.05 slice=visit; 
RUN;
Results of the MMRM (N, LS-means with SE and 95% CI per dose group and time point) will 
be presented in tables and displayed graphically. The effect used in the MCP-Mod analysis
will be the LS means of the HbA1c change from baseline to week 16 (measurement at week 
17, cf. Section 5) for each treatment group.
MCP-Mod Analysis
The multiple comparison procedure will then be implemented using optimal contrast tests 
which control the family-wise type I error rate at a one-sided α = 0.025. For the MCP-Mod 
test, the optimal contrasts of each candidate model are calculated using the R-function 
optCont using weights (w) proportional to the sample size of each dose group, respectively, 
and are shown in Table 7.4: 2. 
Table 7.4: 2
Contrast coefficients.
Contrast coefficients for treatment group
Model
Placebo
Very 
low 
dose:
0.3 mg 
BI
Low 
dose:
0.9 mg 
BI
Medium-
low dose:
1.8 mg BI
Medium 
dose:
2.4 mg 
BI
Medium-
high 
dose:
2.7 mg 
BI
High 
dose:
3.6 mg 
BI
Linear
0.568  
0.386  
0.211
-0.051
-0.226
-0.313
-0.576
Exponential
0.537
0.378
0.229
-0.020
-0.203
-0.301
-0.620
Emax 1
0.833  
0.225
-0.063
-0.201
-0.244
-0.259
-0.291
Emax 2
0.712  
0.363
0.071
-0.170
-0.269
-0.309
-0.399
Sigmoid 
Emax
0.504
0.417
0.319
-0.084
-0.299
-0.370
-0.487
   BI: BI 456906 dose.
In order to avoid estimating all nuisance parameters that are contained in the covariance 
matrix, these contrasts will be updated using the estimated variance-covariance matrix of the 


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LSmeans extracted from the MMRM model. The updated contrast coefficients will be 
reported in the CTR. 
Once the significance of a dose-response signal is established, the dose-response profile and 
the target dose can be estimated using a model averaging approach. Here, the final model is 
derived as a weighted average over all significant model shapes. Here, the weights for each 
significant model () are given by
() =

(.∙())
∑

(.∙())


,
where () is the Akaike Information Criterion (AIC) of model .
Estimates for each dose group will be calculated and will be based on the final dose-response 
model. The choice of the target dose to be investigated in Phase 3 will be based upon efficacy 
as well as considering safety and other relevant information. 
R code to perform the evaluations is available in Section 9.4.
The following displays are planned.
-
Table of the updated contrast coefficients per dose group and candidate model, together 
with the MCP-Mod test statistics and p-values for each model and the critical value.
-
For averaging model, figure of the dose-response curve.
-
For all significant model shapes, figures of the dose-response curve plus 95% 
confidence band (of the predicated shape) overlayed with adjusted mean and 
corresponding 95% CI per dose (estimated from MMRM).
-
For all significant model shapes, figure with the placebo corrected dose-response curve 
(of the predicated shape). 
In addition, the following sensitivity analyses for MCP-Mod will be considered.
-
MI using follow reference method (see Section 6.6.2) will be utilized to impute the 
missing values and MCP-Mod model will be repeated using the imputed data as a 
sensitivity analysis.
-
The MMRM with MCP-Mod will be repeated excluding the patients in DG 4 or 6 with 
dose adjustments as pre-planned in the protocol.
-
The MMRM with MCP-Mod using original data as well as MI imputed data will be 
repeated on the PPS.
-
 
-
For the purpose of further model refinement, MCP-Mod may be repeated on the primary 
endpoint but with an extended set of shapes including the original candidates (i.e.,
addition of inverse u-shape).
 


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Descriptive statistics 
Descriptive displays of absolute change from baseline in HbA1c will be presented by 
treatment.
Additionally, the frequency of patients with HbA1c <7% will be presented for each visit.
 
 
 
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoint
The relative body weight change will be evaluated using MMRM model and MCP-Mod in the 
same way as for the primary endpoint including all measurement time points until week 17
(weeks 2, 3, 4, 5, 6, 7, 8, 12, 16 and 17) based on the FAS excluding semaglutide patients.
This includes the same displays and sensitivity analyses as for the primary endpoint.
Additionally, descriptive statistics and subgroup analysis as done for the primary endpoint 
and as described in Section 6.4 will be performed.
7.5.2
Secondary endpoints
The primary analysis of secondary endpoints will be based on the FAS.
Continuous secondary endpoints
MMRM
Absolute body weight change from baseline as well as change from baseline in waist 
circumference will be assessed using an MMRM analysis as for the primary endpoint analysis
including all measurement time points until week 17. The estimates of average response to 
week 17 for each dose group will be presented.
Descriptive statistics 
Descriptive displays of change from baseline will be presented by treatment.
 


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Binary secondary endpoints
The two binary secondary endpoints, patients with 5% or greater body weight loss and
patients with 10% or greater body weight loss from baseline to 16 weeks (measurement at 
week 17, cf. Section 5), will be analysed using logistic regression and descriptive statistics.
Logistic regression analysis
For binary endpoints, the difference in the proportion of patients with a response between BI 
456906/ semaglutide and placebo will be analysed, using a logistic regression approach with a 
logit link via PROC LOGISTIC in SAS®. The fixed classification effect will be treatment. In 
case 0 event is observed in any treatment group a penalized regression based on the Firth’s 
bias reduction method (17, 18) will be used.
The estimates from the logistic regression are on the logit scale, and the difference in 
proportions will be calculated as the difference between the predicted probabilities in the 
treatment groups on the original scale. Odds ratio will be also reported between each BI 456906/
semaglutide arm vs. placebo.
Confidence intervals will be calculated using the cumulative distribution function method of 
Reeve (14). More specifically, as suggested in Reeve (14), a numerical search algorithm will 
be employed to find the quantiles xA of the cumulative distribution function, F 
! , such that 
F 
! (x#) = A, where A = 2.5% and A = 97.5% and F 
! is given by equation [10] in Reeve 
(14). R code that will be used to implement this is provided in Section 9.2.
 
Descriptive statistics
Descriptive statistics and graphical displays (line plots) of the response on each binary 
endpoint will be produced. The method to provide confidence intervals for unadjusted single 
proportions will be based on Wilson (15). The method to provide confidence intervals for 
unadjusted risk differences is derived from the Wilson method by Newcombe (16).
 


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7.7
EXTENT OF EXPOSURE
The total duration of exposure will be represented descriptively by treatment group.
The number of patients who received a dose of trial drug will be tabulated on the TS. The 
number of injections will be summarised by descriptive statistics for each treatment phase (N, 
mean, SD, minimum, median, maximum) on the TS.
The number and percentage of patients receiving ≤6, ≤8, ≤10, ≤12, ≤14, ≤15, ≤16 weeks
(dose escalation phase of DGs 1-6) of treatment will be given on the TS.
7.8
SAFETY ANALYSIS
All safety analyses will be performed following BI standards. No hypothesis testing is 
planned. All safety analyses will be performed on TS.
Off-treatment data (AEs) will be listed only.
7.8.1
Adverse events
AEs will be coded with the most recent version of MedDRA.
The analyses of AEs will be descriptive in nature. All analyses of AEs will be based on the 
number of patients with AEs and not on the number of AEs. System organ classes (if 
applicable) will be sorted according to the standard sort by frequency, preferred terms (if 
applicable) will be sorted by total frequency (within system organ class) across all treatment 
arms, or, if a total column across all arms is not foreseen in the table, by total frequency 
(within system organ class) across the BI arms.


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For details on summarization of AE data, please refer to "Analysis and Presentation of 
Adverse Event Data from Clinical Trials " (7) and "Handling of missing and incomplete AE
dates" (4).
The analysis of AEs will be based on the concept of treatment emergent AEs. That means that
all AEs will be assigned to ‘screening’, ‘dose escalation’, ‘maintenance’ or ‘follow-up’ phases 
as defined in Section 6.1.
The following is considered an Adverse event of special interest (AESI) in this trial:

Pancreatitis

Hepatic injury as defined in the protocol, Section 5.2.6.1.4.
The investigator had to classify on the eCRF whether an observed AE was an AESI or not.
Based on the specification provided in ICH E3 (9), the sponsor has defined AEs which are to 
be classified as ‘other significant’. For the current trial, these will include those non-serious 
AEs which were reported with ‘action taken = Drug withdrawn’ or ‘action taken = Dose 
reduced’.
Analysis
All AEs tables will be presented by dose escalation and maintenance phase as well as by 
overall treatment phase. AEs will be only assigned to one phase depending on their start date.
According to ICH E3 (9), in addition to Deaths and serious adverse events, ‘other significant’ 
AEs (as described above) need to be listed in the clinical trial report.
An overall summary of AEs will be presented by treatment. 
The frequency of patients with AEs will be summarised by treatment, primary system organ 
class and preferred term. Separate tables will also be provided for patients with Serious 
adverse events (SAEs), AESIs, patients with AE leading to discontinuation of the trial
medication, AEs of at least moderate severity and related AEs. AEs will also be summarized 
by maximum intensity.
For disclosure of AE data on ClinicalTrials.gov, the frequency of patients with non-serious 
AEs occurring with an incidence of greater than 5 % (in preferred terms) will be summarised 
by treatment, primary system organ class and preferred term. The frequency of patients with 
SAEs and drug related SAEs will also be summarised respectively.
For disclosure of AE data in the EudraCT register, the frequency of patients with AEs, the 
frequency of patients with non-serious AEs with an incidence of greater than 5 % (in 
preferred terms) and the frequency of patients with SAEs will be summarised. Furthermore, 
the total number of treated patients by country and by age group will be summarized.


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7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standards 
(8). Note that data from the central Laboratory will be used for all displays described below, 
unless otherwise specified.
For continuous safety laboratory parameters, normalized values will be derived.
Normalisation means transformation to a standard unit and to a standard reference range. The 
process of normalisation, handling of repeat values at the same visit for by-visit displays, as 
well as standard analyses for safety laboratory data are described in the BI guidance for the 
Display and Analysis of Laboratory Data (8). All analyses considering multiple times of the 
upper limit of normal range (ULN) (as described below) will be based on standardized and 
not normalized values. The original values will be analysed if the transformation into standard 
unit is not possible for a parameter. For continuous safety laboratory parameters, differences 
to baseline will be calculated. For all outputs, the last assessment before the first randomized 
treatment at Day 1 is chosen as the baseline value.
All individual laboratory data will be listed. Values outside the reference range will be 
flagged.
Descriptive statistics of laboratory values and for the difference from baseline on-treatment
(see Section 6.7) will be based upon normalized values and provided by visit and dose group. 
All visits will be reported including summaries of the last value, the minimum value and the 
maximum value on treatment period based on TS.
Laboratory values will be compared to their reference ranges.
Potentially clinically significant abnormalities will be identified based on BI standard rules 
which are based on normalized converted lab values, i.e., using SI units. These rules will be 
listed in the SDL appendix of the CTR. Frequency tables will summarize the number of 
patients with potentially clinically significant abnormalities. Patients having an abnormal lab 
value at baseline will be presented separately. A separate listing will present potentially 
clinically significant abnormal lab values; for each functional lab group all patient’s lab 
values will be listed, if there exists at least one lab value with clinically significant 
abnormality within the group.
The frequency of patients with Aspartate aminotransferase (AST) or Alanine 
aminotransferase (ALT) elevations ≥ 3xULN, ≥ 5xULN, ≥ 10xULN, and ≥ 20xULN will be 
displayed based on standardized laboratory values. To support analyses of liver related 
adverse drug effects, the frequency of patients with AST and/or ALT ≥ 3xULN combined 
with a total bilirubin ≥ 2xULN in a 30 day period after AST/ALT elevation will be displayed.
A patient will be included in each relevant category, defined using the maximum post-
baseline ALT and AST values observed on-treatment, regardless of the baseline AST and 
ALT values. 
Clinically relevant findings in laboratory data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such.


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For each NASH score a table with descriptive statistics will be created by treatment group.
7.8.3
Vital signs
The analyses of vital signs (blood pressure, pulse rate, respiratory rate, temperature) will be 
descriptive in nature. Descriptive statistics of vital signs and for the difference from baseline 
(see Section 6.7) will be provided by visit and dose group based on TS.
Clinically relevant findings in vital signs data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such.
7.8.4
ECG
Abnormal findings will be reported as baseline conditions (at screening) or as AEs (during the 
trial) if judged clinically relevant by the investigator. 
The analyses of ECG data will be based on the TS.
The ECG recordings will be centrally evaluated and rated as normal, abnormal, or not 
evaluable. 
ECG data will be summarized descriptively by visit (only for the quantitative endpoints) and 
dose group and listed. Occurrences of values above thresholds (see Section 5.4.1) will be 
flagged in the listings. For QTcB and RR, only listings will be provided.
Categorical endpoints
For the categorical endpoints (see Section 5.4.1), frequency tables will be provided.
Categorical endpoints will also include morphological findings that might be attributable to 
treatment. In particular, new onsets of findings not present at baseline will be explored. A 
morphological finding observed on treatment that was not reported at baseline will be 
categorized as a ‘new onset’ of this finding.
For all subjects with any notable finding in ECG intervals, a separate listing will be created as 
end-of-text display, and the corresponding time profiles will be shown.
Quantitative endpoints
Descriptive statistics (N, mean, SD, min, median, max) will be provided for the changes from 
baseline over time of QTcF, HR, QT, PR and QRS by visit and dose group. For each endpoint 
(QTcF, HR, QT, PR and QRS) the time profiles of mean and associated SD for the changes 
from baseline on treatment will be displayed graphically for each dose group.
From the four cardiac cycles of a single ECG, the HR (measured in beats per minute, 
beats/min) will be calculated as
HR [beats/min] = 60 000
RR
4444


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where RR is the mean of the four RR intervals (measured in msec).
Similarly, the QT interval corrected for HR according to Fridericia’s formula (QTcF) for a 
single ECG will be derived as
QTcF
4444444 [msec] = 81000
RR
4444 :
;/<
∗QT
4444[msec],
where QT
4444 is the mean of the four QT intervals and RR
4444 is the mean of the corresponding 
preceding RR intervals of the four cardiac cycles for this ECG.
Likewise, the HR-corrected QT interval according to Bazett’s formula (QTcB) for a single 
ECG is given by
QTcB
4444444 [msec] = 81000
RR
4444 :
;/@
∗QT
4444[msec].
In case of triplicate ECGs at a time point, the respective ECG variable will be averaged over 
the triplicate ECG measurements at this time point (arithmetic mean). Note that in case of 
missing values the averaging is simply done for the available values.
Additionally, descriptive statistics will be calculated for the absolute values over time of all 
ECG variables.
A scatterplot of QTcF at baseline and the maximum change from baseline (based on all on-
treatment values, independent of whether these were selected for analysis based on time 
windows described in Section 6.7) will be produced. The plot will include diagonal reference 
lines at absolute QTcF being equal to 450 msec, 480 msec and 500 msec (thus, the occurrence 
of new onsets of high categories for absolute values can be directly seen), as well as 
horizontal reference lines at 30 msec and at 60 msec for the maximum QTcF change from 
baseline.
Frequency tables will be provided for the categorical variables described, which are determined 
from the quantitative ECG variables: 
Appropriateness of heart rate correction methods of QT interval
To evaluate the appropriateness of the heart rate correction methods, the slope of the 
relationship of QTcF interval versus RR interval will be estimated separately for off-drug 
values and active treatment by applying a random coefficient model described in Section 9.6.2
using the QTcF and RR variable values per time point. A scatterplot of QTcF vs RR including 
the overall regression line will be included in the Statistical Appendix of the CTR. The 
resulting (fixed effect) slope together with two-sided 95% confidence intervals will be 
included in the footnote for this plot.


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7.8.7
Other
Suicidality assessment - Columbia Suicidal Severity Rating scale (C-SSRS)
The C-SSRS will be assessed at the screening visit and after the baseline visit at each clinic or 
phone visit. Visits documented in the TMF in BIRDS will be excluded (due to source data 
verification issues) from all analyses.
The results will be listed only. If applicable, the following sentence will be sufficient: No 
patients with suicidal ideation, suicidal behavior, or self−injurious behavior without suicidal 
intent.
7.9
ANALYSIS OF COVID-19 IMPACT 
There is currently an outbreak of respiratory disease, COVID-19 worldwide which has 
impacted the conduct of this trial. This public health emergency has raised more difficulties 
for patients to meet protocol-specified procedures, including administering or using the 
investigational product or adhering to protocol-mandated visits and laboratory/diagnostic 
testing. Site personnel or trial patients are also under the risk to get infection with COVID-19. 
Consequently, there are unavoidable protocol deviations due to COVID-19 illness and/or 
COVID-19 public and individual health control measures. To assess the impact on patients’ 
safety and drug efficacy in this trial, the following analyses are planned:


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Disposition and iPD:
Frequency of the patient with missed relevant visits or early discontinued from study 
treatment or study due to COVID-19 and related PDs will be listed and analysed 
descriptively. 
SARS-CoV-2 infection as well as AEs related to SARS-CoV-2 infection will be listed (if 
applicable). 


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8.
REFERENCES
1
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline 
Topic E9; Note For Guidance on Statistical Principles for Clinical Trials, current 
version
2
001-MCS-40-413: “Identify and Manage Important Protocol Deviations (iPD)”, 
current version; KMed
3
BI-KMED-BDS-TMP-0059: "iPD specification document (sdtm-dv-domain-
specification)", template, current version; KMed
4
BI-KMED-BDS-HTG-0035: "Handling of missing and incomplete AE dates", 
current version; KMed
5
BI-KMED-TMCP-MAN-0014: “Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies”, current version; KMed
6
BI-KMED-TMCP-MAN-0012 “Standards and processes for analyses performed 
within Clinical Pharmacokinetics/Pharmacodynamics”, current version; KMed
7
BI-KMED-BDS-HTG-0066: "Analysis and Presentation of Adverse Event Data 
from Clinical Trials", current version; KMed
8
BI-KMED-BDS-HTG-0042: "Handling, Display and Analysis of Laboratory Data", 
current version; IDEA for CON
9
CPMP/ICH/137/95: "Structure and Content of Clinical Study Reports", ICH 
Guideline Topic E3; Note For Guidance on Structure and Content of Clinical Study 
Reports, current version
10
BI-KMED-BDS-HTG-0045: "Standards for Reporting of Clinical Trials and Project 
Summaries", current version; KMed.
11
Pinheiro J, Bornkamp B, Bretz F. Design and analysis of dose-finding studies 
combining multiple comparisons and modelling procedures. J Biopharm Stat 16 
(5), 639-56 (2006). [R10-1424]
12
Pinheiro J, Bornkamp B, Glimm E, Bretz F. Model-based dose finding under model 
uncertainty using general parametric models. Stat Med 33 (10), 1646 – 1661 
(2014). [R15-4293]
13
BI-KMED-TMCP-MAN-0010 “Description of Analytical Transfer Files and PK/PD 
Data Files”, current version; KMed
14
Reeve R. Confidence interval of difference in proportions in logistic regression in 
presence of covariates. Statistical Methods in Medical Research: 27 issue: 2, 451-
465, 2016. [R16-4414]


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15
Brown LD, Cai TT, DasGupta A. Confidence intervals for a binomial proportion 
and asymptotic expansions. Ann Statistics 30, 160-201, 2002 [R12-3710]
16
Newcombe R.G. Interval estimation for the difference between independent 
proportions: Comparison of eleven methods. Stat Methods Med Res 17, 873-890 
1998. 
17
Heinze G, Schemper M. A solution to the problem of separation in logistic 
regression. Statistics in Medicine 21: 2409-2419 (2002)
18
Firth D. Bias reduction of maximum likelihood estimates. Biometrika 80, 27–38
(1993)
19
Crosby RD, Kolotkin RL, Williams GR. Defining clinically meaningful change in 
health-related quality of life. J Clin Epidemiol 56, 395 - 407 (2003) [R07-1182]
20
Cappelleri JC, Bushmakin AG, Gerber RA, Leidy NK, Sexton CC, Lowe MR, et al.
Psychometric analysis of the Three-Factor Eating Questionnaire-R21: results from 
a large diverse sample of obese and non-obese participants. Int J Obes 2009; 33(6); 
611-620 [R19-0059]
21
Bornkamp B, Pinheiro J, Bretz F Package 'DoseFinding' (February 19, 2015).
http://cran.r-project.org/web/packages/DoseFinding/DoseFinding.pdf (access date: 
28 April 2015); Comprehensive R Archive Network (2015). [R15-2001]
22
Rubin D. B. Multiple imputation for nonresponse in surveys (2004). John Wiley & 
Sons. [R12-2378]
23
Nassiri V, Lovik A, Molenberghs G, Verbeke G: On using multiple imputation for 
exploratory factor analysis of incomplete data; Behavior Research Methods (2018) 
50:501–517, https://doi.org/10.3758/s13428-017-1013-4
24
Angulo P, Jason M, Machesini G, et al. The NAFLD Fibrosis Score: A 
Noninvasive System That Identifies Liver Fibrosis in Patients with NAFLD. 
Hepatology 2007; 45;846-854. [R17-3207]
25
Sterling RK, Lissen E, Clumeck N, et. al. Development of a simple noninvasive 
index to predict significant fibrosis patients with HIV/HCV co-infection. 
Hepatology 2006; 43:1317-1325. [R17-3206]
26
Lin ZH, Xin YN, Dong QJ, et al. Performance of the aspartate aminotransferase-to-
platelet ratio index for the staging of hepatitis C-related fibrosis: an updated meta-
analysis. Hepatology. 2011; 53:726-36. [R17-3205]
27
Levey AS, Stevens LA, et al. A New Equation to Estimate Glomerular Filtration 
Rate. Ann Intern Med. 2009; 150:604-612. [R12-1392]


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
     1
10-August-21
None 
This is the final TSAP
1.1
26-November-21
All
This is the final revised TSAP. Main 
changes are the inclusion of the ECG 
analyses. All other changes are minor 
clarifications and adaptions in all 
sections.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c35576269
2.0
8-01-tsap-core
A Phase II, randomized, parallel group, dose-finding study of subcutaneously
administered BI 456906 for 16 weeks, compared with placebo and open-label
semaglutide in patients with type 2 diabetes mellitus
Author-Trial Statistician
26 Nov 2021 19:13 CET
Approval-Clinical Trial Leader
28 Nov 2021 14:30 CET
Approval-Team Member Medicine
28 Nov 2021 20:34 CET
Approval-Project Statistician
29 Nov 2021 12:44 CET
Approval
29 Nov 2021 12:49 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c35576269
2.0