Clinical trial NCT04667377
Conditions: Obesity
Sponsor: Boehringer Ingelheim
Start date: 2021-03-08; Completion date: 2022-10-07
Enrollment: 387 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is open to adults, aged 18 to 75 years, with overweight or obesity. People with body mass index (BMI) of 27 or higher to join the study. People who have diabetes cannot participate. The purpose of this study is to find out whether a medicine called BI 456906 helps people lose weight.

Participants are put into 5 groups by chance. 4 groups get different doses of BI 456906. The fifth group gets placebo. Participants get BI 456906 or placebo as injections under the skin once a week. Placebo injections look like BI 456906 injections but do not contain any medicine.

Participants are in the study for about a year. During this time, there are about 20 in-person visits to the study site. At the study site visits, doctors measure participants' body weight. Results are compared between the BI 456906 groups and the placebo group. The doctors also regularly 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
Interventions: intervention 1: BI 456906 intervention 2: Placebo
Intervention descriptions: intervention 1: BI 456906 intervention 2: Placebo

Protocol documents:
Prot_000.pdf: 


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim 
Protocol date
20 Aug 2020
Revision date
29 Apr 2022
BI trial number
1404-0036
Title of trial
A Phase II, randomized, double blind, parallel group,46 weeks dose-
finding study of BI 456906 administered once weekly 
subcutaneously compared with placebo in patients with obesity or 
overweight
Coordinating 
Investigator
Tel 
Trial site(s)
Multi-centre trial conducted in 13 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 obesity or overweight using 
multiple escalation schemes and doses and will support dose 
selection for phase 3 clinical development of BI 456906.
Trial objective(s)
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
Percentage change in body weight (%) from baseline to week 46
Secondary endpoints
∀
Weight loss of ≥ 5% of baseline weight at week 46
∀
Weight loss of ≥ 10% of baseline weight at week 46
∀
Weight loss of ≥ 15% of baseline weight at week 46
∀
Absolute change in body weight (kg) from baseline to week 
46
∀
Absolute change in waist circumference (cm) from baseline 
to week 46
∀
Absolute change in systolic blood pressure (mmHg) from 
baseline to week 46
∀
Absolute change in diastolic blood pressure (mmHg) from 
baseline to week 46
Trial design
Randomized, double blind, parallel group, placebo-controlled trial
Total number of 
patients randomised 
350


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Number of patients on 
each treatment
70
Diagnosis
Obesity or Overweight defined as BMI≥27kg/m2
Main in- and exclusion 
criteria
Key inclusion criteria:
1. Adult ≥ 18 years and < 75 years of age at screening
2.
Obesity or Overweight defined as BMI ≥27 kg/m2 at 
screening
3.
A minimum absolute body weight of 70 kg for females and 
80 kg for males at screening
4. Patients must have undergone at least one previous 
unsuccessful nonsurgical weight-loss attempt
Key exclusion criteria:
1. Body weight change of +/- 5% in the past 12 weeks
2. A HbA1c ≥ 6.5% at screening or diagnosed with type 1 or 
type 2 diabetes mellitus
3. Screening calcitonin ≥ 20 ng/L (pg/mL) (≥5,84 pmol/L)
4. Personal or family history of medullary thyroid carcinoma or 
multiple endocrine neoplasia syndrome type 2
5.
History of pancreatitis (acute or chronic)
6.
Obesity induced by endocrine disorders (i.e. Cushing 
Syndrome, hypogonadism, growh hormone deficiency. 
However, well controlled hypothyroidism, polycystic ovarian 
disease are still allowed)
7. Treatment with medication that potentially induce a change 
in body weight (e.g., steroids, antipsychotics), or anti-obesity 
medication including over-the-counter medications, or 
participating in an organized weight loss program (e.g. 
® or 
®) within 3 months before 
screening
8. Previous irreversible surgical treatment for obesity. Previous 
treatment with reversible weight loss devices such as gastric 
banding, or intragastric balloon and removed longer than 12 
months before screening should not be excluded.
9. Any suicidal behaviour in the past 2 years, any suicidal 
ideation of type 4 or 5 in the C-SSRS within 3 months before 
screening, or during screening period
10. History of major depressive disorder within 2 years before 
randomisation 
11. Women who are pregnant, nursing, or who intend to become 
pregnant while in the trial
Test product(s)
BI 456906
dose
Multiple doses 
mode of 
administration
Subcutaneous (s.c.)
Comparator product(s)
Placebo
dose
Matching


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mode of
administration
Subcutaneous (s.c.)
Duration of treatment
46 weeks
Statistical methods
The analysis for PoCC and 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. A plausible and 
diverse range of monotone dose response patterns will be used for 
this purpose, with placebo mean response assumed to be zero and 
the mean response at the highest BI 456906 dose assumed to be -
10.0 (i.e. a percentage reduction from baseline in body weight of 
10%).
A mixed model for repeated measures (MMRM) analysis will first 
be carried out. The MMRM will include fixed effects for baseline 
body weight and baseline by visit interaction as continuous 
covariates, and treatment, gender, visit and treatment-by-visit 
interaction as factors. Unstructured covariance will be used to model 
the relationship between pairs of endpoint measurements taken at 
different visits on the same patient. Adjusted mean percentage 
change in body weight at Week 46 for each treatment group and the 
covariance matrix will be extracted from the MMRM fit and used 
for the subsequent MCPMod analysis. 
PoCC will be established if at least one model is statistically 
significant, rejecting the null hypothesis of a flat dose response 
relationship for percentage change in body weight jointly over the 
candidate dose response models, with a contrast test controlled for 
the family–wise type I error rate at one sided α = 2.5%. If PoCC is 
established, the statistically significant (best fitting) model(s) from 
the above candidate set will be refitted to the data to generate new 
estimates for all model parameters from the data. The target dose(s) 
will be estimated from the best fitting model(s) by incorporating 
information on the minimum clinically relevant effect and 
accounting for safety. 
The primary analysis of percentage change from baseline in body 
weight at Week 46 will be performed using the full analysis set 
(FAS), defined as all randomised patients who received at least one 
dose of study treatment and who have analysable data for at least 
one efficacy endpoint. Patients will be assigned to the randomised 
maintenance dose. The analysis will include all available data 
without regard to whether patients started the maintenance period 
with a lower dose than the one randomised to. For patients who 
discontinued treatment early, a distinction will be made according to 
whether this is due to a COVID-19 pandemic-related reason or not. 
Patients who discontinued treatment early due to a pandemic-related 
reason will have data handled after discontinuation as if they were 
missing (hypothetical strategy). Patients who discontinued treatment 


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early for any other reason will have all available data included after 
discontinuation (treatment policy strategy).


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FLOW CHART (VISIT 1 TO 11)
Trial period
scree
ning
Randomized treatment – Dose escalation phase
Visit
1
2
3
4
5
6
7
8
9
10
11
Weeks
-12 
to -1
2
4
6
8
10
12
14
16
18
Days
-84 
to -7
11
15
29
43
57
71
85
99
113
127
Time window for visits (days)
+/-1
+/-1
+/-1
+/-1
+/-1
+/-1
+/-1
+/-1
+/-1
Informed consent
X
Informed consent for 
biobanking 2
X
Demographics
X
Medical history
X
Obesity clinical staging
X
Physical examination
X
X
X
X
X
X
Vital signs3
X
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
X
Waist circumference
X
X
X
X
X
Pregnancy testing4
Xs
Xu
Xu
Xu
Xu
Xu
Laboratory tests 5
X6
X7
X
X
X
X
X7
X
X
X
X
12-lead ECG8
X
X
X
X
X
X
X
X
X
X
X
Review of in-/exclusion criteria
X
X
Randomisation
X
Check discontinuation criteria
X
X
X
X
X
X
X
X
X
Instructions for control of 
sickness
X
X
X
X
X
X
X
X
X
X
Train patients for self-injection
X
X
Dispense trial drugs for home 
injections
X
X
X
X
X
X
X
X
X
X
Trial drug injection during visit
X
X
X
X
X
X
X
X
X
X
PK Sampling 9
X
X
X
X
X
X
X
X
X
X
Blood – ADA /NAb 9
X
X
X
X
X
Biomarkers10
X
X
HbA1c
X
X
X
Pharmacogenomic Biomarker 
sample
X
Blood sampling for 
biobanking11
X
X
PRO completion12 : BI-de novo 
eating questionnaire and PGI-S 
questionnaire
X
X
PRO completion12: PGI-D, 
SF36PF10 and TFEQ 
X
Distribute and explain the 
patient material13
X
X
3-days food diary14
X
Check e-diary and paper diary
X
X
X
X
X
X
X
X
X
X


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FLOW CHART (VISIT 1 TO 11) (CONT)
Trial period
scree
ning
Randomized treatment – Dose escalation phase
Visit
1
2
3
4
5
6
7
8
9
10
11
Weeks
-12 
to -1
2
4
6
8
10
12
14
16
18
Diet and physical activity 
counselling
X
X
X
X
X
C-SSRS and PHQ-9
X
X
X
X
X
X
X
X
X
X
X
All AEs/SAEs/AESIs15
X
X
X
X
X
X
X
X
X
X
X
Assessment of breast neoplasm, 
colon neoplasm
X
Compliance check 
X
X
X
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
Check medication change for 
hypertension and dyslipidaemia
X
X




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FLOW CHART (VISIT 12 TO END OF PARTICIPATION) (CONT)
Trial Periods
Randomized treatment - Maintenance phase
Follow-up 17
Visit
12
13
14
15
16
17
18
1917
EOT17
F-up
Weeks
20
24
28
32
36
40
44
46
EOT+3 w
Completion of patient 
participation 
X
Vital status data 18
X
Footnotes for Flow Charts:
1.
Day of Randomisation 
2.
Blood sample collection for biobanking is optional and requires a separate informed consent 
3.
Measurements of vital signs should preceed blood sampling and be assessed at all dosing visits according to 
section 5.2.2. Vital signs include DBP/SBP measurement, pulse rate, respiration rate, and body temperature
4.
Women of childbearing potential only. Xs =serum testing by central laboratory; Xu= onsite urine testing; Serum 
pregnancy testing is done at screening and as a reflex when urine testing is positive. Pregnancy testing at and after 
Visit 2 should be performed prior to administration of trial medication
5.
Safety lab include haematology, clinical chemistry, infectious serology, lipids and urinalysis. For details refer to 
Table 5.2.3:1. All blood samples should be collected before the administration of trial medication. 
6.
PCR Test on SARS-CoV-2 to be performed at Visit 1
7.
FASTING sample: on these days, blood samples will also include some efficacy parameters including fasting 
glucose, insulin and C-peptide, and fasting lipid battery These visits would preferably be scheduled on mornings
8.
Centralized ECG. ECG should be recorded before blood samples are taken. ECG recording may be repeated by 
investigator for medical or quality reasons. ECG at follow up, only in case abnormal at previous visit. For ECG 
measurement, follow guidelines in Section 5.2.4.
9.
PK and ADA/NAb sampling at trough prior to administration of next dose. In case of systemic hypersensitivity, 
also draw a plasma sample for IgE and ADA as detailed in the Lab Manual (ISF). Also include the evaluation of 
histamine, serum tryptase, and complement components
10. Blood sample for exploratory biomarkers at Visit 2 should be collected before the administration of trial 
medication (pre-dose value)
11. DNA biobanking requires one blood sample (preferably at Visit 2), serum and plama samples are taken at several 
timepoints.
12. PRO should be completed prior to assessment of vital signs and in the pre-specified order (ref to section 6.2.2)
during respective visits
13. Patient’s material include paper food diary distributed at screening. Once patient is randomised distribute a scale to 
have home weight measurements and e-diary (on their own device or on a provided smartphone).
14. 3 days food diary to be completed before the visit : includes two weekdays and one weekend day
15. After the  End Of Study visit (=individual patient’s end of the study) the investigator should report only any 
cancers of new histology and exacerbations of existing cancer, trial treatment related SAEs and trial treatment 
related AESIs of which the investigator may become aware of and only via the BI SAE form.
16. Visit 18 is organised only for the patient to collect his medication for the remaining 2 weeks. There is no need to 
visit the site staff other than pharmacy, and injection can be done at home. If, due to site organisation, the patient 
comes to the site and reports AEs, these will be recorded. Last drug injection will be on week 45, day 316. 
17. When a patient discontinues treatment, he/she has to complete a End of Treatment visit ; if he/she has reached the 
normal end, the EOT visit and the visit 19 (week 46) will be combined in only one visit, containing all exams due 
for both visits (but not in duplicate). Patients who discontinue trial treatment prematurely should undergo the End 
of Treatment (EOT) visit 7 days after last drug intake, as well as a follow-up visit 3 weeks later. All efforts should 
be made to keep these patients in the trial, have regular weight measurements as described in section 6.2.2 and 
have a visit conducted at week 46. E-diary checks and patient counselling is optional at visit 19 for patients who 
had withdrawn drug prematurely
18. All efforts should be made at least to conduct the week 46 visit for all patients including patients who discontinue 
trial treatment prematurely and have agreed to be contacted. However, if this is not possible, a phone contact
should be made at week 46 to obtain vital status and body weight measured at home. 


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART (VISIT 1 TO 11)...........................................................................................6
FLOW CHART (VISIT 12 TO END OF PARTICIPATION)............................................8
TABLE OF CONTENTS ......................................................................................................10
ABBREVIATIONS................................................................................................................14
1.
INTRODUCTION...............................................................................................18
1.1
MEDICAL BACKGROUND.............................................................................18
1.2
DRUG PROFILE................................................................................................19
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................20
1.4
BENEFIT - RISK ASSESSMENT.....................................................................21
1.4.1
Benefits.................................................................................................................21
1.4.2
Risks .....................................................................................................................21
1.4.3
Discussion.............................................................................................................24
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................25
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........25
2.1.1
Main objectives....................................................................................................25
2.1.2
Primary endpoint(s)............................................................................................25
2.1.3
Secondary endpoint(s) ........................................................................................25
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................28
3.1
OVERALL TRIAL DESIGN.............................................................................28
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................29
3.3
SELECTION OF TRIAL POPULATION .......................................................30
3.3.1
Main diagnosis for trial entry ............................................................................30
3.3.2
Inclusion criteria .................................................................................................31
3.3.3
Exclusion criteria ................................................................................................31
3.3.4
Withdrawal of patients from treatment or assessments..................................33
3.3.4.1
Discontinuation of trial treatment .........................................................................33
3.3.4.2
Withdrawal of consent to trial participation .........................................................35
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................35
4.
TREATMENTS...................................................................................................36
4.1
INVESTIGATIONAL TREATMENTS ...........................................................36
4.1.1
Identity of the Investigational Medicinal Products..........................................36
4.1.2
Selection of doses in the trial and dose modifications......................................37
4.1.3
Method of assigning patients to treatment groups...........................................37
4.1.4
Drug assignment and administration of doses for each patient......................37






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8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........82
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................82
8.6
TRIAL MILESTONES.......................................................................................82
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................83
9.
REFERENCES....................................................................................................85
9.1
PUBLISHED REFERENCES............................................................................85
9.2
UNPUBLISHED REFERENCES......................................................................86
10.
APPENDICES.....................................................................................................87
10.1
AVAILABLE DOSING BY COMBINATION OF SYRINGES.....................87
10.2
BLOOD PRESSURE MEASUREMENT PROCEDURE...............................87
10.3
TIME SCHEDULE FOR PHARMACOKINETIC (PK) BLOOD 
SAMPLING.........................................................................................................88
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................89
11.1
GLOBAL AMENDMENT 1 ..............................................................................89
11.2
GLOBAL AMENDMENT 2 ..............................................................................89
11.3
GLOBAL AMENDMENT 3 ............................................................................105
11.4
GLOBAL AMENDMENT 4 ............................................................................108


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ABBREVIATIONS
ADA
Anti Drug antibody
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
AP
Alkaline phosphatase
AST
Aspartate transaminase
AUC
Area under the curve 
AUC0-t
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to time t
BI
Boehringer Ingelheim
BMI 
Body Mass Index
BMR
Basal metabolic rate
CCS grading
Canadian Cardiovascular Society grading
CEC
Clinical event committee
CI
Confidence interval
CK
Creatinine kinase
CNS
Central Nervous system
C-SSRS
Columbia Suicide Severity Rating Scale
CTM 
Clinical trial manager
Cmax
Maximum measured concentration of the analyte in plasma
CMDS
Cardiometabolic disease staging
CRO
Contract research organization
CTR
Clinical trial report
DILI
Drug induced liver injury
DNA
Deoxyribonucleic acid
DMC
Data-monitoring committee
ECG
Electrocardiogram
ED
Early discontinuation
eDC
Electronic data capture
EOSS
Edmonton obesity staging system
EOT
End of treatment
ER
Extended release


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EudraCT
European clinical trials database
FAS
Full analysis set
FC
Flow chart
FFA
Free fatty acids
FPG
Fasting Plasma Glucose
GCGR
Glucagon Receptor
γ-GT
Gamma-glutamyl transferase
GI
Gastro-intestinal
GLP1R
Glucagon-Like-Peptide 1 Receptor 
HA 
Health Authority
HbA1C
glycosylated Hemoglobin, Type A1
HDL
High-Density lipoprotein
HR
Heart rate
ICH
International Conference on Harmonisation
IWQoL-Lite CT Impact of Weight on Quality of Life-Lite questionnaire in Clinical Trial
IB
Investigator Brochure
IPD
Important protocol deviation
IRT
Interactive Response Technology
ISF
Investigator site file
IUD
Intrauterine device
IUS
Intrauterine system
LDh
Lactate deshydrogenase
LDL
Low-density lipoprotein
Mar
Missing at Random
MCPMod
Multiple comparison procedure - Modelling
MedDRA
Medical Dictionary for Drug Regulatory Activities 
MMRM
Mixed model for repeated measures
MRD
Multiple rising dose
NAb
Neutralizing antibody
NASH
Non alcoholic steato hepatitis
NYHA
New York Health Association
OTC
Over the counter
PCR
Polymerase chain reaction


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PD
Pharmacodynamics
PG
Pharmacogenomics
PGI
Patients Global Impression 
PHQ
Patient Health Questionnaire
PK
Pharmacokinetics
p.o.
per os (oral)
PoCC
Proof of Clinical Concept
PPS
Per protocol set
p.r.n..
Pro re nata 
PRO
Patient reported outcomes
q.d.
quaque die (once a day)
QT
Q wave and T wave
QTcF
QT interval corrected by Fredericia’s formula
RA
Regulatory Authority
REP
Residual Effect Period
SAE
Serious adverse event
s.c.
subcutaneous
SC
Steering Committee
SF-36
36-Item Short Form Health Survey
SOP
Standard Operating Procedure
SR
Sustained realease
SRD
Single rising dose
SUSAR
Suspected Unexpected Serious Adverse Reactions
T2DM
Type 2 diabetes mellitus
TG
Triglycerid
TIA
Transient ischemic attack
TFEQ
Three Factor Eating Questionnaire
t.i.d.
ter in die (3 times a day)
t1/2
Half Life Time
tmax
Timepoint of Maximum Plasma Concentration
TMF
Trial Master File
TS 
Treated set
TSAP
Trial statistical plan


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TSH
Thyroid stimulating hormone
ULN
Upper Level of Normal
VAS
Visual Analog Scale
VLDL
Very low-density lipoprotein
WBC
White blood cells
WHO
World Health Organisation
WOCBP
Woman of childbearing potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Obesity is a chronic, complex, heterogeneous disease caused by disruption of physiological 
control of overall adiposity resulting in excessive fat accumulation. Obesity substantially 
increases the risk of metabolic diseases (for example type 2 diabetes mellitus and fatty liver 
disease), cardiovascular diseases (hypertension, myocardial infarction and stroke), 
musculoskeletal disease (osteoarthritis), Alzheimer disease, depression and some types of 
cancer (for example, breast, ovarian, prostate, liver, kidney and colon). In addition, obesity 
can lead to reduced quality of life, employment disparities, lower productivity and social 
disadvantages. For example, osteoarthritis — a common consequence of obesity — is one of 
the leading causes of disability and early retirement. Importantly, the World Obesity 
Federation and other organizations, including the American and Canadian Medical 
Associations, have declared obesity a chronic progressive disease clearly distinct from being 
a risk factor for other diseases and suggest that weight loss can improve these outcomes
[R20-1944].
Obesity was previosly regarded solely as a lifestyle or behavioural disorder caused by 
increased calorie intake or reduced physical activity; however, current evidence suggests that 
obesity is caused by a disruption of homeostatic control of body weight and a failure to 
maintain constant body fat mass. Regulation of physiological body weight set point involves
numerous arrays of central nervous system circuitry and peripheral metabolic feedback 
signals of either energy abundance or deficit, influenced by a 
 of genetic, 
developmental, biological, environmental, behavioural and iatrogenic factors. The abnormal 
regulation of body weight triggers a biological resistance to weight loss and a predisposition 
to weight gain. 
Currently, there are four major FDA-approved medications for chronic weight management: 
orlistat, phentermine/topiramate extended release (ER), naltrexone sustained release 
(SR)/bupropion SR and liraglutide, however those medications only provide modest 
reduction of body weight. Most of these drugs work through CNS pathways that either reduce 
appetite or enhance satiety, with the exception of orlistat, which decreases the absorption of 
fat [R20-1943]. Considering neurobiological resilience to energy homeostatic perturbations, 
combined with the heterogeneous pathophysiology of human metabolic disorders, targeting 
of multiple signalling pathways (including CNS and peripheral organs) is probably necessary. 
This will help patients with obesity to achive more significant improvements in weight 
management and might reverse the progression of these metabolic disorders and related co-
morbidities. Targeting multiple pathways has become a standard treatment strategy in other 
diseases such as T2DM, hypertension, heart failure. It is anticipated that obesity will prove no 
different, with simultaneous activation of multiple target mechanisms, i.e. anorectic and 
thermogenic pathways, producing enhanced metabolic benefits such as improved glucose 
intolerance and lipid metabolism thereby producing meaningful and sustained clinical outcomes 
for treating obesity and related co-morbidities. 


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1.2
DRUG PROFILE
Mode of action
BI 456906 is a dual agonist of GLP-1 and Glucagon receptors. Targeting both GLP-1 and 
Glucagon signalling pathways is expected to provide synergistic clinical benefit for chronic 
weight management and obesity. 
Simultaneous dual activation of GLP-1R and GCGR by BI 456906 is anticipated to achieve 
improved glycaemic control, reduction in body weight and improvement in NASH. BI 456906 
leads to full activation of the GLP-1R at the predicted therapeutic exposure, but only to a partial 
activation of the GCGR, which seems sufficient to achieve greater weight loss than GLP-1R 
activation alone, without hyperglycaemia.
In a 4-week study in mice with diet-induced obesity, BI 456906 was able to induce a body 
weight loss greater than liraglutide. BI 456906 dose-dependently increased energy 
expenditure while the pure GLP-1R agonist liraglutide had no effect even at supra-therapeutic 
exposure. It is expected that the increased energy expenditure will contribute to a longer 
lasting negative energy balance than GLP1-R agonism alone, while achieving a favourable 
benefit/risk profile (c14085752-05)
Key pharmacokinetic characteristics
Drug interactions
Data from non-clinical studies


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Data from clinical studies
GLP-1R agonists are known to be associated with GI and cardiac side effects. 
Multiple studies and clinical experience from GLP-1R agonists suggest that GI side effects 
can be mitigated by dose escalation. Rates of nausea, vomiting, and diarrhoea appeared to be 
dose dependent for GLP-
 agonists, and the proportion of patients reporting nausea was 
20% lower in patients with dose escalation than without dose escalation [R17-4311].
Accordingly, for a number of compounds of this class it has been shown that dose escalation 
steps are able to significantly improve tolerability in clinical practice. 
Cardiac conduction disorders were described for GLP-1R agonists in clinical trials and in the 
prescribing information for Saxenda [R19-1407], reported as first-degree atrioventricular 
block, right bundle branch block, or left bundle branch block, as well as QT-prolongation. 
BI 456906 has been studied in healthy volunteers in a single rising dose trial (1404-0001). 
Similar to other GLP-1 agonists, nausea and vomiting were seen with increasing doses up to 
1.2 mg and the study was discontinued early due to severe nausea and vomiting in a number 
of healthy volunteers. 
BI 456906 has also been studied in otherwise healthy volunteers with obesity or overweight 
in a multiple rising dose trial (c21168858-06) with dose escalation to investigate the safety 
and tolerability of different dose escalation schemes to determine a dose escalation scheme 
that minimizes gastrointestinal adverse events. Data from the completed 6-week MRD trial
(c21168858-06) where BI 456906 was administered in 4 different escalation schemas (one 
once-daily dose group and 3 once-weekly dose groups, all with weekly dose escalation) were 
analysed. The most frequent AEs were gastrointestinal (GI) disorders, such as nausea, 
vomiting, diarrhoea, in participants who received BI 456906 treatment compared to placebo. 
Most of the reported GI AEs were transient, mild or moderate in intensity. 
Preliminary data out of the 16-week MRD trial where BI 456906 was administered in three 
different escalation schemas showed comparable safety profile to the 6-week data. The most 
frequent AEs were GI disorders, and most of the reported GI AEs were transient, mild or 
moderate in intensity. Severe AEs of gastrointestinal disorder were reported for 9 out of 45 
patients treated with BI 456906. 
No deaths, SAEs, or protocol specified AESIs, were reported in this trial to date. 
For a more detailed description of the BI 456906 profile, please refer to the current 
Investigator’s Brochure (IB).
1.3
RATIONALE FOR PERFORMING THE TRIAL
BI 456906 is a long acting dual GLP-1R and GCGR agonist being evaluated for the treatment 
of T2DM, chronic weight management for obesity/overweight, and NASH. 
The action of dual GLP-1R and GCGR agonist likely results from a combination of central 
and peripheral mechanisms, at multiple target tissues. 




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Table 1.4.2:1 Overview over trial related risks 
Possible or known risks of clinical 
relevance for this trial
Summary of data, rationale for the 
risk
Mitigation strategy
Investigational Medicinal Product 
Gastrointestinal disorders, or 
Metabolism and nutrition 
disorders
Well-known side effects for 
GLP1-R agonist-based therapies
Slow and careful dose escalation. 
Instructions to be given 
Cardiac disorders
Well-known side effects for 
GLP1-R agonist-based therapies
Centralised 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.
Acute pancreatitis 
To date there is no evidence that 
BI456906 causes such adverse 
events.
Well-known side effects for 
GLP1-R agonist-based therapies
* Well-known side effects for 
GLP1-R agonist-based therapies, 
and well-known adverse event of 
rapid significant weight loss  
An extensive safety laboratory 
will be performed. 
Timely detection, evaluation, and 
follow-up of laboratory alterations 
in selected liver laboratory 
parameters to ensure patients´ 
safety.
Medullary thyroid carcinoma 
(MTC), or Multiple endocrine 
neoplasm (MEN)Type 2
Acute biliary disease*  
Systemic hypersensitivity reaction
After administration of any 
biologic agent or protein, there is 
a possibility of occurrence of 
adverse immune reactions which 
can be local (e.g redness, pruritus, 
and or swelling at the injection 
site) or systemic (e.g. 
anaphylactic reactions).
Patients with a history of 
allergy/hypersensitivity to the 
systemically administered trial 
medication agent or its excipients 
are excluded from the trial.
In case of systemic 
hypersensitivity reactions 
including anaphylactic reaction 
emerging during or after 
administration of trial medication, 
the investigator should consider in 
accordance with severity of the 
reaction and local standard of care 
to interrupt and treat the 
condition. 


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Table 1.4.2:1 Overview over trial related risks (cont.)
Trial procedures
Insufficient weight loss 
Patients who will receive placebo 
may not achieve sufficient weight 
loss during the trial.  
Patients in placebo group will 
remain on standard of care that 
includes diet and exercise 
counselling.
Administration site conditions 
Well-known side effects for 
injectables 
Instructions to be given 
Injection site will be monitored 
during the physical exam in every 
visit
Other risks
Drug-induced liver injury (DILI)
Rare but severe event, thus under 
constant surveillance by sponsors 
and regulators
Timely detection, evaluation, and 
follow-up of laboratory alterations 
in selected liver laboratory 
parameters to ensure patients´ 
safety
Acute kidney injury (pre-renal)
Related to severe GI AEs of GLP-
1RA class (severe vomiting may 
cause dehydration)
-In case of vomiting, nausea and 
diarrhea, increase fluid intake 
- Monitor decreased renal 
function
Suicide risk, depression and mood 
disorder
Not observed in clinical trials so 
far.
BI456906 could potentially act on 
central GLP-1 receptor. 
Columbia Suicide Severity Rating 
Scale (C-SSRS) will be applied at 
every visits;
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 trial the following safety measures will be applied in order to minimize the risk for trial 
patients:
An extensive safety laboratory will be performed.
∀
Patients in all groups, including placebo group will receive standard of care that 
includes diet and exercise counselling.
∀
There are no risks expected by stopping the trial medication during the trial.
∀
Centralised 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.
∀
Instructions are to be given to the patients to help improve tolerability especially during 
escalation phase. In addition, patients who do not tolerate the assigned escalation 
schedule, can modify dose escalation schedule. Details are described in section 4.1.4.
∀
During the trial, 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).
∀
Paediatric patients (less than 18 years old) 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 


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trial including the 4-week follow-up period are excluded from the trial 
(Section 4.2.2.2)
∀
To continue the assessment of the safety of BI 456906, adjudication of some events 
will be performed in that trial. The progress of the trial will also be assessed at 
regular intervals by an independent Data Monitoring Committee (DMC). Further 
details are described in Section 8.7, the adjudication charter and the DMC charter.
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. Section 5.2.6.1.4 provides guidance for the investigators on how to evaluate and treat 
patients with suspected DILI.
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 derived 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 such as SARS-
CoV-2. 
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. Single s.c. doses of 0.3 
mg and 0.5 mg, but not 1.2 mg of BI 456906 were well tolerated in a single rising dose trial. 
In a multiple rising dose trial with weekly dose escalation up to 4.8 mg, as once weekly and 
twice weekly dose administrations, 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 
cardiac conduction disorders, and are in line with other GLP-1 R agonist-based therapies. 
Most of the reported AEs were transient, and mild or moderate in intensity. To date, one 
Always serious AE from study 1404.3 occurred. It was reported as‘paroxysmal atrial 
fibrillation differential diagnosis ventricular tachycardia’. A 24-hour ECG (Holter Monitor) 
recorded from the subject at baseline (the subject had not received any dose of BI 456906) 
identified isolated polymorphic ventricular extrasystoles, a ventricular salve (9 beats), 
isolated supraventricular extrasystoles, and a supraventricular salve (4 beats). The Holter 
(V6/D5) used for diagnosis of the above events confirmed these findings. Initially, the 
investigator assessed the event as not serious. However, the event was recently upgraded to 
serious due to the medical significance, according to the BI Global Pharmacovigilance case 
processing procedure linked with the new version of the ‘Always Serious Events List’ that 
was implemented on 04 May 2020 and in which the event Ventricular Tachycardia was 
included. No deaths, or protocol specified AESIs, were reported.
Overall, the potential benefits, coupled with an acceptable safety profile and a well-controlled 
clinical trial environment support the initiation of the trial.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
The overall purpose of this trial is to assess the efficacy on weight loss and maintenance, and 
tolerability of four different doses of BI 456906 compared to placebo in patients with obesity 
or overweight (BMI ≥ 27kg/m2), without type 1 or type 2 diabetes, in order to characterize 
the dose-response relationship within the therapeutic range, and to select the target dose(s) for 
phase III clinical development. The results of this dose-finding study will serve as Proof of 
Clinical Concept in patients with obesity or overweight.
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
This trial will characterize the dose response curve for BI 456906 in patients with BMI ≥ 27 
kg/m2 (without diabetes) by assessing 4 doses and placebo. The response is defined as the 
percentage change from baseline in body weight at Week 46. 
The main trial objectives are to demonstrate a non-flat dose response curve, to evaluate the 
size of the treatment effect (using the difference in mean percentage change between BI 
456906 and placebo at Week 46), and to characterise the dose-response relationship. 
The primary treatment comparison will be randomised, without regard to whether patients 
discontinued treatment early (and whether they subsequently received any permitted anti-
obesity treatments), or whether patients started the maintenance period with a lower dose than 
the dose that they were randomised to.
2.1.2
Primary endpoint(s)
The primary endpoint is:
-
Percentage change in body weight (%) from baseline to week 46
2.1.3
Secondary endpoint(s)
Secondary endpoints are:
-
Weight loss of ≥5% of baseline weight at week 46
-
Weight loss of ≥10% of baseline weight at week 46
-
Weight loss of ≥ 15% of baseline weight at week 46 
-
Absolute change in body weight (kg) from baseline to week 46
-
Absolute change in waist circumference (cm) from baseline to week 46
-
Absolute change in systolic blood pressure (mmHg) from baseline to week 46
-
Absolute change in diastolic blood pressure (mmHg) from baseline to week 46


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN 
This is a 46 week randomised, double-blind, parallel-design, placebo-controlled, multi-
national and multi-centre study with 4 different maintenance doses (ranging from 
0.6mg/week to 4.8mg/week) in patients with obesity or overweight (BMI ≥ 27kg/m2), and 
without diabetes. Patients in all treatment arms including placebo will receive counselling for 
a reduced-calorie diet with an energy deficit of approximately 500 kcal/day by a dietician, as 
well as increased physical activity counselling (recommended minimum 150 minutes/week) 
by a qualified person on a monthly basis.
Participants will be randomly assigned to one of the 4 active dose arms of BI 456906 or 
placebo at a 1:1:1:1:1 ratio.
The different treatment arms and the dose escalation scheme are presented in Table 4.1.4:1.
There will be a screening period of minimum one week (time needed to obtain all 
examination results), that could be extended up to 12 weeks as needed to check eligibility 
criteria. The lab criteria “at screening” remain sufficient for checking lab eligibility criteria at 
randomisation. 
The treatment duration is 46 weeks in total including a dose escalation phase of 20 weeks to 
minimize GI side effects of BI 456906. This is followed by a 26-week maintenance phase, 
and a 3-week (4 weeks after last dose) follow-up period.
Figure 3.1:1  Dose escalation scheme 
Screening period: Minimum 1 week, and up to 12 weeks maximum
Randomisation period: 
-
Dose escalation phase: up to 20 weeks (see section 4.1.4)
-
Maintenance phase: 26 weeks
Follow up: 4 weeks after last drug injection
One interim analysis will be performed during the trial. Please refer to section 7.2.7




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composition of the committee, its procedures and interactions will be provided in a separate 
CEC charter.
3.3
SELECTION OF TRIAL POPULATION
A sufficient number of patients will be screened to ensure that an adequate number of 
patients will be randomized.
A total of 350 patients in approximately 45 sites, 13 countries will be randomised. More sites 
may be initiated depending on recruitment rate. To ensure sufficient enrolment of men, 
recruitment of women will be capped at 70 % and the randomisation will be stratified 
according to sex.
Screening of patients for this trial is generally competitive, i.e. screening for the trial will stop 
at all sites at the same time once a sufficient number of patients has been screened. The 
sponsor may require some site or country to stop recruitment in case they dominate the 
recruitment in a way that might cause variety or quality issues. Investigators will be notified 
about screening completion and will then not be allowed to screen additional patients for this 
trial.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the Investigator Site File (ISF) irrespective of whether they have been treated 
with investigational drug or not.
If a patient is enrolled in error (does not meet all inclusion criteria or meets one or more 
exclusion criteria on the day of enrolment), the sponsor should be contacted immediately.
Re-screening is not allowed. Re-testing (of assessments) should be discussed with Clinical 
Trial Manager (CTM). 
Re-testing: 
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 re-screened. The retest should be carried out as soon as possible so the laboratory test 
results will be received within the next planned visit windows in order to avoid protocol 
window violations. 
Patients must have had a stable weight for 3 months before entering the trial. If this criterion
cannot be documented, it is possible to extend the screening period up to 12 weeks to allow 
checking the weight stability. Documentation upon patients’ interview is acceptable. 
3.3.1
Main diagnosis for trial entry
The main diagnosis for patients to enter the trial is BMI ≥27 kg/m2 without diabetes at 
screening.
Please refer to section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.


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3.3.2
Inclusion criteria
1. Adult ≥ 18 years and < 75 years of age at screening
2. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial.
3. Obesity or Overweight defined as BMI ≥27 kg/m2 at screening
4. A minimum absolute body weight of 70 kg for females and 80 kg for males at screening  
5. Male or female participants. Women of childbearing potential (WOCBP)1 must be willing
and able to use two forms of effective contraception where at least one form is 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. See section 4.2.2.2.
6. Patients must have undergone at least one previous unsuccessful nonsurgical weight-loss 
attempt per investigator’s judgement
3.3.3
Exclusion criteria
1. Body weight change of over +/- 5% or more in the past 12 weeks prior to randomization. 
There must be documentation of weight in the past 12 weeks before randomization. 
2. Obesity induced by an endocrinologic disorder (i.e. Cushing Syndrome, hypogonadism, 
growh hormone deficiency. However, well controlled hypothyroidism, polycystic ovarian 
disease are still allowed)
3. A HbA1c ≥ 6.5% at screening or diagnosed with type 1 or type 2 diabetes mellitus
4. Exposure to GLP-1Ra based therapies within three months prior to screening
5. Any suicidal behaviour in the past 2 years, any suicidal ideation of type 4 or 5 in the C-
SSRS within 3 months before screening, or during screening period
6. History of major depressive disorder within 2 years before randomization
7. Major depressive symptoms (defined as a screening Patient Health Questionnaire-9 
[PHQ-9] score ≥15) at screening and/or during screening period
8. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders at screening
9. Screening calcitonin ≥20 pg/mL (≥5,84 pmol/L)
10. Personal or family history of medullary thyroid carcinoma or multiple endocrine 
neoplasia syndrome type 2, manifest hypo- or hyperthyroidism at screening
                                                
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. 
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Please note that tubal ligation is NOT accepted as a method of permanent sterilisation and therefore a woman who 
underwent tubal ligation is still considered as WOCBP. However tubal ligation is considered as a method of highly effective 
birth control. 


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11. History of chronic or acute pancreatitis or elevation of serum lipase/amylase > 2x ULN, 
or fasting serum triglyceride levels of > 500 mg/dL (>5,65 mmol/L) at screening
12. Treatment with medication that potentially induce a change in body weight (e.g., steroids, 
antipsychotics) , or anti-obesity medication including over-the-counter [OTC] 
medications, or participating in an organized weight loss program (e.g. 
®
or 
® ) within 3 months before screening
13. Prior surgery of the GI tract that could interfere with body weight (including minimally 
invasive/endoscopic bariatric devices, bariatric surgery including metabolic operation that 
involves resection and/or reconstruction of any portion of the gastrointestinal tract) except 
appendectomy and simple hernia repair before randomization.However, a patient 
previously treated with reversible weight loss devices such as gastric banding, or 
intragastric balloon and removed longer than 12 months before screening should not be 
excluded.
14. Resting Heart Rate >100 bpm at screening or randomisation
15. Systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 95 mmHg at 
screening.
16. History or currently diagnosed with congestive heart failure, New York Health 
Association (NYHA) class III-IV at screening
17. A marked prolongation of QT/QTc (Fridericia) interval that is greater than 450 ms at 
screening or at the randomisation or any other abnormal clinically significant ECG 
finding at screening (e.g., type 2 second-degree AV block (Type Mobitz II) or third-
degree AV block) – see section 5.2.4.
18. 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.
19. Treatment with medications known to cause heart block or bradycardia, such as beta-
blockers, verapamil and diltiazem, unless these drugs are indicated for heart rate control 
or hypertension treatment
20. Any of the following conditions or procedures within the last six months prior to 
screening: myocardial infarction, unstable angina (e.g. CCS grading of Angina pectoris 
grade III and IV), arterial bypass graft (e.g. coronary bypass, carotid bypass, peripheral 
vascular disease bypass), percutaneous coronary intervention (diagnostic angiograms are 
permitted), transient ischaemic attack(TIA), cerebrovascular accident (stroke) 
21. Women who are pregnant, nursing, or who plan to become pregnant while in the trial
22. 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 


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major, linear immunoglobulin A dermatosis, toxic epidermal necrolysis, anaphylaxis, 
angioedema, or exfoliative dermatitis)
23. Chronic or relevant acute infections (including but not limited to respiratory tract 
infections, urinary tract infection, bladder infection, enterocolitis, abscess, tuberculosis, 
meningitis, influenza, Epstein-Barr virus, HIV/AIDS, and hepatitis B or C, and SARS-
CoV-2(as confirmed by PCR test, see section 5.2.3)), within 2 weeks from screening or 
during screening.
24. Any condition which might jeopardize patient’s safety or compliance with the protocol as 
judged by the investigator 
25. Any documented active or suspected malignancy or history of malignancy within 5 years 
prior to screening, except appropriately treated basal or squamous cell carcinoma of the 
skin
26. Participation in another clinical trial within 90 days before 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 sections 3.3.4.1 and 
3.3.4.2 below.
Every effort should be made to keep the patients in the trial: if possible on treatment, or at 
least to collect important trial data.
Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the trial requirements and procedures prior to trial enrolment, as well as the
explanation of the consequences of withdrawal. 
Patients should be made aware of potential anticipated GI side effects and investigators should 
provide guidance on how to avoid or 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 CRF. If applicable, consider the 
requirements for Adverse Event collection reporting (please see sections 5.2.6.2.1 and 
5.2.6.2).
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.
∀
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 cannot tolerate the drug despite all efforts taken
∀
The patient requires hospitalization due to drug related gastrointestinal adverse event 
assessed by investigator 
∀
The patient needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment. Refer to section 4.2.2.1


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∀
The patient can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events, other diseases, or pregnancy).
∀
Sustained symptomatic hypotension or hypertension: For hypotension, episode of 
symptoms (such as light-headedness or dizziness) associated with a systolic blood 
pressure <100 mmHg for > 60 minutes or for hypertension, episode of symptoms such as 
headaches, shortness of breath or nosebleeds associated with a systolic blood pressure > 
160 mmHg in at least three consecutive measurements, each at least 30 minutes apart.
∀
Clinically relevant changes in ECG (QT prolongation >500 ms or an increase of 60 ms 
versus baseline, 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 experiences an infection with Sars-CoV-2 (as confirmed by PCR test, see 
Section 5.2.3) and presents with signs or symptoms requiring discontinuation of treatment 
as per investigator’s discretion. 
∀
Patients newly diagnosed T2DM requires anti-diabetic treatments other than metformin
∀
Patients newly diagnosed acute pancreatitis 
∀
Patients newly diagnosed medullary thyroid carcinoma
∀
Surgical treatment for obesity
∀
The patient develops suicidal ideation of type 4 or 5 in the C-SSRS (i.e. active suicidal 
thought with intent but without specific plan, or active suicidal thought with plan and 
intent). The patient should immediately be referred to a mental health professional for 
further work-up.
∀
Inadequate psychotherapy and/or pharmacotherapeutic treatment of a subject’s 
psychiatric disorder 
∀
The subject refuses mental health professional referral and, in investigator’s opinion, it is 
unsafe for the subject to continue 
∀
Treatment with orlistat, zonisamide, topiramate, lorcaserin, phenteremine, bupropion, 
naltrexone, GLP-1 RAs alone or in combination prescribed for weight loss or any 
medication that could provide weight change in the opinion of the investigator
∀
Out of compliance with study drug (missing doses). Refer to missing dose section 4.1.4
Given the patient’s agreement, a patient who discontinue drug should stay in the trial and 
follow procedures and visits as described in section 6.2.2 except patients taking GLP-1 RA 
who should be withdrawn from trial.


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For all patients the reason for withdrawal from trial treatment (e.g. adverse events) must be 
recorded in the CRF. These data will be included in the trial database and reported.
Pregnancy
If a patient becomes pregnant during the trial, the trial medication will be stopped, the patient
will be followed up during the trial and until birth or termination of the pregnancy (see further
details in section 5.2.6.2.3). The patient will be expected to attend the regularly scheduled 
study visits as outlined above.
There is no evidence of risk for partners of male participants, thus no need for male 
contraception.
Malignancies
In case of occurrence of malignant neoplasm, the Investigator should discontinue treatment 
with the trial medication, and notify the Sponsor. Diagnostics and treatment should be initiated 
according to local standard of care.
Suicidality
In case of signals of suicidal ideation or behaviour, the Investigator should discontinue 
treatment with the trial medication, notify the Sponsor and the patient should be referred to an 
appropriate psychiatric clinic.
If new efficacy/safety information becomes available, Boehringer Ingelheim will review the 
benefit-risk-assessment and, if needed, pause or discontinue the trial treatment for all patients 
or take any other appropriate action to guarantee the safety of the trial patients. 
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 enrolment goals overall or at a particular trial site.
2. New efficacy or safety information invalidating the earlier positive benefit-risk-
assessment, please see section 3.3.4.1.
3. Deviations from GCP, the trial protocol, or the contract impairing the appropriate conduct 
of the trial.
Further follow up of patients affected will occur as described in section 3.3.4.1.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Products
Table 4.1.1: 1
Test product 1
Substance:
BI 456906
Pharmaceutical formulation:
Solution for subcutaneous injection
Source:
Boehringer Ingelheim Pharma GmbH & Co KG, 
Biberach, Germany
Unit strength:
Filling Volume: 0,5 mL
Concentrations: 0,6 mg/mL, 1,8 mg/mL, 3,6 mg/mL, 
4,8 mg/mL, 6,0 mg/mL
Posology:
Multiple maintenance dose (0,6 mg; 2,4 mg; 3,6 mg; 
4,8 mg) obtained by injection of two syringes 
weekly (on same injection day). Intermediate 
dosages are used during titration phase. See 
appendix 10.1 for details on how each dose is made 
of 2 syringes 
Method and route of administration:
s.c. injections
Table 4.1.1: 2
Reference product 
Substance:
Placebo
Pharmaceutical formulation:
Solution for subcutaneous injection
Source:
Boehringer Ingelheim Pharma GmbH & Co KG, 
Biberach, Germany
Unit strength:
Filling Volume: 0,5 mL
Posology:
Multiple placebo dose to match the active 
maintenance doses (0,6 mg; 2,4 mg; 3,6 mg; 4,8 mg)
as well as titration doses; injection of two syringes 
weekly
Method and route of administration:
s.c. injections




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Tolerability assessment after 10 weeks 
Tolerability will be assessed after 10 weeks of treatment prior to dosing (visit 7). Patients 
who cannot tolerate medication in the week after dosing of week 10, will not continue 
titration to the next step, but will be moved to the next lower dosing available at week 11 and 
continue with this new scheme for the remaining visits
-
Patients of Group D will then follow scheme of group C
-
Patients of Group C and B will then follow scheme of group A
-
For patients of group A, there is no lower dose possible. They will be maintained 
with same scheme, and if they again cannot tolerate at next visit they will be 
discontinued
Flexible dose escalation phase (week 11- week 20)
During this time, the investigator should make every effort to follow every two weeks dose 
escalation however, adjusting dosing scheme based on the patient tolerability of GI AEs will 
be allowed, in a blinded manner, as per the below:
Tolerability will be assessed every two weeks, at every visit (prior to week 13, week 15, 
week 17, and week 19) and information will be entered in IRT system accordingly. 
-
Patients who do not experience or who tolerate GI AEs will follow bi-weekly 
escalation schedule as described in the Table 4.1.4:1 
-
Patients who cannot tolerate GI AEs will be maintained on same dose for a third 
week before next escalation. If AEs remain not tolerable despite moving to 
escalation every 3 weeks, that will trigger discontinuation. Training materials 
explaining possible options for flexible escalation will be provided to the 
investigators with details and examples.
Maintenance dosing phase (week 21- week 46)  
No dose adjustments or titrations will be allowed during the maintenance phase. No patients 
will start the maintenance phase at week 21 with any dose which is not one of the planned 
maintenance doses (0.6, 2.4, 3.6 or 4.8mg), and the dose will not be changed from week 21 
until the final study visit at week 46. Patients who cannot tolerate study drug during this 
period despite of all the efforts taken, will be discontinued from treatment.
Injections of two syringes will occur on a weekly basis (+/- 1 day). Instructions on how to do 
self-injections will be given to patients. The patients will record the exact date and time of 
injections in their e-diary. If the patient does not feel comfortable giving a self-injection, this 
has to be discussed with site staff so that injections can be organised locally (depending on 
local rules, can be done eg by a local nurse, or additional visits to the site can be organized)
Missed dose (delayed or skipped) 
∀
If a dose is missed on the planned dosing day, patients should take the planned dose 
within 48 hours. 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 is 
required. Patients should record the reason for a missed injection into their e-diary
∀
Total skipped doses during the trial must not exceed 4 doses (2 during escalation 
phase (0-20 weeks), 2 during maintenance phase (weeks 21-46)), and must not be 
consecutive 2 doses. Skipping more than 4 doses will be considered as non-


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compliance of trial medication and patients who missed more than 4 doses will 
discontinue trial medication. 
∀
In case of consecutive 2 skipped doses, the treatment discontinuation should be 
considered (general rule). In some exceptional circumstances (e.g. COVID-19 like 
pandemic situation), sponsor must be contacted for alternative option. 
If 2 consecutive doses of study medication are missed, the patient may recommence 
the study treatment if considered safe as per the investigator’s discretion and the 
patient does not meet any of the discontinuation criteria”.
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, for more 
details see section 6.2.2
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
Patients, investigators, central reviewers, and everyone involved (except as noted below) in
trial conduct or analysis or with any other interest in this double-blind trial will remain 
blinded with regard to the randomised treatment assignments until after database lock.
The DMC will be provided with unblinded data in order to allow them to review safety and to 
fulfil their tasks as outlined in the data monitoring committee charter. An independent team, 
not otherwise involved in the conduct of the trial, will provide the unblinded results to the 
DMC.
The randomisation codes will be provided to bioanalytics during the course of the trial to 
allow for the exclusion from the analyses of pharmacokinetic (PK) and antidrug antibodies 
(ADA) samples taken from placebo patients. Bioanalytics will not disclose the randomisation 
code or the results of their measurements until the trial is officially unblinded.
One interim analysis will be performed by an independent statistics and programming team at 
the Sponsor for internal phase III planning purposes after approximately two thirds of
randomised patients have reached Week 20. Details are given in Section 7.2.7, including how 
access to unblinded data and results will be controlled.
The access to the randomisation code will be kept restricted until its release for analysis.
The ECGs do not represent a risk of unblinding.
4.1.5.2
Unblinding and breaking the code
Emergency unblinding will be available to the investigator via IRT. It must only be used in
an emergency situation when the identity of the trial drug must be known to the investigator
in order to provide appropriate medical treatment or otherwise assure safety of trial


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participants. The reason for unblinding must be documented in the source documents and/or 
appropriate CRF page along with the date and initials of the person who broke the code.
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 randomisation code for individual patients during trial conduct. The access to the 
code will only be given to authorised Pharmacovigilance representatives for processing in the 
PV database system and not be shared further. 
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI or a designated CRO. Syringes 
will be packaged and labelled in accordance with the principles of Good Manufacturing 
Practice (GMP). Re-supply to the sites will be managed via an 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 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 for documentation.
If the storage conditions are found to be outside the specified range, the Clinical Research 
Associate CRA (as provided in the list of contacts) must 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 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, if applicable 
∀
Availability of FDA Form 1572 for USA sites 
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. Patients should be instructed to return 
unused investigational drug.


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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 / 
drug distribution centre or alternative disposal of unused products. If applicable, the sponsor 
or warehouse / drug distribution centre 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 (CTP) and reconcile 
all investigational medicinal products received from the sponsor. At the time of return to the 
sponsor 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
4.2.1.1
Diet and physical activity counselling 
During the trial, subjects in all treatment arms including placebo will receive diet and 
physical activity counselling every month. Patients will be given an e-diary in which they 
will keep tracking their level of activity everyday as well as a paper diary to track their daily 
dietary compliance. The subject’s dietary compliance and the average daily level of physical 
activity will be evaluated and recorded every month by site staff into the e-CRF
Diet Counselling
At visit 2 (randomisation) subjects will receive diet counselling by a dietician or equivalent 
qualified delegates according to local standard with an energy deficit of approximately 500 
kcal/day compared to the subject’s estimated total energy expenditure (TEE).[R20-2315]
TEE = Basal metabolic rate (BMR) x Physical activity level (PAL) of 1.3 
The hypocaloric diet is to be continued after randomisation and throughout the treatment 
period. The TEE should be re-calculated at regular intervals based on the changes in body 
weight and daily physical activities during the treatment period. If a BMI ≤ 22 kg/m2 is 
reached the recommended energy intake should be recalculated with no kcal deficit 
(maintenance diet) for the remainder of the trial. All subjects will receive short dietary 
guidance materials and will be instructed by dieticians or delegates to keep a food diary. 
Whether or not the subject is in compliance with the prescribed diet is at the discretion of the 
dietician after review of the food diary


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Table 4.2.1.1:1 Equations for estimating BMR 
Sex 
Age: years 
BMR: kcal/day
Men 
18-30  
15.057 x actual weight in kg + 692.2
31-60  
11.472 x actual weight in kg + 873.1
> 60  
11.711 x actual weight in kg + 587.7
Women
18-30  
14.818 x actual weight in kg + 486.6
31-60  
8.126 x actual weight in kg + 845.6
> 60  
9.082 x actual weight in kg + 658.5
Table 4.2.1.1:2 Classification of lifestyles in relation to the physical activity, or PAL
Category of lifestyle
PAL value
Inactive
less than 1.4 
Sedentary or light activity lifestyle
1.40-1.69
Active or moderately active lifestyle
1.70-1.99
Vigorous or vigorously active lifestyle
2.00-2.40* 
* PAL values > 2.40 are difficult to maintain over a long period of time.
Physical activity counselling 
An increase in physical activity, at least 150 to 300 minutes a week of moderate intensity 
combining aerobic and muscle strengthening exercise, will be encouraged and re-enforced.
4.2.1.2
Systemic hypersensitivity including infusion reaction and anaphylactic 
reaction
In case of systemic hypersensitivity including anaphylactic reaction emerging during or after 
injection(s) of trial medication, the investigator should consider in accordance with severity 
of the reaction and local standard of care to
-
Immediately stop further injections
-
Treat with systemic anti-histamines, i.v. steroids, and in case of a severe allergic 
reaction (eg, anaphylactic reaction) epinephrine
Also draw a plasma sample for IgE and ADA as detailed in the Lab Manual (ISF). Also 
include the evaluation of histamine, serum tryptase, and complement components. 
In case of systemic hypersensitivity, based on patient’s clinical course and medical judgment, 
the injection(s) may be continued in case of mild or moderate systemic hypersensitivity.


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In case of anaphylactic reaction based on the criteria discussed in the statement paper from 
Sampson HA [R11-4890] suspected to be caused by the trial medication, the investigator 
should permanently discontinue treatment with the BI456906
When a non-acute hypersensitivity reaction related to immune complexes (i.e., serum 
sickness) is suspected, please draw a sample for the laboratory assessment for circulating 
immune complexes.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
The following is not allowed during the whole trial period (including patients who 
discontinued study medication): 
∀
GLP-1 RA
The following is not allowed during screening and until after 4 weeks after the last drug 
intake:
∀
Treatment with orlistat, zonisamide, topiramate/phentermine, phenteremine, 
bupropion/ naltrexone, alone or in combination or any medication that could provide 
weight change in the opinion of the investigator. 
∀
Obesity OTC medications or supplements, or participating in an organized weight loss 
program (e.g. 
® or
®) 
∀
Treatment with medications known to cause heart block or bradycardia, such as beta-
blockers, verapamil and diltiazem, unless these drugs are indicated for heart rate 
control or hypertension treatment
∀
Oral medications with Narrow Therapeutic Index unless dosing can be adapted 
according to standard of care monitoring ( e.g., Levothyroxine dosing appropriately 
adapted to thyroid stimulating hormone levels)
∀
Medications known to significantly prolong the QT or QTc interval administered for a 
period of > 2 weeks 
When discontinuing trial products, the investigator should discuss potential weight 
management options with the subject.
4.2.2.2
Contraception requirements
Contraception of male participants is not needed. 
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 


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and for a period of at least 5 weeks after last study drug intake. Male partner of a female trial 
participant must use a condom if their sexual partner is a WOCBP or be vasectomised with 
documented absence of sperm 
Female participants of childbearing potential must use highly effective method 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.
∀
Combined (oestrogen 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
Oral contraceptives are not permitted in female participants during the study. WOCBP who 
use oral contraceptives at screening should change to non-oral contraceptives listed above. 
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 will be provided with an e-diary to record all the injections of the study drug (at 
home or at the clinic during on site visits).
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.
Patients should be compliant on the dosing schedule when they self-administer the study drug 
at home with pre-filled syringes.
Compliance check of the trial medication will be performed at each clinic visit to ensure the 
weekly injection is being administered correctly at both the trial site and by the patient at 
home. In case of missed doses, the site should instruct patient as indicated in section 4.1.4.
The investigator/site staff should explain to the patient the importance of treatment 
compliance and discuss with the patient any tolerability issue.
Patients will be provided with a medication bag to store unused and empty cartons of trial 
medication and a sharp bin to store all used syringes. Patients are requested to bring all 
unused trial medication and empty cartons with them to their next scheduled visit for 
compliance check. Any discrepancies should be discussed with the investigator or the 
designee. 


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
5.1.1
Anthropometry 
5.1.1.1
Weight measurement
It is important to minimise variability in body weight measurement. On site, weight 
measurements should be done on the same scale for one patient throughout the course of the 
trial (mechanical and digital scales are acceptable), and the equipment must be calibrated 
according to the directions for use and at a minimum once a year. Weight should be recorded 
with one decimal (kg)
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 consistently worn for all weight 
measurement in the trial. Patient should empty the bladder before weight is measured. 
5.1.1.2
Self-measurement of body weight at home
All patients will be provided a scale for use at home during the trial for self- measurement of 
body weight. Patients must use the provided scale for all home weight measurements and 
measure body weight on a weekly basis. The body weight should be measured with an empty 
bladder, without shoes and only wearing light clothing, in fasting state at the same time of the 
day, preferably morning fasting time, throughout the trial. The measure is then recorded in an 
eDiary.
5.1.1.3
Height 
Height is measured at screening without shoes in centimetres (one decimal) 
5.1.1.4
Body mass index (BMI)
Body mass index will be calculated within the eCRF from visit 1 (screening) data.
5.1.1.5
Waist measurement
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. 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 should be measured against the skin, at the midpoint between the lowest rib 
and the iliac crest.






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In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (section 5.2.6.1.4 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
Time points
Haematology
Haematocrit
Hemoglobin
Reticulocyte Count (reflex test if Hb outside 
normal range)
Red Blood Cells / Erythrocytes
White blood cells / Leukocytes
Platelet Count / Thrombocytes
Differential Automatic (relative and absolute 
count): 
Neutrophils, Eosinophils, Basophils, Monocytes, 
Lymphocytes
All visits
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)
γ-GT (gamma-glutamyl transferase)
Glucose (plasma)
Lactate dehydrogenase (LDH)
Lipase
Magnesium 
Phosphate 
Potassium
Protein total 
Sodium
Urea (blood urea nitrogen)
Uric acid
Thyroid stimulating hormone (TSH)
Calcitonin
eGFR (CKD EPI Equation for adults)
All visits
Except Calcitonin and 
eGFR not needed during 
follow up
Fasting Glucose 
Insulin 
C-peptide
At visits 2,7,12 and end of 
treatment
βHCG (for women only)
At screening and 
whenever a urine test is 
positive


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Table 5.2.3: 1
Safety laboratory parameters: (cont.)
Infectious serology
Hepatitis B surface antigen
Hepatitis C antibodies
HIV-1/2 combination
Screening only
SARS-CoV2
SARS-CoV2 PCR test
Screening only
Lipids
Cholesterol (total)
HDL cholesterol 
LDL cholesterol (including VLDL)
Triglycerides
All visits
Urinalysis 
Semi quantitative
Nitrite
Protein
Ketone
Urine pH
Leukocyte esterase (for WBC)
Blood (erythrocytes)
Quantitative
Albumin
Creatinine
Albumin/creatinine ratio in spot urine will be 
calculated at the central lab.
All visits
Pregnancy test
(done on site using tests provided by central lab)
All visits except screening 
If positive: do a serum test
Urine drug screen
Cannabis
Cocaine
Benzodiazepine
Amphetamines
Barbiturates
Methadone
Opiates
Screening only
5.2.4
Electrocardiogram
A 12-lead ECGs should be collected prior to the dosing at the time points specified in the 
Flow Chart. Centralized ECG services will be provided by an external 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 must be supine for approximately 5-10 minutes before ECG collection. Patients 
should remain supine, but awake, during the ECG collection process.
The investigator has the responsibility to complete an initial review as soon as the ECG 
recordings are obtained at the site 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 significant 


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abnormalities in the ECG, and would prefer to wait until the results from the central reading 
are available.
The digital ECG recordings will be transmitted to the 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 reported to the site. The site investigator must review the report. If the 
ECG is rated as abnormal, the Investigator will have to determine if the abnormal findings are
clinically significant.
After the screening visit, the investigator must complete a review of the ECG results from 
central reading to ensure patient has met all the entry criteria for the study. Any pre-existing 
conditions should be recorded as baseline conditions. 
At visit 2 eligibility decisions may be made based on the local reading of the screening ECG 
only exceptionally, if the results of the central ECG have not been received prior to 
randomisation visit. 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, it is strongly recommended that the 
investigator wait until the results from central reading are available, and the randomization 
visit should be rescheduled.
The site investigator will have the responsibility of following up with the patient if there are 
any clinically significant findings in the ECG report.It is strongly recommended to repeat 12-
lead ECG recording and/ or a referral to a cardiologist and/or perform additional cardiac tests 
(ie. Cardiac enzymes) if there is an indication of significant abnormalities or in case of 
doubts.
Clinically relevant abnormal findings will be reported either as baseline condition (if 
identified at the screening visit) or otherwise as AEs and will be followed up and/or treated as 
medically appropriate.
After the patient is randomized, if a clinically significant increase in the QT/QTc 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 study. The investigator 
must also ensure that patient does not meet any criteria for discontinuing study treatment (see 
section 3.3.4.1), such as tachycardia, arrhythmia or conduction disorders. Any new findings 
or deterioration of previous findings observed during the trial will be recorded as AEs/SAEs 
and will be followed up and/or treated as medically appropriate.
All ECGs that are read in the central location will be stored in the vendor’s database, and 
transmitted to the sponsor periodically
5.2.5
Other safety parameters
All cases of malignancies that are detected during the trial will be reported as SAEs. Patients 
with a history of malignancy (except for specific cancers) will be excluded from this trial per 
the exclusion criteria (section 3.3.3)


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Local tolerability at the administration site of BI 456906 will be assessed by the investigator 
during the study drug administration visit and at the time of AE assessment by questioning 
retrospectively since the last visit. Any observed local tolerability reaction, e.g. “swelling”, 
“induration”, “heat”, “redness” should be reported as adverse event.
5.2.5.1
Breast neoplasm 
For all female subjects, information whether any new mammograms have been performed 
since screening must be recorded at the end of the treatment and the follow up visits. If yes, 
reason and diagnosis should be recorded to the extent possible.
5.2.5.2
Colon neoplasms 
Information whether any new endoscopic examination(s) of the colon have been performed 
since screening must be recorded at the end of the treatment and the follow up visits. If yes, 
reason and diagnosis should be recorded to the extent possible.
5.2.5.3
Hypoglycemia 
All subjects will at randomisation be instructed in symptom recognition and handling of
hypoglycaemia. 
Hypoglycemic events will be defined as 
∀
The subject reported typical symptoms of hypoglycaemia or required external 
assistance.  
∀
The subject’s plasma glucose concentration was <54 mg/dL (3.0 mmol/L), 
∀
The investigator considered the event to be hypoglycaemia event. 
All symptomatic hypoglycaemic events will be recorded as a hypoglycaemic event on the 
'adverse event' CRF page. 
5.2.5.4
Mental health questionnaires
The mental health status of subjects will be assessed by C-SSRS and PHQ-9 questionnaires.
The C-SSRS is a semi-structured, investigator-rated interview, developed by clinical experts 
in cooperation with the FDA, assessing both suicidal behaviour and suicidal ideation.  It does 
not give a global score but provides some categorical and some severity information 
specifically for behaviour and ideation.
The C-SSRS interview may be administered by any type of physician, psychologist, clinical 
social worker, mental health counsellor, 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 behaviour and may be expanded to up to 17 items in case of positive 
responses.
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 lifetime history of suicidal ideation and behaviour. 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 


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clinical relevance. Doubtful reports may be repeated, or reports may be validated by a 
consulting psychiatrist. If there is a positive report of suicidal behaviour 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 behaviour must be 
reported as separate SAEs by the investigator. For ‘Self-injurious behaviour, 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.
The PHQ-9 is the 9-item depression module of the patient health questionnaire, which is a 
self-administered diagnostic tool used for assessment of mental disorders. The questionnaire 
takes approximately 10 minutes to complete
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of AEs 
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 unfavourable 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 CRF and BI SAE form (if applicable):
∀Worsening of the underlying disease or of other pre-existing conditions 
∀Changes in vital signs, ECG, 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 hospitalisation or prolongation of existing hospitalisation


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-
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 
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 hospitalisation 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 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 in section 5.2.6.2.
Adverse Event (AE) coded shall cross referenced against the Always Serious List (ASL). 
Non serious cases will be upgraded to serious. Cardiac related events included in the ASL, 
shall be fully processed as serious and expedited
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
The term adverse events of special interest (AESI) 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:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 
∀
an elevation of AST (Aspartate Aminotransferase) and/or ALT (Alanine 
Aminotransferase) ≥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.


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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 the eDC 
system
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 
analysed, 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.
5.2.6.1.5
Adverse events require additional data collection 
Some pre-specified AEs critical for the assessment of safety of BI 456906 will require 
additional data collection with separate eCRF page, some of these events will be centrally 
adjudicated in a blinded fashion by an independent external Clinical Event Committee 
(CEC). 
Definitions of the adjudicated endpoint events and the principles of standardised data 
collection in the centralised CEC adjudication process are outlined in the separate CEC 
Charter and process guideline.  
Events require adjudications 
∀
All death (CV death, non-CV death) 
∀
Cardiovascular event (revascularization due to coronary vascular disease, myocardial 
infarction, hospitalization due to unstable angina)  
∀
Cerebrovascular disease (Stoke, TIA)
∀
Heart failure hospitalisation. 
∀
Pancreatitis 
∀
Neoplasm 
∀
Thyroid mass requires surgery 
Events require additional data collection 
∀
Acute gall bladder disease
∀
Acute pancreatitis 
∀
Thyroid mass 
5.2.6.1.6
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 easily 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 is defined as follows for this
clinical trial:
Nausea
Mild:
Queasy sensation and/or the urge to vomit without decreased oral fluid or


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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 
30min); 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
Diarrhoea
Mild:
Increase of <3 stools in 24 hours over baseline
Moderate:
Increase of 3 to 5 stools in 24 hours over baseline; may require 
pharmacologicintervention
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
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 QTcF corrected interval prolonged
Mild:
QTcF increase from baseline of more than 30s and QTc 450-480 ms


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Moderate:
QTcF increase from baseline of more than 30s and QTc 481-500 ms
Severe:
QTcF increase from baseline of more than 30s and QTc >= 501 ms on at least
two separate ECGs
5.2.6.1.7
Causal relationship of AEs
Medical judgement should be used to determine whether there is a reasonable possibility of a 
causal relationship between the adverse event 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, considering 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.
∀
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 trial 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.


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The following must be collected and documented on the appropriate CRF(s) by the 
investigator:
•
From signing the informed consent onwards until the individual patient’s end of study:
all AEs (serious and non-serious) and all AESIs.
•
After the individual patient’s end of study: 
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 
section 5.2.6.2.2), but not on the CRF.
Vital Status Data Collection
Patients who discontinue trial medication prematurely, who agree to be contacted further but 
do not agree to physical visits, should be followed up as described in section 3.3.4.1, 
withdrawal from trial treatment. From then on until the individual patient’s end of the trial the 
investigator must report all deaths/fatal AEs regardless of relationship, and trial treatment 
related SAEs and trial treatment related AESIs the investigator becomes aware of. 
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 via fax immediately (within 24 hours ) to the 
sponsor’s unique entry point (country specific contact details 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 fax 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 trial medication, 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 Studies (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Studies (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 Studies 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 be completed in addition.


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5.2.6.2.4
Exemptions to SAE reporting
Not Applicable


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5.5
BIOBANKING
Participation in biobanking is voluntary and not a prerequisite for participation in the trial.
Biobanking will only occur after a separate biobanking informed consent has been given in
accordance with local ethical and regulatory requirements. No samples will be taken for 
biobanking from patients at sites in China due to regulatory restrictions.
In order to be able to address future scientific questions, patients will be asked to voluntarily
donate biospecimens for banking. If the patient agrees, banked samples may be used for
future biomarker research and drug development projects, e.g. to identify patients that are
more likely to benefit from a treatment or experience an AE, or to gain a mechanistic or
genetic understanding of drug effects and thereby better match patients with therapies.
Samples will be stored for testing for a period consistent with local regulations.
5.5.1
Methods and timing of sample collection
Detailed instructions on sampling, preparation, processing, shipment and storage are provided 
in the laboratory manual. For sampling timepoints see Flow Chart.
Approximately 48 mL blood will be drawn for DNA, Plasma, and Serum banking.


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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 evaluate efficacy and tolerability of BI456906 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 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. The pharmacokinetic parameters and 
measurements outlined are generally used assessments of drug exposure. 


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
For a detailed overview of the trial procedures and time windows for visits, please refer to the 
Flow Chart.
The trial consists of a screening visit followed by a 46-week treatment period and a follow-up 
visit. 
The study will last until every randomised patient has completed the last follow-up visit.
After giving his/her Informed Consent, the patient will be screened for inclusion and 
exclusion criteria for the study at visit 1. Visit 2 will be scheduled after visit 1, after results 
from central laboratory are obtained, as well as ECG central review. The minimum interval 
between screening and randomization is 1week. The patient will be randomized at visit 2 if 
all inclusion and none of the exclusion criteria are fulfilled.
During the treatment period, there will be a dose escalation period of 20 weeks followed by a 
dose maintenance period. Total treatment period is 46 weeks.
Windows of ±1 or ±2 days is allowed to accommodate scheduling problems. If a delay is 
observed for a particular visit, the original calendar schedule should be kept for subsequent 
visits (delays should not accumulate). If a visit is missed the patient should be instructed to 
reach out to the investigator as soon as possible. Handling of missed drug injections is 
described in section 4.1.4. Investigator should contact the BI monitor to discuss further 
schedule.
Follow up visits have to be organized a minimum of 28 days after last drug injection. 
Patients with obesity are in general at higher risk for severe illness from COVID-19. In 
exceptional cases, if standard visits at the trial sites are impossible because of COVID-19 
related safety risks, trial conduct may need to be adjusted, strictly consistent with local public 
health guidance and regulations.
If, in order to minimize the risk of exposure to COVID-19, physical visits should be avoided , 
the use of remote visits (via phone and/or internet-based means of communication) and local 
laboratory services for safety and efficacy parameters measurements should be considered if 
possible. However, study drug shipment to patients might not be possible in all countries to 
be included. In such situations, picking up trial medication could be done by patient’s 
delegate or by patient at a sterile pharmacy (e.g. “drive -through” , “isolated” pharmacy).
Investigators should complete study procedures according to the protocol to the extent 
possible. The max. number of missing doses of study medication is defined in section 4.1.4 .
Considering all aspects, the investigator will decide upon each patient’s (continued) 
participation in the planned trials. BI as the sponsor, where required, will support the 
investigator in their decision finding. It is acknowledged that the investigator may decide to 
implement protocol deviations where this protects the safety, wellbeing and/or is in the best 
interest of the patient. All home/remote visits need to be discussed with and approved by the 
sponsor`s trial team. Local regulatory and legal requirements of the participating country still 
apply
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. 


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6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening and run-in period(s)
Screening Period
Following informed consent, the patient will undergo visit 1/screening assessments as 
indicated in the Flowchart. Once the patient has consented, the patient is considered to be 
enrolled in the trial. The patient should be recorded on the enrolment log and be registered in 
the IRT.
The assessments must all fall within the acceptable screening visit window but do not need to 
be performed on the same day.
Re-testing for certain eligibility criteria can be performed once as outlined in section 3.3. 
The screening phase can be extended up to a maximum of 12 weeks (from visit 1 to visit 2), 
when needed to allow proper documentation of weight stability. If the patient meets the entry
criteria, visit 2 should occur as soon as possible once it has been confirmed that the patient is
eligible to continue.
If the patient does not meet the entry criteria, (i.e. fail to meet one or more of the inclusion
criteria, and/or meet one or more of the exclusion criteria) following Visit 1 procedures, they 
should be registered as a screen failure in IRT.
6.2.2
Treatment period(s)
Before visit 2, patients will have to record their food intake in a 3-days food diary (see 
section 5.1.5). 
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 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. On days when fasting is 
required, the clinic visit should ideally be scheduled in the mornings, if this is convenient for 
the patient.




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6.2.3
Follow-up period and trial completion
A follow up visit has to be organized after a minimum of 4 weeks after last drug injection as 
outlined in the Flow Chart (FC). 
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.
If a patient had withdrew drug prematurely, he should also come for that follow-up visit. In 
addition, the patient will be asked to return to clinic every 4 weeks to measure body weight 
until the end of the planned treatment period, i.e. week 46. All efforts should be made at least 
to conduct the week 46 visit for all patients.
However, if this is not possible, a phone contact should be made at week 46 to obtain vital 
status and body weight measured at home on the study scale.


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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 both multiple comparison 
procedures and modelling techniques (MCPMod).
7.1
NULL AND ALTERNATIVE HYPOTHESES
The null hypothesis is that there is a flat dose response curve across the placebo and the BI 
456906 dose groups, with regard to the primary endpoint of percentage change in body 
weight from baseline to Week 46. 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 2.5%). 
The pre-specified models and their parameters used for this test are outlined in Section 7.2.2.
No confirmatory hypothesis testing will be performed in this trial.
7.2
PLANNED ANALYSES
7.2.1
General considerations
Analysis Sets
Statistical analysis will be based on the following analysis sets: 
The Full Analysis Set (FAS) is defined as all randomised patients who received at least one 
dose of study treatment and who have analysable data for at least one efficacy endpoint.
The Treated Set (TS) is defined as all randomised patients who received at least one dose of 
study treatment.
The Pharmacokinetic Set (PKS) is defined as all patients in the TS who provided at least one 
BI 456906 concentration which was not excluded due to non-evaluability or an important 
protocol deviation relevant for PK. 
Important Protocol Deviations
Important protocol deviation (IPD) categories will be defined in the IPD specification 
document. IPDs will be identified no later than in the Report Planning Meeting (RPM).
IPDs may include (but not necessarily be limited to) the following:
∀
Violation of inclusion or exclusion criteria
∀
Major deviations from scheduled timing of assessments
∀
Non-compliance with trial medication


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∀
Treatment dispensing errors
∀
Use of prohibited or restricted concomitant medication.
Definition of baseline
In general, unless otherwise specified in the TSAP, the last non-missing measurement on or 
prior to the date of first dose of study treatment will be used as baseline for efficacy and 
safety variables. 
Definition of on-treatment
For the purposes of on-treatment efficacy analyses, the definition of “on-treatment” will be 
given in the TSAP.
For the purposes of on-treatment safety analyses, an assessment (or AE start date) will be 
considered “on-treatment” if the assessment date (or AE start date) is between the date of first 
dose and 28 days after the date of last dose of study treatment.
7.2.2
Primary endpoint analyses
The analysis for PoCC and dose-finding will be performed using multiple comparison and 
modelling techniques (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 repeated body weight measurements over time and for inclusion of baseline 
covariates in the model, a mixed model for repeated measures (MMRM) analysis will first be 
carried out. The MMRM will include fixed effects for baseline body weight and baseline by 
visit interaction as continuous covariates, and treatment, gender, visit and treatment-by-visit 
interaction as factors. Unstructured covariance will be used to model the relationship between 
pairs of endpoint measurements taken at different visits on the same patient. The Kenward-
Roger approximation will be used to estimate the denominator degrees of freedom. The 
TSAP will specify approaches to be taken to resolve possible non-convergence issues, 
including if necessary, the selection of a simpler covariance structure.
Covariate-adjusted fixed effect estimates of mean percentage change in body weight at Week 
46 for each treatment group and the covariance matrix will be extracted from the MMRM fit. 
These will be used for the subsequent MCPMod analysis. 
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. The following model assumptions and resulting 
graphs (Figure 7.2.2: 1) have been selected to cover a plausible and diverse range of 
monotone dose response patterns, with placebo mean response assumed to be zero and the 
mean response at the highest BI 456906 dose assumed to be -10.0 (i.e. a percentage reduction 
from baseline in body weight of 10%):
∀
Linear
∀
Exponential: 50% of maximum effect achieved at dose 3.6 mg 
∀
Emax1: 90% of maximum effect achieved at dose 4.8 mg


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∀
Emax1: 70% of maximum effect achieved at dose 4.8 mg
∀
Sigmoid Emax: 50% of maximum effect achieved at dose 2.4 mg; 90% of max effect 
achieved at dose 4.8 mg
Figure 7.2.2: 1 
Dose response patterns considered for the MCPMod analysis.
PoCC will be established if at least one model is statistically significant, rejecting the null 
hypothesis of a flat dose response relationship for percentage change in body weight jointly 
over the candidate dose response models, with a contrast test controlled for the family–wise 
type I error rate at one sided α = 2.5%. 
If PoCC is established, the statistically significant (best fitting) model(s) from the above 
candidate set will be refitted to the data to generate new estimates for all model parameters 
from the data. The target dose(s) will be estimated from the best fitting model(s) by 
incorporating information on the minimum clinically relevant effect and accounting for 
safety. 
The primary analysis of percentage change from baseline in body weight at Week 46 will be 
performed using the FAS and will assign patients to the randomised maintenance dose. It will 
include all available data without regard to whether patients started the maintenance period 


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with a lower dose than the one randomised to. For patients who discontinued treatment early, 
a distinction will be made according to whether this is due to a COVID-19 pandemic-related 
reason or not. Patients who discontinued treatment early due to a pandemic-related reason 
(e.g. direct COVID-19 infection, drug supply issue, site closure, quarantine preventing site 
access) will have data handled after discontinuation as if they were missing. Patients who 
discontinued treatment early for any other reason will have all available data included after 
discontinuation, irrespective of whether such patients subsequently received any permitted 
anti-obesity treatments.
The above approach to the primary analysis specifies a hypothetical strategy for the 
intercurrent event of pandemic-related early treatment discontinuation, and a treatment policy 
strategy for the intercurrent event of non-pandemic-related early treatment discontinuation.
The primary endpoint will be summarised descriptively overall, and by pre-specified 
subgroups (to be specified in the TSAP, but which may include e.g. subgroups based on 
gender, baseline BMI and age at screening).
7.2.3
Secondary endpoint analyses
The responder secondary endpoints (percentage change from baseline < -5.0% and < -10.0%
in body weight at Week 46, respectively) will be summarised descriptively. 
Logistic regression with treatment group and gender as factors and baseline body weight as a 
continuous linear covariate will be used to estimate the odds ratio for each active BI 456906 
dose compared with placebo, and to provide covariate-adjusted estimates of the proportion of 
responders at each BI 456906 dose. 


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The analyses of the responder endpoints will be aligned with the treatment policy and 
hypothetical strategy approaches respectively in Section 7.2.2 for handing early treatment 
discontinuation and missing data. As a first step, multiple imputation will be performed on 
the underlying continuous endpoint to generate multiple imputed datasets, each one 
containing complete data for every patient. A minimum of 100 imputed datasets will be used 
for this purpose. The imputation model will assume that a patient with missing data follows a 
similar trajectory to a patient without missing data in the same treatment group (with similar 
baseline covariates and observed values). The responder endpoints will be derived from the 
complete data in each of the imputed datasets, and then analysed using the logistic regression 
model specified above. Finally, the estimates from the logistic regression model will be 
combined across the imputed datasets in a way which correctly accounts for the within and 
between imputation variance. Further technical details of the multiple imputation will be 
provided in the TSAP.
Continuous secondary endpoints measured repeatedly over time will be summarised 
descriptively and analysed using an MMRM similar to the one specified in Section 7.2.2, 
except that baseline body weight will be replaced in the model by the baseline value of the 
relevant endpoint. The model will be used to obtain covariate-adjusted mean estimates of 
differences between active BI 456906 doses and placebo at the relevant time point. 
MCPMod dose finding analyses will not be performed for any secondary endpoints.


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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 residual effect period (REP), a period 
of 28 days after the last dose of trial medication, will be assigned to the on-treatment period 
for evaluation.
Safety analyses will be performed on the Treated Set (TS), using the actual maintenance 
treatment received. Key safety analyses will also be performed using the randomised 
maintenance treatment (if this is different for any patient). 
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.
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 Medical 
Dictionary for Drug Regulatory Activities (MedDRA) at database lock.
The adjudicated events specified in Section 5.2.6.1.5 will be summarised descriptively for 
each treatment group.
Laboratory data will be analysed 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 summarised. 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 and 12-lead ECG 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.
7.2.6
Other Analyses
Not applicable.
7.2.7
Interim Analyses
Data Monitoring Committee






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∀
An overall significance level of 2.5% (one-sided) for the contrast test of the null 
hypothesis of flat dose response
∀
The (monotone) dose response shapes specified in Section 7.2.2
∀
A placebo effect size (mean percentage change from baseline in body weight at Week 
46) of zero
∀
A maximum effect size (mean percentage change from baseline in body weight at 
Week 46) in the highest dose group of -10.0%
∀
A standard deviation of 7.0% [R20-0479].
Simulations were also performed to investigate departures from the assumed true maximum 
effect stated above, as well as for different scenarios for the true nature of the dose response 
relationship. The probability of success for each of these scenarios is summarised in Table 
7.5: 1 below. 
A success was defined as meeting all 3 of the following criteria:
1. Null hypothesis of flat dose response was rejected in favour of at least one of the 
alternative candidate models, and  
2. A target dose was selected within the dose range using the following criterion: 
difference in mean between selected dose and placebo < -9.0%, and
3. Proportion of patients in the highest dose group meeting the responder definition 
(percentage change in body weight from baseline < -10.0%) was greater than 35%.
Table 7.5: 1
Probability of success with N=70 patients in each treatment group and
SD = 7.0%.
True 
maximum 
effect (%)
Probability of success (%)
Linear
Exponential
Emax1
Emax2
SigEmax
AVERAGE
-9.0
48.9
48.9
48.8
49.0
65.3
52.2
-9.5
67.8
68.3
69.1
67.9
79.2
70.5
-10.0
82.8
83.3
83.8
83.3
89.0
84.4
-10.5
92.4
92.6
93.2
92.2
95.6
93.2
-11.0
97.1
97.3
97.8
96.5
98.4
97.4
A sample size of 70 patients per treatment group gives a probability of success of greater than 
80% for all assumed dose response shapes, with the assumed maximum dose effect and 
standard deviation as stated earlier.
Further simulations were performed to investigate the sensitivity of the probability of a 
successful trial outcome (as presented in Table 7.5: 1) to different possible allocation ratios 
which might be observed in practice in an analysis which uses actual maintenance dose. It is 
possible that some patients may not be able to reach the BI 456906 maintenance dose they 


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were randomised to according to the planned titration steps in Section 4.1.4, and will receive 
a lower maintenance dose instead. The scenarios investigated consider the possibility of 
tolerability issues for patients randomized to the highest BI 456906 dose only, and tolerability 
issues for patients randomized to one of the top two BI 456906 doses.
All other assumptions other than the allocation ratio are unchanged from what is presented in 
Table 7.5: 1. For each scenario, 10000 simulations were again used. For simplicity, only the 
average probability of a successful outcome across the different assumptions on functional 
form (linear, exponential etc.) is presented in Table 7.5: 2 below. The notation “X-X-X-X-X” 
is used to refer (from left to right) to the number of patients who received maintenance doses 
of 0 mg (Placebo), 0.6 mg, 2.4 mg, 3.6 mg and 4.8 mg respectively.
Table 7.5: 2
Probability of success for unequal allocation scenarios in an analysis 
of actual maintenance dose
Average probability of successful trial outcome (%)
Unequal 
Allocation 
ratio
True maximum effect (%)
-9.0
-9.5
-10.0
-10.5
-11.0
70-70-70-80-60
52.0
69.4
83.5
92.4
97.2
70-70-70-90-50
51.7
68.7
82.7
91.8
96.6
70-70-80-80-50
51.5
68.6
82.4
91.6
96.7
70-70-90-60-60
51.6
69.7
83.7
92.4
97.0
70-70-100-60-50
52.0
68.6
82.2
91.3
96.6
The average probability of success remained above 80% for the assumed maximum dose 
effect for all unequal allocation scenarios investigated.


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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 (GCP), relevant BI Standard Operating Procedures (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 as 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
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 Institutional Review Board (IRB / Independent Ethics Committee 
(IEC and competent authority (CA) 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 (or the patient’s legally accepted representative) 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 or the 
patient’s legally accepted representative.”
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.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.


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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 subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan 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
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 CRF 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 at least one documented attempt to 
retrieve previous medical records. If this fails, a verbal history from the patient, documented 
in their medical records, would be acceptable.
Copies of source documents necessary for adjudication of events and ECG central reading
will be provided to the corresponding vendors. Before sending or uploading those copies, 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. The electronic version of the ECG is regarded as 
source data. Dated and signed printouts will be stored in the participant’s medical file.
For eDiary, the electronic record is the source document.


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If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the CRF, 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 trial medication
∀
Medical history. Weight stability in previous 12 weeks can be obtained by investigator 
during the interview led at screening visit. The investigator should document this in the 
patient file.
∀
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, verbal documented feedback of the patient 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 investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF 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 CRFs 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 site(s):
The trial site(s) 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:
Personalised 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 have 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, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place
∀
A fit for the 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. 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.


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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. 
An independent external committee (Clinical Event Committee, [CEC]) will be established to 
adjudicate some events, as specified in section 5, jointly with trial 1404-0043 (BI 456906 
dose finding trial in patients with non-alcoholic steatohepatitis (NASH)).
Events will be adjudicated by external independent event adjudication committee; both in a 
blinded fashion. Events to be reviewed will be defined in a charter.
Events may either be defined by abnormal laboratory values and/or relevant adverse events or 
both.
For qualifying events, relevant source documents generated from any medical evaluations of 
these events will be requested including for example laboratory values, histological analysis, 
reports from ultrasound, CT, MRI, scintigraphy, hospital discharge letters, and medical 
reports from other physicians. All evaluations will be performed in a blinded fashion. 
A Data Monitoring Committee (DMC) will be established, jointly with trial 1404.43.
Members of the DMC are independent of BI, they are physicians experienced in the treatment 
of the disease under investigation and a statistician. The DMC will evaluate safety data. The 
DMC will receive urgent significant safety concerns, and cases of DILI, for immediate 
evaluation. While DMC members may be unblinded, measures are in place to ensure the 
blinding for everyone else involved in the trial. Regular DMC meetings will be held at 
specified intervals. The DMC will recommend continuation, modification or termination of 
the trial as detailed in the DMC charter. DMC recommendations as well as the final BI 
decision will be reported to the appropriate Regulatory Authorities (RAs)/Health Authorities 
(HAs), IRBs/ECs, and to investigators as requested by local law. The tasks and 
responsibilities of the DMC are specified in a charter.
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF.


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The investigators will have access to the BI web portal Clinergize to access documents 
provided by the sponsor.
BI has appointed a Clinical Trial Leader (CT 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,
-
ensure appropriate training and information of Clinical Trial Managers (CT 
Managers), Clinical Research Associates (CRAs), and investigators of participating 
countries.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and BI SOPs, or by a Contract Research Organisation (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 organise, 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 IRT Manual and Central Laboratory Manual, 
available in the ISF.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
R10-1424    
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 - 656 (2006)
R11-4890 
Sampson HA, et al. Second symposium on the definition and management 
of anaphylaxis: summary report - second National Institute of Allergy and 
Infectious Disease/Food Allergy and Anaphylaxis Network symposium.
2nd Symp of the National Institute of Allergy and Infectious Disease 
(NIAID)/Food Allergy and Anaphylaxis (FAA) Network on the Definition 
and Management of Anaphylaxis, Jul 2005. J Allergy Clin Immunol 2006 ; 
117(2) ; 391- 397. 
R17-4311   
Nauck MA, Petrie JR, Sesti G, Mannucci E, Courreges JP, Lindegaard ML, 
et al, Study 1821 Investigators A phase 2, randomized, dosefinding 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)
R19-1407    
Saxenda (liraglutide [rDNA origin] injection), solution for subcutaneous 
use (Novo Nordisk) (U.S. prescribing information,revised: 12/2014) (access 
date: 17 April 2019) (2014)
R20-0479   
O’Neil PM et al. Efficacy and safety of semaglutide compared with 
liraglutide and placebo for weight loss in patients with obesity: a 
randomized, double-blind, placebo and active controlled, dose ranging 
phase 2 trial. The Lancet 2018; 392:639-649.
R20-1943   
Matthias Blüher. Obesity: global epidemiology and pathogenesis. Nature 
Reviews Endocrinology 2019(15): 288–298.
R20-1944   
Gitanjali Srivastava, Caroline M Apovian. Current pharmacotherapy for 
obesity. Nature Reviews Endocrinology 2018(14):12-24.
R20-1982  
AM Sharma and RF Kushner. A proposed clinical staging system for 
obesity International Journal of Obesity 2009;(33):289–295  
R20-1983   
F Guo et al. The progression of cardiometabolic disease: Validation of a 
new cardiometabolic disease staging system applicable to obesity. Obesity 
2014;(22):110-118 


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R20-2315
Human energy requirements. Report of a joint FAO/WHO/UNU expert 
consultation. FAO:food and nutrition technical report series 1. 
FAO/WHO/UNU 2004 (Access date 21 Jul 2020)
9.2
UNPUBLISHED REFERENCES
c14085752-05
Investigator’s Brochure: BI 456906, Version 5.0; Indication 1404.P01, 
1404.P02
c21168858-06
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 (24 Jul
2019).
c28750666 
Explorative safety analysis for all dose groups. 1404-0003 trial. 08 Jul 2019


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10.
APPENDICES
10.1
AVAILABLE DOSING BY COMBINATION OF SYRINGES 
Five concentrations of BI 456906 are available, all available in syringes of 0,5 mL. The 
below combination of two syringes at every injection day will be used to obtain the various 
dosages used during the trial, in a blinded manner. Exceptionnally, and when possible, a 
different combination may be used to avoid missing supplies.
Dose to be 
achieved 
per injection 
(mg)
Syringe 1
Syringe 2
syringe 
concentration
dose 
dispensed 
by syringe
syringe 
concentration
dose 
dispensed 
by syringe
0,3
0,6 mg/mL
0,3 mg
Placebo
0 mg
0,6
0,6 mg/mL
0,3 mg
0,6 mg/mL
0,3 mg
0,9
1,8 mg/mL
0,9 mg
Placebo
0 mg
1,2
0,6 mg/mL
0,3 mg
1,8 mg/mL
0,9 mg
1,8
3,6 mg/mL
1,8 mg
Placebo
0 mg
2,4
4,8 mg/mL
2,4 mg
Placebo
0 mg
3
6,0 mg/mL
3,0 mg
Placebo
0 mg
3,3
4,8 mg/mL
2,4 mg
1,8 mg/mL
0,9 mg
3,6
3,6 mg/mL
1,8 mg
3,6 mg/mL
1,8 mg
4,2
3,6 mg/mL
1,8 mg
4,8 mg/mL
2,4 mg
4,8
4,8 mg/mL
2,4 mg
4,8 mg/mL
2,4 mg
10.2
BLOOD PRESSURE MEASUREMENT PROCEDURE
Initially, blood pressure should be taken in both arms. If the pressures differ by more than 10 
mmHg (as in the presence of a subclavian steal syndrome), obtain readings in both arms. The 
arm with the highest pressure (either systolic or diastolic) should be used for all subsequent 
measurements.  
Blood pressure measurements should be performed on the same arm and, if possible, by the
same person. The same method and device must be used throughout the trial for a patient.
After patients have rested quietly, in the seated position for five minutes, three blood pressure
measurements will be taken two minutes apart and all three results will have to be entered in
the CRF. The seated pulse rate will be taken during the two-minute interval between the
second and third blood pressure reading.
Blood pressure measurements should be recorded to the nearest 2 mmHg when applicable


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10.3
TIME SCHEDULE FOR PHARMACOKINETIC (PK) BLOOD 
SAMPLING
PK samples will be taken together with safety samples, before drug injection on the days of 
the visits 


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of Version 
22 Oct 2020
EudraCT number
EU number
2020-002479-37
BI Trial number
1404-0036
BI Investigational Medicinal 
Product(s)
BI 456906
Title of protocol
A Phase II, randomized, double blind, parallel 
group,46 weeks dose-finding study of BI 456906 
administered once weekly subcutaneously 
compared with placebo in patients with obesity or 
overweight
Version 2.0 of this Clinical trial Protocol is considered initial version of the CTP and 
includes some modifications shortly after the version 1.0 was archived. Version 1.0 dated 
20 Aug 2020 has not been submitted to any IRB or HA.
11.2
GLOBAL AMENDMENT 2
Date of Version 
24 Sep 2021
EudraCT number
EU number
2020-002479-37
BI Trial number
1404-0036
BI Investigational Medicinal 
Product(s)
BI 456906
Title of protocol
A Phase II, randomized, double blind, parallel 
group,46 weeks dose-finding study of BI 
456906 administered once weekly 
subcutaneously compared with placebo in 
patients with obesity or overweight
Global Amendment due to urgent safety reasonsl
Global Amendment
X


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Section to be changed
Synopsis key exclusion criteria
Description of change
1.Body weight change of +/- 5% in the past 3 
months
Was changed to 
1. Body weight change of +/- 5% in the past 12 
weeks
Rationale for change
Harmonized wording with section 3.3.3 
exclusion criteria
Section to be changed
Synopsis key exclusion criteria
Description of change
2.Screening calcitonin ≥ 20 ng/L (pg/mL)
Was changed to
2.Screening calcitonin ≥ 20 ng/L (pg/mL)
(≥5,84 pmol/L)
Rationale for change
Harmonized respective changes in the section 
3.3.3 exclusion criteria
Section to be changed
Synopsis key exclusion criteria
Description of change
6.Obesity induced by an endocrinologic 
disorder (e.g. Cushing Syndrome)
Was changed to
6.Obesity induced by an endocrinologic 
disorder (i.e. Cushing Syndrome, 
hypogonadism, growh hormone deficiency. 
However, well controlled hypothyroidism, 
polycystic ovarian disease are still allowed)
Rationale for change
Harmonized respective changes in the section 
3.3.3 exclusion criteria
Section to be changed
Synopsis key exclusion criteria
Description of change
8.Previous surgical treatment for obesity   
Was changed to
8.Previous irreversible surgical treatment for 
obesity. Previous treatment with reversible 
weight loss devices such as gastric banding, 
or intragastric balloon and removed longer 
than 12 months before screening should not 
be excluded.
Rationale for change
Harmonized respective changes in the section 
3.3.3 exclusion criteria
Section to be changed
Flow Chart


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Description of change
It is specified that pregnancy test at End of 
Treatment visit is a urinary test 
Rationale for change
Specification was missing
Section to be changed
Flow Chart
Description of change
12-lead ECG is added to visits 14, 16, 17, 19
Rationale for change
ECG will be done at every visit (except visit 18 
which is only to collect medication) during 
treatment phase as requested by Authorities
Section to be changed
Flow Chart
Description of change
Foot note 7 : FASTING sample: on these days, 
blood samples will also include some efficacy 
parameters including fasting glucose and fasting 
lipid battery These visits would preferably be 
scheduled on mornings
Was changed to
FASTING sample: on these days, blood 
samples will also include some efficacy 
parameters including fasting glucose, insulin 
and C-peptide, and fasting lipid battery These 
visits would preferably be scheduled on 
mornings
Rationale for change
The insulin and C-peptide are mentioned in 
section 5.4.1 but were not repeated here in flow 
chart
Section to be changed
Flow Chart foot note 17 
Description of change
The following is added to foot note 17 :
E-diary checks and patient counselling is 
optional at visit 19 for patients who had 
withdrawn drug prematurely
Rationale for change
After drug discontinuation patients are 
encouraged to stay in the trial until its planned 
end. In order to minimize the number of trial 
withdrawals, focus is made on primary endpoint 
and safety. Thus, records in e-diary are made 
optional to relief the daily burden. 
Section to be changed
1.4.3 Discussion


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Description of change
However, the event was recently upgraded to 
serious due to the medical significance, 
according to the BI GPV case processing 
procedure
Was changed to
However, the event was recently upgraded to 
serious due to the medical significance, 
according to the BI Global Pharmacovigilance
case processing procedure
Rationale for change
Replace abbreviation 
Section to be changed
3.3.2. Inclusion criteria
Description of change
Reference to section 4.2.2.2 is added to 
inclusion criterion 5 (contraception)
Rationale for change
Refer to the corresponding paragraph of 
protocol where details are given
Section to be changed
3.3.3. Exclusion criteria and flow chart
Description of change
2.Obesity induced by an endocrinologic 
disorder (e.g. Cushing Syndrome)
Was changed to
2.Obesity induced by an endocrinologic 
disorder (i.e. Cushing Syndrome, 
hypogonadism, growh hormone deficiency. 
However, well controlled hypothyroidism, 
polycystic ovarian disease are still allowed)
Rationale for change
Clarification and examples given
Section to be changed
3.3.3. Exclusion criteria
Description of change
9. Screening calcitonin ≥20 pg/mL
11. History of chronic or acute pancreatitis or 
elevation of serum lipase/amylase > 2x ULN, or 
fasting serum triglyceride levels of > 500 
mg/dL at screening
Were changed to
9. Screening calcitonin ≥20 pg/mL (≥5,84
pmol/L)
11. History of chronic or acute pancreatitis or 
elevation of serum lipase/amylase > 2x ULN, or 
fasting serum triglyceride levels of > 500 
mg/dL (>5,65 mmol/L) at screening


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Rationale for change
Provide both SI and Conventional units 
Section to be changed
3.3.3 Exclusion criteria
Description of change
13. Prior surgery of the GI tract that could 
interfere with body weight (including minimally 
invasive/endoscopic bariatric devices, bariatric 
surgery) except appendectomy and simple 
hernia repair before randomization.
Was changed to
13. Prior surgery of the GI tract that could 
interfere with body weight (including minimally 
invasive/endoscopic bariatric devices, bariatric 
surgery including metabolic operation that 
involves resection and/or reconstruction of 
any portion of the gastrointestinal tract) 
except appendectomy and simple hernia repair 
before randomization. However, a patient 
previously treated with reversible weight loss 
devices such as gastric banding, or 
intragastric balloon and removed longer 
than 12 months before screening should not 
be excluded.
Rationale for change
Clarifications and details to answer queries 
from sites
Section to be changed
3.3.3 Exclusion criteria
Description of change
17. A marked baseline prolongation of QT/QTc 
interval (such as QTc intervals that are greater 
than 450 ms at screening or an increase of 30 
ms versus screening) 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)
Was changed to
17. A marked prolongation of QT/QTc 
(Fridericia) interval that is greater than 450 ms 
at screening or an increase of 30 ms versus 
screening or at the randomisation 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) see section 5.2.4
Rationale for change
Specify what correction of QT is used and 
simplify the criterion
Rationale for change
Simplification of reading


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Section to be changed
3.3.3 Exclusion criteria
Description of change
25.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
Was changed to
25.Any documented active or suspected 
malignancy or history of malignancy within 5 
years prior to screening, except appropriately 
treated basal or squamous cell carcinoma of 
the skin.
Rationale for change
Clarification
Section to be changed
3.3.4.1. discontinuation of trial treatment
Description of change
Addition of one criterion
∀
The patient requires hospitalization due 
to drug related gastrointestinal adverse 
event assessed by investigator 
Rationale for change
Authority request
Section to be changed
3.3.4.1. discontinuation of trial treatment
Description of change
Given the patient’s agreement, a patient who 
discontinue drug should stay in the trial and 
follow procedures and visits as described in 
section 6.2.2.
Was changed to
Given the patient’s agreement, a patient who 
discontinue drug should stay in the trial and 
follow procedures and visits as described in 
section 6.2.2 except patients taking GLP-1 
RA who should be withdrawn from trial.
Rationale for change
To aligned with section 4.2.2.1
Section to be changed
4.1.4 Drug assignment and administration of 
doses for each patient


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Description of change
Fixed dose escalation phase (week 1- week 10)
During this phase the patient will receive 
planned dose as described Table 4.1.4:1 and 
titration within the dose group will not be 
allowed. 
Was changed to 
Fixed dose escalation phase (week 1- week 10)
During this phase the patient will receive 
planned dose as described Table 4.1.4:1 and 
titration within the dose group will not be 
allowed. Patients who cannot tolerate study 
drug during this period despite of all efforts 
taken, will be discontinued from treatment
Rationale for change
Authority request
Section to be changed
4.1.4 Drug assignment and administration of 
doses for each patient
Description of change
Maintenance dosing phase (week 21- week 46)  
No dose adjustments or titrations will be 
allowed during the maintenance phase. No 
patients will start the maintenance phase at 
week 21 with any dose which is not one of the 
planned maintenance doses (0.6, 2.4, 3.6 or 
4.8mg), and the dose will not be changed from 
week 21 until the final study visit at week 46
Was changed to 
Maintenance dosing phase (week 21- week 46)  
No dose adjustments or titrations will be 
allowed during the maintenance phase. No 
patients will start the maintenance phase at 
week 21 with any dose which is not one of the 
planned maintenance doses (0.6, 2.4, 3.6 or 
4.8mg), and the dose will not be changed from 
week 21 until the final study visit at week 46. 
Patients who cannot tolerate study drug 
during this period despite of all the efforts 
taken, will be discontinued from treatment.
Rationale for change
Authority request
Section to be changed
4.2.2.1. Restrictions regarding concomitant 
treatment 


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The following is not allowed during screening 
and treatment phase:
∀
Treatment with orlistat, zonisamide, 
topiramate/phentermine, phenteremine, 
bupropion/ naltrexone, GLP-1 RAs 
alone or in combination or any 
medication that could provide weight 
change in the opinion of the 
investigator. 
Was changed to :
The following is not allowed during the whole 
trial period (including patients who 
discontinued study medication) : 
∀
GLP-1 RAs
The following is not allowed during screening 
and until after 4 weeks after the last drug 
intake treatment phase:
∀
Treatment with orlistat, zonisamide, 
topiramate/phentermine, phenteremine, 
bupropion/ naltrexone, GLP 1 RAs
alone or in combination or any 
medication that could provide weight 
change in the opinion of the 
investigator. 
Rationale for change
To precisely assess dose response relationship 
of BI456906 on body weight without an 
interference of the medication that poses the 
same mode of action
Section to be changed
4.2.2.1 Restrictions regarding concomitant 
treatment
Description of change
The following bullet point was added in the list 
of restricted drugs :
∀
Medications known to significantly 
prolong the QT or QTc interval 
administered for a period of > 2 weeks 
Rationale for change
To align with exclusion criteria
Section to be changed
5.1.4 efficacy laboratory parameters


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Description of change
Some of the lab parameters will be analysed as 
part of efficacy criteria (see section 2.2.2 and 
5.4.1). In addition to parameters that are already 
collected for safety, fasting glucose and lipid 
battery, as well as HbA1c are to be measured at 
the visits specified in the flow chart.
Was changed to 
Some of the lab parameters will be analysed as 
part of efficacy criteria (see section 2.2.2 and 
5.4.1). In addition to parameters that are already 
collected for safety, fasting glucose, insulin, C-
peptide and lipid battery, as well as HbA1c are 
to be measured at the visits specified in the flow 
chart.
Rationale for change
Clarifications : these parameters were already 
mentioned in section 5.4.1 and are added here 
for clarity
Section to be changed
5.2 Assessment of safety
Description of change
The following text is added :
Safety is monitored during the trial conduct 
as per the below procedures.
Investigators are encouraged to repeat ECG 
and/or additional imaging, laboratory testing 
if any abnormal finding are observed
Rationale for change
Clarification requested by Authorities
Section to be changed
5.2.3 safety lab parameters 
Description of change
Addition of C-peptide and Insulin in the table
Rationale for change
Clarifications : these parameters were already 
mentioned in section 5.4.1 and are added here 
for clarity
Section to be changed
5.2.4 Electrocardiogram


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Description of change
A 12-lead ECGs should be collected at the time 
points specified in the Flow Chart. Centralized 
ECG services will be provided by an external 
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 must be supine for 
approximately 5-10 minutes before ECG 
collection. Patients should remain supine, but 
awake, during the ECG collection process.
The investigator has the responsibility to 
complete an initial review as soon as the ECG 
recordings are obtained at the site 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 significant 
abnormalities in the ECG, and would prefer to 
wait until the results from the central reading 
are available.
The digital ECG recordings will be transmitted 
to the 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 reported to the site. The site 
investigator must review the report. If the ECG 
is rated as abnormal, the Investigator will have 
to determine if the abnormal findings 
areclinically significant.
The site investigator will have the responsibility 
of following up with the patient if there are any 
clinically significant findings in the ECG report.
Clinically relevant abnormal findings will be 
reported either as baseline condition (if 
identified at the screening visit) or otherwise as 
AEs and will be followed up and/or treated as 
medically appropriate.
After the screening visit, the investigator must 
review the ECG results to ensure patient has 
met all the inclusion criteria and does not meet 
any of the exclusion criteria. Any pre-existing


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conditions should be recorded as baseline 
conditions.
Was changed to :
A 12-lead ECGs should be collected prior to 
the dosing at the time points specified in the 
Flow Chart. Centralized ECG services will be 
provided by an external 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 must be supine for approximately 5-10 
minutes before ECG collection. Patients should 
remain supine, but awake, during the ECG 
collection process.
The investigator has the responsibility to 
complete an initial review as soon as the ECG 
recordings are obtained at the site 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 significant 
abnormalities in the ECG, and would prefer to 
wait until the results from the central reading 
are available.
The digital ECG recordings will be transmitted 
to the 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 reported to the site. The site 
investigator must review the report. If the ECG 
is rated as abnormal, the Investigator will have 
to determine if the abnormal findings are 
clinically significant. After the screening visit, 
the investigator must complete a review of 
the ECG results from central reading to 
ensure patient has met all the entry criteria 
for the study. Any pre-existing conditions 
should be recorded as baseline conditions. 
At visit 2 eligibility decisions may be made 
based on the local reading of the screening 
ECG only exceptionally if the results of the 
central ECG have not been received, prior to 
randomisation visit. ECG recorded at the 


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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, it is strongly 
recommended that the investigator wait until 
the results from central reading are 
available, and the randomization visit should 
be rescheduled.
The site investigator will have the responsibility 
of following up with the patient if there are any 
clinically significant findings in the ECG report.
It is strongly recommended to repeat 12-lead 
ECG recording and/ or a referral to a 
cardiologist and/or perform additional 
cardiac tests (e.g. cardiac enzymes) if there is 
an indication of significant abnormalities or 
in case of doubts.
After the screening visit, the investigator must 
review the ECG results to ensure patient has 
met all the inclusion criteria and does not meet 
any of the exclusion criteria. Any pre existing 
conditions should be recorded as baseline 
conditions.


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Rationale for change
Clarification on the role of investigator review 
and central review, as requested by some local 
authorities
Section to be changed
5.2.6.1.3 AEs considered as “Always serious”
Description of change
The following text was added :
Adverse Event (AE) coded shall cross 
referenced against the Always Serious List 
(ASL). Non serious cases will be upgraded to 
serious. Cardiac related events included in 
the ASL, shall be fully processed as serious 
and expedited
Rationale for change
Clarification of process as requested by 
Authority
Section to be changed
5.2.6.1.6 Intensity (severity) of AEs
Description of change
Electrocardiogram QT corrected interval 
prolonged
Mild:
QTc increase from baseline of 
more than 30s and QTc 450-480 
ms
Moderate:
QTc increase from baseline of 
more than 30s and QTc 481-500 
ms
Severe:
QTc increase from baseline of 
more than 30s and QTc >= 501 
ms on at least two separate 
ECGs
Was changed to 
Electrocardiogram QTcF corrected interval 
prolonged
Mild:
QTcF increase from baseline of 
more than 30s and QTc 450-480 
ms
Moderate:
QTcF increase from baseline of 
more than 30s and QTc 481-500 
ms
Severe:
QTcF increase from baseline of 
more than 30s and QTc >= 501 
ms on at least two separate 
ECGs
Rationale for change
To be more specific on what QT correction is 
applied


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Section to be changed
Foot note of table in section 5.7.1 (CMDS)
Description of change
Low HDL: high-density lipoprotein (HDL) 
cholesterol <40 mg/dL in men, <50 mg/dL in 
women
High TG Fasting triglycerides ≥150 mg/dL or 
on antihyperlipidemia medication
High BP : SBP ≥130mmHg and/or DBP ≥85 
mmHg or on antihypertensive medication 
Prediabetes: fasting plasma glucose ≥100 mg/dl, 
and/or 2-hour OGTT ≥140 mg/dl.
Was changed to
Low HDL: high-density lipoprotein (HDL) 
cholesterol <40 mg/dL(1,04mmol/L) in men, 
<50 mg/dL (1,30 mmol/L) in women
High TG Fasting triglycerides ≥150 mg/dL(1,69 
mmol/L) or on antihyperlipidemia medication
High BP : SBP ≥130mmHg and/or DBP ≥85 
mmHg or on antihypertensive medication 
Prediabetes: fasting plasma glucose ≥100 
mg/dL (5,55 mmol/L), and/or 2-hour OGTT 
≥140 mg/dL.(7,77 mmol/L)
Rationale for change
Provide both SI and Conventional units 
Section to be changed
6.2.2 treatment period
Description of change
At the visits where PRO questionnaires are 
completed by the patient, the C-SSRS 
questionnaire should be administered only after 
receiving the completed PRO questionnaires
Was changed to
At the visits where PRO questionnaires are 
completed by the patient, the PHQ-9 
(completed by the patient) and the C-SSRS 
questionnaire (completed by qualified site 
staff) should be administered only after 
receiving the completed PRO questionnaires.
Rationale for change
Clarification on the completion of 
questionnaires
Section to be changed
6.2.2 treatment period


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Description of change
At each visit, patients should be advised to 
follow the recommended diet and exercise plan
and to record their compliance daily on the 
provided diary.  Diet and exercise counselling 
sessions are held at visits indicated in the Flow 
Chart. 
Was changed to
At each visit, patients should be advised to 
follow the recommended diet and exercise plan
and to record their compliance daily on the 
provided diary. Diet and exercise counselling 
sessions are held at visits indicated in the Flow 
Chart. When necessary from a logistical point 
of view it is possible to have the diet/exercise 
counselling on a different day than the actual 
dosing visit, but within the time window of 
the visit.
Rationale for change
Give flexibility
Section to be changed
6.2.2 treatment period
Description of change
The following text was added : 
Safety lab, other laboratory tests during the 
treatment period (from V3 to visit 17) : 
If blood sampling for central lab at the trial 
site is not possible, safety lab analyses can be 
performed at a local lab. The results of the 
lab tests must be transferred to the 
investigator who ensures medical review and 
proper documentation in the eCRF.
Minimum required safety lab parameters are 
Haematology: Haematocrit, Hemoglobin, 
Red Blood Cells / Erythrocytes, White blood 
cells / Leukocytes, Platelet Count / 
Thrombocytes
Clinical chemistry: ALT (alanine 
aminotransaminase, SGPT), AST (aspartate 
aminotransaminase, SGOT), Bilirubin total, 
Amylase, Lipase
Rationale for change
Due to COVID-19sanitary crisis it may happen 
that central lab cannot provide tubes or results 
Section to be changed
6.2.2 treatment period


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The following text was added : 
Exceptionally, and after consultation with 
sponsor, one visit could be completed a few 
days in advance to accommodate for 
patient’s imperatives. The call to IVRS and 
drug allocation would be made, but the 
injection would occur as per the initial 
schedule and allowed time-window.
Rationale for change
Avoid too many withdrawals due to patients 
missing a visit and therefore would miss 2 
consecutive doses
Section to be changed
10.1 Available dosing by Combination of 
syringes
Description of change
Five concentrations of BI 456906 are available, 
all available in syringes of 0,5 mL. The below 
combination of two syringes at every injection 
day will be used to obtain the various dosages 
used during the trial, in a blinded manner. 
Was changed to 
Five concentrations of BI 456906 are available, 
all available in syringes of 0,5 mL. The below 
combination of two syringes at every injection 
day will be used to obtain the various dosages 
used during the trial, in a blinded manner. 
Exceptionnally, and when possible, a 
different combination may be used to avoid 
missing supplies
Rationale for change
Give flexibility to the IRT system
Section to be changed
10.2 Blood pressure measurement procedures
Description of change
The following text is deleted :
The preferred method of blood pressure 
measurement is by a standard mercury 
sphygmomanometer. If a standard mercury 
sphygmomanometer is not available, alternative 
devices according to 
homepage:dableducational.org may be used 
after consultation with the Clinical Trial Leader
Rationale for change
Sphygmomanometer is not widely used 
anymore and this requirement is obsolete


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11.3
GLOBAL AMENDMENT 3
Date of Version 
16 Feb 2022
EudraCT number
EU number
2020-002479-37
BI Trial number
1404-0036
BI Investigational Medicinal 
Product(s)
BI 456906
Title of protocol
A Phase II, randomized, double blind, parallel 
group,46 weeks dose-finding study of BI 
456906 administered once weekly 
subcutaneously compared with placebo in 
patients with obesity or overweight
Global Amendment due to urgent safety reasons
Global Amendment
X


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Section to be changed
Synopsis statistical methods
Description of change
The following text was added :
One interim analysis will be performed by 
the Sponsor for internal planning purposes 
after approximately two-thirds of 
randomised patients have reached Week 20.  
The interim analysis will include body weight 
reduction at Week 20 and descriptive 
summaries of safety and tolerability. In 
addition, exploratory model based 
longitudinal population PKPD analyses of 
1404.0036 interim data, pooled with data 
from other studies with BI 456906, will be 
conducted for weight reduction and 
incidence of nausea and vomiting AEs
The interim analysis results are not intended 
to be used to stop the trial, nor to make 
confirmatory claims.
Rationale for change
An interim analysis will be performed for 
sponsor planning purposes only.
Section to be changed
3.1 Overall Trial Design
Description of change
The following text was added :
One interim analysis will be performed 
during the trial. Please refer to section 7.2.7
Rationale for change
An interim analysis will be performed for 
sponsor planning purposes only
Section to be changed
4.1.5.1 Blinding
Description of change
The following text was added :
One interim analysis will be performed by an 
independent statistics and programming 
team at the Sponsor for internal phase III 
planning purposes after approximately two 
thirds of randomised patients have reached 
Week 20. Details are given in Section 7.2.7,
including how access to unblinded data and 
results will be controlled.
Rationale for change
An interim analysis will be performed for 
sponsor planning purposes only.
Section to be changed
7.2.7 Interim Analysis


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Description of change
No interim analysis is planned in this trial.
A Data Monitoring Committee (DMC) will be 
implemented, with tasks as described in Section 
8.7.
was changed to
Data Monitoring Committee
A Data Monitoring Committee (DMC) will be 
implemented, with tasks as described in Section 
8.7.
Interim Analysis
One interim analysis will be performed after 
approximately two-thirds of randomised 
patients have reached Week 20. 
The interim analysis will include body weight 
reduction at Week 20 and descriptive 
summaries of safety and tolerability. Details 
of the proposed analyses will be specified in an 
interim TSAP. In addition, exploratory model 
based longitudinal population PKPD analyses 
of 1404.0036 interim data, pooled with data 
from other studies with BI 456906, will be 
conducted for weight reduction and incidence 
of nausea and vomiting AEs.
The interim analysis will be performed for 
Sponsor internal phase III planning purposes. 
The interim analysis results are not intended 
to be used to stop the trial, nor to make 
confirmatory 
claims. 
No 
statistical 
adjustments to Type I error are therefore 
considered necessary.
The interim analysis will be performed by the 
Sponsor, using the steps below to protect the 
integrity of the trial. The external DMC will 
be informed of the results of the interim 
analysis and will be given opportunity to 
review them at the scheduled DMC meeting 
following their availability.


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The interim analysis will be performed by an 
independent statistics and programming team 
within BI. Personnel involved with trial 
conduct at study sites will not have access to 
unblinded data from the interim analysis. 
Secure folders with restricted access will be 
used for the storage of unblinded interim data 
and results. Further operational details of 
who will perform the interim analysis, and the 
steps to be taken to protect the integrity of the 
ongoing trial, will be specified in a Logistics 
Plan. Details of the BI personnel who will have 
access to unblinded interim data or results, 
and how interim results will be communicated 
within BI, will be specified in an Access Plan. 
These documents will be finalised prior to 
unblinding treatments at interim database 
lock
Rationale for change
An interim analysis will be performed for 
sponsor planning purposes only.
11.4
GLOBAL AMENDMENT 4
Date of Version 
29 Apr 2022
EudraCT number
EU number
2020-002479-37
BI Trial number
1404-0036
BI Investigational Medicinal 
Product(s)
BI 456906
Title of protocol
A Phase II, randomized, double blind, parallel 
group,46 weeks dose-finding study of BI 
456906 administered once weekly 
subcutaneously compared with placebo in 
patients with obesity or overweight
Global Amendment due to urgent safety reasons
Global Amendment
X


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Section to be changed
3.3.4.1 Discontinuation of trial treatment
Description of change
The patient experiences an infection with Sars-
CoV-2 (as confirmed by PCR test, see Section 
5.2.3).
Was changed to:
The patient experiences an infection with Sars-
CoV-2 (as confirmed by PCR test) and
presents with signs or symptoms requiring 
discontinuation of treatment as per
investigator’s discretion.
Rationale for change
Provide further clarification about whether trial 
treatment should be discontinued in the event a 
subject experiences an infection with Sars-CoV-
2. In line with the COVID-19 benefit-risk 
assessment for BI 456906, the investigator will 
take the totality of information related to each 
single patient and the local COVID-19 situation 
into consideration when performing the 
individual benefit-risk assessment on a case-by-
case basis.
Considering all aspects, the investigator will 
determine whether each individual patient 
should continue trial treatment.
In the event trial treatment was stopped due to 
an infection with Sars-CoV-2, the investigator 
may decide to continue the trial treatment based 
on a thorough risk assessment.
Section to be changed
4.1.4  Drug assignment and administration of 
doses for each patient


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Description of change
∀
In case of consecutive 2 skipped doses, 
the treatment discontinuation should be 
considered (general rule). In some 
exceptional circumstances (e.g. COVID-
19 like pandemic situation), sponsor 
must be contacted for alternative option.
Was changed to 
∀
In case of consecutive 2 skipped doses, 
the treatment discontinuation should be 
considered (general rule). In some 
exceptional circumstances (e.g. COVID-
19 like pandemic situation), sponsor 
must be contacted for alternative option. 
If 2 consecutive doses of study 
medication are missed, the patient 
may recommence the study treatment 
if considered safe as per the 
investigator’s discretion and the 
patient does not meet any of the 
discontinuation criteria”.
Rationale for change
In the event that trial treatment was stopped two 
consecutive weeks, in circumstances that do not 
meet discontinuation criteria, give the 
investigator the possibility to decide to continue 
the trial treatment based on a thorough risk 
assessment
Section to be changed
4.1.5.1.Blinding


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Description of change
The randomisation codes will be provided to 
bioanalytics during the course of the trial to 
allow for the exclusion from the analyses of 
pharmacokinetic (PK) samples taken from 
placebo patients. Bioanalytics will not disclose 
the randomisation code or the results of their 
measurements until the trial is officially 
unblinded.
Was changed to : 
The randomisation codes will be provided to 
bioanalytics during the course of the trial to 
allow for the exclusion from the analyses of 
pharmacokinetic (PK) and antidrug antibodies 
(ADA) samples taken from placebo patients. 
Bioanalytics will not disclose the randomisation 
code or the results of their measurements until 
the trial is officially unblinded.
Rationale for change
ADA analyses are run in parallel to PK analyses
Section to be changed
7.2.1 General considerations
Description of change
The following text is deleted : 
In “Analysis set” :
The Per Protocol Set (PPS) is defined as all 
patients in the FAS who were without an 
important protocol deviation relevant for 
efficacy.
In “Important protocol deviations”
IPD categories which lead to exclusion form 
analysis sets will also be specified in the TSAP
Rationale for change
Removal of description of Per Protocol Set 
(PPS) and removal of statement that important 
protocol deviations (IPDs) may lead to 
exclusion from analysis sets. Expected to be 
covered by analyses using other estimands and 
sensitivity analyses (details to be specified in 
trial statistical analysis plan).
Section to be changed
7.2.2  Primary endpoint analyses




 
 
 
APPROVAL / SIGNATURE PAGE 
Document Number: 
 
Technical Version Number:
Document Name: 
                                                                                                                 
 
Title: 
                                                                                                                   
Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Boehringer Ingelheim 
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Document Number: 
Technical Version Number:
(Continued) Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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SAP_001.pdf: 
001-MCS-50-415_RD-01 (3.0) / Saved on: 18 Jan 2021
 
TRIAL STATISTICAL ANALYSIS PLAN
c36897808-01
BI Trial No.:
1404-0036
Title:
A Phase II, randomised, double blind, parallel group, 46 weeks 
dose-finding study of BI 456906 administered once weekly 
subcutaneously compared with placebo in patients with obesity or 
overweight
Investigational
Product(s):
BI 456906
Responsible trial 
statistician(s):
Trial Statistician
Tel.: 
Email: 
Date of statistical 
analysis plan:
08NOV2022 SIGNED
Version:
1.0
Page 1 of 58
Proprietary confidential information
! 2022 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.


Boehringer Ingelheim
TSAP for BI Trial No: 1404-0036
c36897808-01
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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................9
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY....................10
5.
ENDPOINT(S).....................................................................................................10
5.1
PRIMARY ENDPOINT(S) ................................................................................10
5.2
SECONDARY ENDPOINT(S) ..........................................................................10
5.2.1
Key secondary endpoint(s).................................................................................10
5.2.2
Secondary endpoint(s) ........................................................................................10
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................21
6.1
TREATMENT(S)................................................................................................21
6.1.1
Study Phases........................................................................................................21
6.1.2
Planned Maintenance Treatment ......................................................................21
6.1.3
Actual Maintenance Treatment.........................................................................22
6.1.4
Handling of Treatment Errors and Discrepancies...........................................23
6.1.5
Pooling Across Doses ..........................................................................................23
6.1.6
Definition of On-Treatment ...............................................................................23
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................24
6.3
SUBJECT SETS ANALYSED...........................................................................24
6.5
POOLING OF CENTRES .................................................................................27
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................27
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................29
7.
PLANNED ANALYSIS......................................................................................34
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........35
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................35
7.3
TREATMENT COMPLIANCE........................................................................36
7.4
PRIMARY ENDPOINT(S) ................................................................................36
7.4.1
Primary analysis of the primary endpoint(s) ...................................................36


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7.5
SECONDARY ENDPOINT(S) ..........................................................................42
7.5.1
Key secondary endpoint(s).................................................................................42
7.5.2
Secondary endpoint(s) ........................................................................................42
7.7
EXTENT OF EXPOSURE.................................................................................46
7.8
SAFETY ANALYSIS..........................................................................................47
7.8.1
Adverse Events ....................................................................................................47
7.8.2
Laboratory data ..................................................................................................49
7.8.3
Vital signs.............................................................................................................51
7.8.4
ECG......................................................................................................................51
7.8.5
Others...................................................................................................................53
7.9
ANALYSIS OF COVID-19 IMPACT...............................................................53
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION.............55
9. 
REFERENCES....................................................................................................56
11.
HISTORY TABLE..............................................................................................58


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LIST OF TABLES
Table 6.1.1: 1 Study phases..................................................................................................... 21
Table 6.1.3: 1 Definition of actual maintenance treatment for patients randomised to active 
BI 456906 maintenance treatment who discontinued treatment during the dose 
escalation period .............................................................................................. 22
Table 6.3: 1
Subject sets analysed........................................................................................ 26
Table 6.7: 1
Visit windows for variables scheduled to be assessed at all or many visits .... 31
Table 6.7: 2
Visit windows for variables with a sparse visit schedule ................................ 32
Table 7.4.1: 1 Optimal contrast coefficients for MCPMod .................................................... 38
Table 11: 1
History table..................................................................................................... 58


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ANCOVA
Analysis of Covariance
ADA
Anti-drug antibodies
AE
Adverse Event
AESI
Adverse Event of Special Interest
AIC
Akaike Information Criterion
ALT
Alanine aminotransferase (SGPT)
AP
Alkaline phosphatase
APRI
AST to Platelet Ratio Index
AST
Aspartate aminotransferase (SGOT)
ATC
Anatomical Therapeutic Chemical
BI
Boehringer Ingelheim
BMI
Body Mass Index
BP
Blood pressure
CI
Confidence interval
CK-18
Cytokeratin 18
CMDS
Cardiometabolic disease staging system
CR
Cognitive Restraint
C-SSRS
Columbia – Suicide Severity Rating Scale
CTX-III
C-terminal crosslinked telopeptide of type III collagen
eCRF
electronic Case report form
CTC
Common Terminology Criteria
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic coefficient of variation
DBL
Database Lock
DMC
Data Monitoring Committee
DTA
Data Transfer Agreement
ECG
Electrocardiogram
EDMS
Electronic Document Management System
EE
Emotional Eating
eGFR
Estimated Glomerular Filtration Rate
ELF
Enhanced Liver Fibrosis score
EOSS
Edmonton obesity staging system


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Term
Definition / description
EOT
End of treatment
FAS
Full Analysis Set
FFA
Free Fatty Acids
FGF-21
Fibroblast Growth Factor 21
Fib-4
Fibrosis-4 index
FPG
Fasting plasma glucose
GGT
Gamma-glutamyl transferase
GIP
Glucose-dependent insulinotropic polypeptide
GLP-1
Glucagon-like Peptide 1
gCV
Geometric coefficient of variation
gMean
Geometric mean
HDL
High Density Lipoprotein
HR
Heart rate
ICH
International Conference on Harmonisation
IPD
Important protocol deviation
IQR
Inter quartile range
IRT
Interactive Response Technology
iSAT
Independent safety analysis team
iSTAT
Independent statistician
LDL
Low Density Lipoprotein
LOQ
Limit of Quantification
KM
Kaplan-Meier
MAR
Missing at random
MCMC
Markov Chain Monte Carlo
MCPMod
Multiple Comparison and Modelling
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
MI
Multiple Imputation
MMRM
Mixed Model for Repeated Measures
MNAR
Missing not at random
NA
Not applicable
NAb
Neutralising antibodies
PCR
Polymerase chain reaction
PD
Protocol deviation


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Term
Definition / description
PGI
Patient Global Impression
PGI-C
Patient Global Impression of Change
PGI-D
Patient Global Impression of Difficulty
PGI-S
Patient Global Impression of Severity
PHQ-9
Patient Health Questionnaire 9 item depression module
PK
Pharmacokinetics
PK-PD
Pharmacokinetic-Pharmacodynamic
PKS
Pharmacokinetic Set
PPS
Per Protocol Set
PRO
Patient Reported Outcome
Pro-C3
N-terminal propeptide of type III collagen
PSTAT
Project Statistician
PYY3-36
Peptide YY-36
PT
Preferred term
Q1
Lower quartile
Q3
Upper quartile
REP
Residual effect period
RPM 
Report Planning Meeting
RS
Randomised Set
SAE
Serious adverse event
SAP
Statistical analysis plan
SD
Standard deviation
SDG
Standardised Drug Grouping
SDTM
Study data tabulation model
SOC
System organ class
SS
Screened Set
TDM
Trial Data Manager
TFEQ
Three Factor Eating Questionnaire
TG
Triglycerides
TMF
Trial Master File
TOC
Table of contents
TPROG
Trial Programmer
TS 
Treated Set
TSTAT
Trial Statistician


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Term
Definition / description
UACR
Urine albumin/creatinine ratio
UE
Uncontrolled Eating
ULN
Upper limit of normal
VLDL
Very Low Density Lipoprotein
WHO
World Health Organisation


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3.
INTRODUCTION
As per ICH E9, the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, 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 Clinical Trial Protocol (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, randomisation.
This document describes the main analysis of study 1404-0036. One interim analysis is planned 
for sponsor planning purposes. This is described in a separate interim statistical analysis plan, 
and is not addressed further in this document. The interim analysis results are not intended to 
be used to stop the trial, nor to make confirmatory claims. No statistical adjustments to Type 1 
error are therefore considered necessary.
This TSAP is based on the 1404-0036 CTP (Version 5.0, 29APR2022), together with the latest 
versions of the eCRF and relevant Data Transfer Agreements (DTAs) for external vendor data.
All statistical analyses defined in this TSAP will be performed by the trial statistician (TSTAT) 
with support from other trial team members following unblinding of the trial at final database 
lock (DBL). This TSAP will be finalized and signed prior to final DBL.
All data will be cleaned and coded, all vendor data transferred (unless documented otherwise),
and all eCRF pages approved by the investigator prior to DBL. A DBL meeting will be held 
prior to taking the final database snapshot. It will be decided at this meeting whether any open 
cleaning issues will be accepted or not. Important protocol deviations (IPDs) will also be 
finalized prior to DBL, except where unblinded dosing information after DBL is needed to 
confirm dose discrepancies for relevant IPDs.
SAS® version 9.4 or later will be used for all analysis. Where statistical analyses require the 
use of R instead of SAS®, R version 4.0.1 or later will be used.
The analyses and outputs specified in this TSAP will be included in the clinical trial report 
(CTR) unless specified otherwise.




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∀
Absolute change from baseline in waist circumference, measured in units of cm, 
at Week 46. 
∀
Absolute change from baseline in systolic blood pressure, measured in units of 
mmHg, at Week 46. 
∀
Absolute change from baseline in diastolic blood pressure, measured in units of 
mmHg, at Week 46. 
For the blood pressure endpoints, there is an additional time point structure within each 
scheduled week. Three measurements are planned to be captured at each of these time points 
within week. The mean of these three measurements (or the mean of the available 
measurements if fewer) will be calculated and used in the endpoint definitions. Further details 
are given in Section 6.7. 


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
6.1.1
Study Phases
The following summarises the study phases defined in the protocol for a patient who completes 
all visits and remains on treatment as planned:
Table 6.1.1: 1 Study phases
Study Phase Description 
Start
End
Screening phase
Date of informed consent
Day before Visit 2 (Week 0)
Treatment phase – dose 
escalation
Date of Visit 2 (Week 0)*
Day before Visit 12 (Week 20)
Treatment phase –
maintenance
Date of Visit 12 (Week 20) 
Date of Visit 19 (Week 46)
Follow-up phase
Day after Visit 19 (Week 
46)
Date of end of study 
participation (expected to be 3 
weeks after Visit 19 (Week 
46))
* See also baseline definitions in Section 6.7.
Patients who discontinue treatment early are nevertheless encouraged to remain in the study as 
specified above, at least for the minimum assessment of key data (including body weight). 
However, for these patients, the follow-up phase is defined in the protocol as up to 4 weeks 
after last dose of study treatment. It should be noted that such patients are therefore expected to
provide data that are later than 4 weeks after last dose of study treatment, in some cases 
considerably later, if the protocol aim to retain these patients off-treatment up to Visit 19 (Week 
46) is successful.
The follow-up period will not exist for any randomised patient who was lost to follow-up whilst 
still receiving treatment.
The definition of on-treatment for analysis purposes is given in Section 6.1.6. The use of a 
residual effect period (REP) means that data captured during the follow-up period specified in 
the protocol could be assigned to the treatment period for analysis.
6.1.2
Planned Maintenance Treatment
Patients are randomised to one of five treatment groups (Placebo, BI 456906 0.6 mg, BI 456906 
2.4 mg, BI 456906 3.6 mg, BI 456906 4.8 mg). These are the planned maintenance treatments 
(weekly doses). 


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6.1.3
Actual Maintenance Treatment
According to the rules for escalating and adjusting the BI 456906 dose given in the CTP, it is 
envisaged that some patients may not receive the planned maintenance treatment according to 
the randomised treatment group, whilst nevertheless remaining on treatment.
Actual maintenance treatment will therefore be defined for analysis as follows:
∀
If the actual dose at the start of the maintenance period is known to be less than the 
planned maintenance dose to which the patient was randomised, then actual 
maintenance treatment will be defined as this dose at the start of the maintenance period 
(which is expected to be one of the lower planned maintenance doses).
∀
If the patient was known to have discontinued treatment during the dose escalation 
period, actual maintenance treatment will be defined as the next planned maintenance 
dose up from the last dose which was taken prior to the dose at the time of 
discontinuation. This is specified in the table below, for all dosing possibilities planned 
in the CTP. The same rule will be applied irrespective of the reason for discontinuing 
treatment during the dose escalation period.
Table 6.1.3: 1 Definition of actual maintenance treatment for patients randomised to active BI 
456906 maintenance treatment who discontinued treatment during the dose 
escalation period
Dose at discontinuation / Previous dose
Actual maintenance treatment
0.3 mg / NA
0.6 mg
0.6 mg / 0.3 mg
0.6 mg
0.9 mg / 0.6 mg
2.4 mg
1.2 mg / 0.9 mg
2.4 mg
1.8 mg / 1.2 mg
2.4 mg
2.4 mg / 1.8 mg
2.4 mg
3.0 mg / 2.4 mg
3.6 mg
3.3 mg / 2.4 mg
3.6 mg
3.6 mg / 3.0 mg
3.6 mg
4.2 mg / 3.3 mg
3.6 mg
4.8 mg / 4.2 mg
4.8 mg


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∀
In all other cases, actual maintenance treatment will be defined equal to planned 
maintenance treatment.
∀
All patients randomised to placebo maintenance treatment will be assigned to placebo 
for actual maintenance treatment.
6.1.4
Handling of Treatment Errors and Discrepancies
In addition to the rules in Section 6.1.3 for handling situations envisaged by the CTP, it is also 
possible that dosing errors may occur. These could either be errors in the site dispensing an 
incorrect treatment and/or giving incorrect instructions about how to take the dispensed 
treatment, or they could be patient administration errors. 
Dosing errors will not change the assignment of any patient to actual maintenance treatment as 
described above, regardless of the reason for the error, and regardless of the unblinded dose 
taken or dispensed at the relevant week(s). However, any such errors and their unblinded doses 
will be identified as part of the analysis.
Blinded identification of potential discrepancies between assigned, dispensed and administered 
medication numbers will be performed prior to DBL as part of ongoing monitoring for possible
IPDs. However, decisions on whether such discrepancies matter in practice (e.g. the BI 456906 
dose taken was different from the intended BI 456906 dose, a patient randomised to placebo 
took an active BI 456906 dose, etc.), and whether the IPD is subsequently confirmed, require 
unblinding. 
6.1.5
Pooling Across Doses
In addition to displays by specific BI 456906 dose on descriptive summary tables, a pooled 
display across doses (i.e. “All BI 456906”) will also be presented. 
Pooled BI 456906 dose will not be used in any statistical models or descriptive summaries of 
efficacy.
Pooled BI 456906 dose will be included on all disposition and demographic/baseline summary 
tables, and in descriptive summaries of treatment exposure and safety.
6.1.6
Definition of On-Treatment
It is particularly noted here that the protocol encourages continued study participation for 
patients who have discontinued treatment early. It is therefore expected that for some patients 
there will be off-treatment data captured during the planned treatment period.
In addition, even for patients who completed treatment according to the protocol, data captured 
during the follow-up period may be relevant for safety.
With these points in mind, it is important to be clear whether all available data will be used in a 
particular summary or analysis, or whether only on-treatment data will be used. The definition 
of “on-treatment” for this purpose is as described below. It is assumed that all patients will have 


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a date of last administration of study medication accurately recorded on the End of Treatment 
eCRF page.
“Off-treatment” refers to data which are captured after baseline but which are not “on-
treatment” as defined below.
Safety
An AE start date or other safety assessment date will be considered “on-treatment” if the AE 
start date or assessment date is between the date of first dose and 28 days after the date of last 
dose of study treatment inclusive (the residual effect period (REP) is defined as 28 days in this 
trial). 
The same on-treatment definition will be used for all types of safety data. 
Efficacy
Efficacy data will also use the same 28 day definition of “on-treatment” as for safety.
The same on-treatment definition will be used for all types of efficacy data, including for all 
exploratory biomarkers (irrespective of whether the latter are specified as further endpoints or 
not).
6.2
IMPORTANT PROTOCOL DEVIATIONS
Handling of IPDs is included in the DV domain specifications and stored within the TMF in 
EDMS. 
IPDs will not lead to exclusion from analysis sets.
6.3
SUBJECT SETS ANALYSED
The following analysis sets will be defined:
Screened Set
The screened set (SS) includes all patients for whom a signed informed consent is available at 
the time of final DBL. It will be used only for display of patient disposition.
Randomised Set
The randomised set (RS) includes all screened patients who were randomised in the trial, 
regardless of whether any study drug was taken. It will be used only for display of patient 
disposition and IPDs. 
Treatment assignment will be as randomised (i.e. planned maintenance treatment). 
Treated Set
The treated set (TS) is defined as all randomised patients who received at least one dose of 
study treatment.


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The TS will be used for presentation of demographic/baseline data, concomitant 
medications/diagnoses, treatment exposure and safety.
Treatment assignment will be according to actual maintenance treatment (see Section 6.1.3), but 
certain AE summaries will also consider assignment according to planned (i.e. randomised)
maintenance treatment.
It is not expected on the database that the situation in which a patient could be treated without 
randomisation will exist. Documentation is in place by the Interactive Response Technology 
(IRT) vendor, which states that, should any patient be given treatment at the site in error 
without randomisation, such a patient will be subsequently randomised to a treatment which is 
not incompatible with the one given in error. 
Full Analysis Set
The full analysis set (FAS) is defined as all randomised patients who received at least one dose 
of study treatment and who have analysable data for at least one efficacy endpoint.
In practice, “analysable” is considered to mean an observed baseline and an observed post-
baseline value for at least one efficacy endpoint.
The FAS will be used for presentation of demographic/baseline data and for summaries and 
analysis of efficacy.
Treatment assignment will be as randomised (i.e. planned maintenance treatment), but certain 
analyses will also consider assignment according to actual maintenance treatment (see Section 
6.1.3).
Pharmacokinetic Set
The pharmacokinetic set (PKS) is defined as all patients in the TS who provide at least one 
evaluable BI 456906 plasma concentration which was not flagged for exclusion.
The table below summarises the analysis sets and their main intended purpose (specific details 
on sensitivity analyses, missing data, etc. are included in the relevant analysis section):


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Table 6.3: 1
Subject sets analysed
Data type
Analysis set
SS
RS
FAS
TS
PKS
Disposition
x
x
Demographic and 
baseline 
characteristics
x
x
Concomitant 
diseases and 
medications
x
Exposure to study 
drug
x
Primary efficacy
endpoint
x
Secondary efficacy 
endpoints
x
Further efficacy 
endpoints
x
Other efficacy and 
biomarkers
x
Adverse events
x
Vital signs
x
Laboratory safety 
data
x
12-lead ECG
x
Other safety
x
Plasma BI 456906 
concentration
x


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6.5
POOLING OF CENTRES
No analysis will be performed in which centre is included in the statistical model.
Subgroup analysis will be performed by country and region, but no other pooling of centres will 
be performed.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Primary efficacy endpoint
Every effort will be made to keep the patient in the trial and taking study treatment, where 
possible. If the patient discontinues from treatment early, every effort will also be made to 
capture body weight post-discontinuation up to and including Week 46, or at least a single 
measurement at Week 46. These data will be used in the treatment policy strategy for handling 
early treatment discontinuation in the analysis (see Section 7.4 for analysis details), noting also 
that the protocol permitted home measurement to be used and entered onto the eCRF in these 
circumstances, if the patient was unable or unwilling to return to site. Nevertheless, there may 
still be some missing data, even using such a treatment policy strategy for analysis. In the 


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hypothetical strategy for handling early treatment discontinuation, off-treatment body weight 
values (as defined in Section 6.1.6) will not be used and will be handled as if these data were 
missing. 
In both cases, missing data will be handled implicitly by the statistical model (mixed model for 
repeated measures (MMRM)). This model makes the assumption that the data are missing at 
random (MAR). Patients who do not have a Week 46 body weight value, but who have earlier 
post-baseline values, still contribute to this analysis. MAR means that a patient who drops out is 
assumed to have behaved like a similar patient within the same treatment group (where 
“similar” means both with regard to baseline covariates in the model and to the observed 
trajectory of body weight values prior to drop out).
A sensitivity analysis for the hypothetical strategy which does not make the MAR assumption, 
and which makes a more conservative assumption, is specified in Section 7.4.2.
Sensitivity analyses for the treatment policy strategy which do not use standard MMRM are 
also expected to be performed. These will be done post-hoc, and they are not described further 
in this TSAP.
Responder secondary efficacy endpoints
For the responder endpoints derived from percentage change from baseline in body weight at 
Week 46, analyses will be performed in which the handling of data after early treatment 
discontinuation and missing data are aligned with the treatment policy and hypothetical strategy 
approaches for the underlying continuous primary endpoint. 
This will be done by performing a multiple imputation (MI) analysis which makes the same 
MAR assumption as the MMRM used to analyse the primary endpoint. Essentially, missing 
data will be imputed under the MAR assumption, to give 1000 complete datasets containing 
body weight values (observed and imputed) for all patients. The responder endpoints at Week 
46 will be derived for each patient from the complete data in each of the imputed datasets, each 
dataset then analysed, and the results combined across the imputed datasets in a way which 
correctly accounts for the within and between imputation variance. Details of both the multiple 
imputation procedure and the subsequent analysis are given in Section 7.5.2.
All other efficacy endpoints
No imputations will be performed for any other efficacy endpoint. Where continuous endpoints 
over time are analysed using a statistical model, this will be MMRM, which implicitly handles 
missing data using the MAR assumption.
Safety/Other
A completely missing concomitant medication start date will be assumed to mean present at 
screening. If only the month and year are available for the AE/concomitant medication start 
date, the first day of the month will be assumed. If only the year is available, then 1st January of 
that year will be assumed. 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.


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If only the month and year are available for date of last administration of study medication, the 
last day of the month will be assumed.
If only the month and year are available for the date of first administration of study medication, 
the date of randomisation will be used if they are in the same month. If randomisation was in 
the month prior to first drug administration, the first day of the month of first administration 
will be assumed.
PK data
Missing data and outliers of PK data are handled according to BI standards.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Definition of baseline
In general, baseline is defined as the last non-missing measurement on or prior to the first 
administration of study medication. In the case that the first dose of study medication is delayed 
beyond the date of randomisation, a post-randomisation value can be used as a baseline value 
provided that it meets the stated requirement.
Where clock times are available (expected to include laboratory safety data, 12-lead ECG, 
plasma BI 456906 concentrations and biomarkers) they will be used in addition to dates to 
define baseline, since it is also expected that the time of first study drug administration will be 
accurately recorded on the eCRF for all patients. 
For vital signs, the baseline definition will make the additional requirement that the data records 
are pre-dose. In practice, this will also be done using the clock times as well as the date. Three 
pre-dose measurements are expected to be captured at the baseline visit (Visit 2); the mean of 
these 3 measurements (or the mean of the available measurements if fewer) will be used as 
baseline. In any situation in which only post-dose measurements are available at Visit 2 and no 
pre-dose measurements, Visit 2 will not be used as baseline; the mean of the 3 measurements 
(or those available if fewer) at the screening visit (Visit 1) will be used as baseline instead. 
Unscheduled and repeat assessments (where available and relevant) are eligible for use as 
baseline values provided that they meet the above criterion.
Visit windows
All summaries and analysis which are presented by week will use a visit window to classify the 
data record, which is derived from the assessment date relative to a reference date, taken here to 
be the date of first administration of study medication. This approach allows appropriate 
classification of visits which may have occurred significantly earlier or later than the protocol 
assessment schedule, as well as the use of data captured at visits which have no fixed timing 
(notably the EOT visit). Relative day will be defined for this purpose as (date of assessment –
date of first administration of study medication) + 1. 
Nominal database visit labels will not be used in any summary or analysis by time point, unless 
otherwise stated.


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Prior to applying the visit windows specified below, it will first be determined whether the data 
record is on-treatment, as defined in Section 6.1.6, for summaries or analysis which require this 
approach.
Unscheduled and repeat assessments (where relevant/available) are eligible for inclusion in visit 
windows.
For all variables except 12-lead ECG, if a patient has more than one non-missing value within 
the same visit window, the value closest to the target day will be selected. If two non-missing 
values are the same distance from the target day, the earlier of the two values will be selected.
For 12-lead ECG (only), scheduled visits take precedence over unscheduled visits. Once this 
rule has been applied, the measurement closest to the target day will be 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 of the two values will be selected.
Derivation of last, minimum and maximum values where relevant in safety analyses will  
consider all available values, regardless of whether they were selected in the visit window.
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 Section 6.1.6 for definition of on-treatment).
Two different situations are envisaged, which are described in the following tables:
∀
Visit windows for variables scheduled to be assessed at all or many visits
∀
Visit windows for variables with a sparse visit schedule.


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Table 6.7: 1
Visit windows for variables scheduled to be assessed at all or many visits
Period
Time Point
Target Day
Visit Window
Dose escalation
Week 2
15
2-21
Week 4
29
22-35
Week 6
43
36-49
Week 8
57
50-63
Week 10
71
64-77
Week 12
85
78-91
Week 14
99
92-105
Week 16
113
106-119
Week 18
127
120-133
Maintenance
Week 20
141
134-154
Week 24
169
155-182
Week 28
197
183-210
Week 32
225
211-238
Week 36
253
239-266
Week 40
281
267-301
Week 46
323
≥ 302
The relevant variables are expected to include body weight measured at the clinic and BMI 
derived from this, vital signs, routine non-fasting laboratory safety variables, 12-lead ECG and 
the mental health questionnaires (C-SSRS, PHQ-9).
These visits windows will also be used for waist circumference, although this is not scheduled 
to be captured at all weeks displayed.


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Table 6.7: 2
Visit windows for variables with a sparse visit schedule
Period
Time Point
Target Day
Visit Window
Dose Escalation
Week 10
71
2-133
Maintenance
Week 20
141
134-231
Week 46
323
≥ 232
The relevant variables are expected to include biomarkers, HbA1c, fasting laboratory variables,
PRO questionnaires, the 3-day food diary and the obesity staging questionnaires (EOSS and 
CDMS).
The suitability of these visit windows for very sparse data capture will be reviewed at the 
Report Planning Meetings (RPMs).
Vital signs
For vital signs, the following windowing rules will be applied within each visit to determine
pre-dose, 15 minutes post-dose (selected visits only) and 60 minutes post-dose from recorded 
clock times:
∀
If the vital signs measurement time is prior to or equal to the time of study drug 
administration, then it is considered eligible for pre-dose, without restriction on how 
long before study drug administration the measurement was done (provided it was still 
done on the same visit date). The mean of the 3 values (or those available if fewer) will 
be used as pre-dose. If more than 3 pre-dose values are identified in this way, the mean 
of the 3 values closest to the time of study drug administration will be used.
∀
If the vital signs measurement time is after the time of study drug administration, then it 
is considered eligible for post-dose, without restriction on how long after study drug 
administration the measurement was done (provided it was still done on the same visit 
date).
o
For visits where only one post-dose time point is scheduled, then all post-dose 
records will be considered eligible for 60 minutes post-dose. The mean of the 3 
values (or those available if fewer) will be used as 60 minutes post-dose. If more 
than 3 values are identified in this way, the mean of the 3 values closest to the 
target 60 minute time point will be used.
o
For visits where two post-dose time points are scheduled, then measurements 
will be considered eligible for 15 minutes post-dose if they were done on or 
before 37.5 minutes after study drug administration, and eligible for 60 minutes 
post-dose if they were done later than this. In both cases, the mean of the 3 
values (or those available if fewer) will be used. If more than 3 values are 
identified in this way, the mean of the 3 values closest to the target 15 minute or 
60 minute time point will be used, respectively. 
The situation in which vital signs measurement time is exactly equal to the time of study drug 
administration is not clinically plausible, and a rule for handling it is included above only for 
completeness, in case this cannot be resolved for any patients and this situation remains on the 
database at DBL.


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Any vital signs record for which no time of study drug administration exists (expected to 
include measurements recorded during the 28 day REP and scheduled Week 46 measurements) 
will be considered “pre-dose” according to the above rules. Only pre-dose measurements will 
be used for efficacy purposes (blood pressure endpoints).
Home-measured body weight
Home-measured body weight will be classified into weeks using the available dates recorded by 
the patient in the eDiary, and using a strict definition of each week relative to the date of first 
administration of study medication. In other words. “Week 1” will be defined as Day 2-8, 
“Week 2” will be defined as Day 9-15, “Week 3” will be defined as Day 16-22, etc.
If a patient has more than one non-missing value within the same week, the mean of all 
available values will be used.


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7.
PLANNED ANALYSIS
Descriptive statistics for continuous variables will generally be N (number of patients with non-
missing values), arithmetic mean, standard deviation (SD), minimum, Q1 (lower quartile), 
median, Q3 (upper quartile) and maximum. In general, means, medians, other quartiles and 
SDs will be presented to one more decimal place than the raw data. Minimums and maximums 
will be presented to the same number of decimal places as the raw data. 
For BI 456906 plasma concentrations, CV (arithmetic coefficient of variation), gMean 
(geometric mean) and gCV (geometric coefficient of variation) will also be presented. The data 
format for descriptive statistics of concentrations will be identical with the data format of the 
respective concentrations.
Tabulations of frequencies for categorical data will include all possible non-missing categories
unless otherwise specified (e.g. AE terms), and will display the number of patients in a category
as well as the percentage (%) relative to the respective treatment group. Percentages will be
rounded to one decimal place. A missing category will be displayed only if there are actually
missing values. Percentages will be based on all patients in the respective patient set whether
they have non-missing values or not.
Disposition
The disposition of patients will be displayed. This table will present the number of patients 
enrolled, randomised and treated. The number treated will be further presented separating the 
dose escalation and maintenance periods. Planned maintenance treatment (see Section 6.1.2) 
will be used for this table.
The number of patients who completed or who prematurely discontinued study treatment will
be summarised, along with the categorization of the primary reason for treatment 
discontinuation. The number of patients and reasons for prematurely discontinuing treatment 
will also be displayed separately for the dose escalation and maintenance periods. 
The number of patients who completed or who prematurely withdrew from the study will be 
summarised, along with the categorization of the primary reason for study withdrawal.
Where shown on the disposition table, the percentages will be of the number of patients treated 
in each treatment group.
Kaplan-Meier estimates will be presented graphically by treatment group for time to early 
treatment discontinuation (defined as treatment discontinuation date – treatment start date + 
1). In this analysis, patients who did not discontinue treatment early will be censored using the 
date on which they completed treatment.
The frequency of patients in each of the different analysis sets (Section 6.3) will also be 
tabulated by treatment. This will be done for both planned and actual maintenance treatment.
IPDs will be summarised and listed for the randomised set using planned maintenance 
treatment.


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7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Descriptive summaries of demographic variables and characteristics measured at baseline will 
be presented, to include: sex, race and ethnicity, age (years) (continuous and categories), height 
(cm), weight (kg) (continuous and categories), BMI (kg/m2) (continuous and categories), waist 
circumference (cm), systolic BP (mmHg), diastolic BP (mmHg), pulse rate (bpm), country and 
region.
Age, body weight and BMI categories will be as defined in Section 6.4.
Summaries of demographic data and baseline characteristics will be presented on both the FAS
using planned maintenance treatment and the TS using actual maintenance treatment. 
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned (number and percentage of patients). Summaries of 
concomitant diseases (medical history and baseline conditions), concomitant medication and 
concomitant non-drug therapy will be based on the TS, and will use actual maintenance 
treatment.
Baseline conditions and concomitant non-drug therapies will be coded according to the most 
recent version of MedDRA at the time of final DBL. This will include coding of trial-specific 
recording of comorbidities of obesity/overweight on the eCRF, which will not be summarised 
separately, but included with the general summary of medical history and baseline conditions.
Concomitant medications will be coded according to the most recent version of the World 
Health Organisation (WHO) Drug Dictionary at the time of final DBL. 
Baseline conditions and medical history will be summarised descriptively by MedDRA system 
organ class (SOC) and preferred term (PT).
A medication or non-drug therapy will be considered concomitant to treatment if either of the 
following applies:
∀
It is ongoing at the start of study treatment
∀
The start date occurs between the start of study treatment and 28 days after the end of 
study treatment inclusive.
A medication or non-drug therapy will be considered prior to treatment if the end date occurs 
before the start of study treatment.
Concomitant medication will be summarised descriptively by ATC3 class and preferred name. 
Prior medication will not be summarised. 
An additional table will be produced of any medications introduced on or after the date of early 
discontinuation of treatment, for the relevant subset of patients (regardless of whether these new 
medications were within or outside the 28-day period defined by the REP).
Concomitant non-drug therapy will be summarised by SOC and PT. Prior non-drug therapy will 
not be summarised. 


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7.3
TREATMENT COMPLIANCE
Treatment compliance based on return of unused and empty syringes will not be analysed in 
this trial. 
Any discrepancies between medication assigned, medication dispensed and medication taken 
will be assessed through the process for determining important protocol deviations (IPDs).
Section 6.1.3 and Section 6.1.4 also describe situations in which the actual maintenance 
treatment may not be the same as the planned (randomised) maintenance treatment. The CTP 
specifies rules for adjusting the BI 456906 dose (or if necessary discontinuing the patient from 
treatment) depending on the number of missed doses and whether missed doses are consecutive. 
Therefore treatment compliance is directly related to the procedure for assigning BI 456906 
dose.
7.4
PRIMARY ENDPOINT(S)
Descriptive summaries of body weight and percentage change from baseline will be presented 
over time. These summaries will be produced in each of the following different ways:
∀
FAS, planned maintenance treatment, all data (i.e. both on-treatment and off-treatment 
as defined in Section 6.1.6, and irrespective of any anti-obesity medications 
subsequently introduced for patients who discontinued treatment early)
∀
FAS, planned maintenance treatment, all data (as above) but censored for any early 
treatment discontinuation related to the COVID-19 pandemic (either direct COVID-19 
infection or other indirect pandemic-related reason)
∀
FAS, planned maintenance treatment, on-treatment data only
∀
FAS, actual maintenance treatment, all data censored for COVID-19 related treatment 
discontinuation
∀
FAS, actual maintenance treatment, on-treatment data only.
The first descriptive summary above, which uses all available body weight data, will be 
repeated split at each time point according to whether the contributing data are on- or off-
treatment.
7.4.1
Primary analysis of the primary endpoint(s)
The primary analysis of the primary endpoint will be performed on the FAS, using planned 
maintenance treatment, and including all data censored for COVID-19 related early treatment 
discontinuation. This specifies a hypothetical estimand strategy for the intercurrent event of 
pandemic-related early treatment discontinuation, and a treatment policy strategy for the 
intercurrent event of non-pandemic-related early treatment discontinuation.
A COVID-19 related early treatment discontinuation is defined as either of the following 
situations):


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∀
Direct patient COVID-19 infection: Reason for early treatment discontinuation is given 
on the End of Treatment eCRF page as “Adverse Event” and a treatment-emergent AE 
of “COVID-19” is recorded.
∀
Other COVID-19 restriction (site access, drug supply, quarantine, etc) which meant that 
study treatment could not be continued: Reason for early treatment discontinuation is 
given on the End of Treatment eCRF page as “Other” and the supporting comments 
indicate clearly “COVID-19”.
Further, “censored for” COVID-19 related treatment discontinuation is clarified to mean in 
practice that for patients who had a COVID-19 related treatment discontinuation (and only for 
these patients), only the on-treatment data will be used, as defined in Section 6.1.6.
Missing data will be modelled based on what was observed up to the occurrence of these 
intercurrent events using direct likelihood approaches, which is a valid approach under the 
assumption that data are MAR.
An MMRM will be fitted to the percentage change in body weight values at each scheduled 
week (calculated as per Section 6.7) for this purpose. The MMRM will include fixed effects for 
baseline body weight as a continuous linear covariate, and treatment, gender, visit, treatment by 
visit interaction and baseline by visit interaction as factors. The Kenward-Roger approximation 
will be used to estimate the denominator degrees of freedom.
Unstructured covariance will be assumed to model the relationship between pairs of 
measurements taken at different weeks on the same patient. If the model fails to converge, all 
reasonable attempts will first be made to encourage convergence on the specified model with all 
scheduled weeks included. These attempts will include (but may not be limited to) first 
adjusting singularity options, then increasing the maximum number of convergence iterations, 
using the Fisher scoring algorithm for the early iterations, and providing starting values for the 
covariance parameters. Only if none of these options is successful will further options which 
simplify the fitted model be considered. In this case, reduction in the number of time points 
(e.g. by omitting one or more weeks during the dose escalation period) will be considered 
before any attempt is made to simplify covariance structure. If the latter needs to be considered
as a last resort, simpler covariance structures will be evaluated in a nested sequence, where each 
covariance matrix is a special case of all which have been tried before.
Adjusted means will be calculated from the MMRM using the observed margins approach, in 
which the contribution of model factors to the estimate is weighted proportionally to the 
presence of these factors in the data (noting in particular that unequal proportions of males and 
females are expected in this trial by design).
A summary table will be produced of the MMRM results at each time point, including adjusted 
means and their standard errors for each treatment group, and including adjusted mean 
differences from placebo for each BI 456906 dose group and their 95% confidence intervals.
Adjusted means from the MMRM will also be displayed graphically over time to assess the 
onset of effect over time.
Adjusted means at Week 46 for each treatment group and the associated covariance matrix for 
those adjusted means will be extracted from the MMRM for use in the subsequent dose finding 
analysis using multiple comparison and modelling (MCPMod) techniques, described below:


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MCPMod
The MCPMod procedure allows for simultaneous evaluation of different potential dose 
response patterns, whilst protecting the overall probability of Type 1 error (one-sided, 2.5%). 
The null hypothesis is that there is a flat dose response curve across the placebo and BI 456906 
dose groups. The alternative hypothesis is that there is a non-flat dose response for at least one 
of the pre-specified dose response patterns specified in the CTP.
The dose response patterns were selected in the CTP to cover a plausible and diverse range of 
monotone patterns, and are summarised as follows:
∀
Linear
∀
Exponential: 50% of maximum effect achieved at dose 3.6 mg
∀
Emax1: 90% of maximum effect achieved at dose 4.8 mg
∀
Emax2: 70% of maximum effect achieved at dose 4.8 mg
∀
Sigmoid Emax: 50% of maximum effect achieved at dose 2.4 mg, 90% of maximum 
effect achieved at dose 4.8 mg.
The placebo mean effect was assumed in the CTP to be zero (no change in body weight from 
baseline). The maximum mean BI 456906 dose effect was assumed in the CTP to be -10
(percentage reduction from baseline in body weight of 10%); since only monotone shapes were 
considered, this is the mean effect in the highest dose group (BI 456906 4.8 mg) for all dose 
response patterns. It should be noted that the multiple contrast test (described below) does not 
use either of these two assumptions.
The multiple comparison part of the MCPMod procedure will be implemented using optimal 
contrast tests which control the family-wise type I error rate at a one-sided α = 0.025. The 
optimal contrasts of each candidate model are calculated using weights proportional to the 
sample size of each dose group, which are therefore weighted equally in this trial, and these are 
shown in the table below:
Table 7.4.1: 1 Optimal contrast coefficients for MCPMod
Contrast coefficients for treatment group
Model
Placebo
BI 456906 
0.6 mg
BI 456906 
2.4 mg
BI 456906 
3.6 mg
BI 456906 
4.8 mg
Linear
0.568
0.418
-0.030
-0.329
-0.627
Exponential
0.427
0.385
0.150
-0.179
-0.784
Emax 1
0.824
0.125
-0.257
-0.327
-0.365
Emax 2
0.707
0.327
-0.199
-0.364
-0.471
Sigmoid 
Emax
0.521
0.507
-0.072
-0.409
-0.547
These contrasts will be updated using the expected model means for each dose group and the 
estimated variance-covariance matrix of the LSmeans extracted from the primary analysis 
model (MMRM, see above), based on the data. The updated contrast coefficients will be 
reported in the CTR. 


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Once the significance of a dose response signal is established, the dose response profile and the 
target dose will be estimated from the best-fitting dose response model, defined as the model 
with the smallest Akaike Information Criterion (AIC). The target dose for MCPMod purposes is 
defined as the smallest BI 456906 dose which is estimated to achieve a mean reduction in body 
weight of 9% more than the mean reduction obtained with placebo. If no dose within the range 
studied by the trial meets this criterion, then it will be concluded that MCPMod has not 
identified a target dose.
Estimates for each dose group will be calculated and will be based on the final dose-response 
model. In practice, the choice of the target dose to be investigated in Phase 3 will be based upon 
efficacy as well as considering tolerability and safety and other relevant information. 
The results of the MCPMod analysis will be displayed in the following ways:
∀
A summary table will be produced containing:
o
The adjusted means from the MMRM for each dose group at Week 46 and their 
estimated variance
o
The updated contrast coefficients for each dose group and for each of the 
candidate dose response models specified above
o
The test statistics, adjusted p-values and critical values for each candidate dose 
response model.
∀
Another summary table will be produced containing:
o
The adjusted means from the MMRM for each dose group and the adjusted mean 
differences from placebo at Week 46
o
Predicted means for each dose group and mean differences from placebo using 
each of the dose response model types fitted to the data (Linear, Exponential, 
Emax and Sigmoid Emax)
∀
For each model shape, the predicted dose response curve and the 95% CI for the 
predicted shape will be plotted and overlaid with the adjusted means from the MMRM 
and their 95% CIs for each dose group at Week 46.
∀
For each model shape, the placebo-corrected dose response curve will be plotted and 
overlaid with the adjusted mean differences from placebo from the MMRM and their 
95% CIs for each dose group at Week 46.
The predicted BI 456906 dose which achieved a 9% mean reduction compared with placebo 
will be tabulated for the significant model shapes (Linear, Exponential, Emax and Sigmoid 
Emax).


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7.5
SECONDARY ENDPOINT(S)
7.5.1
Key secondary endpoint(s)
This section is not applicable as no key secondary endpoint has been specified in the protocol.
7.5.2
Secondary endpoint(s)
No MCPMod dose finding analyses or subgroup analyses will be performed for secondary 
endpoints.
Responder secondary endpoints
The analysis of responder secondary endpoints will be performed on the FAS, using planned 
maintenance treatment, and including all data censored for COVID-19 related early treatment 
discontinuation.
A frequency table will be presented of those patients achieving percentage change from 
baseline in body weight at each time point (up to and including Week 46) of ≤-5%, ≤-10%, 
≤-15% and ≤ -20%, respectively.
The analysis of responder secondary endpoints (which are defined only at Week 46) will be 
aligned with the estimand strategy specified in Section 7.4.1 for the primary analysis. This will 
be done using a multiple imputation approach on the underlying continuous body weight 
values, as specified below. Missing body weight measurements will be imputed using actual 
values of body weight, not changes from baseline. The same random seed will be used as 
specified for the multiple imputation sensitivity analysis of the primary endpoint in Section 
7.4.2.
As the first step, non-monotone (intermediate) missing values will be imputed using the MCMC 
method. The details of the MCMC imputation step are exactly the same as those given in 
Section 7.4.2.
Next, the remaining monotone missing values at each week will be imputed using the sequential 
regression method on each of the 1000 partially imputed datasets above. The imputations will 
be performed using the MAR assumption, which assumes that a patient with a missing value 
follows a similar trajectory to a similar patient without missing data in the same treatment group
(where “similar patient” means with regard to both baseline covariates and non-missing values). 
The order in which the imputation model is specified is important for this step, and will be as 
follows: treatment, gender, baseline body weight, body weight at each scheduled post-baseline 
week in numeric week order.






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7.7
EXTENT OF EXPOSURE
Exposure to study drug will be presented on the TS using actual maintenance treatment. 
A descriptive summary and frequency table will be produced of the extent of exposure, as 
defined in Section 5.4.3. The total patient-years exposure will also be summarised; the 28-day 
REP after the last dose of study treatment (see Section 6.1.6) will not be included for this 
purpose.
A frequency table will be produced of duration on study (regardless of whether the patient 
remained on-treatment) using the same categories as extent of exposure, to provide a simple 
assessment of the extent to which patients who discontinued treatment early were successful 
in being retained in the study.


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7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS, using actual maintenance treatment, and 
including only on-treatment data (unless otherwise specified in Section 7.8.1), regardless of 
whether early treatment discontinuation was COVID-19 related.
Selected AE summaries will also be presented on the TS using planned maintenance 
treatment. Where this is also planned, it is clearly specified.
7.8.1
Adverse Events
The analyses of adverse events 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.
The analysis of adverse events will be based on the concept of treatment emergent adverse 
events. AEs will be considered “on-treatment” if the AE start date meets the 28-day REP 
criterion (see Section 6.1.6). AEs occurring prior to the start of treatment will be assigned to 
“screening”. AEs occurring more than 28 days after the last dose of study treatment will be 
assigned to “follow-up”. Unless otherwise specified, on-treatment AEs will be pooled across 
dose escalation and maintenance periods. It should also be noted that the protocol encourages 
continued study participation for patients who have discontinued treatment early. It is 
therefore expected that for some patients there will be off-treatment data captured during the 
planned treatment period, which will make the “follow-up” period included in AE summaries 
longer than the 4-week definition of scheduled “follow-up” used in the protocol, perhaps in 
some cases considerably longer than this.
An overall summary of adverse events will be presented for all treated patients. This summary 
will show the number and percent of patients with any AE, any investigator defined drug-
related AE, any AE leading to the discontinuation of study medication, any AESI (as 
determined by the investigator), any serious AE (including reason for serious (death, life-
threatening, disability/permanent damage, required or prolonged hospitalization, congenital 
anomaly/birth defect and other medically important events)), and any drug-related serious AE.
The overall summary will be presented:
∀
Using actual maintenance treatment, with the treatment period pooled across, and split 
into, dose escalation and maintenance periods, respectively.
∀
Using planned maintenance treatment, with the treatment period pooled across dose 
escalation and maintenance periods only.
AEs will be coded using the version of the MedDRA coding dictionary in force at final DBL. 
The frequency of patients with all AEs will be summarised by treatment, primary system 
organ class (SOC) and preferred term (PT). A patient with multiple on-treatment occurrences 
of the same preferred term meeting the criteria for inclusion in the table will be counted only
once in these tabulations. SOCs will be sorted by descending overall frequency; PTs will be
sorted by descending overall frequency (within SOC). The summary of all AEs will be 
presented:
∀
Using actual maintenance treatment, with the treatment period pooled across, and split 
into, dose escalation and maintenance periods, respectively.


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∀
Using planned maintenance treatment, with the treatment period pooled across dose 
escalation and maintenance periods only.
The AE summary by primary SOC and PT will also be repeated for each of the following, 
using actual maintenance treatment with the treatment period pooled across dose escalation 
and maintenance periods, only:
∀
AEs leading to treatment discontinuation
∀
Serious AEs
∀
Investigator-defined drug-related AEs
∀
Drug-related serious AEs.
An additional table will present the frequency of patients with AEs by worst intensity (mild, 
moderate, severe) and by primary SOC and PT. Where no events meet the criteria for
inclusion in one of these tables, the table will be shown as indicating no events of that
intensity have occurred.
The following tables will be produced by baseline body weight subgroup (< 100 / ≥ 100 kg):
∀
Overall AE summary
∀
Summary of all AEs by primary SOC and PT
∀
Summary of AEs leading to treatment discontinuation by primary SOC and PT.
For disclosure of AE data on ClinicalTrials.gov, the frequency of patients with non-serious 
AEs occurring with an incidence of greater than 5% (PT occurring in more than 5% of treated
patients in one or more treatment groups) will be summarised by treatment, primary SOC and 
PT. The frequency of patients with serious AEs and drug related serious AEs 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% (as above)
and the frequency of patients with serious AEs will be summarised. Furthermore, the total 
number of treated patients by country and by age group will be summarised.
An exposure-adjusted summary of all AEs by primary SOC and PT will also be produced. For 
this purpose, the time at risk will be defined for specific AEs as follows:
∀
For patients with no events, the time at risk is the number of days on-treatment
(inclusive), as defined in Section 6.1.6
∀
For patients with one or more event, the time at risk is the number of days from the 
start of treatment to the start of the first on-treatment event (inclusive).
The total time at risk (years) for a treatment group is the sum of the individual patient times at 
risk for that treatment group (days) divided by 365.25. Multiple occurrences of the same event 
for a particular patient will not be counted as separate events in this summary; a patient will 
either be considered to have no events of the type being summarised, or to have one or more 
occurrences of that event. 


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Additional trial-specific information captured in the eCRF for acute gall bladder disease, 
acute pancreatitis and thyroid mass will be listed only and not summarised.
A frequency table will be produced of symptoms of injection site reaction (swelling, 
induration, heat, redness, pain, other) for the subset of patients with the event.
AESIs
Hepatic injury is the only AESI pre-specified in the CTP. No further AESIs have been 
identified through increasing knowledge of the drug safety profile during the conduct of the 
trial.
AESIs as recorded by the investigator on the eCRF page will be summarised as part of the 
overall AE summary, described above.
Investigator-recorded AESIs will also be summarised by treatment, primary SOC and PT.
An additional table will present the frequency of patients with AEs possibly indicating hepatic 
injury as defined by the four MedDRA subSMQ definitions given below: 
∀
Liver related investigations, signs and symptoms (narrow subSMQ)
∀
Cholestasis and jaundice of hepatic origin (narrow subSMQ)
∀
Hepatitis, non-infectious (narrow subSMQ)
∀
Hepatic failure, fibrosis and cirrhosis and other liver damage-related conditions 
(narrow subSMQ).
This table will be summarised by treatment, MedDRA subSMQ, primary system organ class 
and preferred term. Any preferred term which is classified under more than one subSMQ will 
be included under each relevant subSMQ.
Adjudicated Events
The number and percent of patients with each of the following confirmed adjudicated events 
(as defined in the CTP) will be presented:
∀
All-cause death
∀
Cardiovascular event
∀
Cerebrovascular disease
∀
Heart failure requiring hospitalization
∀
Pancreatitis
∀
Neoplasm
∀
Thyroid mass requiring surgery.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards. Central laboratory data will be used for all displays described below, unless 
otherwise specified. Summaries of eGFR and UACR will be included as part of the routine 
summaries of laboratory variables.


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For continuous safety laboratory variables where reference ranges exist, normalised values 
will be derived (i.e. transformation to both a standard unit and to a standard reference range).
Descriptive statistics will be presented over time for absolute values and changes from 
baseline in each of the laboratory variables where normalised values are possible. All
scheduled weeks will be presented as well as last value, minimum value and maximum value 
on-treatment.
For continuous safety laboratory variables where reference ranges exist, a shift table will be 
produced summarising the shifts from baseline to the last value on treatment, and displaying 
categories “Low”, “Normal” and “High” with respect to the relevant reference range. 
Standardised values (i.e. transformation to a standard unit only) will be used for this purpose.
For categorical safety laboratory variables, a shift table will be produced summarising the 
shifts from baseline to the last value on treatment, and displaying each relevant category. For 
any semi-quantitative variables (i.e. those recorded as either “Normal” or with a continuous 
numerical value otherwise), the shift table will display categories “Normal” and “Abnormal” 
only, without further categorisation of the continuous values into different degrees of 
abnormality.
Potentially clinically significant abnormalities will be identified using BI standard rules. A 
listing containing these rules (including for each variable whether a low range applies, or a 
high range applies, or both) will be included in the CTR. A frequency table will be used to 
summarise the number and percentage of patients with potentially clinically significant 
abnormalities, for each variable where a BI standard rule exists. Patients with an abnormal 
value at baseline will be presented separately on this table. 
A separate listing will present potentially clinically significant abnormal lab values; for each 
functional lab group all patient’s laboratory values will be listed, if there exists at least one
value with clinically significant abnormality within the group.
The following additional investigations will be made for elevated liver enzymes:
A frequency table will be produced of the following categories. A patient will be included in 
each relevant category, defined using the maximum post-baseline ALT and AST values 
observed on-treatment (Section 6.1.6), regardless of the baseline AST and ALT values:
∀
ALT or AST ≥ 3 x ULN
∀
ALT or AST ≥ 5 x ULN
∀
ALT or AST ≥ 8 x ULN
∀
ALT or AST ≥ 10 x ULN
∀
ALT or AST ≥ 20 x ULN
∀
ALT or AST ≥ 3 x ULN with total bilirubin ≥ 2 x ULN.
In the above categories, each occurrence within a patient of a post-baseline elevation ALT or 
AST ≥ 3 x ULN will be used as a trigger for the determination of the elevation of total 
elevation of bilirubin ≥ 2 x ULN. The proposed time interval for the follow-up of total 
bilirubin is 30 days after the occurrence of the post-baseline ALT or AST elevation.


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7.8.3
Vital signs
Descriptive statistics will be presented over time for absolute values and changes from 
baseline in each of the vital signs variables.
The time points to be presented will follow the expected data structure for each vital signs 
variable as follows:
∀
For systolic and diastolic BP, three measurements are planned to be captured at each 
of pre-dose (all weeks), 15 minutes post-dose (selected weeks only) and 60 minutes 
post-dose (all weeks). The descriptive summary will therefore display all relevant time 
points within week. Multiple measurements at each time point will be handled using 
the rules in Section 6.7.
∀
For pulse rate, one measurement is planned to be captured at each of pre-dose (all 
weeks), 15 minutes post-dose (selected weeks only) and 60 minutes post-dose (all 
weeks). The descriptive summary will therefore also display all relevant time points 
within week.
∀
For respiratory rate and temperature, a single measurement is expected to be captured 
at each week. The descriptive summary will therefore not display a time point within 
week.
Body weight and waist circumference over time are covered entirely within the relevant 
efficacy sections, and are not considered further as part of safety.
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 ECG recordings will be centrally evaluated and rated as normal, abnormal, or not 
evaluable. 
All derivations relating to 12-lead ECG variables are given in Section 5.4.1.
Occurrences of values above thresholds will be flagged in the listings. For QTcB and RR, 
only listings will be provided.
Quantitative variables
Descriptive statistics will be presented over time for absolute values and absolute changes 
from baseline in the following quantitative ECG variables: QTcF, HR, QT, QRS, PR.
Percentage changes used to derive the categorical variables (see below) will be listed only.
Categorical variables
Frequency tables will be provided for the categorical variables described below, which are 
determined from the specified quantitative ECG variables:


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∀
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.
∀
New onset (not present any time at baseline) of uncorrected QT interval > 500 msec at any 
time on treatment
∀
Maximum change from baseline of QTcF ≤ 30 msec, > 30 to ≤ 60 msec, or > 60 msec on 
treatment.
∀
Maximum change from baseline of QT ≤ 60 msec, or > 60 msec on treatment.
For assignment of a particular patient to one of the above categories, all available time points 
on-treatment will be considered.
The occurrence of any of the following will be considered as “notable findings” and 
summarised using frequency tables:
∀
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
∀
Percentage change from baseline of HR ≥ 25%, when corresponding on-treatment value of 
HR is > 100 beats/min, or percentage change from baseline of HR # - 25%, when 
corresponding on-treatment value of HR is < 50 beats/min, at any time on-treatment
∀
Percentage change from baseline of PR ≥ 25%, when corresponding on-treatment value of 
PR interval is > 200 msec, at any time on treatment
∀
Percentage change from baseline of QRS ≥ 10%, when corresponding on-treatment value 
of QRS duration is > 110 msec, at any time on treatment.
Frequency tables will also include morphological findings (determined and categorized based 
on SDTM terminology) 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 patients 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.
A shift table will be produced for QTcF, summarising the shifts from baseline to the 
maximum value on treatment, and displaying categories “≤ 450 msec”, “> 450 to 480 msec”, 
“> 480 to 500 msec and “> 500 msec”.
A scatter plot of QTcF at baseline and the maximum change from baseline (based on all on-
treatment values as defined in Section 6.1.6, and the maximum evaluated regardless of 
whether these were selected based on visit windows described in Section 6.7) will be 
produced. The plot will include diagonal reference lines for absolute QTcF equal to 450 msec, 
480 msec and 500 msec, as well as horizontal reference lines for QTcF maximum changes 
from baseline equal to 30 msec and 60 msec.
Appropriateness of heart rate correction methods of QT interval




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this purpose, “SARS-CoV-2 infection” is defined by the broad BIcMQ of SARS-CoV-2 
infections with search ID 32010051. The broad BIcMQ differs from the narrow BIcMQ only 
by the inclusion of the PT for “Suspected COVID-19”.
AEs related to SARS-CoV-2 infection will also be summarised and listed. For this purpose, 
“related to SARS-CoV-2 infection” is defined by the MedDRA broad SMQ for COVID-19.


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8.
TIMEPOINT OF RELEASE OF TREATMENT 
INFORMATION
The treatment information will be released to unblind the trial database after the last patient 
has completed their End-of-Study/Follow-up visit and all data has been entered and cleaned as 
defined in the “Data Ready to be Unblinded and/or Final Trial Closure Notification” (RUN) 
form.


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9.
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.
BI-KMED-BDS-MAN-0011: “Link to Statistical Position Papers Homepage”, current 
version; KMed
3.
BI-KMED-TMCP-MAN-0014: “Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies”, current version; KMed
4.
BI-KMED-TMCP-MAN-0010 “Description of Analytical Transfer Files and PK/PD 
Data Files”, current version; KMed
5.
BI-KMED-TMCP-MAN-0012 “Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics”, current version; KMed
6.
001-MCS-40-413: “Identify and Manage Important Protocol Deviations (iPD)”, current 
version; KMed
7.
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]
8.
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]
9.
Firth D. Bias reduction of maximum likelihood estimates. Biometrika 80, 27–38
(1993). [R20-2291]
10. 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]
11. Rubin D. B. Multiple imputation for nonresponse in surveys (2004). John Wiley & 
Sons. [R12-2378]


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11.
HISTORY TABLE
Table 11: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
1.0
08NOV2022
None
This is the final TSAP