Clinical trial NCT04771273
Conditions: Non-alcoholic Steatohepatitis (NASH)
Sponsor: Boehringer Ingelheim
Start date: 2021-04-27; Completion date: 2023-12-21
Enrollment: 295 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is open for men and women with a liver disease called nonalcoholic steatohepatitis (NASH) and liver fibrosis. The purpose of the study is to find out whether a medicine called BI 456906 helps patients with NASH and liver fibrosis. The study tests 3 different doses of BI 456906 to find the dose that helps best. Participants are put into 4 groups randomly, which means by chance. There are 3 groups that each receive a different dose of BI 456906 and there is 1 group that receives placebo. BI 456906 and placebo are given as an injection under the skin once per week. The placebo injection looks like the BI 456906 injection but does not contain any medicine.

Participants are in the study for a little over 1 year (60 weeks). During this time, they visit the study site several times and have some video calls in addition. At the visits, the study doctors take different measurements. To see whether the treatment works, the doctors take a very small sample of liver tissue (biopsy) from each participant at the start and at the end of the study. They also examine the liver by ultrasound and MRI. 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
Interventions: intervention 1: Survodutide intervention 2: Placebo
Intervention descriptions: intervention 1: Survodutide intervention 2: Placebo

Protocol documents:
Prot_000.pdf: 


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
14 September 2020
Revision date
27 July 2023
BI trial number
1404-0043
Title of trial
Multicenter, double-blind, parallel-group, randomised, 48 weeks, 
dose-ranging, placebo-controlled phase II trial to evaluate efficacy, 
safety and tolerability of multiple subcutaneous (s.c.) doses of BI 
456906 in patients with non-alcoholic steatohepatitis (NASH) and 
fibrosis
Coordinating 
Investigator
Phone:
Email:
Trial site(s)
Multi-center trial conducted globally
Clinical phase
II
Trial rationale
The prevalence of non-alcoholic steatohepatitis (NASH) is increasing 
worldwide. Currently, the cornerstone treatment is lifestyle 
modifications focusing on diet and exercise resulting in weight loss, 
however, weight loss is difficult to achieve and maintain. Thus, novel 
therapeutic approaches are highly demanded. 
This trial will serve as a proof of clinical concept, as it will 
investigate potential improvement in liver histology in patients with 
NASH and fibrosis following treatment with BI 456906. Furthermore, 
it will help to determine the most suitable dose that will be used in 
phase III trial(s). Liver biopsy and imaging will be used to confirm 
the diagnosis of NASH at baseline and to assess the treatment 
response. The 48-week treatment duration is expected to be sufficient 
to show improvement in NASH with no worsening of fibrosis.
Trial objective(s)
The main trial objectives are to demonstrate a non-flat dose response 
curve, to evaluate the size of the treatment effect (using the absolute 
difference in proportions of patients with histological improvement 
between BI 456906 and placebo at Week 48), and to characterize the 
dose-response relationship.
Trial endpoints
The primary endpoint is the improvement (yes/ no) from baseline in 
liver histological findings based on liver biopsy after 48 weeks of 
treatment in patients with NASH (NAS ≥4, fibrosis F1-F3).
Improvement in histological findings is defined as a composite of: 
Improvement in NASH:
Decrease of at least two points in NAS, with at least one point


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decrease in NAS sub-score for lobular inflammation or ballooning 
and
No worsening of fibrosis, defined as an absence of any increase in the 
fibrosis stage 
Secondary efficacy endpoints include:
∀
Improvement of liver fat content (yes/ no) defined as at least 30% 
relative reduction in liver fat content after 48 weeks of treatment
compared to baseline assessed by magnetic resonance imaging 
proton density fat fraction measurement (MRI-PDFF) 
∀
Absolute and relative change of liver fat content from baseline 
after 48 weeks of treatment assessed by MRI-PDFF
∀
Improvement of fibrosis (yes/ no) defined as at least one stage 
decrease in fibrosis stage after 48 weeks of treatment assessed by 
liver biopsy
∀
Absolute change from baseline in NAS after 48 weeks of 
treatment assessed by liver biopsy
Trial design
Multi-center, randomised, dose-ranging, double
blind, placebo-
controlled, parallel-group trial
Total number of patients
randomised
240 patients
Number of patients on 
each treatment
60 patients on BI 456906 2.4 mg (Group 1)
60 patients on BI 456906 4.8 mg (Group 2)
60 patients on BI 456906 6.0 mg (Group 3)
60 patients on placebo (Group 4)
Diagnosis
Non-alcoholic steatohepatitis (NASH) and fibrosis
Main in- and exclusion 
criteria
Inclusion criteria:
∀
Male or female patients ≥ 18 years (or who are of legal age in 
countries where that is greater than 18 years) and ≤ 80 years of 
age at time of consent.
∀
Diagnosis of NASH (NAS ≥ 4, with at least 1 point in 
inflammation and ballooning each) and fibrosis stage F1–F3 
proven by a biopsy conducted during the screening period or by a 
historical biopsy conducted within the last 6 months prior to 
randomization and stable body weight defined as less than 5% 
self-reported change in body weight between the historical biopsy 
and randomization if a historical biopsy is used.
∀
Liver fat fraction ≥ 8% measured by MRI-PDFF and liver 
stiffness > 6.0 kPa measured by FibroScan® at Visit 1 (if biopsy is 
scheduled during the screening period MRI-PDFF and FibroScan®
assessments have to be performed prior to the biopsy). However, 
the diagnosis of NASH and fibrosis at liver biopsy (including 
historical biopsy) is the primary assessment to establish patient 
eligibility.
∀
Patients willing and able to undergo liver biopsies per protocol as 
judged by the Investigator.
∀
BMI ≥ 25 kg/m2 and a body weight ≥ 70 kg at Visit 1.


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Exclusion criteria:
∀
Current or history of significant alcohol consumption (defined as 
intake of > 210 g/ week in males and > 140 g/ week in females on 
average over a consecutive period of more than 3 months) or 
inability to reliably quantify alcohol consumption based on 
Investigator judgement within the last 5 years.
∀
Intake of medications historically associated with liver injury, 
hepatic steatosis, or steatohepatitis within 12 weeks prior to Visit 
1. Intake of restricted medications or any medications considered 
likely to interfere with the safe conduct of the trial.
∀
History of other forms of chronic liver disease (e.g., viral 
hepatitis, autoimmune liver disease, primary biliary sclerosis, 
primary 
sclerosing 
cholangitis, 
Wilson`s 
disease, 
hemochromatosis, 
A1At 
deficiency, 
history 
of 
liver 
transplantation). 
∀
Suspicion, diagnosis, or history of hepatocellular carcinoma 
(HCC), or 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 or in situ 
carcinoma of uterine cervix.
∀
Diagnosis of a serious or unstable disease including hepatic (other 
than NASH), renal, gastroenterologic, respiratory, cardiovascular 
(including ischemic heart disease), endocrinologic, neurologic, 
psychiatric, immunologic, or hematologic disease and other 
conditions that, in the clinical judgment of the Investigator, are 
likely to interfere with the analyses of safety and efficacy in this 
trial. Patients with a history of organ transplantation except for 
corneal transplantation
and patients with an expected life 
expectancy of less than 2 years are also excluded.
Test product(s)
Solution for injection BI 456906: 0.6 mg/mL, 1.8 mg/mL, 3.6 
mg/mL, 4.8 mg/mL and 6.0 mg/mL
Pre-filled syringes, 0.5 mL fill volume
dose
Group 1: Starting dose of 0.3 mg followed by a dose escalation up to 
the maintenance dose of 2.4 mg, two pre-filled syringes once weekly
Group 2: Starting dose of 0.3 mg followed by a dose escalation up to 
the maintenance dose of 4.8 mg, two pre-filled syringes once weekly
Group 3: Starting dose of 0.3 mg followed by a dose escalation up to 
the maintenance dose of 6.0 mg, two pre-filled syringes once weekly
mode of 
administration
Subcutaneous, s.c.
Comparator product(s)
Group 4: Placebo
dose
Matching
mode of
administration
Subcutaneous, s.c.
Duration of treatment
48 weeks of treatment consisting of up to 24 weeks dose escalation
period and at least 24 weeks maintenance period






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FLOW CHART
Trial Period
Screening
Treatment – Dose escalation
Visit
1
1a1
22
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Week (w)4
Up to -10w6
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Day (d)
1
8
15
22
29
36
43
50
57
64
71
78
85
92
99
106
Visit window (in days)
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
Visit Type5
S
S
S
S
S
S
S
T
S
T
S
T
S
T
S
T
T
T
Informed consent7
X
Demographics
X
Medical history
X
Physical examination8
X
Vital signs9
X
X
X
X
X
X
X
X
X
X
X
Height
X
Weight10
X
X
X
Waist and hip circumference11
X
X
X
Laboratory tests (safety)12, 13, 14
X
X
X
X
X
X
X
X
12-lead ECG15
X
X
X
X
X
X
X
X
In-/exclusion criteria review
X
X
X
Randomization
X
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
All AEs/SAEs/AESIs16
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy testing17
Xs
Xu
Xu
Xu
Xu
IRT call18
X
X
X
X
X
X
X
X
X
X
(X)
Dispense trial medication18, 19
X
X
X
X
X
X
X
X
X
(X)




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FLOW CHART (cont.)
Trial Period
Treatment – Dose escalation
Treatment - Maintenance
Follow-up
Visit
18
19
20
21
22
23
24
25
26
27
28
29
30
31
323
(EOT/ED)
33
Week (w)4
16
17
18
19
20
21
22
23
24
28
32
36
40
44
48
EOT/ED+4
Day (d)
113
120
127
134
141
148
155
162
169
197
225
253
281
309
337
EOT/ED+28
Visit window (in days)
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
+5
Visit Type5
S
T
T
T
S
T
T
T
S
S
S
S
S
S
S
S
Informed consent7
Demographics
Medical history
Physical examination8
Vital signs9
X
X
X
X
X
X
X
X
X
X
Height
Weight10
X
X
X
X
Waist and hip circumference11
X
X
X
X
Laboratory tests (safety)12, 13, 14
X
X
X
X
X
X
X
X
X
X
12-lead ECG15
X
X
X
X
X
X
X
X
X
In-/exclusion criteria review
Randomization
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
All AEs/SAEs/AESIs16
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy testing17
Xu
Xu
Xu
Xu
Xu
Xu
Xu
Xu
Xu
Xu
IRT call18
X
(X)
X
(X)
X
X
X
X
X
X
X
Dispense trial medication18, 19
X
(X)
X
(X)
X
X
X
X
X
X




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Footnotes for Flow Chart:
1. Visit 1a is not required if a historical biopsy with sufficient and analysable material was collected within the last 6 months prior to 
randomisation (refer to Section 3.3.1 and 5.1.1).
2. Day of randomisation and the first administration of trial medication.
3. In case of early discontinuation (ED), Visit 32 should be completed instead of the planned treatment period visit, as soon as possible after 
trial medication is stopped. Liver biopsy should be performed at the ED visit providing the patient has been on treatment with trial 
medication for at least 40 weeks. MR imaging does not need to be performed at the ED visit if the patient discontinues before Visit 22 or if 
another MR imaging was performed within 12 weeks before the ED. 
 
 Follow-up Visit 33 should be performed 4 weeks/28 days after the ED visit.
4. Number of weeks since randomization.
5. Trial visits will be conducted in two ways: 1/ at site (indicated by “S” in the Flow Chart) and 2/ remotely via telemedicine from patient’s 
home (indicated by “T” in the Flow Chart). Method of visit conduct (on-site or remote) can be modified. Modifications from an on-site to a 
remote visit require Sponsor approval.
6. Visit 1 can be conducted within less than 10 weeks of randomization. Before randomization, the Investigator should ensure that all safety 
laboratory results, ECG reading, imaging and liver biopsy results are available to ensure that the patient meets all inclusion criteria and does 
not meet any exclusion criteria. In the event of logistical issues with the reporting of results by the central vendor(s) a patient who meets all 
inclusion criteria and does not meet any exclusion criteria should be considered for participation in the clinical trial even if he/ she exceeds
the screening period of 10 weeks. Extension of the screening period requires a Sponsor approval. If more than 12 weeks elapse from Visit 1 
safety laboratory tests, ECG and vital signs should be repeated and results should be available before randomization.
7. Patient must be informed and written informed consent must be obtained prior to starting any trial procedure. Fasting is considered part of a 
trial procedure. For the historical biopsy, if applicable, a written non-trial specific informed consent has been obtained (per local standard). 
8. Physical examination after screening is required only if patient reports symptoms. 


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9. Vital signs measurement should be performed prior to blood sample collection. At dosing visits a second vital signs measurement should be 
performed approx. 10 minutes post-dose. Vital signs include DBP/ SBP measurement and pulse rate. Vital signs measurement at Visit 1a is 
optional but recommended.
10. Body mass index will be calculated automatically. For weight measurement, follow guidelines in Section 5.1.4.
11. For waist and hip circumference measurement, follow guidelines in Section 5.1.5.
12. Safety laboratory tests include haematology, clinical chemistry, coagulation, lipids and urinalysis. For details refer to Table 5.2.3:1. 
In the event of systemic hypersensitivity ADAs, NAbs, level of BI 456906, IgE, histamine, serum tryptase, and complement components will 
be analyzed as detailed in the laboratory manual. 
13. All blood samples should be collected before the administration of trial medication. Fasting condition is not required for routine trial blood 
sample collection.
14. RT-PCR test on SARS-CoV-2 will be performed at Visit 1.
15. ECG should be recorded in triplicate at Visit 1. ECG should be recorded before blood samples are taken. ECG recording may be repeated by 
the Investigator for medical or quality reasons. For ECG measurement, follow guidelines in Section 5.2.4.
16. After the individual patient’s end of the trial 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 SAE 
form.
17. For female patients of childbearing potential only. Xs = serum testing, Xu = urine testing. Serum pregnancy testing will be performed at Visit 
1 and thereafter as a reflex test when urine testing is positive. Pregnancy testing must be completed prior to trial medication intake. Refer to 
Section 6.1.
18. At Visit 16, 20 and 24 the IRT call will only be made if a patient visits the site due to tolerability issues and requires a new assignment of 
trial medication.


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19. During site visits IRT will assign trial medication kits for use until the next scheduled site visit. For example, kits assigned at Visit 14 will 
include trial medication to be administered at the site for Visit 14 and trial medication needed for the patient for use at home at Visit 15, 16 
and 17. However, if a patient experiences tolerability issues with the dose administered at Visit 14 and 15, new trial medication kits will be 
dispensed to him/ her at Visit 16.
20. Patient and/ or designated person should be trained on how to administer the trial medication. If the patient is not willing to self-administer 
the injections, he/ she should be given the option to visit the site and/or to have the medication administered by a qualified site personnel or 
designated person. During site visits the trial medication should be preferably administered by a qualified site personnel. 
21. Medication compliance should be monitored throughout the treatment period to ensure the required compliance criteria are met (refer to 
Section 4.3).
22. Patients will be using a smartphone for trial-related application (Science 37 platform which may include patient diary, 
 
patient-facing materials). Training will be provided to patients on how to use the application.
23. C-SSRS, Columbia-Suicide Severity Rating Scale questionnaires will be administered at Visit 1 using the “baseline/screening” version. The 
“since last visit” version will be used at the following visits. Paper forms will be used for the assessment of C-SSRS (refer to Section 
5.2.5.1).
25. T2DM patients taking antidiabetic medication will be provided with a self-monitoring blood glucose (SMBG) device for use at home during 
the treatment period.  Patients may also use their own device for self-monitoring of blood glucose.




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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................7
TABLE OF CONTENTS ......................................................................................................15
ABBREVIATIONS................................................................................................................19
1.
INTRODUCTION...............................................................................................24
1.1
MEDICAL BACKGROUND.............................................................................24
1.2
DRUG PROFILE................................................................................................24
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................27
1.4
BENEFIT - RISK ASSESSMENT.....................................................................28
1.4.1
Benefits.................................................................................................................28
1.4.2
Risks .....................................................................................................................28
1.4.3
Discussion.............................................................................................................31
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................32
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........32
2.1.1
Main objectives....................................................................................................32
2.1.2
Primary endpoint(s)............................................................................................32
2.1.3
Secondary endpoint(s) ........................................................................................32
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................35
3.1
OVERALL TRIAL DESIGN.............................................................................35
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................36
3.3
SELECTION OF TRIAL POPULATION .......................................................37
3.3.1
Main diagnosis for trial entry ............................................................................37
3.3.2
Inclusion criteria .................................................................................................38
3.3.3
Exclusion criteria ................................................................................................38
3.3.4
Withdrawal of patients from treatment or assessments..................................40
3.3.4.1
Discontinuation of trial treatment .........................................................................41
3.3.4.2
Withdrawal of consent to trial participation .........................................................43
3.3.4.3
Discontinuation of the trial by the Sponsor ..........................................................43
4.
TREATMENTS...................................................................................................44
4.1
INVESTIGATIONAL TREATMENTS ...........................................................44
4.1.1
Identity of the Investigational Medicinal Products..........................................44
4.1.2
Selection of doses in the trial and dose modifications......................................44
4.1.3
Method of assigning patients to treatment groups...........................................46
4.1.4
Drug assignment and administration of doses for each patient......................47


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4.1.5
Blinding and procedures for unblinding...........................................................49
4.1.5.1
Blinding.................................................................................................................49
4.1.5.2
Unblinding and breaking the code ........................................................................49
4.1.6
Packaging, labelling, and re-supply...................................................................50
4.1.7
Storage conditions...............................................................................................50
4.1.8
Drug accountability.............................................................................................50
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................51
4.2.1
Other treatments and emergency procedures..................................................51
4.2.2
Restrictions ..........................................................................................................52
4.2.2.1
Restrictions regarding concomitant treatment ......................................................52
4.2.2.2
Restrictions on diet and lifestyle...........................................................................53
4.2.2.3
Contraception requirements..................................................................................53
4.3
TREATMENT COMPLIANCE........................................................................54
5.
ASSESSMENTS..................................................................................................55
5.1
ASSESSMENT OF EFFICACY........................................................................55
5.1.1
Liver biopsy .........................................................................................................55
5.1.2
Fibroscan Assessment of Liver Stiffness 
..............................56
5.1.3
Magnetic resonance imaging..............................................................................56
5.1.4
Weight ..................................................................................................................56
5.1.5
Waist and hip circumference .............................................................................57
5.2
ASSESSMENT OF SAFETY.............................................................................57
5.2.1
Physical examination ..........................................................................................57
5.2.2
Vital signs.............................................................................................................57
5.2.3
Safety laboratory parameters ............................................................................57
5.2.4
Electrocardiogram ..............................................................................................60
5.2.5
Other safety parameters.....................................................................................61
5.2.5.1
Suicidal risk assessment and reporting .................................................................61
5.2.5.2
Self-monitoring of blood glucose .........................................................................62
5.2.6
Assessment of adverse events.............................................................................62
5.2.6.1
Definitions of AEs ................................................................................................62
5.2.6.1.1
Adverse event........................................................................................................62
5.2.6.1.2
Serious adverse event............................................................................................63
5.2.6.1.3
AEs considered “Always Serious”........................................................................63
5.2.6.1.4
Adverse events of special interest.........................................................................64
5.2.6.1.5
Adverse events requiring adjudication..................................................................64
5.2.6.1.6
Intensity (severity) of AEs....................................................................................65
5.2.6.1.7
Causal relationship of AEs....................................................................................65
5.2.6.2
Adverse event collection and reporting ................................................................65
5.2.6.2.1
AE Collection........................................................................................................65
5.2.6.2.2
AE reporting to the Sponsor and timelines...........................................................66
5.2.6.2.3
Pregnancy..............................................................................................................66




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8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................92
8.6
TRIAL MILESTONES.......................................................................................93
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................93
9.
REFERENCES....................................................................................................95
9.1
PUBLISHED REFERENCES............................................................................95
9.2
UNPUBLISHED REFERENCES......................................................................96
10.
APPENDICES.....................................................................................................98
10.1
REMOVAL OF INDIVIDUAL PATIENTS IN CASE OF INCREASED 
LIVER ENZYMES .............................................................................................98
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .......................................100
11.1
GLOBAL AMENDMENT 1 ............................................................................100
11.2
GLOBAL AMENDMENT 2 ............................................................................104
11.3
GLOBAL AMENDMENT 3 ............................................................................113
11.4
GLOBAL AMENDMENT 4 ............................................................................118
11.5
GLOBAL AMENDMENT 5 ............................................................................119


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ABBREVIATIONS
A1At
Alpha-1 Antitrypsin
ADA
Anti-Drug Antibody
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALCOA
Attributable, Legible, Contemporaneous, Original, Accurate 
ALT
Alanine Aminotransferase
AMLN
Amylin Liver NASH
AP
Alkaline Phosphatase
 
AST
Aspartate Aminotransferase
AUC
Area under the Curve
AV
Atrioventricular
BI
Boehringer Ingelheim
BMI
Body Mass Index
Cmax
Maximum measured concentration of the analyte in plasma
Cmin
Minimum measured concentration of the analyte in plasma
CA
Competent Authority
CCS
Canadian Cardiovascular Society
CEC
Clinical Event Committee
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
COVID-19
Coronavirus Disease 19
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as 
eCRF”)
CRN
Clinical Research Network
CRO
Contract Research Organisation
C-SSRS
Columbia Suicide Severity Rating Scale
CTCAE
Common Terminology Criteria for Adverse Events
CT Leader
Clinical Trial Leader


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CT Manager
Clinical Trial Manager
CTR
Clinical Trial Report
DILI
Drug Induced Liver Injury
DIO
Diet Induced Obesity
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic Acid
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eDC
Electronic Data Capture
eGFR
Estimated Glomerular Filtration Rate
ED
Early Discontinuation
EDTA
Ethylenediaminetetraacetic Acid
EOT
End of Treatment
EudraCT
European Clinical Trials Database
F1, F2…
Fibrosis stage 1, 2…
FAS
Full Analysis Set
 
GCP
Good Clinical Practice
GCGR
Glucagon Receptor
γ-GT 
Gamma-Glutamyl Transferase 
GI
Gastrointestinal
GLP-1R
Glucagon-like-peptide 1 Receptor
GMP
Good Manufacturing Practice
HA
Health Authority
HbA1c
Glycosylated Haemoglobin
HCC
Hepatocellular Carcinoma
HCV
Hepatitis C Virus


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HDL
High-Density Lipoprotein
HIV
Human Immunodeficiency Virus
HR
Heart Rate
IB
Investigator’s Brochure
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IFU
Instructions for Use
IgE
Immunoglobulin E
IPD
Important Protocol Deviation
IQRMP
Integrated Quality and Risk Management Plan
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
iSTAT
Independent Statistician
IUD
Intrauterine Device
IUS
Intrauterine Hormone-Releasing System
IV
Intravenous
LDL
Low-Density Lipoprotein
LPLT
Last Patient Last Treatment
MAR
Missing at Random
MCPMod
Multiple Comparison Procedures and Modelling Techniques 
MedDRA
Medical Dictionary for Drug Regulatory Activities
MMRM
Mixed Model For Repeated Measurements
MRD
Multiple Rising Dose
MRI
Magnetic Resonance Imaging
NAb
Neutralizing Antibody
NAFLD
Non-alcoholic Fatty Liver Disease
NAS
NAFLD Activity Score
NASH
Non-Alcoholic Steatohepatitis
NOAEL
No Observed Adverse Effect Limit
NYHA
New York Heart Association
OPU
Operative Unit
PD
Pharmacodynamics


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PDFF
Proton Density Fat Fraction
PFS
Pre-filled syringe
PG
Pharmacogenomics
 
 
PK
Pharmacokinetics
 
 
PPS
Per Protocol Set
 
q.d.
Quaque die (once a day)
q2d
Every other day
QT
Time between start of the Q-wave and end of the T-wave in 
electrocardiogram
QTcF
QT interval corrected for heart rate using the method of Fridericia
RA
Regulatory Authority
REP
Residual Effect Period
RPM
Report Planning Meeting
RT-PCR 
Reverse Transcription Polymerase Chain Reaction
s.c.
Subcutaneous
SAE
Serious Adverse Event
SARS-CoV-2
Severe Acute Respiratory Syndrome Coronavirus 2
SCD
Skin to Liver Capsule Distance
SGLT-2
Sodium-Glucose Co-Transporter 2
SMBG
Self-Monitoring of Blood Glucose
SOC
Standard of Care
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reactions
T2DM
Type 2 Diabetes Mellitus
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
ULN
Upper Level of Normal
VCTE
Vibration Controlled Transient Elastography


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VLDL
Very-Low-Density Lipoprotein
WHO
World Health Organisation
WOCBP
Woman of childbearing potential


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1.
INTRODUCTION
BI 456906 is being developed in two indications, namely NASH and obesity. The target 
indications read as follows:
1) Non-alcoholic steatohepatitis (NASH) in NASH patients (NAFLD activity score 
(NAS) ≥4, with at least one point in ballooning and inflammation each) with 
advanced liver fibrosis (fibrosis stages 2 and 3). A relevant subpopulation has to be 
defined.
2) Weight management in patients with obesity or overweight with co-morbidities, plus 
cardiovascular risk reduction in patients with increased cardiovascular risk.
These diseases are highly prevalent and are increasing at an alarming rate. Non-alcoholic 
fatty liver disease (NAFLD), the hepatic component of the metabolic syndrome, is the most 
common chronic liver disease. Currently, no approved pharmacotherapy for NASH, the 
progressive form of NAFLD, is available, relying on treatment of the comorbidities of the 
metabolic syndrome. Obesity is associated with a variety of medical conditions, including all 
components of the metabolic syndrome, cardiovascular, pulmonary, gastrointestinal, 
endocrine, joint and psychosocial disorders. Currently, the available weight loss medications 
lack sufficient efficacy, safety, tolerability, and convenience to reduce body weight and 
improve its associated co-morbidities/ conditions.
1.1
MEDICAL BACKGROUND
It is estimated that about 1/3 of the population (in US, EU5, Japan and urban China) have 
NAFLD, and about 17 Mio. (2-5%) have NASH with advanced fibrosis (F2 and F3). It is also 
estimated that this number will double (approx. 36 Mio) within the next 15 years [R20-1255].
Approximately 1-2% of patients with NASH and advanced fibrosis (F2 and F3) are at risk to 
develop cirrhosis, with its complications including decompensation, need for transplantation, 
HCC and liver–related death.
In addition to these late complications, patients with NASH have little to no liver-related 
symptoms, however, more and more data suggest that the quality of life in patients with 
NASH is reduced. These new data have led to a shift in the paradigm from characterizing 
patients with NASH as asymptomatic to exhibiting non-specific symptoms. Most common 
symptoms are fatigue, abdominal discomfort, and pain. The reduction in quality of life 
experienced by NASH patients is also probably associated with the comorbidities such as 
obesity, type 2 diabetes and others. In addition, some studies suggest that NASH itself is a 
risk factor for cardiovascular complications.
1.2
DRUG PROFILE
Mode of action
BI 456906 is a dual agonist of Glucagon-like-Peptide 1 (GLP-1) and Glucagon (GCG) 
receptors. GLP-1R agonists lower body weight by the inhibition of food intake and also by 
delaying gastric emptying and intestinal transit. GCGR agonist is expected to reduce body 


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weight by increasing energy expenditure and might directly increase the fatty acid oxidation 
in the liver, potentially reducing the lipotoxicity. 
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 more efficacy
compared to GLP-1R activation alone. Simultaneous dual activation of GLP-1R and GCGR 
by BI 456906 is anticipated to improve glycemic control, body weight loss as well as NASH
and fibrosis.  
Key pharmacokinetic characteristics
Pharmacokinetics of BI 456906 were investigated after single subcutaneous doses of 0.3, 0.5 
and 1.2 mg. Tmax was reached between 9 and 60 hours. Cmax was 7, 13 and 34 nM, 
respectively. T1/2 ranged from 10 to 15h. Dose proportionality was demonstrated for Cmax, 
AUC0-168, and AUC0-∞. Further details, also on multiple dosing, can be found in the 
Investigator’s Brochure (IB).
Drug interactions
GLP-1R agonism reduces gastric emptying. This was assessed by measuring the effect of BI 
456906 on the absorption of paracetamol. Paracetamol Cmax, AUC0-10, and AUC0-∞were 
slightly lower after a single dose of 0.3 mg BI 456906, and strongly decreased after a single 
dose of 1.2 mg BI 456906 compared with administration of paracetamol alone.
Residual Effect Period
The Residual Effect Period (REP) of BI 456906 is 28 days. This is the period after the last 
dose with measurable drug levels and/or pharmacodynamic effects still likely to be present.
Data from non-clinical studies
Liver steatosis improvement was more pronounced by BI 456906 than with liraglutide. In a 
4-week study in Diet Induced Obesity (DIO) mice, BI 456906 at a subcutaneous dose of 10 
nmol/kg q.d. (Cmin 109 nM) reduced liver triglycerides by 31% (from 203 mg/g in vehicle-
treated animals to 140 mg/g) and Alanine Aminotransferase (ALT) in plasma by 62% (from 
403 U/l in vehicle-treated animals to 154 U/l). These effects were superior to those of 
liraglutide (176 mg/g; 215 U/l) at supra-therapeutic exposure (10 nmol/kg bid; Cmin 39 nM). 
Overall, the effects on plasma lipids of BI 456906 at predicted therapeutic exposure were 
comparable to liraglutide at supra-therapeutic exposure (n00254747-01). In C57Bl/6J mice 
on Amylin Liver NASH diet ([AMLN], a high fat, high fructose, high cholesterol diet) as a 
DIO NASH model, BI 456906 at 20, 30 and 40 nmol/kg q.d. was compared with liraglutide at 
100 nmol/kg q.d. and dulaglutide at 2 nmol/kg q2d. After 8 weeks of treatment, body weight 
vs. vehicle-treated animals on AMLN diet was reduced by 10% and 13% with dulaglutide 
and liraglutide, and dose-dependently by 15-21% with BI 456906. Cmin exposure was 160 
nM, 234 nM, 321 nM and 322 nM, respectively, for low, medium and high dose BI 456906 
and liraglutide. ALT and Aspartate Aminotransferase (AST) in plasma were significantly
reduced by all treatments. Liver triglycerides were dose-dependently reduced by 51-66% with 
BI 456906 compared to liraglutide (-33%) and dulaglutide (-10%, not significant). Thus, the 
effect of BI 456906 on body weight and liver triglyceride content was superior to 
liraglutide/dulaglutide. Histological analysis of the liver for the lowest dose of BI 456906 
showed an improvement of the steatosis score in all animals vs. the pre-treatment value (6/13 
animals improved by one unit, 7/13 animals improved by two units). The effects for the 
medium and high dose of BI 456906 were comparable to the low dose but with a higher share 


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of animals in improving their steatosis score by two units. BI 456906 had a better effect on 
improvement of liver steatosis score than liraglutide or dulaglutide. All treatments prevented 
worsening of the liver inflammation score between pre-treatment and post-treatment analysis. 
Inflammation score was comparably improved by one unit in some animals. Overall, BI 
456906, liraglutide and dulaglutide showed comparable effects on liver inflammation 
(n00267699-01).
BI 456906 was well tolerated in safety pharmacology studies and the effects observed mainly 
reflected the intended pharmacological activity of the compound. There were no 
toxicologically meaningful cardiovascular effects in cynomolgus monkey. BI 456906 is 
considered to have a low pro-arrhythmic potential (c14085752).
Data from clinical studies
GLP-1R agonists are known to be associated with gastrointestinal (GI) and cardiac side 
effects. Multiple studies and clinical experience from GLP-1R agonists suggest that GI side 
effects including nausea, vomiting and diarrhea, appear to be dose dependent. Moreover, dose 
escalation has been shown to significantly improve tolerability in clinical practice for a 
number of these compounds. For example, the proportion of patients reporting nausea was 20% 
lower for semaglutide with dose escalation than without dose escalation [R17-4311].
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 (c15175923-02). 
Similar to other GLP-1R agonists, nausea and vomiting were seen with increasing doses up to 
1.2 mg and the trial was discontinued early due to severe nausea and vomiting in a number of 
healthy volunteers. Currently, BI 456906 is being studied in a multiple rising dose trial
(c21168858-05) with dose escalation to investigate the safety and tolerability of different 
dose escalation schemes in otherwise healthy patients with obesity/overweight to determine 
a dose escalation scheme that minimizes gastrointestinal adverse events (AEs).
Preliminary data out of the multiple rising dose (MRD) trial (c21168858-05) trial where BI 
456906 was administered for 6 weeks in 4 different titration schemas (one once-daily dose 
group and three once-weekly dose groups, all with weekly dose escalation) showed the
frequent AEs were gastrointestinal disorders.  Specifically, symptoms included nausea in up 
to 70% of patients on BI 456906 vs 23% on placebo, dyspepsia in up to 39% vs. 8% in 
placebo, and abdominal distention in up to 37% vs. 8% in placebo, all of mild to moderate 
intensity. Among other frequently reported AEs in the metabolism and nutrition disorders 
class were decreased appetite in up to 67% vs 39% in placebo, and early satiety in up to 46% 
vs 15% on placebo. Mild fatigue was reported in 8% of patients on BI 456906 and 15% of 
patients on placebo while moderate fatigue was reported only on BI 456906 in only 6% of 
patients. Cardiac disorders were only reported in the BI 456906 treated group with 9% AV 
block first degree, 9% AV block second degree, 8% sinus tachycardia and 6% ventricular 
extrasystoles (c28750666).
Most of the reported AEs were mild or moderate in intensity. Severe AEs diarrhea (2) and 
vomiting (1) were reported for 3 out of 67 patients treated with BI 456906. No deaths, serious 


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adverse events (SAEs), protocol-specified adverse event of special interest (AESI), or other 
significant AEs were reported in this trial to date (c28750666).
For a more detailed description of the profile, please refer to the current Investigator’s 
Brochure for BI 456906.
1.3
RATIONALE FOR PERFORMING THE TRIAL
BI 456906 is a dual GLP-1R and GCGR agonist being evaluated in the indications of
glycemic control in patients with Type 2 Diabetes Mellitus (T2DM), chronic weight 
management in patients with obesity/overweight and treatment of patients with NASH and 
fibrosis.
This trial is a 48-week phase II trial to examine three dose levels of BI 456906 administered 
once weekly compared to placebo in patients with NASH and fibrosis.
It is designed to evaluate safety, tolerability, 
 
of BI 456906 in male and female patients with NASH and fibrosis using multiple 
escalation schemes and doses and will function as dose-finding trial for phase III clinical 
development of BI 456906 in patients with NASH and fibrosis.
There is still no treatment approved for patients with NASH and fibrosis, leaving a huge 
unmet medical need to develop treatments. This dose-finding trial is important to assess the 
most suitable dose to be brought forward in the pivotal phase III/IV trial, in which the 
histological improvement as well as long-term outcomes will be evaluated. It also functions 
as confirmatory trial to the planned pivotal trial for approval.
Multiple clinical trials indicate that GLP-1 receptor agonists improve NASH and weight, 
however, there is no data available for a dual agonist with agonism on GLP-1 and GCG
receptors for patients with NASH and fibrosis. It is anticipated that patients participating in 
this trial, if on active treatment, will have benefit in their weight management, metabolic 
status as well as NASH. GLP-1R agonism achieves glucose lowering by inducing glucose-
dependent insulin-secretion at the pancreatic β-cell. In addition, GLP-1R activation lowers
body weight by inducing inhibition of food intake at the hypothalamic appetite regulation 
centers and also by inducing delay of gastric emptying and intestinal transit. In addition, 
GCGR agonism reduces body weight by increasing energy expenditure and is supposed to 
increase fatty acid oxidation in the liver, and subsequently reducing lipotoxicity. In patients
with NASH and fibrosis, dual agonism at the GLP-1R and GCGR is expected to result in 
improvements in glycemic control, reduction of body weight and improvement of NASH and 
fibrosis, thereby targeting not only NASH, but also the underlying metabolic syndrome.
Patients with NASH and any pre-cirrhotic stage of fibrosis (F1 to F3) will be included in this 
trial. The targeted patient population for the compound however is patients with NASH and 
advanced fibrosis. This patient population will be investigated in phase III, especially in 
regards of long-term outcome events as histological progression to cirrhosis, liver 
transplantation, all-cause mortality. However, as no significant number of events are 
anticipated in this trial due to the treatment duration of 48 weeks and the sample size of about 
240, the primary outcome of this trial is improvement of NASH, which is anticipated to be 


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related to these long-term outcome events. This can be also seen in patients with earlier 
disease stage (F1), therefore, these patients are also allowed to participate in this trial. 
This trial investigates adult patients of both genders, pediatric development will be initiated at 
a later timepoint with supportive data from the adult trials.
In order to be able to address future scientific questions, patients will be asked to voluntarily 
donate biospecimens for banking (please see Section 5.6). 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 adverse 
event (AE), or to gain a mechanistic or genetic understanding of drug effects and thereby 
better match patients with therapies.
1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
In the proposed patient population with NASH and fibrosis, improvements in NASH and 
fibrosis, as well as body weight and metabolic status, are anticipated. The expected benefit 
for the selected patient population is improvement of NASH with no worsening of fibrosis, as 
well as exploratory resolution of NASH and improvement of fibrosis. Body weight and 
metabolic status are also anticipated to be improved in patients with NASH and fibrosis, 
therefore, improving the overall health of the patients.
This trial functions as a dose-finding trial for phase III and beyond, therefore, more than one
dose is being tested. To achieve a proper dose finding, at least 3 doses should be compared. 
Also, as currently no gold standard, besides any approved therapy is available, placebo is 
chosen as comparator.
Patients on placebo will receive standard of care (SOC), which is currently stable diet and 
exercise (lifestyle) regimen and will be guided by their physicians as per local standard. Also,
these patients will be assessed and monitored extensively, which has been shown in addition 
to SOC to already have a substantial effect on NASH and fibrosis in clinical trials.
Patients receiving 2.4 mg/ week as maintenance dose are anticipated to have benefit on their 
metabolic status, as this dose is most likely equivalent to the doses of the available GLP-1R
agonists for T2DM, as well as on their weight. The effect on NASH however is anticipated to 
be not statistically significant compared to placebo.
Patients in the higher dose groups (4.8 mg/ week and 6.0 mg/ week) are anticipated to have a
substantial benefit regarding their metabolic status, weight and NASH and fibrosis.
1.4.2
Risks
There is no identified risk for BI 456906, based on the toxicology programme or any clinical 
trials conducted for this product to date. There are three important potential risks based on 
other GLP-1 receptor agonists currently approved, providing information on identified and 


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potential risks in molecules of this class. The three important potential risks include 
medullary thyroid cancer (C-cell carcinogenicity), pancreatic cancer, and acute pancreatitis.
NASH diagnosis and assessment of treatment response is based on liver biopsies. Liver 
biopsy is an invasive procedure and represents certain risks for patients such as bleeding, pain
or organ perforation. To minimize those risks sites will be expected to follow local standard 
processes considering the suitability of a patient for the procedure, and whilst conducting the 
procedure. In this trial the initial biopsy will be performed only after all other eligibility 
parameters have been confrmed for a patient. Furthermore, use of historical biopsy will be 
permitted, if sufficient and analysable material is available from that biopsy and if it was 
performed within 6 months of randomization. 
Patients will undergo magnetic resonance imaging (MRI) examinations. While exposure to a 
high magnet field does not pose additional risks to patients, contraindications to MRI exist; 
patients with these contraindications will be excluded from the trial (refer to Section 3.3.3).
The risks for patients caused by the trial procedures and the risks related to the exposure to 
the trial medication are reasonably low and do not outweigh the potential benefits. The 
expected side effects are known to be temporary, dose dependent, easy to monitor and
manageable in clinical trials.
Among the expected and well-known side effects for GLP-1R agonist-based therapies are:
∀
Gastrointestinal disorders, as delayed gastric emptying, nausea and vomiting, as well 
as diarrhea or obstipation. Also, pancreatitis (acute and acute-on-chronic) is known to 
occur under treatment with GLP-1R agonists.
∀
Metabolism and nutrition disorders, as low blood glucose in patients with diabetes, 
delayed absorption of nutrition or medications
∀
Cardiac disorders, as cardiac conduct disorder (e.g., AV-block, prolonged QTc time)
∀
C-cell tumors of the thyroid, black box warning in established GLP-1R agonist, due to 
findings in rodents and of unknown risk to humans
∀
Administration site conditions, as rash, itching, infection
∀
Anti-drug antibodies (ADA) and neutralizing antibodies (NAb), peptides as BI 
456906 are able to induce antibody development
These side effects, which are known to be dose dependent, can be reduced by careful dose 
escalation, are easy to monitor, and, therefore, are manageable in clinical trials. In addition, 
tolerability and safety data is very important in this drug class and plays an essential role in 
the optimal dose finding. It is also well known that the gastrointestinal disorders are 
temporary, and most patients adapt to GLP-1R agonist-based compounds during dose 
escalation and/ or maintenance period.
In this trial the following safety measures will be applied in order to minimize the risk for 
trial patients:
∀
An extensive safety laboratory testing will be performed at all site visits.
∀
Patients with T2DM taking antidiabetic medication will be recommended to measure 
their fasted blood glucose at home daily and to contact the Investigator for safety 
related measures.


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∀
If patients develop persistent or recurrent severe hypoglycemic episodes (fasted 
blood glucose level of 54 mg/dL (3.0 mmol/L) or below) they will be asked to reduce 
the dose of or discontinue any concomitant antidiabetic medication. Antidiabetic 
medications are allowed to be interrupted under certain clinical circumstances in 
order to avoid hypoglycemia. Investigators may decide to keep patients solely on trial 
treatment if there is evidence of glycemic normalization, which is a well-known 
effect of glucagon receptor agonists. Hypoglycemic episodes as well as their 
relationship to the trial treatment will be strictly monitored by investigators and 
appropriately reported. In patients experiencing hypoglycemia, characteristics of 
episodes, including frequency and severity, will determine whether hypoglycemia 
needs to be classified as treatment-related adverse events.
∀
Patients in the placebo group will remain on standard of care that includes diet and 
exercise counseling as per local standard, and thorough surveillance.
∀
There are no risks expected by stopping the trial medication during the course of the 
trial and no down titration is needed.
∀
Electrocardiogram (ECG) monitoring will be performed at screening, randomization 
and at all site visits during the trial, and criteria for heart rate, QT prolongation and
cardiac conduction disorders are defined.
∀
To minimize the risk of development of C-cell tumors in patients, patients with 
personal or family history of medullary thyroid carcinoma or multiple endocrine 
neoplasia syndrome type 2, manifest hypo- or hyperthyroidism at screening visit will 
not be enrolled.
∀
Dose escalation will happen in small increments (0.3 mg/ dose escalation step at the
beginning, 0.6mg/ dose escalation step at higher doses) and at a slow pace (every two
weeks) to improve the tolerability and safety of the patients.
∀
Patients will be on-site or have a virtual visit to choose the correct pre-filled syringes 
(PFS) to minimize the risk of wrong dosing.
∀
The patients will be thoroughly trained on handling and administration of the doses 
via the PFS within the first 4 weeks of the treatment period. The patient can come to 
the site, if he/she feels uncomfortable self-administrating.
∀
Patients who do not tolerate the assigned maintenance dose are allowed to reduce the 
maintenance dose to the next lower dose after Visit 14 (during dose escalation until 
Visit 14, no dose reduction is allowed. If the patients do not tolerate the dose 
escalation until Visit 14, they will be discontinued from the trial).
∀
During the trial, patients will be under medical observation and thoroughly monitored 
for both expected and unexpected AEs.
∀
Consistent with the FDA draft guidance intitled “Suicidal Ideation and Behavior: 
Prospective Assessment of Occurrence in Clinical Trials”, prospective assessment of 
suicidal ideation and behaviour is included in this trial using the C-SSRS.
∀
ADA and NAb are assessed throughout the trial and analysed for safety and effect on 
efficacy.
∀
Pediatric patients are excluded from the trial.
∀
Females of childbearing potential who are pregnant, breast-feeding or intend to 
become pregnant or are not using an adequate contraceptive method throughout the 
trial including the 4-week follow-up period are excluded from the trial 
(Section 4.2.2.3).


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Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure patients´ 
safety. Section 10.1 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 COVID-19 
infection. There are no restrictions for trial participants to receive vaccination for COVID-19 
during or after treatment period.
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 was well tolerated in a single rising dose 
trial. In a multiple rising dose trial with weekly dose escalation up to 4.8 mg once a week, BI 
456906 did not reveal relevant safety signals although drug-related gastrointestinal and 
cardiac side effects were reported. All side effects were expected in nature such as nausea, 
dyspepsia, decreased appetite, heart rate increase and conduction disorders and are in line 
with other GLP-1R agonist-based therapies. Most of the reported AEs were mild or moderate 
in intensity. Severe AEs diarrhea (2) and vomiting (1) were reported for 3 out of 67 patients 
treated with BI 456906.  No deaths, SAEs, protocol-specified AESIs, or other significant AEs
were reported in this trial to date.
The above-mentioned risks will be closely monitored, and it is anticipated, that the benefit 
will outweigh the risks, especially as the GI tolerability issues are temporary and most 
patients adapt to the medication.
The expected benefit for the selected patient population is improvement in NASH and
improvement of fibrosis, improved metabolic status and body weight loss.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
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 NASH 
(NAS ≥4, fibrosis F1-F3) by assessing three doses and placebo. The response is the 
proportion of patients with improvement from baseline in liver histological findings after 48 
weeks (as defined in Section 2.1.2).
The main trial objectives are to demonstrate a non-flat dose response curve, to evaluate the 
size of the treatment effect (using the absolute difference in proportions of patients with 
histological improvement between BI 456906 and placebo at Week 48), and to characterize 
the dose-response relationship. 
2.1.2
Primary endpoint(s)
The primary endpoint is the improvement (yes/ no) from baseline in liver histological 
findings based on liver biopsy after 48 weeks of treatment in patients with NASH (NAS ≥4, 
fibrosis F1-F3). NAFLD activity score (NAS) represents the sum of scores for steatosis (0-3), 
lobular inflammation (0-3) and ballooning (0-2), refer to Table 5.1.1: 1 for NAS and fibrosis 
stage.
Improvement in histological findings is defined as a composite of: 
Improvement in NASH:
Decrease of at least 2 points in NAS with at least 1 point decrease in NAS sub-
score of either lobular inflammation or ballooning 
AND
No worsening of fibrosis, defined as absence of any increase in the fibrosis stage.
A patient who has improvement in histological findings after 48 weeks of treatment will be 
defined as a responder. A patient with the intercurrent event of early discontinuation of the 
treatment for any reason will be defined as a non-responder unless biopsy results are 
available, in which case they will be used to determine responder status.
2.1.3
Secondary endpoint(s)
Secondary efficacy endpoints include:
∀
Improvement of liver fat content (yes/ no) defined as at least 30% relative reduction in 
liver fat content after 48 weeks of treatment compared to baseline assessed by magnetic 
resonance imaging proton density fat fraction measurement (MRI-PDFF)
∀
Absolute and relative change of liver fat content from baseline after 48 weeks of 
treatment assessed by MRI-PDFF


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∀
Improvement of fibrosis (yes/ no) defined as at least one stage decrease in fibrosis stage 
after 48 weeks of treatment assessed by liver biopsy
∀
Absolute change from baseline in NAS after 48 weeks of treatment assessed by liver 
biopsy
For the responder secondary endpoints, patients who meet the criteria of the endpoint 
definition are responders. The handling of intercurrent events for these responder secondary 
endpoints is similar to the primary endpoint.


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One interim analysis will be performed during the trial. Please refer to Section 7.2.7.
The end of the trial is defined as “last patient out”, i.e., the last Follow-up visit (Visit 33) 
completed by the last patient in the trial.
The trial will apply a hybrid trial management approach that will employ telemedicine 
technology for interactions between the Investigator/ trial personnel and patients. The method 
of telemedicine allows for practice of medicine using technology to deliver care remotely at a 
distance. For further details refer to Section 6.1.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
A randomised, double blind, placebo-controlled design was chosen for this trial as an 
accepted standard trial design for a phase II trial.
The treatment duration of 48 weeks was chosen as sufficient to potentially show changes in 
liver pathology.
A placebo control was chosen to be included in order to evaluate the absolute effects of BI 
456906 on safety and efficacy and to better characterize the nature of the dose response
relationship. This is acceptable as no standard treatment for NASH and/or fibrosis is available
and in accordance with the guidelines provided by regulatory authorities.
The hybrid trial management approach was chosen in order to make the trial participation 
more convenient for patients by reducing travel burden and time spent at the site. 
Furthermore, as some trial procedures will be performed at patient’s home, the site burden 
will also be reduced. Approximately 60% of the visits is expected to occur at the site. The 
remaining visits should be conducted remotely at patient’s home, the patient will interact with 
the Investigator and/or site personnel via a video conferencing feature. For the method of 
visit conduct (on-site or remote) please refer to the Flow Chart. Modifications from on-site to 
remote visits require Sponsor approval.
Data Monitoring Committee
A Data Monitoring Committee (DMC), independent from the Sponsor, will be established to 
review the safety unblinded data at regular intervals, and to recommend to the Sponsor 
whether to continue, modify, or stop the trial. An unplanned DMC meeting may be called if 
there is an emergency concern on the safety of the patients (Section 3.3.4.1). The tasks and 
responsibilities of the DMC members will be detailed in the DMC charter. Please refer to 
Section 8.7.
Clinical Event Committee
The trial will be set-up with prospective adjudication of all cardiovascular, pancreatic, thyroid 
and oncological trigger events as described in Section 5.2.6.1.5. The prospectively defined 
adjudication process will assess cardiovascular, pancreatic, thyroid and oncological events 
through an independent, blinded, external Clinical Event Committee (CEC). Details on the 
composition of the committee, its procedures and interactions will be provided in a separate 
CEC charter. Adjudication was implemented in the trial in accordance with the FDA draft 


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guidance for industry and in order to support future discussions with compentent authorities 
related to patient safety.
3.3
SELECTION OF TRIAL POPULATION
240 patients with biopsy proven NASH and fibrosis will be randomised to one of the four
treatment groups in a 1:1:1:1 ratio. Approximately 180 sites in multiple countries are planned
to participate in the trial.
It is anticipated that approximately two patients will be randomised at each site. If enrolment 
is delayed additional sites may be recruited. Permission to randomise more than 20 patients 
per site must be obtained from the Sponsor. This will only be allowed after a careful review 
of the enrolment status.
Recruitment of patients for this trial will be competitive, i.e., screening for the trial will stop 
at all sites at the same time once a sufficient number of patients has been randomised. 
Investigators will be notified about screening completion and will then not be allowed to 
screen additional patients for this trial.
Re-testing during the screening period and re-screening, if a patient is not eligible initially, is 
each allowed once.
If a patient is randomised 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.
Patients who discontinue following randomization will not be replaced and may not be re-
enrolled at a later date.
To ensure sufficient enrolment of patients with advanced fibrosis, recruitment of patients 
with fibrosis stage F1 will be capped at 30% of randomized patients.
A log of all patients enrolled into the trial (i.e., who have signed informed consent) will be 
maintained in the ISF irrespective of whether or not they have been treated with trial 
medication.
3.3.1
Main diagnosis for trial entry
The trial will include patients with NASH with NAS ≥ 4 (with at least 1 point in ballooning 
and inflammation each) and fibrosis stage F1-F3, as confirmed by liver biopsy conducted 
during the screening period or from a historical biopsy conducted within the last 6 months 
prior to randomization.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the inclusion and exclusion criteria.


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3.3.2
Inclusion criteria
1. Male or female patients ≥ 18 years (or who are of legal age in countries where that is 
greater than 18 years) and ≤ 80 years of age at time of consent.
2. Diagnosis of NASH (NAS ≥ 4, with at least 1 point in inflammation and ballooning 
each) and fibrosis stage F1–F3 proven by a biopsy conducted during the screening 
period or by a historical biopsy conducted within the last 6 months prior to 
randomization and stable body weight defined as less than 5% self-reported change in 
body weight between the historical biopsy and randomization, if a historical biopsy is 
used.
3. Liver fat fraction ≥ 8% measured by MRI-PDFF and liver stiffness > 6.0 kPa
measured by FibroScan® at Visit 1 (if biopsy is scheduled during the screening period 
MRI-PDFF and FibroScan® assessments have to be performed prior to the biopsy). 
However, the diagnosis of NASH and fibrosis at liver biopsy (including historical 
biopsy) is the primary assessment to establish patient eligibility.
4. Patients willing and able to undergo liver biopsies per protocol as judged by the 
Investigator.
5. BMI ≥ 25 kg/m2 and a body weight ≥ 70 kg at Visit 1.
6. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial.
7. 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.
3.3.3
Exclusion criteria
1. Current or history of significant alcohol consumption (defined as intake of > 210 g/ 
week in males and > 140 g/ week in females on average over a consecutive period of 
more than 3 months) or inability to reliably quantify alcohol consumption based on 
Investigator judgement within the last 5 years.
2. Intake of medications historically associated with liver injury, hepatic steatosis or 
steatohepatitis within 12 weeks prior to Visit 1. Intake of restricted medications or any 
medications considered likely to interfere with the safe conduct of the trial; please 
refer to Section 4.2.2.
3. History of other forms of chronic liver disease (e.g., viral hepatitis, autoimmune liver 
disease, primary biliary sclerosis, primary sclerosing cholangitis, Wilson’s disease, 
1A 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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hemochromatosis, A1At deficiency, history of liver transplantation). Hepatitis B and 
C testing will be done at Visit 1. Patients with positive HBsAg should be excluded. 
Patients treated for hepatitis C must have a negative RNA test at screening and also be
HCV RNA negative for at least 3 years prior to screening in order to be eligible for 
the trial.
4. Suspicion, diagnosis, or history of hepatocellular carcinoma (HCC), or 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 or in 
situ carcinoma of uterine cervix.
5. Personal or family history of medullary thyroid carcinoma or multiple endocrine 
neoplasia syndrome type 2, manifest hypo- or hyperthyroidism at Visit 1.
6. 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.
7. Known history of HIV (Human Immunodeficiency Virus) infection and/or
tuberculosis and/or an acute COVID-19 infection at Visit 1 (confirmed by SARS 
CoV-2 RT-PCR test, see Section 5.2.3).
8. Abnormal laboratory values at Visit 1 as listed below:
a) Estimated Glomerular Filtration Rate (eGFR) < 45 mL/min/1.73 m2 (Chronic 
Kidney Disease Epidemiology Collaboration [CKD-EPI] formula);
b) Platelet count < 150.000/μL (< 150x109/L);
c) Bilirubin level > 1.5x ULN (except for known Gilbert’s syndrome with a 
conjugated bilirubin of < 0.3 mg/dL (< 5.13 μmol/L);
d) ALT and/or AST > 5x ULN;
e) Glycosylated haemoglobin (HbA1c) ≥9.5%;
f)
Calcitonin ≥ 20pg/mL (≥5.84 pmol/L).
9. Diagnosis of a serious or unstable disease including hepatic (other than NASH), renal, 
gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), 
endocrinologic, neurologic, psychiatric, immunologic, or hematologic disease and 
other conditions that, in the clinical judgment of the Investigator, are likely to 
interfere with the analyses of safety and efficacy in this trial. Patients with a history of 
organ transplantation except for corneal transplantation and patients with an expected 
life expectancy of less than 2 years are also excluded.
10. Any suicidal behavior or history of major depressive disorder requiring inpatient 
treatment or escalation of care in the past 2 years before randomization, any suicidal 
ideation of type 4 or 5 in the C-SSRS in the past 3 months prior to Visit 1.
11. Bariatric surgery, prior to or planned during trial conduct; except gastric-band surgery 
more than 2 years prior to screening (including adjustments) with a stable body 
weight within the last 12 months. Any other major surgery (major according to 
Investigator’s assessment) performed within 12 weeks prior to randomization or 
planned during trial conduct.


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12. Resting heart rate > 100 beats per minute (bpm) and/or blood pressure ≥160/ 95 
mmHg at Visit 1. Blood pressure measurement should be repeated 10 minutes apart. 
Patient should be excluded only if the second measurement confirms a blood pressure 
≥160/ 95 mmHg.
13. A marked prolongation of QT/ QTc (Fridericia) interval that is greater than 450
ms at Visit 1 or any other abnormal clinically significant ECG finding at Visit 1 (e.g.,
type 2 second-degree AV block (Type Mobitz II) or third-degree AV block).
14. History of ventricular tachycardia, type 2 second-degree AV block (Type Mobitz II),
third-degree AV block or congestive heart failure NYHA III-IV.
15. Heart rhythm disturbances (e.g., bradycardia with baseline heart rate < 50 bpm, in the 
absence of heart rate lowering medications), 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 Visit 1. Family history 
of long QT syndrome, use of prescription or over-the-counter medications known to 
significantly prolong the QT/ QTc interval at Visit 1.
16. Any of the following conditions or procedures within the last six months prior to Visit 
1: myocardial infarction, unstable angina (e.g., Canadian Cardiovascular Society
(CCS) grading of Angina pectoris grade III and IV), artery bypass (e.g., coronary 
artery bypass graft, carotid bypass, peripheral artery bypass), percutaneous coronary 
intervention (diagnostic angiograms are permitted), transient ischaemic attack, 
cerebrovascular accident (stroke) or decompensated congestive heart failure.
17. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
18. Contraindication to magnetic resonance imaging including, but not limited 
to severe claustrophobia, extensive tattoos, inner ear implant, pacemakers or other 
implanted cardiac rhythm management devices, intracranial aneurism clips 
incompatible with MRI, any other metallic, non-MR compatible implanted 
devices (e.g., insulin pump, hip joint replacement), a history of intra-orbital metal 
fragments that have not been removed, and weight or girth that exceeds scanner 
capabilities.
19. Ongoing participation in another interventional device or drug trial or prior 
participation during the previous 6 months or 5 times the half-life of the 
investigational drug, whichever is longer, before Visit 1.
20. Any other clinical condition that, in the opinion of the Investigator, would jeopardize 
patient safety while participating in the trial.
3.3.4
Withdrawal of patients from treatment or assessments
Patients may discontinue trial treatment or withdraw consent to trial participation as a whole
(“withdrawal of consent”) with very different implications; please see Section 3.3.4.1 and
3.3.4.2 below.
Every effort should be made to keep the patients in the trial, if possible, on treatment.
Measures to control the withdrawal rate include careful patient selection, appropriate 


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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 eCRF. If applicable, consider the 
requirements for Adverse Event collection reporting (please see Section 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.
∀
An AE (CTCAE Grade 3 or higher) occurred, and the AE was assessed by the 
Investigator as related to the trial treatment (Section 5.2.6.1.6 and 5.2.6.1.7).
∀
A clinically significant laboratory change or abnormality occurred and the Investigator 
judges to warrant discontinuation of trial treatment.
∀
The patient develops a sinus tachycardia (HR >120/min in two consesutive measurements 
5 minutes apart and/or tachyarrhythmia (HR >110/min) or cardiac condition requiring 
medical intervention.
∀
Ventricular tachycardia is seen on ECG or syncope.
∀
Clinically relevant changes are seen on the ECG (QTcF prolongation >500 ms or an 
increase of 60 ms from baseline (Visit 2), or Type Mobitz II, or third-degree AV block, or 
Torsade de Pointes) or the patient develops any symptomatic AV block, atrial fibrillation 
or atrial flutter requiring medical intervention.
∀
The patient develops a clinically relevant coronary artery disease (e.g., CCS grading of 
Angina pectoris grade III-IV, or congestive heart failure NYHA class III-IY, or any major 
adverse cardiovascular event)
∀
Signs of suicidal behaviour or ideation are detected.
∀
The patient develops a malignant neoplasm.
∀
The patient experiences systemic hypersensitivity. Refer to Section 4.2.1.
∀
The patient develops a clinically significant elevation of liver enzymes. Refer to Section 
10.1.
∀
The patient experiences an infection with SARS-CoV-2 (as confirmed by RT-PCR test)
and presents with signs or symptoms requiring discontinuation of trial treatment as per 
Investigator’s discretion.
∀
The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the Investigator and Sponsor representative, is not willing or 
able to adhere to the trial requirements in the future.
∀
The patient needs to take concomitant medication that interferes with the trial treatment
for more than 2 weeks. Refer to Section 4.2.2.1 and 4.2.2.2.
∀
The patient experiences tolerance issues with the dose due to AEs over 2 weeks within 
the treatment period before Visit 14 (Section 4.1.2).
∀
The patient is out of compliance with trial medication (missing doses), please see Section 
4.3.


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The patient can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events and other diseases not mentioned above, or pregnancy). If the patient becomes
pregnant during the trial the trial medication must be stopped, the patient will be discontinued 
from the trial and followed up until birth or otherwise termination of the pregnancy. For 
further information, including the process for follow-up of the outcome of the pregnancy 
please see Section 5.2.6.2.3.
If the trial treatment is permanently discontinued, the patient should undergo the procedures 
of the EOT and Follow-up visit (Visit 32 and 33 resp.) as outlined in the Flow Chart and 
Section 6.2.3.
In case of a temporary reason, trial treatment should be restarted if it is possible from the 
compliance perspective and if medically justified, please refer to Section 4.1.4.
Boehringer Ingelheim will closely monitor and medically review all adverse events CTCAE 
Grade 3 and higher.
If one of the following occurs:
1) three patients who were randomised to any of the three active treatment groups
develop the same Grade 3 CTCAE adverse event* assessed by the Investigator as 
related to the trial treatment;
2) two patients who were randomised to any of the three active treatment groups develop 
any Grade 4 CTCAE adverse event assessed by the Investigator related to the trial 
treatment;
3) one patient who was randomised to one of the three active treatment groups develops 
any Grade 5 CTCAE adverse event assessed by the Investigator related to the trial 
treatment.
Boehringer Ingelheim will pause the enrolment of new patients in the trial and, taking into
consideration the DMC recommendations, discontinue the trial treatment for all patients, if 
needed.
*For adverse events of nausea, vomiting, diarrhoea, constipation, or anorexia, hospitalization 
or prolongation of hospitalization caused by these respective events plus at least one of the 
following additional criteria specified below it is required to pause enrolment of new patients
in the trial.
∀
Nausea: IV hydration; tube feeding, or total parenteral nutrition indicated
∀
Vomiting: IV hydration; tube feeding, or total parenteral nutrition indicated
∀
Diarrhoea: IV hydration; increase of ≥7 stools per day over baseline
∀
Constipation: obstipation with manual evacuation indicated
∀
Anorexia: IV hydration; tube feeding, or total parenteral nutrition indicated
Trial-specific procedures have been defined in case of increased liver enzymes after 
randomization. For details refer to Section 10.1.


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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
Substance:
BI 456906
Pharmaceutical formulation:
Solution for injection
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG, 
Germany
Unit strength:
BI 456906 0.6 mg/mL, 1.8 mg/mL, 3.6 mg/mL, 4.8 
mg/mL, 6.0 mg/mL
Pre-filled syringes, 0.5 mL fill volume
Posology:
One dose weekly (two pre-filled syringes)
Mode of administration:
s.c. injection
Table 4.1.1:2 Reference product
Substance:
Placebo to match BI 456906
Pharmaceutical formulation:
Solution for injection
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG, 
Germany
Unit strength:
Placebo to match BI 456906 
Pre-filled syringes, 0.5 mL fill volume
Posology:
One dose weekly (two pre-filled syringes)
Mode of administration:
s.c. injection
4.1.2
Selection of doses in the trial and dose modifications
For this trial, target maintenance doses of 2.4 mg, 4.8 mg and 6.0 mg once weekly dosing 
were selected based on the following considerations:
Safety and tolerability of BI 456906 is being evaluated in healthy volunteers with obesity or 
overweight up to 6 weeks for doses ranging from 0.7 to 3.15 mg/ week (daily administration)


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and 0.3 to 3.0 mg/ week (weekly administration) and up to 16 weeks for doses ranging from 
0.6 to 4.8 mg/ week (once or twice weekly administration) in trial 1404-0003 (c21168858-
05). The first part of the trial with the treatment duration up to 6 weeks has already been 
completed. The available clinical data indicate that the estimated human dose for 
maintenance in obesity might be reached with 4.8 mg/ week to achieve the anticipated 
exposure.
The safety margin for the 4.8 mg/ week dose has an exposure multiple of 5.3 fold (Cmax,ss) 
and 4.1 fold (AUCτ,ss) to the no-observed-adverse-effect level in mice and cynomolgus 
monkeys.
However, pre-clinical models showed that higher exposures than in obesity might be needed 
in NASH to show meaningful efficacy (n00254747-01 and n00267699-01). This is 
potentially based on the effect of the GCGR agonism which is assumed to increase directly 
the lipid and fatty acid oxidation in the liver. The effect of the GCGR agonism is anticipated 
to be more pronounced at higher doses. Since this trial is intended to be a dose-finding trial, 
6.0 mg/ week dose was selected.
The safety margin for the 6.0 mg/ week dose has an exposure multiple of 3.1 fold (Cmax,ss) 
and 3.1 fold (AUCτ,ss) to the no-observed-adverse-effect level of the 26-week toxicological 
study in mice. Safety margins to the no-observed-adverse-effect level of the 39-week 
toxicological study of 2.4 and 0.8 based on Cmax and 2.6 and 0.7 based on AUC were derived 
for male and female cynomolgus monkeys, respectively. These calculations are based on a 
population PK model, set up with PK data from trial 1404-0001 (c22991258-01) and 1404-
0003 (c21168858-05). It should be noted that the expected Cmax and AUC refer to the 
enrolment criteria (70 kg and BMI 25 kg/m2) and is hence a worst-case scenario. A heavier 
individual will have lower Cmax and AUC.
The NOAEL for BI 456906 in cynomolgus monkeys is only limited by the effect on body 
weight loss which reflects the pharmacology of the compound. Obviously, especially female 
monkeys with a profound lower initial body weight than male monkeys have to be considered 
oversensitive.
The lowest dose of 2.4 mg/ week in this trial is predicted to achieve sub-therapeutic PD 
response comparable to placebo in patients with NASH and fibrosis, however, still providing 
weight loss and improvement in the metabolic status.
The results from the 1404-0003 indicate that the most common GI adverse events such as 
nausea and vomiting occur at the beginning of the drug exposure and can be mitigated by a 
careful dose escalation. The tolerability of GLP-1 receptor agonists is known to improve over 
time, so is assumed that even higher doses of BI 456906 will be tolerated [R20-0479]. In 
addition, close monitoring is implemented in this trial to assure patients´ safety.
Overall, the three selected maintenance doses are anticipated to support robust dose-
exposure-response analyses for multiple safety and efficacy measures to serve as a basis for 
selection of the suitable dose regimen for the phase III trial. 


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Selected doses cover a safe starting dose of 0.3 mg/ week with different dose escalation 
schemes up to the target maintenance dose. The first 10 weeks of the dose escalation period 
will be identical for all three active treatment groups. The duration of the dose escalation up 
to the target maintenance dose differs among the active treatment groups from 14 to 22
weeks.
Dose adjustment will be allowed in all groups during the dose escalation period after Visit 14
as well as any time during the maintenance period based on the occurrence of AEs. If a 
patient does not tolerate a dose due to AEs in the previous two weeks and wishes to reduce 
the dose, then the dose should be decreased to the next lower tolerated target maintenance 
dose. The assignment of the lower dose will occur in a blinded fashion via IRT. 
Examples:
∀
If a patient who does not tolerate a dose of 2.4 mg over two weeks during the dose 
escalation period and wishes to reduce the dose will be changed to placebo;
∀
If a patient who does not tolerate a dose of 3.6 mg over two weeks during the dose 
escalation period and wishes to reduce the dose will be changed to 2.4 mg;
∀
If a patient who does not tolerate a dose of 4.8 mg over two weeks during the 
maintenance period and wishes to reduce the dose will be changed to 2.4 mg.
Dose adjustment should be done at the site. A patient is allowed to adjust the dose two times 
during the entire treatment period, once during the dose escalation and once during the 
maintenance period. 
Dose escalation period
During the dose escalation period a dose adjustment may only occur at Visit 16, 18, 20, 22
and 24. If a patient experiences tolerance issues with a dose due to AEs over the last two 
weeks before a remote visit (i.e., Visit 16, 20 or 24) and believes that a dose adjustment is 
needed, the patient will be asked to come to the site and to return the unused trial medication
dispensed to him/ her during the previous site visit. The Investigator will assess together with 
the patient, if a dose adjustment is needed, and a new trial medication will be dispensed to the 
patient for the next two administrations.
If a patient experiences tolerance issues with a dose due to AEs over two weeks within the 
treatment period before Visit 14, the trial medication should be discontinued, and the patient 
should undergo the procedures of the EOT and Follow-up visit (Visit 32 and 33 resp.).
Maintenance period
If required, a dose adjustment during the maintenance period should occur at the site either 
during a planned or an unscheduled visit.
4.1.3
Method of assigning patients to treatment groups
After the assessment of all in- and exclusion criteria, each eligible patient will be randomised 
to treatment groups according to a randomisation plan in a 1:1:1:1 ratio at Visit 2 via
Interactive Response Technology (IRT). Details on randomization are provided in Section 
7.4. Patient assignment to the treatment groups will be determined by a computer-generated 
random sequence. Access to the randomization code will be controlled and documented. For 
further details please refer to Section 4.1.5.


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4.1.4
Drug assignment and administration of doses for each patient
Table 4.1.4: 1 shows the dose escalation scheme within each dose group.
Table 4.1.4: 1
Dose escalation schemes
Target 
dose
Visit
2
3
4
5
6
7
8
9
10
11
12
13
Weeks on treatment
1
2
3
4
5
6
7
8
9
10
11
Weekly dose (in mg)
2.4 mg
0.3
0.3
0.6
0.6
0.9
0.9
1.2
1.2
1.8
1.8
1.8
1.8
4.8 mg
0.3
0.3
0.6
0.6
0.9
0.9
1.2
1.2
1.8
1.8
2.4
2.4
6.0 mg
0.3
0.3
0.6
0.6
0.9
0.9
1.2
1.2
1.8
1.8
2.4
2.4
Target 
dose
Visit
14
15
16
17
18
19
20
21
22
23
24
25
Weeks on treatment
12
13
14
15
16
17
18
19
20
21
22
23
Weekly dose (in mg)
2.4 mg
2.1
2.1
2.4
2.4
2.4
2.4
2.4
2.4
2.4
2.4
2.4
2.4
4.8 mg
3.0
3.0
3.6
3.6
4.2
4.2
4.8
4.8
4.8
4.8
4.8
4.8
6.0 mg
3.0
3.0
3.6
3.6
4.2
4.2
4.8
4.8
5.4
5.4
6.0
6.0
BI 456906 or placebo will be provided in pre-filled syringes. Each patient will be 
administered two injections at every dosing day. Trial medication will be administered 
preferably by a qualified site personnel during site visits. During remote visits and between 
site visits during the maintenance period trial medication will be administered by the patient
or a designated person. Patient and a designated person (if appointed) will be properly trained 
before starting the administration at home. Furthermore, during remote visits the 
administration of trial medication will be monitored by a qualified site personnel via the 
video conferencing function available on the Science 37 platform. If the patient is not willing 
to self-administer the injections, he/ she should be given the option to visit the site and to 
have the medication administered by a qualified site personnel. 
“Instructions for Use” (IFU) with step-by-step instructions on how to use the pre-filled 
syringe will be provided to each patient. A copy of the IFU will be placed in the ISF. The 
IFU will also contain important safety information and storage instructions. The injection site 
should be the abdomen, as shown in the instructions. Each dose (both pre-filled syringes) 
should be administered on one side of the abdomen, and the next dose should be administered 
on the alternate side of the abdomen. 


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Electronic diary (eDiary) will be maintained by the patient. Date and time of administration 
(of the first of two pre-filled syringes) and site of injection will be recorded by the patient 
when the trial medication is administered at patients’ home. Patient should also answer 
questions regarding side effects in the eDiary. The Investigator will have immediate access to 
the eDiary through Science 37 platform. In case of technical issues with the platform, a paper 
diary will be used. 
Dose escalation period
During the dose escalation period the treatment with trial medication may be interrupted at 
maximum two occasions. On each occasion only one dose of trial medication can be missed. 
At the re-start the patient will continue with the dose escalation scheme without any changes. 
Examples:
∀
If a patient misses a dose at Visit 15, he/ she should re-start the treatment at Visit 16
with the planned dose of Visit 16.
∀
If a patient misses Visit 14, he/ she should come to the site not later than at Visit 15 to 
re-start the treatment with the planned dose of Visit 15 and to pick-up the trial 
medication for self-administration during the next two remote visits (Visit 16 and 17).  
Maintenance period
During the maintenance period the treatment with trial medication may also be interrupted on
maximum two occasions. Two consecutive doses of trial medication may be missed at each 
occasion. In the event of one missed dose the patient should re-start at the dose from before 
the temporary discontinuation. In the event of two missed consecutive doses, the dose at re-
start will be decreased by two dose escalation steps and re-escalated to the maintenance dose
in weekly steps within two weeks. 
Examples: 
∀
If a patient misses two consecutive doses at Week 25 and 26, he/ she should come for 
the next dose administration at Week 27 to the site (unscheduled visit) and return the 
unused trial medication to the site. During the unscheduled visit a new trial 
medication (reduced dose) will be administered to the patient. Then patient will 
continue with the planned visit schedule, i.e., Week 28 visit (Visit 27) will occur at 
the site. From Week 29 on the patient will be back at the maintenance dose.
∀
If a patient misses two consecutive doses at Week 27 and 28, he/she should come for 
the next dose administration at Week 29 to the site (unscheduled visit) and return the 
unused trial medication to the site. During the unscheduled visit a new trial 
medication (reduced dose) will be administered and trial medication for the next two 
administrations at Week 30 and 31 will be dispensed to the patient. Then patient will 
continue with the planned visit schedule, i.e., Week 32 visit (Visit 28) will occur at 
the site. From Week 31 on the patient will be back at the maintenance dose.
If a patient misses the last dose from the dose escalation period and the first dose from the 
maintenance period, this should be handled like two missed consecutive maintenance doses.
During the COVID-19 pandemic, visits to the sites may need to be replaced by remote visits 
to ensure patient safety. Based on a thorough assessment of the benefits and risks, the 




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In case the automated unblinding option via IRT is malfunctioning, the IRT service provider 
can be contacted (24/7 coverage) and the treatment allocation can be obtained. IRT support 
has direct access to the database and the treatment information can be manually obtained.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs) and the assessment of pre-defined stopping criteria, it may be necessary for a 
representative from BI’s Pharmacovigilance group or independent statistician 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 or for assessment of a safety signal and will not be shared further. 
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by Boehringer Ingelheim Pharma 
GmbH & Co. KG, Biberach, Germany. They will be packaged and labelled in accordance 
with the principles of Good Manufacturing Practice (GMP). Re-supply to the sites will be 
managed via the IRT system, which will also monitor expiry dates of supplies available at the 
sites.
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
Drug supplies will be kept 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 procedure described in the ISF has to be followed and the 
Clinical Research Associate (CRA), as provided in the list of contacts, should be contacted
immediately.
Pre-filled syringes dispensed to the patient at site visits (Flow Chart) should be transported in 
insulated bags with cooling gel packs (or other similar cooling tools) from the site to patient’s 
home. Patients should store the medication at home according to the recommended storage 
conditions on the medication label as instructed by the site personnel. Patients will not 
maintain a temperature log.
4.1.8
Drug accountability
The Investigator or designee will receive the trial medication 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;
∀
Availability of FDA Form 1572 (if applicable).


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Trial medication is not allowed to be used outside the context of this clinical trial protocol. It
must not be forwarded to other investigators or clinics. Transfers of trial medication between 
sites should occur in exceptional events only and should be coordinated by the Sponsor. 
Patients should be instructed to return all unused trial medication (cartons with the pre-filled 
syringes), and the empty cartons from used trial medication, to the site at the next site visit.
The sharps container (dispensed to the patient) where the used pre-filled syringes are stored 
should be returned to the site when it is full or at Visit 32.
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 and reconcile all 
investigational medicinal products received from the Sponsor. At the time of return to the 
Sponsor and/or appointed CRO, the Investigator or designee must verify that all unused or 
partially used drug supplies have been returned by the clinical trial patient and that no 
remaining supplies are in the Investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
No rescue medication, emergency procedure or additional treatments are foreseen for this 
trial.
Stable doses of concomitant therapies for chronic conditions, for which neither the condition 
nor the treatment are judged to exclude the patient from participation (refer to Section 3.3) 
are permissible. All concomitant therapy should be carefully evaluated by the Investigator 
and the Sponsor should be contacted when there are questions.
In case of AEs in need of treatment, symptomatic therapy according to Investigator judgment 
will be permitted. All concomitant therapies will be recorded on the appropriate pages of the 
eCRF.
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.


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Hypoglycemic events
T2DM patients should contact the site any time their fasted blood glucose level measured 
with a SMBG device drops below 70 mg/dL (3.9 mmol/L).
Investigators are asked to assess the frequency of detection of the glucose alert value of 70 
mg/dL (3.9 mmol/L) or less and to carefully assess hypoglycemic episodes following the 
2017 American Diabetes Association position statement on glycemic targets. Investigators
should consider lowering the dose of or to discontinue the concomitant antidiabetic 
medication and to implement additional glucose monitoring as needed.
Systemic hypersensitivity incl. 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 antihistamines, i.v. steroids, and in case of a severe allergic 
reaction (e.g., anaphylactic reaction) epinephrine.
Blood will be drawn for the analysis of ADAs, NAbs, level of BI 456906, IgE, histamine, 
serum tryptase, and complement components as detailed in the laboratory manual.
In the event 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.
In the event 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 medications are prohibited during the entire duration of the trial:
∀
Amiodarone, methotrexate, systemic glucocorticoids for more than 2 weeks, 
tetracyclines, tamoxifen, estrogens (excluding estrogen substitution with serum 
estrogen levels within the normal range), anabolic steroids, valproic acid and anti-
obesity medications
∀
Pioglitazone or GLP-1R agonists within 6 months of randomization
∀
Initiation of SGLT-2 inhibitors within 6 months of randomization
∀
Beta-blockers, verapamil and diltiazem, unless indicated for heart rate control or 
hypertension treatment


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∀
Initiation or change in dose of Vitamin E
∀
Oral medications with Narrow Therapeutic Index (NTI), unless dosing can be 
adapted according to standard of care monitoring (e.g., levothyroxine dosing 
appropriately adapted to thyroid hormone levels)
∀
Medications 
known 
to 
significantly 
prolong 
the 
QT/ 
QTc 
interval
(website.crediblemeds.org)
4.2.2.2
Restrictions on diet and lifestyle
Patients participating in this trial should refrain from donating blood during the entire 
duration of the trial including the follow-up period.
Dietary supplements that potentially induce change in body weight, over-the-counter or
prescribed weight loss products, and products including St. John’s wort (Hypericum 
perforatum) are not permitted starting 4 days before the first administration of trial 
medication until the end of the trial.
There are no other restrictions on diet, exercise, alcohol consumption or smoking except that 
the patient’s usual habits, including nicotine, alcohol, and caffeine intake, should be within 
acceptable daily amounts and not be drastically changed throughout the trial conduct. All 
patients should be on a stable (i.e., no changes within 6 months of randomization) diet and 
exercise (lifestyle) regimen according to the sites standard of care throughout the trial, 
without substantial modifications. Assessing the restrictions on diet and lifestyle of trial
patients is left to the Investigator. Counceling by the site staff on lifestyle per local standard 
of care should be documented in the patient´s source documents.
4.2.2.3
Contraception requirements
Female patients
Women of child-bearing potential (WOCBP, for the definition please refer to Section 3.3.2) 
and their male sexual partner able to father a child must use two medically approved methods 
of birth control throughout the trial and for a period of at least 5 weeks after last trial 
medication intake. Male partner of a female trial participant must use a condom if his sexual 
partner is a WOCBP or be vasectomised with documented absence of sperm.
WOCBP (trial participant) must use a highly effective method of birth control per ICH M3 
(R2) that results in a low failure rate of less than 1% per year when used consistently and 
correctly if their sexual partner is a man able to father a child. 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.


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WOCBP who use oral contraceptives at screening visit should change
to non-oral 
contraceptives listed above. Oral contraceptives are not permitted in female participants 
during the trial. 
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 trial medication; and withdrawal are not acceptable.
Male patients
There are no specific contraceptive requirements for male participants and their female 
partners.
4.3
TREATMENT COMPLIANCE
Patients should be encouraged to be fully compliant with the trial medication dosing schedule 
(Flow Chart). 
If a dose is missed on the planned dosing day, patients should take the planned dose within 
two days. If more time has elapsed since the missed dose, then the patients should wait to 
take the next planned dose. A minimum of five days between doses is required.
Patients are considered out of compliance, and should be discontinued from the trial:
1)
if they miss two or more consecutive doses OR if they miss one dose at more than two 
occasions during dose escalation period;
2)
if they miss three or more consecutive doses OR if they miss one dose or two 
consecutive doses at more than two occasions during maintenance period.
The total maximum number of allowable missed doses during the entire treatment period is 
six, i.e., two during the dose escalation and four during the maintenance period.
Patients should be instructed to return all unused trial medication (cartons with the pre-filled 
syringes), and the empty cartons from used trial medication, to the site at the next site visit. 
Compliance will be determined by the site personnel.


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
5.1.1
Liver biopsy
Liver biopsy specimens will be collected at the time points specified in the Flow Chart. A 
large needle, preferably 16G but not less than 18G, should be used and a biopsy core with a 
total length of at least 20 mm, not too much fragmented (1 to 3 fragments) should be obtained 
in order to meet the quality requirements for an accurate histological evaluation. Unstained 
slides will be prepared locally and sent to the central pathology laboratory. Alternatively, 
biopsy blocks can be sent to the central pathology laboratory. Guidelines for biopsy specimen 
collection and preparation are provided in the manuals from the central pathology laboratory. 
If a historical biopsy is intended to be used for eligibility assessment and as a baseline, 
sufficient and suitable material must be available for this purpose. Central pathology 
laboratory will process the biopsy specimens for reading by the central pathologist.
Assessment of liver biopsy specimens will be set-up in a blinded fashion. It will be based on 
the NAFLD scoring system (NAS), developed by the NASH clinical research network (CRN). 
The NAS represents the sum of scores for steatosis, lobular inflammation and ballooning, and 
ranges from 0 to 8. The total score for the fibrosis stage ranges from 0 to 4 (Table 5.1.1: 1).
Table 5.1.1: 1
NAFLD scoring system (NAS) for liver biopsies
Gene expression analysis
A fraction of the liver tissue collected during biopsy will be used to conduct gene expression 
analysis (refer to Liver biopsy in the Flow Chart). For any liver biopsies conducted during the 
trial, the generation of slides for the histological staging of NASH will take precedence over 
sample collection for gene expression analysis. For further details refer to Section 5.5.3. 




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acceptable, but this should be worn for all weight measurements in the trial. The patient 
should empty the bladder before weight is measured.
5.1.5
Waist and hip circumference
Waist circumference should be determined by measuring the midpoint between the lowest rib 
and the iliac crest. The measuring tape should be made of a material that is not easily 
stretched. The tape should be placed perpendicular to the long axis of the body and horizontal 
to the floor and applied with sufficient tension to conform to the measurement surface. Waist 
circumference measurements should be made around a patient’s bare midriff, after the patient 
exhales while standing without shoes and with both feet touching the ground and arms 
hanging freely.
Hip circumference measurement should be taken around the widest portion of the buttocks.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
A complete physical examination will be performed at the screening visit. Further physical 
examinations during the trial are required only if patient reports symptoms (please refer to in 
the Flow Chart). The physical examination should be conducted according to the local 
medical practice. It includes at a minimum general appearance, neck, lungs, cardiovascular 
system, abdomen, extremities, and skin. 
Measurement of height and body weight will be performed at the time points specified in the 
Flow Chart. The results must be included in the source documents available at the site. 
5.2.2
Vital signs
Vital signs will be assessed at the time points specified in the Flow Chart, prior to blood 
sampling. Blood pressure will be measured twice at Visit 1 (10 minutes apart). Vital signs 
measurement at Visit 1a is optional but recommended. At dosing visits another vital signs 
assessment will be done approx. 10 minutes post dose (i.e., after the administration of the 
second of two pre-filed syringes). Vital signs assessment consists of systolic and diastolic 
blood pressure and pulse rate (electronically or by palpation count for 1 minute) in a seated 
position without crossed legs, after 5 minutes of rest. The results must be included in the 
source documents available at the site.
5.2.3
Safety laboratory parameters
Safety laboratory parameters to be assessed are listed in Table 5.2.3: 1. For the sampling time 
points please see the Flow Chart. Patients do not have to be fasted for the blood sampling for 
the safety laboratory.
Analyses will be performed by a central laboratory; the respective reference ranges will be 
provided in the ISF. Instructions regarding sample collection, sample handling/ processing 
and sample shipping are provided in the laboratory manual. 


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The central laboratory will send reports to the Investigator. It is the responsibility of the 
Investigator to evaluate the laboratory reports. Clinically relevant abnormal findings as 
judged by the Investigator will be reported as AEs (please refer to Section 5.2.6).
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.6.1) and the DILI Checklist provided in the ISF. The 
amount of blood taken from the patient concerned will be increased due to this additional 
sampling.
The central laboratory will transfer the laboratory data to the Sponsor periodically.


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Table 5.2.3:1 
Safety laboratory tests
Category
Test name
Haematology
Haematocrit
Hemoglobin
MCV (Mean Corpuscular Volume)
MCH (Mean Corpuscular Haemoglobin)
MCHC (Mean Cellular Haemoglobin Concentration)
Red Blood Cell Distribution Width (RDW)
Red Blood Cells (RBC) Count/ Erythrocytes
WBC Count/ Leukocytes
Platelet Count / Thrombocytes
Differential Automatic (relative and absolute count): 
Neutrophils, Eosinophils, Basophils, Monocytes, Lymphocytes
Clinical chemistry
Albumin 
Alkaline phosphatase
Amylase
ALT (alanine aminotransaminase, SGPT)
AST (aspartate aminotransaminase, SGOT) 
Bicarbonate
Bilirubin total, fractionated if increased 
Calcium 
Clinical chemistry
Chloride 
Creatinine
Creatine kinase (CK)
CK-MB, troponin (reflex tests if CK is elevated)
Ferritin
#-GT (gamma-glutamyl transferase)
Glucose (plasma, not fasted)
HbA1c/ Insulin/ C-Peptide**
Lactate dehydrogenase (LDH)
Lipase
Magnesium 
Phosphate 
Serum Free Fatty Acids
Potassium
Protein total 
Sodium
Urea (blood urea nitrogen, BUN)
Uric acid
Thyroid stimulating hormone (TSH)*
Calcitonin*
eGFR (CKD-EPI formula)
Coagulation
Activated Partial Thromboplastin Time (aPTT)
Prothrombin Time (INR) 
Fibrinogen
Lipids
Cholesterol (total)
HDL cholesterol 
LDL cholesterol (including VLDL)
Triglycerides


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Table 5.2.3:1 
Safety laboratory tests (cont.)
Infectious serology
Hepatitis B surface antigen (HBsAg)*
Hepatitis B surface antibodies (anti-HBs)*
Total hepatitis B core antibodies (anti-HBs)*
Hepatitis C antibodies (anti-HCV)*
Urinalysis 
Semi quantitative
Nitrite
Protein
Ketone
Urine pH
Leukocyte esterase (for WBC)
Blood (erythrocytes)
Quantitative***
Albumin
Creatinine
Urine drug screen*
Cannabis
Cocaine
Benzodiazepine
Amphetamines
Barbiturates
Methadone
Opiates
* Measured only at Visit 1.
** Measured only at Visit 1, Visit 2, Visit 27 and at the EOT/ED visit.
*** Albumin/creatinine ratio in spot urine will be calculated at the central laboratory.
SARS-CoV-2 RT PCR test will be performed at Visit 1.
ADAs, NAbs, level of BI 456906, IgE, histamine, serum tryptase, and complement 
components will be analyzed in the event of systemic hypersensitivity.
If the assessment of safety laboratory tests in the central laboratory is not possible due to 
emergency, pandemic or other unforeseen circumstances, the assessment will be performed in 
the local laboratories.
5.2.4
Electrocardiogram
The 12-lead ECG should be collected at the time points specified in the Flow Chart. ECG 
will be recorded in triplicate at the screening visit, but as a single measurement at the 
following visits. 
Centralized ECG services will be provided by an external vendor for all site visits (including 
unscheduled visits). Standardized equipment and user manual will be provided by the vendor.
ECG should be collected according to the trial-specific recommendations, using the 
standardized equipment provided by the vendor. ECGs may be repeated for quality or safety 
reasons. Patients should be supine for approximately 5-10 minutes before ECG collection. 
Patients should remain supine, but awake, during the ECG collection process.


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ECG recordings will be transmitted electronically to a vendor for central reading. The ECG 
recordings will be centrally evaluated and rated as normal, abnormal, or unable to evaluate, 
and the results will be sent to the site. The Investigator should review the report. If the ECG 
is rated as abnormal, the Investigator will have to determine if the abnormal findings are 
clinically significant. The Investigator will have the responsibility to follow up with the 
patient if there are any clinically significant findings in the ECG report.
After the screening visit, the Investigator must review the ECG results from central reading to 
ensure patient has met all the entry criteria for the trial. Any pre-existing conditions should be 
recorded as baseline conditions. ECG recorded at the randomization visit should be evaluated 
by the Investigator before the patient receives the first dose of trial medication. If 
abnormalities are observed by the Investigator in the ECG reading at randomization visit, the 
Investigator may wait until the results from central reading are available, and the 
randomization visit may be rescheduled.
After the patient is randomised, 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 trial. The Investigator 
must also ensure that patient does not meet any of the stopping criteria, such as tachycardia, 
arrhythmia or conduction disorders (Section 3.3.4.1). Any new findings or deterioration of 
previous findings observed during the trial will be recorded as AEs or SAEs and should be 
followed up and/or treated as medically appropriate per local standards.
Although the ECGs are transmitted to the vendor for central reading, the Investigator has the 
responsibility to complete an initial review as soon as the ECG recordings are obtained at the 
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.
All ECGs that are read in the central location will be stored in the vendor’s database and will 
be transmitted to the Sponsor periodically.
5.2.5
Other safety parameters
5.2.5.1
Suicidal risk assessment and reporting
The C-SSRS is an investigator-rated interview, developed by clinical experts in cooperation 
with the FDA, assessing both suicidal behavior and suicidal ideation. It does not give a global 
score but provides some categorical and some severity information specifically for behavior 
and ideation.
The C-SSRS interview may be administered by any type of physician, psychologist, clinical 
social worker, mental health counselor, nurse, or research coordinator with C-SSRS training.
It has a typical duration of five minutes and causes only a low burden on patients. At a 
minimum, the interview consists of 2 screening questions related to suicidal ideation and 4 


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related to suicidal behavior and may be expanded to up to 17 items in case of positive 
responses. In this trial paper forms will be used for the assessment of the C-SSRS.
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 behavior. After the baseline 
visit, the assessment “since last visit” will be performed at clinic visits as specified in the 
Flow Chart. The Investigator is to review positive and negative reports for plausibility and 
clinical relevance. Doubtful reports may be repeated, or reports may be validated by a 
consulting psychiatrist. If there is a positive report of suicidal behavior or suicidal ideation 
type 4 or 5 after start of trial, the Investigator is to immediately interview the patient during 
the clinic visit and advise the patient to consult with a psychiatrist. If the positive report is 
confirmed, appropriate actions for the patient’s safety must be initiated. Treatment with trial 
medication should be stopped and patient should be discontinued from the trial. Additionally, 
all C-SSRS reports of suicidal ideation type 4 or 5 and all reports of suicidal behavior must 
be reported as separate SAEs by the Investigator. For ‘Self-injurious behavior, no suicidal 
intent’ (Type 11) standard AE / SAE reporting rules are to be applied. For each negative 
report (suicidal ideation type 1, 2 or 3) after start of the trial, the Investigator is to decide 
based on clinical judgment whether it represents an AE as defined in the protocol, and if it is 
considered an AE then it must be reported accordingly.
5.2.5.2
Self-monitoring of blood glucose
T2DM patients taking antidiabetic medication will be provided with a SMBG device for use 
at home during the treatment period for self-measurement of blood glucose. Patients may also 
use their own device for SMBG monitoring. The SMBG device will be dispensed to the 
patients at randomization (Visit 2). Instructions on the proper use of the SMBG equipment 
will be provided to the patient by the site staff. 
SMBG measurements in a fasted state (fasting for at least 10 hours) should be performed 
regularly. Recommendations are as follows:
∀
daily during the treatment period;
∀
at any time, they experience signs/ symptoms of hypoglycemia.  
Refer to Section 4.2.1 for information on handling of hypoglycemic events.
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.


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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 eCRF 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,
-
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. 
For Japan only: the following events will be handled as “deemed serious for any other 
reason”. AEs which possibly lead to disability will be reported as SAEs.
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.
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the trial medication and must be reported 


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as described in Section 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.
Hepatic injury is considered as AESI. It is defined by the following alterations of hepatic 
laboratory parameters as defined by the removal and stopping criteria in Section 3.3.4.1. and 
Section 10.1.
These laboratory findings constitute a hepatic injury alert and the patients showing these 
laboratory abnormalities need to be followed up according to the “DILI checklist” provided 
in the ISF. 
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without laboratory
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 requiring adjudication
Pre-specified AEs critical for the assessment of safety of BI 456906 will be centrally 
adjudicated in a blinded fashion by an independent external Clinical Event Committee 
(CEC). 
Definitions of the adjudicated events and the principles of standardised data collection in the 
centralised CEC adjudication process are outlined in the separate CEC Charter. For further 
details refer to Section 8.7.
AEs requiring adjudication
∀
All-cause death 
∀
Cardiovascular event 
∀
Cerebrovascular disease 
∀
Heart failure requiring hospitalisation
∀
Pancreatitis 
∀
Neoplasm 
∀
Thyroid mass requiring surgery 


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5.2.6.1.6
Intensity (severity) of AEs
The intensity (severity) of adverse events should be classified and recorded in the eCRF 
according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 
released on 27 November 2017 [R18-1357].
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 trial treatment, considering all 
relevant factors, including pattern of reaction, temporal relationship, de-challenge or re-
challenge, confounding factors such as concomitant medication, concomitant diseases and 
relevant history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:
∀
The event is consistent with the known pharmacology of the drug.
∀
The event is known to be caused by or attributed to the drug class.
∀
A plausible time to onset of the event relative to the time of drug exposure.
∀
Evidence that the event is reproducible when the drug is re-introduced.
∀
No medically sound alternative aetiologies that could explain the event (e.g., pre-
existing or concomitant diseases, or co-medications).
∀
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g., Stevens-Johnson syndrome).
∀
An indication of dose-response (i.e., greater effect size if the dose is increased, 
smaller effect size if dose is reduced).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:
∀
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g., pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned).
∀
Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g., after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.
∀
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 eCRF(s) by the 
Investigator:
•
From signing the informed consent onwards until the individual patient’s end of trial: all 
AEs (serious and non-serious) and all AESIs.
•
After the individual patient’s end of trial: the Investigator does not need to actively 
monitor the patient for new AEs but should only report any 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 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 eCRF.
5.2.6.2.2
AE reporting to the Sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form immediately (within 24 hours) to the Sponsor’s 
unique entry point (country specific reporting process will be provided in the ISF). The same 
timeline applies if follow-up information becomes available. In specific occasions, the 
Investigator could inform the Sponsor upfront via telephone. This does not replace the 
requirement to complete and send the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information. All (S)AEs, including those persisting after individual patient’s end of trial must 
be followed up until they have resolved, have been assessed as “chronic” or “stable”, or no 
further information can be obtained.
5.2.6.2.3
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken 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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5.6
BIOBANKING
Participation in sampling for biobanking is voluntary and not a prerequisite for participation 
in the trial. Samples (blood and stool) will be collected only after a separate biobanking
informed consent has been given in accordance with local ethical and regulatory 
requirements. Countries may opt out of biobanking sample collection based on regulatory 
requirements. 
5.6.1
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 83 mL of blood will be drawn for DNA, plasma and serum banking purposes.
In addition, stool samples will be biobanked for fecal biomarker assessments at Visit 2, 27 
and 32 as indicated in the Flow Chart.


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5.8
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are considered standard measurements in the 
clinical development of a treatment for NASH and will be performed in order to monitor 
safety aspects and to determine efficacy 
Therefore, the 
appropriateness of all measurements applied in this trial is given.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
The trial consists of a screening period, treatment period with a dose escalation and a 
maintenance period, and a follow-up period:
Screening : 
up to 10 weeks
Dose escalation : 
up to 24 weeks
Maintenance : 
at least 24 weeks 
Follow-up : 
4 weeks
All patients are to adhere to the visit schedule specified in the Flow Chart with a time 
window for rescheduling. Any deviations from the planned visit schedule are to be 
documented. If any visit has to be rescheduled, subsequent visits should follow the original 
visit schedule (calculated from the randomization Visit 2). Additional visits for the purpose of 
retesting laboratory paramaters or AE monitoring may be included as deemed necessary by 
the Investigator.
Approximately 40% of the visits is expected to be conducted remotely from patient’s home 
through Science 37 platform. The platform offers the patient a direct line of communication 
with the Investigator and/or site personnel via a video conferencing feature. If the patient 
does not feel comfortable with remote visits, these can be replaced by site visits. However, 
such modification has to be arranged with the site personnel in a timely manner.
If visits to site are impossible because of COVID-19 or other unforeseen circumstances 
posing safety risks to patients, these visits may be performed as remote visits from patient’s 
home via Science 37 platform. When scheduling such visits every effort should be made to 
ensure a continuous supply of trial medication for the patient, whilst also taking into account 
that the next kit(s) of trial medication may need to be shipped to the patient’s home (refer to 
Section 4.1.4) and, that medical prerequisites, i.e., at minimum monthly safety laboratory 
tests and ECGs, should be fulfilled prior to shipment of new supplies.
All COVID-19 related deviations from the original schedule of visits and trial procedures will 
be documented, and the implications will be considered for the analysis of trial data.
Science 37 application will be installed on patient’s smartphone. Alternatively, a smartphone 
can be provisioned to the patient for the duration of the trial. Apart from using the video 
conferencing function, patients will complete eDiary 
 through 
the smartphone’s Science 37 app. Patients will be instructed on the use and access of Science 
37 platform and on the use of the installed app at Visit 2.
For detailed description of trial procedures, please refer to the Flow Chart.
Vital signs measurement and ECG recording should be performed before blood samples are 
taken.


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Pregnancy tests:
All women of childbearing potential will undergo serum pregnancy test at the screening visit 
(Visit 1). The test will be done in the central laboratory. Patients with a positive result of the 
serum pregnancy test will be excluded from the trial. Urine pregnancy tests will be done
monthly starting from Visit 2. They will be done locally. If the urine pregnancy test is 
positive, a serum pregnancy test will be done in the central laboratory to confirm pregnancy. 
If the serum pregnancy test is positive, trial medication will be discontinued, and patient will 
be discontinued from the trial.  If the serum pregnancy test is negative, the patient may 
continue in the trial. If the urine pregnancy test is positive at the randomization visit (Visit 2), 
the patient must not be randomised into the trial unless the serum pregnancy test is negative.
In the event of disruptive circumstances (e.g., pandemic, war) the investigational plan as per 
this clinical trial protocol may not be feasible at a site. In this case, Sponsor, and Investigator, 
with the informed consent of the patient, may agree on alternative, back-up methodology 
which may include but will not be limited to allowing local labs for safety assessments, 
providing options to either consider paper diaries or paper PROs for patients, and other 
measures that may be required to ensure trial continuity while mainitaining patient safety and 
data integrity of primary endpoint. 
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening and run-in period(s)
Screening Period:
All patients must sign an informed consent consistent with ICH-GCP guidelines prior to any 
trial specific procedures. Please refer to Section 8.1 for details. If a patient is willing to 
provide blood and/or stool samples for biobanking, a separate consent must be obtained.
Once the patient has consented, the patient is considered as enrolled in the trial. The patient 
should be recorded on the enrolment log and registered in IRT.
The screening period, i.e., the period before the first administration of trial medication, starts 
at Visit 1 and may be as long as 10 weeks, but should be kept as short as possible. After all 
Visit 1 results including MR imaging are received and the patient is considered eligible, the 
Visit 1a for liver biopsy should be scheduled. When scheduling a liver biopsy as part of 
screening procedures sufficient time should be allowed to receive the results before preceding 
to Visit 2. In the event of logistical issues with the reporting of results by the central 
vendor(s) a patient who meets all inclusion criteria and does not meet any exclusion criteria 
should be considered for participation in the clinical trial even if he/ she exceeds the 
screening period of 10 weeks. Extension of the screening period requires a Sponsor approval. 
If more than 12 weeks elapse from Visit 1 safety laboratory tests, ECG and vital signs should 
be repeated and results should be available before randomization.
Run-in Period:
There will be no run-in period in this trial.


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Demographics and Medical Conditions:
Information on race (if allowed by local law) will be collected because certain ethnic groups 
are at higher risk for NASH. Moreover, this information is required for the calculation of 
eGFR (CKD-EPI formula). 
The following medical conditions will be specifically asked for: type and history of diabetes 
mellitus, history of arterial hypertension, history of hyperlipidemia, history of cardiac 
dysrhythmias, and metabolic syndrome, alcohol and caffeine consumption, and nicotine use. 
In addition, information will be collected in the eCRF for relevant chronic diseases, current 
observable conditions and other relevant conditions (as per Investigator’s judgment) which 
may not be necessarily manifest at the day of examination, e.g., because therapy is given.
Re-screening and re-testing:
If patients discontinue from the trial during the screening period, no additional assessments or 
site visits are required. The patients will be marked as screen failures and registered as such 
in IRT. A patient may be re-screened once with the approval from the Clinical Trial Leader.
Re-screening of a previously screen failed patients will be permitted providing the reasons for 
screen failure were reversible and have been resolved, based on Investigator’s judgement.
The patient who will be re-screened needs to be re-consented and subsequently registered in 
IRT. A new patient number will be assigned. All procedures of Visit 1 must be repeated
except for FibroScan® and MR imaging. FibroScan® and MR imaging from the initial 
screening can be used if the assessments were performed within 1 month prior to re-
screening.
If the Investigator believes that an ineligible laboratory test result is the result of an error or 
extenuating circumstance, then the test can be repeated once without the patient having to be 
re-screened. 
6.2.2
Treatment period(s)
Patients who meet all eligibility criteria will be randomised at Visit 2. After randomization, 
patients will start the treatment period which includes a dose escalation, followed by the 
maintenance period as shown in Figure 3.1: 1.
Unscheduled visits may be arranged if necessary. Procedures completed during an 
unscheduled visit will depend on the circumstances under which the visit was planned, and at 
the descretion of the Investigator. 
Measurement of vital signs should be performed before blood samples are taken (pre-dose) 
and approx. 10 minutes after dosing (post-dose).
Data concerning adverse events and concomitant medications will be collected throughout 
the trial, as specified in the Flow Chart. These data will be obtained at scheduled or 


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unscheduled visits based on the information provided actively by the patient or as a result of 
questioning the patient.
After completion of the treatment period or after a premature trial discontinuation, patient 
will have the End of Treatment visit (Visit 32) and will be registered as completed or 
discontinued in IRT, as applicable. Trial medication will not be administered at Visit 32, the 
last administration of the trial medication will occur one week before the visit.
6.2.3
Follow-up period and trial completion
The patients should make all efforts to complete the trial including the 4-week follow-up 
period which extends from Visit 32 until Visit 33. The residual effect period (REP) of 28 
days will be fully covered by the period between the last administration of the trial 
medication and the end of the follow-up period. Procedures to be completed at the Follow-up 
visit (Visit 33) can be found in the Flow Chart. The sequence of the procedures will be the 
same as in the treatment period. With the conduct of Visit 33 the observation period has 
ended. Trial completion should be recorded on the corresponding eCRF page.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
The main trial objectives are to demonstrate a non-flat dose response curve, to evaluate the 
size of the treatment effect (using the absolute difference in proportions of patients with 
histological improvement between BI 456906 and placebo at Week 48), and to characterize 
the dose-response relationship. 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
For both the primary endpoint (improvement from baseline in NASH and no worsening in 
fibrosis at Week 48) and the secondary endpoint (at least 30% reduction in liver fat content 
assessed by MRI-PDFF at Week 48), the null hypothesis is that there is a flat dose response 
curve across the placebo and the BI 456906 dose groups. The alternative hypothesis is that 
there is a non-flat dose response curve indicating a benefit of BI 456906 over placebo. 
The MCPMod procedure allows for simultaneous evaluation of different potential dose 
response patterns, whilst protecting the overall probability of Type I error (one sided 5%).
Additionally, the probability to continue the program with a non-effective drug is further 
limited by specifying that an effect of at least “delta” relative to placebo is achieved (see 
Section 7.5 for details). The pre-specified models and their parameters used are outlined in 
Section 7.2.2 and Section 7.2.3, respectively.
No confirmatory hypothesis testing is planned to be performed in this trial. Where p-values 
are given, these are to be interpreted as exploratory. Given the exploratory nature of the trial, 
no adjustment will be made to Type I error levels for the testing of the null hypothesis of flat 
dose response on more than one endpoint.
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 trial treatment (efficacy analysis).
The Treated Set (TS) is defined the same as the FAS (safety analysis).
The Per Protocol Set (PPS) is defined as all patients in the FAS who were without an 
important protocol deviation relevant for efficacy.




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diverse range of dose response patterns, with placebo response rate assumed to be 20% [R16-
5487; R16-5489; R18-2781] and maximum BI 456906 response rate assumed to be 45%. The 
maximum BI 456906 response rate occurs at the highest BI 456906 dose under monotone 
assumptions; one non-monotone dose response pattern is also included here, to allow for the 
possibility that this is not the case. Note: specifications here are made on the original 
response scale, but the MCPMod analysis itself must use the logit scale, i.e., in which the 
assumed placebo response rate is log(0.20/(1-0.20)) and the maximum BI 456906 response 
rate is log(0.45/(1-0.45)):
∀
Linear
∀
Exponential1: 25% of maximum effect achieved at dose 3.0 mg (Note: a 3.0 mg dose 
is only used to specify the models here and below. This dose is not proposed for 
inclusion in the trial.)
∀
Exponential2: 5% of maximum effect achieved at dose 3.0 mg
∀
Emax1: 50% of maximum effect achieved at dose 3.0 mg
∀
Emax2: 80% of maximum effect achieved at dose 3.0 mg
∀
Quadratic: Maximum effect achieved at dose 4.8 mg.


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Figure 7.2.2: 1 Dose response patterns considered for the MCPMod analysis of the primary 
endpoint
A non-flat dose response relationship will be established if at least one model is statistically 
significant, rejecting the null hypothesis of a flat dose response relationship jointly over the 
candidate dose response models, with a contrast test controlled for the family–wise type I
error rate at one sided α = 5%.
If a non-flat dose-response relationship 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 
(“delta”) and accounting for safety.
The primary analysis will be performed using the FAS, as defined in Section 7.2.1. 
The primary MCPMod analysis will use the actual maintenance dose (i.e., as treated). Actual 
maintenance dose is defined as the dose the patient was receiving at the start of the 
maintenance period (which is expected to be one of the planned maintenance doses). Rules 
for handling any special situations (e.g., any patient who was not receiving the same dose at 
the end of the maintenance period as at the start of the maintenance period) will be addressed 
in the TSAP. Any patient who discontinued treatment prior to starting the maintenance period 
will be assigned to the next target maintenance dose up from the last dose which was 
tolerated during the dose escalation period. For example, if a patient was randomised to a 






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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. 
For the binary secondary endpoint of a one stage decrease in fibrosis stage after 48 weeks, a 
logistic regression analysis will be performed and used to obtain covariate-adjusted odds 
ratios between active BI 456906 doses and placebo. The logistic regression model will 
include the same model terms as specified in Section 7.2.2. Where biopsy data are available 
between Week 40 and Week 48 for patients who prematurely discontinued early, these data 
will be used directly to determine the response for such patients (similarly to Section 7.2.2).
MCPMod dose finding analyses are not planned to be performed for secondary endpoints, 
other than as specified above for the MRI-PDFF responder endpoint. If additional MCPMod 
analyses are required, these will be specified in the TSAP, together with the dose response 
shapes to be evaluated.
All secondary endpoints will be summarised descriptively.  
Secondary endpoints will be analysed using the FAS.


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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 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 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.


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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
Exploratory analyses may be performed which investigate the relationship between endpoints 
derived from liver imaging (MRI-PDFF, 
) and those obtained from biopsy. This 
may form part of a separate analysis plan and not be part of the CTR. 
Intra-rater variability of biopsy readings
To assess the intra-rater variability of the screening biopsy reading, the screening and end of 
treatment biopsies will be read at the end of the trial, fully blinded to the initial eligibility 
biopsy reading, and to patient identification and visit timing. Intra-class correlation 
coefficients will be calculated. Further details will be provided in the TSAP.
7.2.7
Interim Analyses
Data Monitoring Committee
An external DMC will be implemented, with tasks and administrative details as briefly 
described in Section 8.7. Full details will be specified in the DMC Charter. The primary role 
of the DMC is the ongoing evaluation of safety.
Interim Analysis
One interim analysis will be performed after approximately half of randomised patients have 
reached Week 28. 




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7.4
RANDOMISATION
BI will arrange for the randomisation and the packaging and labelling of trial medication. The 
randomisation list(s) will be generated using a validated system, which involves a pseudo-
random number generator so that the resulting treatment will be both reproducible and non-
predictable. The block size will be documented in the Clinical Trial Report (CTR). Access to 
the codes will be controlled and documented.
Patients will be randomised in blocks using equal allocations to one of 4 double-blind 
treatment groups. Randomisation will be performed at the start of the dose escalation period, 
with allocation to one of the following maintenance period treatments:
∀
Placebo once weekly
∀
BI 456906 2.4 mg once weekly
∀
BI 456906 4.8 mg once weekly
∀
BI 456906 6.0 mg once weekly.
Randomisation will be stratified by presence of any type of diabetes (Yes, No).
7.5
DETERMINATION OF SAMPLE SIZE
Calculations were performed using R Version 3.6.1.
One aim of this trial is to show a significant non-flat dose-response curve across the different 
doses and placebo. Additionally to that, at least one modelled dose within the dose range 
considered should show a benefit of at least "delta" in the primary endpoint responder rate 
compared to placebo. The probability of success of this trial is therefore defined as the 
probability to (1) obtain a significant test for non-flat dose-response curve and (2) to observe 
for at least one of the modelled doses an effect difference of at least delta compared to 
placebo.
The sample size calculation is based on an assumed maximum difference in the primary 
endpoint responder rate (BI 456906 vs. placebo) of 25%, as well as on the pre-specified 
models listed in Section 7.2.2. For placebo, a response rate of 20% at Week 48 will be 
considered [R16-5487; R16-5489; R18-2781].
Using a total sample size of 240 evaluable patients (60 per treatment group), the probability
of a successful trial (as defined above) was estimated using simulations. For each dose group, 
samples of the required size were drawn from a binomial distribution.
Based on these assumptions, the success probability under a delta of 20% (i.e., non-flat curve 
achieved, and at least one BI 456906 dose shows a difference to placebo of at least 20%) is 
approximately 76% when assuming a linear dose response curve. Assuming a different form 


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for the underlying dose response curve (Emax, exponential, quadratic), the success 
probability is between 73% and 82% (data not shown). For a delta of 10% the respective 
success probability is 92% assuming a linear dose response shape, and between 92% and 
95% for the other dose response shapes (data not shown).
If the difference between placebo and active BI456906 doses is low, i.e., 5% (which is 
assumed to be clinically not relevant) the success probability is approximately 2% and 16% 
for a delta of 20% and 10%, respectively (assuming a linear dose response curve). In the case 
that there is no treatment benefit, the false positive probability is limited by the α-level for the 
significance testing of the non-flat dose-response curve of 5% (one-sided). Additionally, this 
probability is further reduced by requesting an effect of at least delta. Thereby, the probability 
of a false decision for a non-effective drug is reduced to less than 1% for a delta of 20% and 
remains at less than 5% for a delta of 10%.
Due to tolerability issues it is possible that not all patients in the higher dose groups can be 
uptitrated to their randomised dose. Since the primary analysis is planned “as treated”, this 
may result in lower sample sizes in highest dose groups and respectively higher sample sizes 
in lower dose groups. Therefore, in addition to the intended equal allocation, four variations 
of this sampling ratio have been considered. The first 2 variations assume that tolerability 
issues occur at the highest dose only (i.e., 60-60-70-50 and 60-70-70-40 for placebo, BI 
456906 2.4 mg, BI 456906 4.8 mg and BI 456906 6.0 mg, respectively). The second 2 
variations assume that tolerability issues could occur at either of the highest two doses (60-
80-50-50 and 60-90-50-40 for placebo, BI 456906 2.4 mg, BI 456906 4.8 mg and BI 456906 
6.0 mg, respectively). The resulting overall success probabilities do not differ meaningfully 
from those of the originally planned sampling sheme.
Table 7.5: 1 provides success probabilities under different scenarios (i.e., different treatment 
effects and allocation ratios).
Table 7.5: 1 Multiplicity-adjusted success probability given expected primary endpoint 
response rate at week 48 and a total sample size of 240 patients based on 
MCPMod nominal alpha-level of 5% (one-sided) and additional treatment 
effect threshold (delta).
Sample 
size per 
dose group
Expected primary 
endpoint  response rate   
(in %)
Exp. max. 
Response 
Difference
Delta
Probability of 
positive MCPMod 
test (multiplicity 
adjusted)
Multiplicity 
adjusted 
overall success 
probability*
Placebo
High dose BI
60/60/60/60
20
45
25
20
92.1%
75.9%
60/60/60/60
20
50
30
20
97.9%
90.9%
60/60/70/50
20
45
25
20
91.1%
75.7%
60/70/70/40
20
45
25
20
89.5%
75.4%
60/80/50/50
20
45
25
20
90.4%
74.9%
60/90/50/40
20
45
25
20
88.1%
74.6%
60/60/60/60
20
25
5
20
15.6%
2.2%


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60/60/60/60
20
20
0
20
4.5%
0.2%
60/60/60/60
20
45
25
10
92.1%
92.1%
60/60/60/60
20
50
30
10
97.9%
97.9%
60/60/70/50
20
45
25
10
91.1%
91.1%
60/70/70/40
20
45
25
10
89.5%
89.5%
60/80/50/50
20
45
25
10
90.4%
90.4%
60/90/50/40
20
45
25
10
88.1%
88.1%
60/60/60/60
20
25
5
10
15.6%
15.6%
60/60/60/60
20
20
0
10
4.5%
4.5%
*Success probabilities under different efficacy assumptions for the defined success criteria of 1) Significant 
non-flat dose-response achieved based on at least one of the candidate set models AND 2) Treatment benefit of 
at least ‘delta’ compared to placebo for at least one modelled dose within the considered dose range. Success 
probabilities have been calculated assuming a linear dose response relationship. All calculations have been done 
using R Version 3.6.1 based on simulations (10000 simulations per scenario). Thereby the calculations for the 
MCPMod step have been performed using DoseFinding R-package 0.9-16 [R15-2001]


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


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The Investigator or delegate must give a full explanation to trial patients based on the patient
information form. A language understandable to the patient should be chosen, technical terms 
and expressions avoided, if possible. 
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the Sponsor’s instructions. The consent and re-consenting 
process should be properly documented in the source documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan (IQRMP) documents the rationale and strategies for risk management
during trial conduct including monitoring approaches, vendor management and other 
processes focusing on areas of greatest risk. Continuous risk review and assessment may lead 
to adjustments in trial conduct, trial design or monitoring approaches. 
A quality assurance audit/ inspection of this trial may be conducted by the Sponsor,
Sponsor’s designees, or by IRB/ IEC or by regulatory authorities. The quality assurance 
auditor will have access to all medical records, the Investigator’s trial-related files and 
correspondence, and the informed consent documentation of this clinical trial.
8.3
RECORDS
Electronic CRFs for individual patients will be provided by the Sponsor. See Section 4.1.5.2
for rules about emergency code breaks. For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements, the Investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow the “ALCOA principles” and be attributable, legible, contemporaneous, 
original and accurate. Changes to the data should be traceable (audit trail). Data reported on 
the eCRF must be consistent with the source data or the discrepancies must be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the Investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case, the Investigator must make at least one documented attempt to 
retrieve previous medical records. If this fails,  verbal feedback from the patient, documented 
in their medical records, would be acceptable.
Copies of source documents necessary for adjudication will be provided to the adjudication 
vendor. 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.


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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 eCRF, data must be derived from source documents, for example:
∀
Patient identification: gender, year of birth (in accordance with local laws and 
regulations)
∀
Patient participation in the trial (substance, trial number, patient number, date patient was 
informed)
∀
Dates of patient’s visits, including dispensing of trial medication
∀
Medical history (including trial indication and concomitant diseases, if applicable)
∀
Medication history
∀
Adverse events and AESIs (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)
∀
Completed C-SSRS questionnaires (paper record) and completed 
 
 diaries (if paper documents are used)
∀
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 the clinical trial protocol) to support inclusion/exclusion criteria 
does not make the patient eligible for the clinical trial.
The electronic version of the ECG is regarded as source data. Dated and signed printouts will 
be stored in the patient’s medical file.
Data entered into Science 37 platform (i.e.,
, eDiary) 
will be regarded as source data.
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 eCRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g., FDA). They may review all eCRFs and informed consents. The accuracy of the data 
will be verified by direct comparison with the source documents described in Section 8.3.1.
The Sponsor will also monitor compliance with the clinical trial protocol and GCP.


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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.
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 clinical 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 
clinical trial need to be available for inspection on request by the participating physicians, the 
Sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection, biobanking and 
future use of biological samples and clinical data, in particular:
∀
Sample and data usage has to be in accordance with the separate biobanking informed 
consent
∀
The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials
∀
An appropriate sample and data management system, including audit trail for clinical 
data and samples to identify and destroy such samples according to ICF is in place
∀
A fit for 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


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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 clinical trial 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.
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, 
jointly with trial 1404-0036 (c31754142-02), to adjudicate all cardiovascular, pancreatic, 
thyroid, and oncological trigger events identified by abnormal laboratory values and/ or 
adverse events. In order to assess the trigger events relevant source documents will be 
requested from investigators. They may include laboratory reports, reports from histology, 
ultrasound, CT, MRI or scintigraphy assessments, hospital discharge letters and medical 
reports from other physicians. The assessment will be blinded to treatment allocation. The 
process of identifying the events for adjudication and the adjudication process will be 
detailed in the CEC charter.


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Data Monitoring Committee (DMC) will be established, jointly with trial 1404-0036
(c31754142-02). The DMC members 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 and 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. 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. Tasks and responsibilities of the DMC 
will be specified in the DMC charter.
Relevant documentation on the participating (Principal) investigators (e.g., their curricula 
vitae) will be filed in the ISF.
The investigators will have access to the BI 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.
Central services for laboratory, pathology, MR imaging and ECG and an IRT vendor will be 
used in this trial. Details will be provided in the respective manuals that will be available in 
the ISF.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
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.
R15-2001
Bornkamp B, Pinheiro J and Bretz F. Package 'DoseFinding' (2015)
webpage.cran.r-project.org/web/packages/DoseFinding/DoseFinding.pdf
R16-5309 
Chalasani N, Regev A. Drug induced liver injury in patients with 
preexisting chronic liver disease in drug development - how to identify and 
manage? Gastroenterology, Accepted Manuscript, Published online: 
October 17, 2016, doi: 10.1053/j.gastro.2016.10.010; 2016.
R16-5487
Neuschwander-Tetri BA et al. Farnesoid X nuclear receptor ligand 
obeticholic acid for noncirrhotic, non-alcoholic steatohepatitis (FLINT): a 
multicentre, randomised, placebo-controlled trial. Lancet 2015; 385(9972); 
956-965.
R16-5489
Ratziu V et al. Elafibranor, an agonist of the peroxisome proliferator-
activated receptor-alpha and -delta, induces resolution of nonalcoholic 
steatohepatitis without fibrosis worsening. Gastroenterology 2016; 150(5); 
1147-1159.
R17-4311 
Nauck MA, Petrie JR, Sesti G, Mannucci E, Courreges JP, Lindegaard ML, 
et al, Study 1821 Investigators. A phase 2, randomized, dose-finding study 
of the novel once-weekly human GLP-1 analog, semaglutide, compared 
with placebo and open-label liraglutide in patients with type 2 diabetes. 
Diabetes Care 2016; 39(2): 231-241.
R18-1357 
U.S. Department of Health and Human Services. Common terminology 
criteria for adverse events (CTCAE) version 5.0 (published: November 27, 
2017). 
webpage.ctep.cancer.gov/protocolDevelopment/electronic_applications/doc
s/CTCAE_v5_Quick_Reference_8.5x11.pdf#search=%22CTCAE%22 
(access date: 9 April 2017); U.S. Department of Health and Human 
Services, National Institutes of Health, National Cancer Institute; 2017.
R18-2781
Friedman SL et al. A randomized, placebo-controlled trial of cenicriviroc 
for treatment of nonalcoholic steatohepatitis with fibrosis. Hepatology 
2018; 67(5); 1754-1767.


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R19-1407 
Saxenda (liraglutide [rDNA origin] injection), solution for subcutaneous 
use (Novo Nordisk) (U.S. prescribing information, revised: 12/2014). 
webpage.accessdata.fda.gov/drugsatfda_docs/label/2014/206321Orig1s000l
bl.pdf (access date: 17 April 2019); 2014. 
R20-0479
O'Neil PM, Birkenfeld AL, McGowan B, Mosenzon O, Pedersen SD, 
Wharton S, et al. Efficacy and safety of semaglutide compared with 
liraglutide and placebo for weight loss in patients with obesity: a 
randomised, double-blind, placebo and active controlled, dose-ranging, 
phase 2 trial. Lancet 2018;392: 637-649.
R20-1255
Younossi ZM. Non-alcoholic fatty liver disease - a global public health   
perspective. J Hepatol 2019;70:531-544.
R20-1981
Regev A, Palmer M, Avigan MI, Dimick-Santos L, Treem WR, Marcinak 
JF, et al. Consensus: guidelines: best practices for detection, assessment and
management of suspected acute drug-induced liver injury during clinical
trials in patients with nonalcoholic steatohepatitis. Aliment Pharmacol Ther
2019;49:702-713.
P09-12413
Guidance for industry: drug-induced liver injury: premarketing clinical 
evaluation (July 2009). Silver Spring: U.S. Department of Health and 
Human Services, Food and Drug Administration, Center for Drug 
Evaluation and Research (CDER), Center for Biologics Evaluation and 
Research (CBER); 2009.
9.2
UNPUBLISHED REFERENCES
c14085752
Investigator Brochure BI 456906
c15175923-02
 Clinical Trial Protocol: Safety, tolerability, pharmacokinetics 
and pharmacodynamics of single rising subcutaneous doses of BI 456906 in 
healthy male subjects (single blind, partially randomized, placebo-
controlled parallel group design), version 2.0, 1404-0001. 09 Oct 2017
c21168858-05 
 Clinical Trial Protocol: 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, version 5.0. 1404-0003. 
May 2019
c22991258-01
Clinical Trial Report: Safety, 
tolerability, pharmacokinetics and pharmacodynamics of single rising 
subcutaneous doses of BI 456906 in healthy male subjects (single-blind, 
partially randomised, placebo-controlled parallel group design), version 1.0. 
1404.1


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c28750666
8-05-outputs-SDSUR19V4-safety-for-IB-update-2019-06-14
c31754142-02
 Clinical Trial 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, 1404-0036. 22 Oct 2020
n00254747-01
 Nonclinical Report: Effect of BI 456906 after multiple 
subcutaneous administrations on lipids in liver and plasma in mice with 
diet-induced obesity. MD2017/12/Lab8. 2017.
n00267699-01
 Nonclinical Report: Effect of 8 weeks of treatment with BI 
compounds on metabolic parameters, hepatic pathology and NAFLD 
Activity Score including Fibrosis Stage in male DIO-NASH mice. BI 
456906. 26 Mar 2019


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10.
APPENDICES
10.1
REMOVAL OF INDIVIDUAL PATIENTS IN CASE OF INCREASED 
LIVER ENZYMES
Trial-specific procedures have been defined in case of increased liver enzymes after 
randomisation as outlined below. 
∀
Normal aminotransferases at baseline
New elevations of aminotransferases to ≥5x ULN (total bilirubin normal* and no liver-
related symptoms) should be followed by a repeat testing within 48 to 72 hours. If elevations
persist, other causes of aminotransferase elevations should be evaluated along with tests of 
hepatic functions. If no other cause is identified, the patient should be monitored closely.
Treatment with trial medication should be discontinued if:
-
ALT or AST increases to ≥8x ULN
-
ALT or AST increases to ≥5x ULN for more than 2 weeks
-
ALT or AST increases to ≥3x ULN and the increase is accompanied by a 
concomitant increase in total bilirubin to  ≥2x ULN** or INR to > 1.5
-
ALT or AST increases to ≥3x ULN and the increase is accompanied by the 
appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash, and/or eosinophilia (> 5%)
∀
Abnormal aminotransferases at baseline
If a patient develops elevations of ALT or AST to ≥3x baseline or ≥300 U/L (whichever is 
lower) with total bilirubin normal* and no liver-related symptoms, the testing should be 
repeated within 48 to 72 hours. If elevations persist, then close observation (testing and 
physical examination 2 to 3 times a week) should be implemented, and discontinuation of 
trial medication should be considered. Decision to discontinue the trial medication should be 
considered based on factors that include how much higher than baseline ALT and AST values 
were relative to ULN and how much the on-treatment ALT and AST values have increased 
relative to baseline.
Treatment with trial medication should be discontinued if:
-
baseline values were < 2x ULN, and ALT or AST increases to ≥5x baseline 
values
-
baseline values were ≥ 2x ULN but ≤5x ULN, and ALT or AST increases to ≥3x 
baseline values
-
ALT or AST increases ≥2x baseline values or ≥300 U/L (whichever is lower)
and the increase is accompanied by a concomitant increase in total bilirubin to ≥
2x ULN** or INR concomitantly increases by > 0.2 (to prevent false positive 
results, another sample should be tested within 24 hours)
-
ALT or AST increases ≥2x baseline values or ≥300 U/L (whichever is lower)
and patient develops signs and symptoms of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%).


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Patients should be followed up until resolution of symptoms or signs in the above stated 
situations [P09-12413]. Treatment with trial medication may be restarted only if another 
aetiology is clearly identified and the liver values have returned to baseline [R20-1981]. 
Otherwise, after resolution or stabilisation the patient should complete the procedures for the 
EOT and Follow-up visit (Visit 32 and 33 resp.) as outlined in the Flow Chart and Section
3.3.4.1 and 6.2.3.
* Patients with Gilbert’s syndrome: no change from baseline total bilirubin 
** Patients with Gilbert’s syndrome: doubling of direct (conjugated) bilirubin 


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
18 December 2020
EudraCT number
EU number
2020-002723-11
BI Trial number
1404-0043
BI Investigational Medicinal 
Product(s)
BI 456906
Title of protocol
Multicenter, double-blind, parallel-group, 
randomised, 48 weeks, dose-ranging, placebo-
controlled phase II trial to evaluate efficacy, safety 
and tolerability of multiple subcutaneous (s.c.) 
doses of BI 456906 in patients with non-alcoholic 
steatohepatitis (NASH) and fibrosis
Global Amendment due to urgent safety reasons
Global Amendment
Section to be changed
Flow Chart
Description of change
1. Dispensation of SMBG device at Visit 2 added 
to the flow chart
2. Footnote #23: Statement about C-SSRS 
questionnaire administration “at each site visit” 
deleted (C-SSRS questionnaire not 
administered at Visit 3 and 5)
3. Footnote #25: Clarification regarding use of 
SMBG device added
4. Footnotes #25 and higher re-numbered
5. “Screening” or “screening visit” replaced with 
“Visit 1” in footnotes
Rationale for change
Ad 1 and 3: Implementation of additional safety 
measure
Ad 2, 4 and 5: Corrections and clarifications
Section to be changed
Section 1.4.2
Description of change
Regular SMBG measurements in T2DM patients 
on antidiabetic medication and safety measures in 
case of hypoglycemic events added
Rationale for change
Request from Health Authority regarding safety 
risk monitoring and mitigation in patients 
vulnerable to hypoglycemia
Sections to be changed
Section 3.1
Description of change
“Visit 1” and “Visit 1a” added to the first and 
second screening visit resp.
Rationale for change
Clarification
Sections to be changed
Sections 3.2 and 4.1.5.1 
Description of change
Information added regarding unplanned DMC 


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meeting and unblinded safety assessment by DMC 
at the occurrence of adverse events that may lead to 
trial discontinuation
Rationale for change
Request from Health Authority regarding trial 
stopping criteria and process
Sections to be changed
Section 3.3.2 and synopsis
Description of change
1. Cut-off for age increased to legal age for 
countries with legal age above 18 years
2. BMI cut-off increased to 25 kg/m2
3. “Screening visit” replaced with “Visit 1”
Rationale for change
Ad 1/ Legal age clarification
Ad 2/ The previous BMI cut-off included normal 
weight Caucasians while overweight Asians. 
BMI cut-off of 25 kg/m2 will homogenously 
include overweight patients of all ethnicities. 
Ad 3/ Clarification
Section to be changed
Section 3.3.3 and synopsis
Description of change
1. Text regarding acute COVID-19 infection and 
testing slightly re-worded
2. Cut-off for eGFR increased to 60 
mL/min/1.73m2
3. Exclusion of patients with history of organ 
transplantation except for corneal 
transplantation added to the criteria
4. Description “requiring inpatient treatment or 
escalation of care” added for patients with 
history of major depressive disorder in the past 
2 years 
5. SI units added to conventional units
6. “Screening visit” replaced with “Visit 1”
Rationale for change
Ad 1 and 6: Clarifications
Ad 2 and 3: Request from Health Authority
Ad 4: Further specification added for identification 
of patients with history of major depressive 
disorder
Ad 5: Laboratory units relevant for investigator 
decisions (e.g., on patient eligibility) aligned with 
units used by the central laboratory when reporting 
results
Section to be changed
Section 3.3.4.1
Description of change
1. Occurrence of an adverse event CTCAE Grade 
3 related to trial treatment added to the trial 
treatment discontinuation criteria for individual 
patients
2. Trial treatment discontinuation criterion for 
individual patients regarding clinically relevant
ECG changes corrected, QTcF increase from 


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baseline changed to 60 ms, Visit 2 defined as 
baseline
3. Information added about close monitoring and 
medical review of all adverse events CTCAE 
Grade 3 and higher. Triggers for 
discontinuation of trial treatment for all patients 
specified. 
Rationale for change
Ad 1 and 3: Request from Health Authority
regarding trial treatment discontinuation criteria
Ad 2: Correction
Section to be changed
Section 4.1.2
Description of change
Duration of escalation period in active treatment 
groups changed to “16 to 22 weeks”
Rationale for change
Correction
Section to be changed
Section 4.1.4
Description of change
Number of weeks on treatment added to Table 
4.1.4.:1 “Dose escalation schemes”
Rationale for change
Clarification
Section to be changed
Section 4.1.5.2
Description of change
Information added regarding unblinding by 
pharmacovigilance group or independent 
statistician for assessment of adverse events that 
may lead to trial discontinuation
Rationale for change
Process clarification
Section to be changed
Sections 4.2.1 and 5.2.5.2
Description of change
Guidance for regular SMBG measurements in 
T2DM patients and safety measures in case of 
hypoglycemic events added
Rationale for change
Request from Health Authority on safety risk 
monitoring and mitigation in patients vulnerable to 
hypoglycemia
Section to be changed
Section 4.3
Description of change
The word “allowable” added in the sentence 
describing the total maximum number of missed 
doses during the entire treatment period
Rationale for change
Clarification
Section to be changed
Section 5.1.1
Description of change
Minimum requirement for collection of liver 
biopsy specimen (i.e., size of biopsy needle, size of 
biopsy specimen) added to define the quality 
standards for an accurate histology evaluation
Rationale for change
Request from Health Authority regarding biopsy 
collection
Sections to be changed
Section 5.2.3
Description of change
1. SARS-CoV-2 RT PCR test deleted from the 
serology subsection of Table 5.2.3:1 “Safety 
laboratory tests” and added below the table


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2. “Screening visit” and “screening” replaced with 
“Visit 1”, and “randomisation” replaced with 
“Visit 2”
Rationale for change
Correction and clarification
Section to be changed
Section 5.5.1
Description of change
Patients from sites in China excluded from 
collection of blood samples for evaluation of 
exploratory biomarkers, but Fib-4 index and APRI 
will be calculated.
Rationale for change
Clarification
Section to be changed
Section 7.2.6
Description of change
Brief statement added regarding blinded biopsy 
readings and subsequent analysis of intra-class 
correlation coefficient.
Rationale for change
Clarification of process and planned evaluation of 
intra-rater variability.
Section to be changed
Synopsis, Abbreviations, Sections 7.2.1, 7.2.2, 
7.2.3, 7.2.4 and 7.2.5
Description of change
Redefine analysis set labels for full analysis set 
(FAS) and treated set (TS) to include rather than 
exclude patients from sites in China. Note: this is a 
labelling issue only and does not change any 
statements about whether patients from sites in 
China are actually included or excluded from the 
specified analyses.
Rationale for change
Consistency with other trials in project
Section to be changed
Section 9.1
Description of change
Reference added to FDA’s drug-induced liver
injury (DILI) guidance
Rationale for change
Administrative change
Section to be changed
Section 10.1
Description of change
Guidelines for removal of individual patients in 
case of increased liver enzymes revised. Trial 
treatment discontinuation criteria defined for 
individual patients in the event of drug-induced 
liver injury.
Rationale for change
Request from Health Authority regarding DILI
Sections to be changed
Cover page, Abbreviations, multiple sections
Description of change
1. Clinical Trial Protocol version and date 
changed
2. “SMBG” and “QTcF” added to abbreviations, 
QT explanation re-worded
3. Typos corrected
Rationale for change
Administrative changes


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11.2
GLOBAL AMENDMENT 2
Date of amendment
14 May 2021
EudraCT number
EU number
2020-002723-11
BI Trial number
1404-0043
BI Investigational Medicinal 
Product(s)
BI 456906
Title of protocol
Multicenter, double-blind, parallel-group, 
randomised, 48 weeks, dose-ranging, placebo-
controlled phase II trial to evaluate efficacy, safety 
and tolerability of multiple subcutaneous (s.c.) 
doses of BI 456906 in patients with non-alcoholic 
steatohepatitis (NASH) and fibrosis
Global Amendment due to urgent safety reasons
Global Amendment
Section to be changed
Synopsis – total number of patients 
Description of change
Removed statement that up to 24 additional 
patients from sites in China will be randomised.
Rationale for change
Patients from sites in China are now part of the 240 
patients planned to be randomised in the trial.
Section to be changed
Synopsis – inclusion criteria 
Description of change
Replaced “Screening visit” with “Visit 1”.
Rationale for change
Clarification
Section to be changed
Synopsis – statistical methods
Description of change
Amended definition of full analysis set (FAS) to 
include all randomised and treated patients and 
removed reference to China in the FAS definition.
Removed statement that a sensitivity analysis of 
the primary endpoint will be performed including 
patients from sites in China.
Rationale for change
Patients from sites in China will now be included 
in the primary analysis and are expected to provide 
timely biopsy data to enable this. 
There is no longer any reason to consider separate 
analyses of the primary endpoint with and without 
patients from sites in China.
Section to be changed
Synopsis – statistical methods
Description of change
Removed wording that the trigger for interim 
analysis (approximately half of randomised 
patients having reached Week 28) will exclude 
patients from sites in China.
Removed statement that the interim analysis will 
exclude data from patients from sites in China.




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Rationale for change
Request from Health Authority 
Section to be changed
Sections 3.1, 6.1 and 6.2.1
Description of change
Extended the screening period to 10 weeks
Rationale for change
Consecutive screening approach and central 
assessments may require more time than 8 weeks.
Section to be changed
Section 3.3
Description of change
Removed text regarding additional recruitment in 
China and increased the number of sites. Removed 
information on a separate cap for patients from 
China. 
Rationale for change
Patients from China will be part of the 240 patients 
planned randomised in the trial. There is no longer 
any reason to separate processes for sites from 
China. 
Section to be changed
Section 3.3.3
Description of change
1. Added information on treated hepatitis C 
patients
2. Replaced “Visit 1” with “screening”
3. Added congestive heart failure NYHA class III-
IV to exclusion criteria
Rationale for change
1. Clarification
2. Fasting condition is not required for blood 
samples collection at any visit. However, serum 
triglycerides may be re-tested at fasting 
condition during screening if the levels at Visit 
1 exceed 500 mg/dL (5.65 mmol/L).
3. Alignment of exclusion criteria across trials 
using the same compound
Section to be changed
Sections 3.3.3 and 5.2.2
Description of change
Added information on a second blood pressure 
measurement at Visit 1
Rationale for change
Increase of blood pressure measurement accuracy
Section to be changed
Section 3.3.4.1
Description of change
1. Added Torsade de Pointes and any major 
adverse cardiovascular events to trial treatment 
discontinuation criteria.
2. Added clinically significant elevation of liver 
enzymes and tolerance issues with the dose to 
trial treatment discontinuation criteria.
Rationale for change
1. Request from Health Authority
2. This information is mentioned in other sections 
of the clinical trial protocol. It was added to the 
list of treatment discontinuation criteria in this 
section for the sake of completeness.
Section to be changed
Section 4.1.2
Description of change
Corrected information on toxicology studies. 
Added information on the selection of 6 mg dose in 


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the trial.
Rationale for change
Request from Health Authority
Section to be changed
Section 4.1.4
Description of change
1. Removed wording that Instructions for Use 
(IFU) will be provided to patients via platform. 
2. Added paper diary as an alternative option to 
eDiary.
Rationale for change
1. Use of both, electronic and a paper document, 
should be possible.
2. In case of non-availability of eDiary backup 
solution should be in place.
Section to be changed
Section 4.1.5.1
Description of change
Removed wording that the trigger for interim 
analysis (approximately half of randomised 
patients having reached Week 28) will exclude 
patients from sites in China.
Rationale for change
If any patients from China have reached Week 28 
before the interim analysis trigger has been met, 
they will be included in the count of half of the 
planned randomised patients.
Section to be changed
Section 5.1.1
Description of change
1. Added alternative option to provide biopsy 
blocks to the central pathology laboratory
2. Removed wording on biopsy process for sites 
in China
3. Removed wording on collection of tissue 
specimens for gene expression analysis in 
China
Rationale for change
1. Consistency with the manuals from the central 
pathology laboratory 
2. Detailed information will be included in the 
manuals from the central pathology laboratory.
3. Any restrictions on specimen collection in a 
specific country will be subject of a local 
amendment.
Section to be changed
Section 5.1.3
Description of change
Removed wording on MRI procedure in China
Rationale for change
Redundant wording
Section to be changed
Section 5.2.2
Description of change
Clarified that measurement of vital signs at Visit 1a 
is optional
Rationale for change
Measurement of vital signs at the primary site on 
the day of the screening biopsy may not be always 
possible.
Section to be changed
Section 5.2.3
Description of change
Added information on the possibility to conduct 
safety laboratory tests in local laboratories




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require definition in the IPD specification 
document.
Rationale for change
Update to Sponsor process.
Section to be changed
Section 7.2.2
Description of change
Removed reference to China in FAS definition.
Removed reference to a main analysis in which 
patients from China are not included in the primary 
analysis.
Removed reference to a final analysis in which 
patients from China are included as a sensitivity 
analysis. Removed subsequent reference to a 
logistic regression model in which an additional 
factor (China, Rest of World) in included.
Rationale for change
Patients from sites in China will now be included 
in the primary analysis and are expected to provide 
timely biopsy data to enable this. 
There is no longer any reason to consider separate 
analyses of the primary endpoint with and without 
patients from sites in China.
Statistical analysis models are updated to reflect 
stratification changes in Section 7.4 (see separate 
description of change).
Section to be changed
Section 7.2.3
Description of change
Removed reference to China in FAS definition.
Removed reference to a main analysis in which 
patients from China are not included.
Removed reference to a final analysis in which 
patients from China are included.
These changes made 1) to the description of 
analysis of the secondary MRI-PDFF responder 
endpoint, and 2) to the description of  analysis of 
other secondary endpoints.
Rationale for change
Patients from sites in China will now be included 
in all analyses.
There is no longer any reason to consider separate 
analyses with and without patients from sites in 
China.
Section to be changed
Description of change


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Rationale for change
Section to be changed
Section 7.2.5
Description of change
Removed reference to China in TS definition.
Removed reference to a main analysis in which 
patients from China are not included.
Removed reference to a final analysis in which 
patients from China are included.
Rationale for change
Patients from sites in China will now be included 
in all analyses.
There is no longer any reason to consider separate 
analyses with and without patients from sites in 
China.
Section to be changed
Section 7.2.7
Description of change
Removed wording that the trigger for interim 
analysis (approximately half of randomised 
patients having reached Week 28) will exclude 
patients from sites in China.
Removed statement that the interim analysis will 
exclude data from patients from sites in China.
Amended statement that data for the interim 
analysis would only be cleaned for patients not 
from sites in China.
Rationale for change
If any patients from China have reached Week 28 
before the interim analysis trigger has been met, 
they will be included in the count of half of the 
planned randomised patients.
Irrespective of whether or not any patients from 
China have reached Week 28 by the time the 
interim analysis is triggered, patients from sites in 
China will be included in the interim analysis as far 
as their available data permit. Data will be cleaned 


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for this purpose accordingly.
Since the primary analysis will now include 
patients from sites in China, there is no longer any 
reason to consider a different requirement for the 
interim analysis with regard to those countries 
included.
Section to be changed
Section 7.2.7
Description of change
Removed considerations relating to the timing of 
liver biopsy results.
Removed reference to a main analysis in which 
patients from China are not included.
Removed reference to a final analysis in which 
patients from China are included.
Removed descriptions of separate database locks to 
handle the above items.
Rationale for change
It is expected that timely reading of liver biopsy
slides by the central pathologist is possible in all 
proposed countries.
There is no longer any reason to consider separate 
analyses with and without patients from sites in 
China.
Section to be changed
Section 7.4
Description of change
Removed stratification variable for country (Rest 
of World/China). Only presence of diabetes 
(Yes/No) is retained for stratification purposes, 
irrespective of country.
Rationale for change
Since China is not being handled differently from 
other countries with regard to 1) inclusion in the 
primary analysis and the expected timely 
availability of biopsy data to permit this, and 2) the 
use of the same central pathology reader as other 
countries, there is no longer any reason for the 
additional stratification.
Section to be changed
Section 7.5
Description of change
Statement removed that the 240 randomised 
patients planned according to statistical 
considerations does not include patients from sites 
in China.
Statement deleted that up to 24 additional patients 
from sites in China will be randomised.
Rationale for change
Patients from sites in China will be included in the 


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primary analysis and, as such, are now part of the 
240 patients planned to be randomised.
Section to be changed
Section 8.1
Description of change
Removed wording on the provision of a signed 
copy of the informed consent to the patient’s 
legally accepted representative
Rationale for change
Legally accepted representative will not be 
involved.
Section to be changed
Section 8.3.1
Description of change
Added paper 
 diaries to 
source documents
Rationale for change
In case of non-availability of 
 
 diaries paper documents may be 
used.
Section to be changed
Section 8.6
Description of change
Statement deleted that data from patients at sites in 
China will not be included in the final report.
Rationale for change
All patients will be included in the clinical trial 
report, regardless of location.
Section to be changed
All sections
Description of change
Corrected typographical errors
Rationale for change
Quality improvement of the document




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receptor agonists
Rationale for change
Accuracy of statement
Section to be changed
Section 3.3
Description of change
Changed the number of sites participating in the 
trial
Rationale for change
More sites are required to reach the patient 
recruitment target.
Section to be changed
Section 3.3.3
Description of change
1. Added information on hepatitis B patients
2. Corrected numbering of exclusion criteria from 
No. 3 to No. 20
3. Modified the cut-off for eGFR
4. Modified the cut-off for platelet count
5. Added information on patient participation in 
another interventional trial
Rationale for change
1. Clarification
2. Correction of the previous formatting error
3. Patients with mild or moderate renal 
impairment represent a relevant part of our 
target patient population. Data from a recently 
completed clinical trial in patients with T2DM 
that included patients with a baseline eGFR of 
45 mL/min/1.73m2 or higher show that the 
overall summary of adverse events in patients 
with eGFR < 60 mL/min/1.73m2 was largely in 
line with that of patients with eGFR ≥ 60 
mL/min/1.73m2.
Furthermore, publicly available eligibility 
criteria of other GLP-1R agonist based 
compounds included patients with eGFR 
between 45 and 60 mL/min/1.73m2 and this did 
not represent a safety concern for the patients. 
GLP-1R agonists with a marketing 
authorization do not require dose adjustments 
for patients with mild or moderate renal 
impairment.
4. Liver cirrhosis is accurately ruled out by 
histology in our trial, therefore patients without 
any sign of liver cirrhosis and a platelet count > 
110 x109/L are assumed to have a non-
significant risk of suffering from portal 
hypertension.
5. Clarification
Section to be changed
Section 3.3.4.1
Description of change
1. Added information on trial treatment 
discontinuation of individual patients who 
experience an infection with SARS-CoV-2


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2. Modified stopping rules of the trial. Instead of 
stopping the trial treatment in all patients 
further enrolment of new patients in the trial 
will be stopped until receiving the DMC 
recommendation. Timeline for the ad-hoc DMC 
meeting has not changed, it will take place 
within one week. Individual patients who 
experience an AE of CTCAE Grade 3 or higher 
that was assessed by the Investigator as related 
to the trial treatment will discontinue the trial 
treatment.
3. Specified criteria for Grade 3 CTCAE adverse 
events of nausea, vomiting, diarrhoea, 
constipation, or anorexia
Rationale for change
1. Investigator will take the totality of information
related to the patient and the local COVID-19 
situation into consideration when performing 
the individual benefit-risk assessment in order 
to determine whether the patient should 
continue to participate in the trial.
Alignment with the latest COVID-19 benefit-
risk assessment for BI 456906
2. GLP-1R agonist compounds require an 
accurate dose-escalation scheme before 
reaching the maintenance dose. In addition, 
certain tolerance is reached with time. Sudden 
stop and possible restart of the trial treatment in 
all patients may lead to drug tolerability issues 
in many patients.
Alignment of stopping rules with another BI 
456906 trial in patients with hepatic 
impairment
3. For the purpose of triggerring an ad-hoc DMC 
evaluation the CTCAE grading was put into a 
more clinically meaningful context to give the 
right value to the AEs which need to be 
considered for stopping the enrolment of new 
patients in the trial and potentially stopping the 
trial following DMC recommendation.
Alignment with another BI 456906 trial in 
patients with hepatic impairment
Rationale for change
Section 4.1.4 and 5.7
Section to be changed
Added information on the use of paper 
 
diaries in case of technical 
issues with the Science 37 platform
Description of change
Clarification
Section to be changed
Sect. 4.1.5.1


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Description of change
Added information on the exclusion of ADA and 
NAb samples taken from placebo patients from the 
analyses
Rationale for change
Consistency with PK samples
Section to be changed
Sect. 4.2.2.1
Description of change
1. Removed SGLT-2 inhibitors from the list of 
restricted concomitant medications
2. Added medications known to significantly 
prolong the QT/ QTc interval to the list of 
restricted concomitant medications
Rationale for change
1. There are no clinical concerns supporting the 
complete exclusion of T2DM patients treated 
with SGLT-2 inhibitors. 
2. Alignment with exclusion criterion No. 15
Section to be changed
Section 5.2.3
Description of change
Corrected the type of specimen for Free Fatty 
Acids 
Rationale for change
Consistency with the central laboratory documents
Section to be changed
Section 5.2.4
Description of change
Added information on a single ECG measurement 
at visits following Visit 1
Rationale for change
Clarification
Section to be changed
Section 5.3.2
Description of change
Removed the timepoint when PK samples may be 
used for further methodological investigations
Rationale for change
There is no reason to restrict the use of the samples 
only after the completion of the trial
Section to be changed
Section 6.1
Description of change
Added information on the minimum medical 
prerequisites that should be fulfilled in order to 
ship trial medication to the patient’s home when a 
patient cannot visit the site due to safety risks  
Rationale for change
Clarification
Section to be changed
Section 6.2.1
Description of change
1. Added information about possible extension of 
the screening period
2. Specified requirement for FibroScan® and MR 
imaging at re-screening
Rationale for change
1. Logistical issues may cause delays in the 
provision of results by the central vendor(s). 
Eligible patients who underwent a liver biopsy 
during the screening period should be 
considered for participation in the trial even if 
results were received more than 10 weeks after 
Visit 1 (ethical aspect).
2. Reduction of addional burden for patients.
FibroScan® and MR imaging do not have to be 


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repeated at re-screening if the assessments were 
performed within previous 1 month during the 
initial screening.
Section to be changed
Section 7.2.7
Description of change
Added information on the population PK/PD 
analysis that should be performed during the 
interim analysis
Rationale for change
Clarification
Section to be changed
Section 9.1
Description of change
Added reference to the consensus guideline for 
detection, assessment and management of 
suspected acute drug-induced liver injury (DILI) 
during clinical trials in patients with NASH
Rationale for change
Administrative change
Section to be changed
Section 10.1
Description of change
Revised guidelines for removal of individual 
patients in case of increased liver enzymes 
Rationale for change
Alignment with the consensus guidelines including 
provisions for patients with Gilbert’s syndrome
Section to be changed
Cover page, Synopsis, Abbreviations
Description of change
1. Changed Clinical Trial Protocol version and 
date
2. Added “IV” to abbreviations
Rationale for change
Administrative changes
Section to be changed
Multiple sections
Description of change
Corrected grammatical and typographical errors
Rationale for change
Quality improvement of the document


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11.4
GLOBAL AMENDMENT 4
Date of amendment
04 August 2022
EudraCT number
EU number
2020-002723-11
BI Trial number
1404-0043
BI Investigational Medicinal 
Product(s)
BI 456906
Title of protocol
Multicenter, double-blind, parallel-group, 
randomised, 48 weeks, dose-ranging, placebo-
controlled phase II trial to evaluate efficacy, safety 
and tolerability of multiple subcutaneous (s.c.) 
doses of BI 456906 in patients with non-alcoholic 
steatohepatitis (NASH) and fibrosis
Global Amendment due to urgent safety reasons
Global Amendment
Section to be changed
Section 1.3
Description of change
Corrected sample size to 240
Rationale for change
Correction was missed during the last two protocol 
amendments.
Section to be changed
Section 3.3.3
Description of change
Modified the cut-off for platelet count to the 
original level
Rationale for change
The trial is in the final stage of recruitment. 
Implementation of alternative non-invasive tests 
and/ or imaging tools for the exclusion of portal 
hypertension as requested by Health Authority 
would require more time than the remaining 
available time for recruitment. 
Section to be changed
Sect. 4.2.2.1
Description of change
Patients recently started on SGLT-2 inhibitors will 
be excluded.
Rationale for change
Recommendation from Health Authority


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11.5
GLOBAL AMENDMENT 5
Date of amendment
27 July 2023
EudraCT number
EU number
2020-002723-11
BI Trial number
1404-0043
BI Investigational Medicinal 
Product(s)
BI 456906
Title of protocol
Multicenter, double-blind, parallel-group, 
randomised, 48 weeks, dose-ranging, placebo-
controlled phase II trial to evaluate efficacy, safety 
and tolerability of multiple subcutaneous (s.c.) 
doses of BI 456906 in patients with non-alcoholic 
steatohepatitis (NASH) and fibrosis
Global Amendment due to urgent safety reasons
Global Amendment
Section to be changed
Section 4.1.5.1 and 7.2.7
Description of change
Modified information on purpose of the interim 
analysis and access to unblinded data from the 
interim analysis
Rationale for change
Considering that the mean BMI of patients 
recruited in this trial is approx. 36 kg/m2, data on 
liver fat reduction (and liver benefit in general) in 
this patient category are very informative for the 
future development program of BI 456906 in 
chronic weight management, going into phase III
by Q4/2023. The availability of this data will help 
enrolling the best patient population into the 
trial(s), targeting patients who may benefit most. 
As the phase II trial in chronic weight management 
(1404-0036) has not generated liver data, as 
opposed to 1404-0043, it is important to inform 
investigators, study personnel, patients and their 
relatives involved in the phase III program of BI 
456906 in chronic weight management about these 
benefits in a timely manner, considering that the 
updated version of the Investigator Brochure 
(planned issue in Q4 2023) will not include interim 
analysis data and, importantly, will not be able to 
appropriately reach and inform patients and 
caregivers.
The availability of this data will help positioning 
BI 456906 among the available drugs in 
development for chronic weight management, 
independently of the NASH indication.
Section to be changed
Section 5.2.3 (Table 5.2.3:1)
Description of change
Corrected information on availability of eGFR 


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results
Rationale for change
Typographical error


 
 
 
APPROVAL / SIGNATURE PAGE 
Document Number: 
 
Technical Version Number:
Document Name: 
                                                                                                                 
 
Title: 
                                                                                                                   
Signatures (obtained electronically) 
Meaning of Signature  
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Boehringer Ingelheim 
Page 2 of 2
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
c38524321-02
BI Trial No.:
1404-0043
Title:
Multicenter, double-blind, parallel-group, randomised, 48 weeks, 
dose-ranging, placebo-controlled phase II trial to evaluate 
efficacy, safety and tolerability of multiple subcutaneous (s.c.) 
doses of BI 456906 in patients with non-alcoholic steatohepatitis 
(NASH) and fibrosis
Investigational
Product(s):
BI 456906
Responsible trial 
statistician(s):
Trial Statistician
Tel.: 
Email: 
Date of statistical 
analysis plan:
19JAN2024 SIGNED
Version:
2.0
Page 1 of 72
Proprietary confidential information
! 2024 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: 1404-0043
c38524321-02
Page 2 of 72
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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.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................9
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY ENDPOINT(S) ..................................................................................9
5.2
SECONDARY ENDPOINT(S) ..........................................................................12
5.2.1
Key secondary endpoint(s).................................................................................12
5.2.2
Secondary endpoint(s) ........................................................................................12
5.4
OTHER VARIABLE(S) .....................................................................................19
5.4.1
Safety....................................................................................................................19
5.4.2
Demographic and other baseline characteristics .............................................22
5.4.3
Treatment exposure and compliance ................................................................22
5.4.5
Immunogenicity variables..................................................................................24
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................25
6.1
TREATMENT(S)................................................................................................25
6.1.1
Study Phases........................................................................................................25
6.1.2
Planned Maintenance Treatment Group..........................................................25
6.1.3
Actual Maintenance Treatment Group.............................................................26
6.1.4
Handling of Treatment Errors and Discrepancies...........................................27
6.1.5
Pooling Across Doses ..........................................................................................28
6.1.6
Definition of On-Treatment ...............................................................................28
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................29
6.3
SUBJECT SETS ANALYSED...........................................................................29
6.5
POOLING OF CENTRES .................................................................................32
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................33
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................34
7.
PLANNED ANALYSIS......................................................................................42
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........43
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................43
7.3
TREATMENT COMPLIANCE........................................................................44
7.4
PRIMARY ENDPOINT(S) ................................................................................44
7.4.1
Primary analysis of the primary endpoint(s) ...................................................45


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7.5
SECONDARY ENDPOINT(S) ..........................................................................47
7.5.1
Key secondary endpoint(s).................................................................................47
7.5.2
Secondary endpoint(s) ........................................................................................48
7.7
EXTENT OF EXPOSURE.................................................................................60
7.8
SAFETY ANALYSIS..........................................................................................60
7.8.1
Adverse Events....................................................................................................61
7.8.2
Laboratory data ..................................................................................................63
7.8.3
Vital signs.............................................................................................................65
7.8.4
ECG......................................................................................................................65
7.8.5
Other ....................................................................................................................67
7.9
ANALYSIS OF COVID-19 IMPACT...............................................................68
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION.............69
9. 
REFERENCES....................................................................................................70
11.
HISTORY TABLE..............................................................................................72


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LIST OF TABLES
Table 5.1: 1
NAS scoring system for liver biopsies .............................................................10
Table 5.1: 2
Fibrosis staging for liver biopsies.....................................................................11
Table 6.1.1: 1 Study phases .....................................................................................................25
Table 6.1.3: 1 Definition of actual maintenance treatment group for patients randomised to 
active Survodutide maintenance treatment who discontinued treatment 
during the dose escalation period .....................................................................27
Table 6.3: 1
Subject sets analysed ........................................................................................31
Table 6.7: 1
Visit windows for variables scheduled to be assessed at all or most visits......37
Table 6.7: 2
Visit windows for biomarkers ..........................................................................38
Table 6.7: 3
Visit windows for variables with an intermediate visit schedule. ....................39
Table 6.7: 4
Visit windows for variables with a sparse visit schedule. ................................40
Table 11: 1
History table .....................................................................................................72


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADA
Anti-drug antibodies
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine aminotransferase (SGPT)
ANCOVA
Analysis of covariance
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
CAP
Control Attenuation Parameter
CI
Confidence interval
CLDQ
Chronic Liver Disease Questionnaire
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
eGFR
Estimated Glomerular Filtration Rate
ELF
Enhanced Liver Fibrosis
EOT
End of treatment


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Term
Definition / description
EQ-5D 5L
European Quality of Life Questionnaire – 5 Dimensions 5 Levels
FAS
Full Analysis Set
FFA
Free Fatty Acids
FGF-21
Fibroblast Growth Factor 21
Fib-4
Fibrosis-4 index
GGT
Gamma-glutamyl transferase
HDL
High Density Lipoprotein
HMW
High Molecular Weight
HR
Heart rate
ICH
International Conference on Harmonisation
IPD
Important protocol deviation
IRT
Interactive Response Technology
iSAT
Independent safety analysis team
iSTAT
Independent statistician
LDL
Low Density Lipoprotein
LLOQ
Lower Limit of Quantification
MAR
Missing at random
MCP-Mod
Multiple Comparison Procedures and Modelling
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
MMRM
Mixed model for repeated measures
MNAR
Missing not at random
MRI-PDFF
Magnetic Resonance Imaging - Proton Density Fat Fraction
NA
Not applicable
NAb
Neutralising antibodies
NAFLD
Non-Alcoholic Fatty Liver Disease
NAS
NAFLD Activity Score
NASH
Non-Alcoholic SteatoHepatitis
PD
Protocol deviation
PK
Pharmacokinetics
PPS
Per protocol set
PRO
Patient Reported Outcome


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Term
Definition / description
Pro-C3
N-terminal propeptide of type III collagen
PT
Preferred term
Q1
Lower quartile
Q3
Upper quartile
REP
Residual effect period
SAP
Statistical analysis plan
SD
Standard deviation
SOC
System organ class
TMF
Trial Master File
TS
Treated Set
UACR
Urine albumin/creatinine ratio
ULN
Upper limit of normal
ULOQ
Upper Limit of Quantification
VLDL
Very Low Density Lipoprotein
WHO
World Health Organisation
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 1404-0043. One interim analysis was
planned. This was described in a separate interim statistical analysis plan, and is not addressed 
further in this document. The interim analysis results were not intended to be used to stop the 
trial (which continued without modification after the interim analysis was performed), nor to 
make confirmatory claims. No statistical adjustments to Type 1 error are therefore considered 
necessary.


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This TSAP is based on the 1404-0043 CTP (Version 6.0, 27JUL2023), together with the latest 
versions of the eCRF and relevant Data Transfer Agreements (DTAs) for external vendor 
data. The local protocol amendment for China (Version 1.0, 20APR2022) is also relevant to 
TSAP details regarding handling of biopsy 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.
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 final DBL.
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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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
The CTP also defined a Full Analysis Set (FAS) for efficacy analyses, which was defined in 
exactly the same way in the CTP as the Treated Set (TS) for safety analyses, i.e. both were 
defined as all randomized and treated patients. Reference to only the TS is retained in this 
document; the TS will be used for all efficacy and safety analyses.
5.
ENDPOINTS
5.1
PRIMARY ENDPOINT(S)
The primary endpoint is the improvement (yes/no) from baseline in histological findings 
based on liver biopsy after 48 weeks of treatment. In practice, patients who discontinued 
treatment early but after 40 weeks of treatment are expected to have a post-baseline liver 
biopsy performed, and will also contribute to the primary endpoint derivation.
Patients are expected to have NAS ≥ 4 and a fibrosis stage of F1a, F1b, F1c, F2 or F3 at 
baseline, according to the entry criteria for the trial.
Improvement in histological findings is defined as a composite of:
1. Improvement in NASH:
∀
Decrease of at least 2 points in NAS, with at least 1 point decrease in NAS 
sub-score of either lobular inflammation or ballooning,
and
2. No worsening of fibrosis
∀
Absence of any increase in fibrosis stage.
The NAS and fibrosis scoring system is summarized below. Details of the meaning of each 
grade/stage are referred to the CTP.


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Table 5.1: 1
NAS scoring system for liver biopsies
Steatosis
Lobular 
Inflammation
Ballooning
NAS (Total 
Score)
Grade 0
Grade 0
Grade 0
Grade 1
Grade 1
Grade 1
Grade 2
Grade 2
Grade 2
Grade 3
Grade 3
Range
0-3
0-3
0-2
0-8
The total score for NAS is the sum of the 3 NAS sub-scores for steatosis, lobular 
inflammation and ballooning respectively. 


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Table 5.1: 2
Fibrosis staging for liver biopsies
Fibrosis stage
Fibrosis score
Stage F0
0
Stage F1a
1
Stage F1b
1
Stage F1c
1
Stage F2
2
Stage F3
3
Stage F4
4
Range
0-4
The fibrosis score is the same as the assigned stage of fibrosis without the distinction whether 
a stage of F1a, F1b or F1c was recorded (for a fibrosis score of 1). A patient who has a 
baseline fibrosis stage of F1a, F1b or F1c and a different post-baseline fibrosis stage of F1a, 
F1b or F1c is not considered to have worsening or improvement in fibrosis.
Central pathology readings of biopsy slides will be used. These will be physical central 
pathology readings for patients at sites in all countries, except in China where digital central 
pathology readings will be used for baseline in the primary endpoint definition (see further 
below). 
All central pathology readings on the database which are considered adequate will be used, 
including any readings which may be performed by the back-up reader instead of the primary 
reader. An adequate liver biopsy reading means that the central pathology reader is able to 
fully read the slides provided (2 different types of staining; 1 per slide), and consequently 
provide values for all of the 3 NAS sub-scores and for the fibrosis stage, using the CTP 
guidance on scoring/staging. An inadequate liver biopsy reading will be completely re-read 
using at least one new stained slide, even if it could be partially read at the first attempt. 
Consequently, only adequate readings are expected to contribute data for analysis, and 
missing data at the level of individual items is not expected. In practice, any data records 
which are not labelled as inadequate on the database will be assumed to be adequate.
For baseline biopsy, either a biopsy performed during the screening period or a historical 
biopsy (within 6 months) will be used to provide baseline data, without any further distinction 
made for analysis purposes between these two situations. 
For patients at sites in China, a single physical central pathology reading of the screening 
biopsy is expected to be available as part of the batch reading (screening reading 2). This will 


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not be used for baseline, since it may generate baseline values which are outside the ranges 
defined by the entry criteria, which may in turn create further issues with applying endpoint 
derivations and statistical models. Therefore, for patients at sites in China, the digital central 
pathology reading of the screening biopsy (screening reading 1) will be used as baseline. The 
potential limitations of using a digital baseline reading versus a physical post-baseline reading 
for primary endpoint purposes in China are acknowledged here. For patients at sites outside
China, two physical central pathology readings of the same screening biopsy are expected to 
be available. The first of these (i.e. as used to assess eligibility) will be used for baseline
(screening reading 1).
All available post-baseline biopsy data from physical central pathology reading will be used 
in the primary endpoint definition, with no restriction on how long the biopsy was done after 
the end of treatment, and using all available post-baseline biopsy results from patients who 
discontinued treatment early (including any results done earlier than Week 40, in the unlikely 
event that this situation exists). Patients without a post-baseline biopsy will be imputed as 
non-responders, regardless of whether a biopsy result was expected or not.
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
There are no key secondary endpoints defined in this trial.
5.2.2
Secondary endpoint(s)
Secondary endpoints are defined as follows:
MRI-PDFF 
∀
Improvement in liver fat content (yes/no), defined as a percentage reduction of 
at least 30% from baseline in liver fat content, measured in units of % using 
MRI-PDFF, after 48 weeks of treatment.
Liver fat content (mean PDFF) in % is defined as the simple (unweighted) arithmetic mean of 
values from each of 9 liver segments obtained from a technically acceptable image reading. 
The mean will be calculated by the vendor and provided in the data transfer. If fewer than 9 
liver segments can be read, the mean value will still be calculated, provided that 3 or more 
liver segments can be read. If fewer than 3 liver segments can be read, the mean will not be 
calculated and liver fat content (mean PDFF) is then expected to be missing. All non-missing 
values of liver fat content will be used for analysis, including those values derived from 3-8 
liver segments.




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5.4
OTHER VARIABLE(S)
5.4.1
Safety
Safety will be assessed based on:
∀
Adverse events
 Routine reporting using the Medical Dictionary for Regulatory 
Agencies (MedDRA) coding dictionary (version in force at final DBL)
 Adverse events of special interest (AESIs)
 Adjudicated adverse events
∀
Laboratory variables
 Specific laboratory tests are listed in CTP Table 5.2.3: 1
∀
Vital signs
 Pulse rate
 Systolic blood pressure
 Diastolic blood pressure
∀
12-lead ECG
Further details regarding 12-lead ECG derivations are given below.
∀
Columbia - Suicide Severity Rating Scale (C-SSRS)
Laboratory data


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Estimated glomerular filtration rate (eGFR) and urine albumin/creatinine ratio (UACR) will 
be used as provided by the central laboratory, i.e. it will not be re-derived for analysis.
Fib-4 index and APRI will also be used as provided by the central laboratory.
12-lead ECG
Single digital ECG recordings are planned to be collected at each relevant visit with the 
exception of screening, where triplicate ECG recordings are planned. Each of the recorded 
single ECGs will then be evaluated for cardiac intervals, which comprise the RR, PR and QT 
interval and the QRS duration. Measurements of these intervals will be made on four cardiac 
cycles from the lead chosen (details not specified here).
The measurements of the cardiac cycles will be stored in the database, i.e. four values per visit 
(for a single ECG). The four cardiac cycles (or however many available) will be averaged, to 
give a single mean value for each visit. This will be done prior to the calculation below of the 
heart rate (HR) and heart rate corrected QT interval (QTc).
For screening only, where a triplicate ECG is expected, the mean values obtained for each 
single ECG will be further averaged across the 3 ECGs (or however many available) to give a 
single mean value for each variable at screening.
The heart rate will be derived from the RR interval as:
HR [beats/min] = 60 000
RR

where RR is the mean of the four RR intervals (measured in msec).
The QT interval corrected for HR according to Fridericia’s formula (QTcF) for a single ECG 
will be derived as:
QTcF
 [msec] = 1000
RR
 
/
∗QT
[msec],
where QT
 is the mean of the four QT intervals and RR
 is the mean of the corresponding 
preceding RR intervals of the four cardiac cycles for this ECG.
Likewise, the HR-corrected QT interval according to Bazett’s formula (QTcB) for a single 
ECG is given by
QTcB
 [msec] = 1000
RR
 
/!
∗QT
[msec].
In the case that more than one ECG is available (i.e. more than one group of cardiac cycles) at 
a visit where a single ECG was planned, then the (first) ECG on that day which is not labelled 
as “UNSCHEDULED” will be used, regardless of the reason for this.
New onsets for categorical endpoints are derived based on the tables below:


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5.4.2
Demographic and other baseline characteristics
Standard demographic variables and baseline characteristics are used as recorded on the 
eCRF. 
The NAS and fibrosis scoring system is summarised in Section 5.1. 
Baseline definitions are given in Section 6.7.
Time since NASH diagnosis will be calculated relative to randomisation date, not relative to 
informed consent date, since some investigators may only have considered the diagnosis to be 
confirmed after the screening biopsy was taken.
5.4.3
Treatment exposure and compliance
Treatment exposure is defined as the number of days from the first dose of study treatment to 
the last dose of study treatment inclusive. Any intermediate gaps in treatment in which the 
patient did not take medication will not be considered. It is assumed that an End of Treatment 
eCRF page will be available and complete for all treated patients at DBL, and that no special 
rules are needed to handle any missing information here.
Treatment exposure duration will be categorized as follows:
<4 weeks; 4-<8 weeks; 8-<12 weeks; 12-<16 weeks; 16-<20 weeks; 20-<24 weeks, 24-<28 
weeks; 28-<32 weeks; 32-<36 weeks; 36-<40 weeks; 40-<44 weeks; 44-<48 weeks; ≥48
weeks.


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Study duration (regardless of whether on-treatment) will also use the same category 
definitions, although significant off-treatment follow-up after stopping treatment is not 
expected in this trial.
No treatment compliance calculations will be performed for analysis purposes based on return 
of unused and empty syringes. Any discrepancies between medication assigned, medication 
dispensed and medication administered will be assessed through the process for determining
IPDs.


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5.4.5
Immunogenicity variables
Immunogenicity will be evaluated using anti-drug antibodies (ADA) and neutralising 
antibodies (NAb). Only ADA is expected to be available for the CTR. 


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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 26 (Week 24)
Treatment phase –
maintenance
Date of Visit 26 (Week 24) 
Date of Visit 32 (Week 48)
Follow-up phase
Day after Visit 32 (Week 
48)
Date of end of study 
participation (expected to be 4 
weeks after Visit 32 (Week 
48))
* See also baseline definitions in Section 6.7.
Patients who discontinue treatment early are not required or expected to complete the planned 
treatment phase. The follow-up phase is defined in the protocol as up to 4 weeks after the end 
of the planned treatment phase for patients who completed treatment, or 4 weeks after the End 
of Treatment visit for patients who discontinued early. It is not therefore expected that there 
will be a significant amount of data captured in this trial for any patients which is more than 
about a month after stopping treatment.
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 Group
Patients are randomised to one of four treatment groups (Placebo, Survodutide 2.4 mg, 
Survodutide 4.8 mg, Survodutide 6.0 mg). These are the planned maintenance treatment
groups (weekly doses). 


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For the purposes of display in outputs, “planned treatment” means the same as “planned 
maintenance treatment”.
6.1.3
Actual Maintenance Treatment Group
According to the rules for escalating and adjusting the Survodutide 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 group will be defined for analysis as follows:
∀
If the patient started the maintenance period, then actual maintenance treatment group 
will be defined in all circumstances to be the dose at the start of the maintenance 
period (which is expected to be one of the Survodutide maintenance doses), regardless 
of whether previous dose escalation was performed in the expected way according to 
the protocol. This includes each of the following situations:
o
Any patient who successfully reached their planned maintenance dose at the 
end of the dose escalation period
o
Any patient who did not reach their planned maintenance dose at the end of the 
dose escalation period, and who only reached a lower maintenance dose
o
Any patient for whom the start and end maintenance dose are not the same, 
regardless of whether the patient started the maintenance period on their
planned maintenance dose, and regardless of whether the permanent dose 
reduction was planned according to the protocol, or whether it was unplanned 
(e.g. where the wrong tolerability information was given to the IRT and the 
dose was not re-escalated back to correct the error).
∀
If the patient discontinued treatment during the dose escalation period, actual 
maintenance treatment group will be defined as the next planned maintenance dose up 
from the dose at discontinuation. The same rule will be applied irrespective of the 
reason for discontinuing treatment during the dose escalation period, and will be 
applied irrespective of whether the dose prior to the dose at discontinuation was as 
anticipated from the protocol dose escalation strategy.


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Table 6.1.3: 1 Definition of actual maintenance treatment group for patients randomised to 
active Survodutide maintenance treatment who discontinued treatment during 
the dose escalation period
Dose at discontinuation
Actual maintenance treatment group
Dose = 0 mg
0.3 mg ≤Dose ≤ 2.4 mg
Placebo
2.4 mg
2.4 mg < Dose ≤ 4.8 mg
4.8 mg
Dose > 4.8 mg
6.0 mg
∀
All patients randomised to placebo maintenance treatment or who were switched to 
placebo during the dose escalation period will be assigned to placebo for actual 
maintenance treatment group.
For the purposes of display in outputs, “actual treatment” means the same as “actual 
maintenance treatment”.
The above rules cover all known and anticipated situations. The possibility of other situations
which are not anticipated from the protocol, and which cannot be identified from blinded data,
cannot however entirely be excluded. A review of unblinded dosing data will be performed 
immediately after unblinding the database at DBL, to identify any dosing situation for which 
the above TSAP rules might not not be adequate. Such situations might include, but not 
necessarily be limited to, unexpected increases in maintenance dose, or starting Survodutide 
maintenance doses which are not one of 2.4 mg, 4.8 mg or 6.0 mg. An attempt will be made 
to find out whether data error or omission is the explanation, or whether a real issue actually 
occurred in any such patients. Any additional decisions required on assigning actual 
maintenance treatment at that time will be documented in the CTR.
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. 


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Dosing errors (other than through incorrect IRT transactions, as described in Section 6.1.3)
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. 
6.1.5
Pooling Across Doses
In addition to specific Survodutide dose columns on descriptive summary tables, a combined 
column across doses (i.e. “All Survodutide”) will also be presented. 
Combined Survodutide dose will not be used in any statistical models or descriptive 
summaries of efficacy.
Combined Survodutide dose will be included on all disposition and demographic/baseline 
summary tables, and in descriptive summaries of treatment exposure and safety.
Where a short treatment label is required on outputs, “Survo X.X mg” and “All Survo” will be 
used for the specific dose groups, and the combination across dose groups, respectively.
6.1.6
Definition of On-Treatment
There is no continued study participation for patients who have discontinued treatment early. 
Consequently off-treatment data capture is expected to be restricted to those data captured 
during the safety follow-up period specified by the CTP, although there may be occasional 
unplanned exceptions to this.
Even for patients who completed treatment according to the protocol, data captured during the 
follow-up period may be relevant for safety.
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, and it includes any temporary treatment interruptions 
which might occur prior to last dose of study treatment. It is assumed that all patients will 
have 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 


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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
All post-baseline efficacy data (including for exploratory biomarkers) will use the same 28-
day definition of “on-treatment” as for safety, where on-treatment analyses are specified (as 
opposed to those efficacy analyses which use all data, both on- and off-treatment).
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.
The TS will be used for presentation of demographic/baseline data, concomitant 
medications/diagnoses, treatment exposure, efficacy and safety.
Treatment assignment will be according to both actual maintenance treatment and planned 
maintenance treatment (i.e. as randomised), depending on the analysis.
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 






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6.5
POOLING OF CENTRES
No analysis will be performed in which centre is included in the statistical model.




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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 Survodutide 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. 
Unscheduled and repeat assessments are eligible for use as baseline values provided that they 
meet the above criterion.
For 12-lead ECG, if a screening value needs to be used for baseline, it will be the average of 
all available triplicate screening ECG measurements (see Section 5.4.1 for derivation details).
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. A single pre-dose measurement is expected to be captured at the baseline visit (Visit 2), 
which will therefore be used as baseline. In any situation in which only a post-dose 
measurement is available at Visit 2 and no pre-dose measurements, Visit 2 will not be used as 
baseline; the screening visit (Visit 1) will be used as baseline instead.
For baseline NAS and fibrosis scores, the following specific considerations will be applied:
∀
Either a biopsy performed during the screening period or a historical biopsy (within 6 
months) will be used to provide baseline data, without any further distinction made for 
analysis purposes between these two situations (both referred to subsequently as 
“screening biopsy”). 
∀
The baseline value will be derived from central pathology readings of screening 
biopsy slides. For sites in all countries except China, central pathology screening 
readings will always be physical readings. For sites in China, central pathology 
screening readings may be digital readings, the handling of which is described below.
∀
All adequate central pathology readings which meet the baseline definition will be 
used, including any (expected to be occasional) readings performed by the back-up 


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reader instead of the primary reader. The meaning of “adequate” is given in Section 
5.1.
∀
The first screening central pathology reading (i.e. as used to assess eligibility) will be 
used for baseline in all cases where a re-reading of the screening biopsy was 
subsequently done, unless otherwise specified for any analysis. For sites in China 
(only), the first screening central pathology reading is a digital reading and this will be 
used.
MRI-PDFF and 
procedures are only scheduled to be performed at screening, and 
not also at the randomisation visit. Therefore, the baseline value is the screening value in 
these cases. 
Visit windows
All summaries and analysis which are presented by week will use a visit window to classify 
the data record. 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.
Prior to applying the rules for handling multiple values in visit windows specified below, it 
will first be determined whether the data record is on-treatment, as defined in Section 6.1.6, 
for all 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).


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Four different situations are envisaged, which are described in the following tables:
∀
Visit windows for variables scheduled to be assessed at all or most clinic visits
∀
Visit windows for biomarker variables
∀
Visit windows for variables with an intermediate clinic visit schedule
∀
Visit windows for variables with a sparse clinic visit schedule


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Table 6.7: 1
Visit windows for variables scheduled to be assessed at all or most visits
Period
Time Point
Target Day
Visit Window
Dose escalation
Week 1
8
2-11
Week 2
15
12-18
Week 3
22
19-25
Week 4
29
26-35
Week 6
43
36-49
Week 8
57
50-63
Week 10
71
64-77
Week 12
85
78-98
Week 16
113
99-126
Week 20
141
127-154
Maintenance
Week 24
169
155-182
Week 28
197
183-210
Week 32
225
211-238
Week 36
253
239-266
Week 40
281
267-294
Week 44
309
295-322
Week 48
337
≥ 323
The relevant variables are expected to include vital signs, routine laboratory safety variables 
(all expected to be non-fasting), 12-lead ECG and the mental health questionnaire (C-SSRS).
In particular, the Week 2 and Week 4 visit windows from this table will still be used for 
laboratory safety variables and 12-lead ECG, even though these are not also scheduled at 
Week 1 and Week 3.


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Table 6.7: 3
Visit windows for variables with an intermediate visit schedule.
Period
Time Point
Target Day
Visit Window
Dose escalation
Week 8
57
2-84
Week 16
113
85-154
Maintenance
Week 28
197
155-266
Week 48
337
≥ 267
The relevant variables are expected to be body weight / BMI derived from this, waist 
circumference and hip circumference.


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Table 6.7: 4
Visit windows for variables with a sparse visit schedule.
Period
Time Point
Target Day
Visit Window
Maintenance
Week 28
197
2-266
Week 48
337
≥ 267
The relevant variables are expected to be MRI-PDFF and the 
.
The use of such a wide visit window for MRI-PDFF at Week 28 means that it will include and 
display/analyse as “Week 28” any MRI assessments which were done unexpectedly early.
Post-baseline biopsy
Patients are scheduled to provide data from a single post-baseline biopsy at Week 48, which 
may be earlier (expected 40 weeks onwards) for patients who discontinued early, but 
nevertheless remained on treatment for long enough to justify performing the biopsy. Two 
different ways of handling this in analysis are planned, and these are expected to be identical 
if the protocol requirements are followed exactly:
∀
All post-baseline biopsy data are used, regardless of how early the biopsy was done 
(this is equivalent to specifying a single visit window for “Week 48” as ≥2 days)
∀
Only post-baseline biopsy data are used which are after 40 weeks (this is equivalent to 
specifying a single visit window for “Week 48” as ≥280 days)
Vital signs
For vital signs, the following windowing rules will be applied within each visit to determine 
pre-dose and 10 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). If this selects more than one value as “pre-dose”, the 
latest 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). If this selects more than one value as “post-dose”, the value closest in time to 
the target 10 minute post-dose time point will be used.
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 final 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 48 
measurements) will be considered “pre-dose” according to the above rules. Only pre-dose 
measurements will be used for efficacy purposes (blood pressure further endpoints).


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7.
PLANNED ANALYSIS
Descriptive statistics for continuous variables will generally include 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. 
Tabulations of frequencies for categorical data will include all possible non-missing 
categories unless otherwise specified, 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. It 
should be noted that in this study, a patient is considered to have completed the study if all 
scheduled safety follow-up procedures have been performed for that patient, including for 
patients who discontinued treatment early. In other words, a patient may complete this study 
without completing treatment.
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 planned maintenance treatment 
group for time to early treatment discontinuation (defined as treatment discontinuation date 


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– 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 planned maintenance treatment.
A shift table will be produced to display differences between planned maintenance treatment 
and actual maintenance treatment.
A shift table will also be produced to display differences between the first and last doses of 
maintenance treatment (for patients who reached the maintenance period). This shift table 
will be produced separately using both dispensed and administered dosing.
IPDs will be summarised and listed for the randomised set using planned maintenance 
treatment.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Descriptive summaries of the following 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), systolic BP (mmHg), diastolic BP (mmHg), pulse rate (bpm), country and 
region.
In addition, the overall baseline NAS and 3 NAS sub-scores, the baseline fibrosis stage and 
the time since NASH diagnosis will be summarised.
Summaries of demographic data and baseline characteristics will be presented on the TS using 
both planned maintenance treatment and 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 all use both of actual 
maintenance treatment and planned 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 medical history (“Medical History – Specific Conditions” eCRF page) for the 
relevant summary table (see below).
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), which will include coded trial-specific 


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medical history. In addition, trial-specific medical history will be summarised using reported 
term from the eCRF page (i.e. Diabetes Mellitus Type 1, Diabetes Mellitus Type 2, Diabetes 
Mellitus Other or Unknown, Arterial Hypertension, Hyperlipidaemia, Cardiac Dysrhythmias, 
Metabolic Syndrome).
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. 
Concomitant non-drug therapy will be summarised by SOC and PT. Prior non-drug therapy 
will not be summarised. 
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 describes 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 Survodutide 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 Survodutide
dose.
7.4
PRIMARY ENDPOINT(S)
Frequency tables will be produced of the primary endpoint (improvement in histological 
findings based on liver biopsy after 48 weeks of treatment, as defined in Section 5.1) in each 
of the following different ways:
∀
TS, actual maintenance treatment, using all post-baseline biopsy data (both on- and 
off-treatment as defined in Section 6.1.6, and irrespective of timing relative to first 
dose of study treatment)
∀
TS, planned maintenance treatment, using all post-baseline biopsy data (as above)


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∀
TS, actual maintenance treatment, using only on-treatment post-baseline biopsy data 
which are at least 280 days (40 weeks) after first dose of study treatment
∀
TS, planned maintenance treatment, using only on-treatment post-baseline biopsy data 
which are at least 280 days (40 weeks) after first dose of study treatment.
The above frequency tables will display the number and proportion of responders and non-
responders respectively. Non-responders will be further split on these tables into those derived 
from the available data without imputation and those which were imputed due to a missing 
response.
7.4.1
Primary analysis of the primary endpoint(s)
The primary analysis of the primary endpoint will be performed on the TS using actual 
maintenance treatment, and using all post-baseline biopsy data (as above). Patients without 
post-baseline biopsy (whether this is expected or not) will be imputed as non-responders in 
this analysis.
A logistic regression will first be performed on the primary endpoint to estimate the treatment 
effects of multiple doses of Survodutide and placebo, together with the corresponding 
variance-covariance matrix. Applying the Multiple Comparison Procedures and Modelling 
(MCPMod) approach, these estimates will then be further used to test for a non-flat dose 
response curve and to identify suitable dose-response shapes out of a selection of candidate 
models.
The MCPMod approach [R10-1424, R15-4293] is implemented in two main steps: (1) trial 
design stage; (2) trial analysis stage. The procedures for the trial design stage, including the 
selection of candidate models covering a suitable range of dose-response shapes, are provided 
in the CTP Section 7.2.2. Additional details for the trial analysis stage are specified below.
Logistic regression
The responses for each dose group, as well as their variance-covariance matrix, for the 
primary endpoint will be estimated using a logistic regression (using a logit link via PROC 
LOGISTIC in SAS®). The logistic regression model will be fitted without an intercept, and 
will include presence of diabetes of any type [yes, no], baseline fibrosis score [F1, F2, F3] and 
the dose group as factors. In the case that 0 events are observed in any combination of dose 
group and strata, a penalized regression based on the Firth bias reduction method [R20-2291] 
will be used. The subsequent MCPMod analysis will be fully carried out on the logit scale, 
and the graphical displays of the fitted models in the Mod step will then be converted from 
the logit scale to the probability scale for interpretation reasons.
A summary table will be produced of the logistic regression results, including estimated odds 
ratios for the comparison of each Survodutide dose against placebo and their 95% confidence 
intervals and associated p-values.
MCPMod
The “DoseFinding” package [R15-2001] will be used for MCPMod analysis.


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The multiple comparison procedure will be implemented using contrast tests which control 
the family-wise type I error rate at a one-sided α = 0.05. Candidate models will be used as 
described in the CTP Section 7.2.2, that is:
∀
Linear
∀
Exponential1: 25% of maximum effect achieved at dose 3.0 mg (note: this dose is 
used for model specification only, it was not included in the trial)
∀
Exponential2: 5% of maximum effect achieved at dose 3.0 mg 
∀
Emax1: 50% of maximum effect achieved at dose 3.0 mg
∀
Emax2: 80% of maximum effect achieved at dose 3.0 mg
∀
Quadratic: Maximum effect achieved at dose 4.8 mg.
For the MCPMod test, the contrast coefficients of each candidate model will be calculated 
using the R-function ‘optContr’ based on observed results from the logistic regression (with 
Firth bias reduction if used), that is, the variance-covariance matrix from the logistic 
regression step will be used as input to ‘optContr’.
If at least one dose-response model is statistically significant, the null hypothesis of a flat 
dose-response curve can be rejected indicating a benefit of Survodutide over placebo.
All dose-response models will be re-fitted to the data (irrespective of statistical significance in 
the previous step) without any parameter assumptions to generate a set of new estimates of the 
model parameters. For all significant models, the generalised Akaike Information Criterion 
(AIC) will be calculated and reported in the displays. The final model will be chosen as the 
model with the best fit according to AIC, that is, the model with the smallest AIC value.
The target dose for MCPMod purposes is defined as the smallest Survodutide dose which is 
estimated to achieve an absolute improvement in the proportion of patients with a histological 
improvement based on liver biopsy after 48 weeks of treatment of 20% or more compared 
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 following tables and displays are planned:
∀
Table of the contrast coefficients per dose group and candidate model, together with 
the MCPMod test statistics and p-values for each model, and the critical value.
∀
For all models fitted to the observed data: Figure of the fitted dose-response curve plus 
95% confidence band overlayed with adjusted mean and corresponding 95% 
confidence interval per dose (estimated from the logistic regression (with Firth bias 
reduction if used)) – this figure is plotted on the logit scale.
∀
For all models fitted to the observed data: Figure of the fitted dose-response curve plus 
95% confidence band overlayed with adjusted mean and corresponding 95% 


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confidence interval per dose (estimated from the logistic regression (with Firth bias 
reduction if used)) – this figure is plotted on the probability scale (figure converted 
from logit-scale to probability scale).
The predicted Survodutide dose which achieved a 20% improvement in absolute responder 
proportions compared with placebo will be annotated onto the above figures on the 
probability scale for the significant model shapes (Linear, Exponential, Emax and Quadratic).
7.4.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the primary 
endpoint(s)
Sensitivity analysis
The analysis of the primary endpoint specified in Section 7.4.1 will be repeated for the 
following, using the same model for estimation (logistic regression with Firth bias reduction if 
necessary) unless otherwise specified, with the same model terms, and using the same 
subsequent MCPMod procedure:
∀
Planned maintenance treatment; using all post-baseline biopsy data (as above)
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.




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All dose-response models will be re-fitted to the data (irrespective of statistical significance in 
the previous step) without any parameter assumptions to generate a set of new estimates of the 
model parameters. For all significant models, the generalised AIC will be calculated and 
reported in the displays. The final model will again be chosen as the model with the best fit 
(smallest AIC).
Estimates for each dose group will be calculated and will be based on the final dose-response 
model. No target dose criterion was pre-specified for the MRI-PDFF responder secondary 
endpoint.
Similar tables and figures will be used to display the results of the MCPMod analysis as were 
described in Section 7.4.1.
The above analysis will be performed on the TS using both actual maintenance treatment and 
planned maintenance treatment. In both cases, all post-baseline MRI-PDFF data within the 
Week 48 visit window will be used, both on- and off-treatment.


MRI-PDFF continuous secondary endpoints - main analysis
Descriptive summaries of liver fat content (measured in units of % using MRI-PDFF), as well 
as absolute and percentage changes from baseline, will be presented over time. These will be 
produced on the TS for both actual maintenance treatment and planned maintenance 
treatment, and will include both on- and off-treatment data in the relevant visit windows. The 


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descriptive summaries will be produced overall, and further split by presence of any type of 
diabetes (Yes, No).
An MMRM will be fitted to the absolute change from baseline in liver fat content values 
(measured in units of % using MRI-PDFF) at each scheduled week (calculated as per Section 
6.7). The MMRM will include fixed effects for baseline liver fat content (%) as a continuous 
linear covariate, and treatment, presence of diabetes of any type [yes, no], baseline fibrosis 
score [F1, F2, F3], 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, removing multi-threading options, 
providing starting values for the covariance parameters, and excluding the fixed effect for 
baseline fibrosis score from the model. Only if none of these options is successful will simpler 
covariance structures be considered, in which case these 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.
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 Survodutide 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.
The above analysis will be performed on the TS for both actual maintenance treatment and 
planned maintenance treatment, and will include both on- and off-treatment data in the 
relevant visit windows.
The MMRM analysis specified above will be repeated for percentage change from baseline in 
liver fat content values (measured in units of % using MRI-PDFF).
MCPMod analysis will not be performed for the continuous MRI-PDFF secondary endpoints.


Liver biopsy responder secondary endpoint
Frequency tables will be produced of the liver biopsy responder secondary endpoint (one 
stage decrease in fibrosis stage from baseline after 48 weeks of treatment) in both of the 
following ways:
∀
TS, actual maintenance treatment, using all post-baseline liver biopsy data within the 
Week 48 visit window, both on- and off-treatment
∀
TS, planned maintenance treatment, using all post-baseline liver biopsy data within 
the Week 48 visit window, both on- and off-treatment.
The above frequency tables will be displayed similarly to those for the primary endpoint.
A logistic regression model will be fitted to the liver biopsy responder secondary endpoint 
without an intercept, and will include presence of diabetes of any type [yes, no], baseline 
fibrosis score [F1, F2, F3] and the dose group as factors. In the case that 0 events are observed 
in any combination of dose group and strata, the Firth bias reduction method will again be 
used.
A summary table will be produced of the logistic regression results, including estimated odds 
ratios for the comparison of each Survodutide dose against placebo and their 95% confidence 
intervals and associated p-values. 
The above analysis will be performed on the TS for both actual maintenance treatment and 
planned maintenance treatment, and will include both on- and off-treatment data in the Week 
48 visit window.
MCPMod analysis will not be performed for the liver biopsy responder secondary endpoint.


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Liver biopsy continuous secondary endpoint
Descriptive summaries of NAS total score from the liver biopsy, as well as absolute change 
from baseline, will be presented at Week 48.
Frequency tables will also be produced for each category of the NAS total score, and for each 
of the 3 NAS sub-scores (steatosis, lobular inflammation and ballooning) at baseline and at 
Week 48. 
The descriptive summaries and frequency tables will be produced on the TS for both actual 
maintenance treatment and planned maintenance treatment, and will include both on- and off-
treatment data in the relevant visit windows.


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7.7
EXTENT OF EXPOSURE
Descriptive summary statistics will be produced of the extent of exposure, as defined in
Section 5.4.3. A frequency table will also be presented of the extent of exposure by categories 
(both weekly and 4-weekly categorisations). 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. These summaries will be produced overall on the TS using both 
actual maintenance treatment and planned maintenance treatment.
A frequency table will be produced of duration on study (regardless of whether the patient 
remained on-treatment) using the same 4-weekly categories as extent of exposure.
A descriptive summary and frequency table will be produced of the extent of exposure for 
patients who discontinued treatment early, using planned maintenance treatment only. This 
table will be produced in the following 4 ways (using weekly categorisations):
∀
All patients who prematurely discontinued treatment
∀
Patients who prematurely discontinued treatment due to AE
∀
Patients who prematurely discontinued treatment not due to AE
∀
Patients who prematurely discontinued treatment due to AE and at least one AE with
SOC ‘Gastrointestinal disorders’ leading to treatment discontinuation.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS, including only on-treatment data (unless 
otherwise specified in Section 7.8.1). No hypothesis testing is planned for safety.
All specified summaries and analysis will be presented for both actual maintenance treatment 
and planned maintenance treatment.


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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. 
An overall summary of adverse events will be presented for all patients in the TS. 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 with the treatment period pooled across, and split into, 
dose escalation and maintenance periods, respectively.
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 with the treatment period pooled across, and split into, dose escalation and 
maintenance periods, respectively.
The AE summary by primary SOC and PT will also be repeated for each of the following, 
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 CTCAE grade (1 
to 5) and by primary SOC and PT. When no events meet the criteria for inclusion, the table
will be shown as indicating no events of that type have occurred.
The following tables will be produced separately by baseline body weight subgroup (< 100 / ≥ 
100 kg) and by presence of diabetes (yes/no):
∀
Overall AE summary
∀
Summary of all AEs by primary SOC and PT
∀
Summary of AEs leading to treatment discontinuation by primary SOC and PT.


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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. 
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.
Additional trial-specific information captured in the eCRF for Grade 3 nausea will be listed 
only and not summarised. 
Adverse Events of Special Interest (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)


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∀
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 Adverse 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 hospitalisation
∀
Pancreatitis
∀
Neoplasm
∀
Thyroid mass requiring surgery.
It should be noted that “Heart failure requiring hospitalisation” is assessed by the same 
committee who are adjudicating cardiovascular events, and is recorded on the same form as 
all of the other cardiovascular event sub-categories (which were not distinguished in the same 
way in the CTP). Therefore the summary table will reflect the data actually captured.
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. 
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” 


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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. 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
∀
ALT or AST ≥ 3 x ULN with INR ≥ 1.5
∀
ALT or AST ≥ 3 x ULN with either total bilirubin ≥ 2 x ULN or INR  ≥ 1.5
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 or INR ≥ 1.5, as applicable. The proposed time interval for 
the follow-up of total bilirubin or INR is 30 days after the occurrence of the post-baseline 
ALT or AST elevation.
The above frequency table will be repeated using the same categories, but restricted further to 
patients with a normal baseline value for ALT and AST, defined as both ALT < ULN and 
AST < ULN.
An additional frequency table will be produced for patients who have an abnormal baseline 
value for ALT or AST, defined as ALT ≥ ULN or AST ≥ ULN (or both), and who fall into 
each of the following categories:
∀
Both baseline ALT and AST < 2 x ULN and post-baseline ALT or AST > 5 x 
baseline value
∀
At least one of baseline ALT or AST ≥ 2 x ULN and < 5 x ULN and post-baseline 
ALT or AST > 3 x baseline value


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∀
At least one of baseline ALT or AST ≥ 5 x ULN and post-baseline ALT or AST > 2 
x baseline value
∀
Post-baseline ALT or AST > 2 x baseline value with total bilirubin ≥ 2 x ULN or 
increase in INR > 0.2.
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, and will include display of pre- and post-dose at 
each scheduled week.
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. 
Graphical summaries over time will also be included.
Categorical variables
Frequency tables will be provided for the categorical variables described below, which are 
determined from the specified quantitative ECG variables:
∀
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.


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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
To evaluate the appropriateness of the heart rate correction methods, the slope of the 
relationship of the (untransformed) QTcF interval versus RR interval will be estimated for 
off-drug values and for each Survodutide maintenance dose group separately by applying a 
random coefficient (random slope and intercept) model. Off-drug values for this purpose are 
defined as only values (either baseline or on-treatment values as defined in Section 6.1.6) 
from patients randomised to placebo, since patients randomised to Survodutide dose groups 
are expected to have a single ECG at baseline only, and therefore cannot contribute a slope for 
estimation of an off-drug random effect for this. For the Survodutide maintenance dose group 
analyses, only on-treatment values will be used, and these will be included regardless of 
Survodutide dose (i.e. data from the dose escalation period will be included). The model will 
be fitted using the QTcF and RR pairs at each time point, using all values within the visit 
windows defined in Section 6.7. A scatter plot of QTcF versus RR will be produced, and will 


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include the overall regression line obtained from the model. The population estimate of the 
slope together with its two-sided 95% confidence interval will be displayed in a footnote to 
the plot.
The slope of the relationship of the log-transformed (uncorrected) QT interval versus log-
transformed RR interval will be estimated for off-drug values and for each Survodutide
maintenance dose group separately by applying a random coefficient (random slope and 
intercept) model similar to above, with off-drug values and data selection defined in the same 
way. A scatter plot of log(QT) versus log(RR) will be produced, and will include the overall 
regression line obtained from the model. The population estimate of the slope together with 
its two-sided 95% confidence interval will be displayed in a footnote to the plot.
7.8.5
Other
Frequency tables will be produced of the information in the C-SSRS questionnaire over time.


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7.9
ANALYSIS OF COVID-19 IMPACT
To assess the impact on patients’ safety and drug efficacy in this trial, the following analyses 
are planned:
The frequency of patients with missed relevant visits or early discontinuation from study 
treatment or study due to COVID-19 and related PDs will be listed and analysed 
descriptively.
Summary tables and listings of AEs of SARS-CoV-2 infection will be produced. The tables 
will include an overall summary, a summary by primary SOC and PT, a summary of relevant 
AEs which led to early treatment discontinuation, and a summary of relevant serious AEs. For 
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.
Firth D. Bias reduction of maximum likelihood estimates. Biometrika 80, 27–38 (1993)
[R20-2291]
4.
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]
5.
Pinheiro JC, Bornkamp, B, Bretz F: Design and analysis of dose-finding studies 
combining multiple comparisons and modeling procedures. Journal of 
Biopharmaceutical Statistics 2006; 16: 639-656.[R10-1424]
6.
Pinheiro JC, Bornkamp, B, Glimm, E, and Bretz, F: Model-based dose-finding under 
model uncertainty using general parametric models. Statistics in Medicine 2014; 
33(10); 1646–1661. [R15-4293]


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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
11DEC2023
None
This is the final TSAP 
2.0 
19JAN2024
Section 
5.1
Section 
6.7
This is the revised TSAP. 
The baseline definition for all biopsy 
endpoints, including the primary 
endpoint, has been changed for 
patients in China, to use the digital 
reading (1st screening reading) instead 
of the physical reading (2nd screening 
reading). 
This has been done in response to 
potential analysis model and endpoint 
derivation issues which were identified 
from review of these data (transferred 
to the database 18DEC2023),
specifically a thorough consideration 
of all the implications of physical 
readings (2nd screening readings) 
which yielded values outside the 
eligibility criteria ranges.