Clinical trial NCT04307186
Conditions: Central Nervous System Pathology
Keywords: CNS
Sponsor: Bayer
Start date: 2020-11-18; Completion date: 2022-09-06
Enrollment: 57 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Researchers in this study want to find the appropriate dose of drug BAY1747846 for adults undergoing MRI for known or highly suspected brain and/or spinal cord conditions so that the image quality is similar to that of drug gadobutrol for adults undergoing MRI. MRI stands for Magnetic resonance imaging which produces body pictures created by using magnetic energy rather than x-ray energy.

Both BAY1747846 and gadobutrol are medicinal products known as gadolinium-based contrast agents (GBCA) which are used in MRI examinations to provide contrast enhancement and improve imaging performance. Gadobutrol (brand name: Gadavist, Gadovist) has been approved worldwide for the diagnosis of various disorders in adult and pediatric patients. BAY1747846 is a new GBCA under development with the goal to provide similar imaging performances in MRI. Participants in this study will receive both BAY1747846 and gadobutrol with a period of 3 - 14 days in between. A MRI examination will be performed after each injection. Participant will stay in this study for 2 - 4 weeks depending on the scheduling of the visits.

Detailed description:

Arms: arm 1: Participants will receive one intravenous (IV) injection of gadobutrol 0.1 millimole(s) gadolinium/kilogram body weight (mmol Gd/kg bw) and one IV injection of Gadoquatrane (BAY1747846).
Interventions: intervention 1: Gadoquatrane (BAY1747846) intervention 2: Gadobutrol (Gadovist/Gadavist)
Intervention descriptions: intervention 1: Solution for IV injection, single dose intervention 2: Solution for IV injection, single dose

Protocol documents:
Prot_000.pdf: 
 
Document Type: 
Clinical Study Protocol 
Official Title: 
Multicenter, single-blind, adaptive dose finding study of 
single intravenous injections of BAY 1747846 with 
corresponding blinded read in adult participants with known 
or highly suspected CNS lesions referred for contrast-
enhanced MRI of the CNS 
NCT Number: 
NCT04307186 
Document Date: 
06-Jan-2022 
 


C O N FI D E N TI A L
I nte grate d Cli nical St u d y Pr ot oc ol
B A Y 1 7 4 7 8 4 6 / 2 0 2 4 1
0 6 J A N 2 0 2 2
Pa ge:  1 of 7 5
Title P a ge
Pr ot oc ol Title:
M ultice nter, si n gle-bli n d, a da pti ve d ose fi n di n g st u d y of si n gle i ntra ve n o us i njecti o ns of 
B A Y 1 7 4 7 8 4 6 wit h c orres p o n di n g bli n de d rea d i n a d u lt partici pa nts wit h k n o w n or hi g hl y 
s us pecte d C N S lesi o ns referre d f or c o ntrast-e n ha nce d M RI of t he C N S
Pr ot oc ol N u m ber:
2 0 2 4 1
Versi o n N u m ber:
5. 0
A m e n d me nt N u m ber:
4
C o m p o u n d N u m ber:
B A Y 1 7 4 7 8 4 6
St u d y P h ase:
2
S h ort Title:
A da pti ve d ose fi n di n g st u d y
S p o ns o r N a me:
Ba ye r A G
Le g al Re gistere d A d dress:
N o n -U S: Ba y er A G, 5 1 3 6 8 Le ver k use n, Ger ma n y
U S territ or y : Ba yer Healt h Care P har mace uticals I nc., 1 0 0 Ba yer B o ule var d, P. O. B o x 9 1 5, 
W hi p pa n y  NJ 0 7 9 8 1-0 9 1 5, U S A
Re g ul at or y A ge nc y I de ntifier N u m ber(s):
E u dra C T: 
2 0 1 9- 0 0 1 5 6 0- 3 0
Pr ot oc ol D ate: 
0 6 J A N 2 0 2 2
Me dical M o nit or na me a n d c o ntact i nf or mati o n
will be pr o vi de d se paratel y.
Na me:
M D M S
R ole:
T his is a n electr o nicall y  ge nerate d d oc u me nt t hat d oes n ot bear a n y s p o ns or si g nat ures. T he 
si g nat ure of t he s p o ns or’s me dicall y  res p o nsi ble pers o n is file d i n t he T M F a n d a vaila ble o n 
re q uest.
C o nfi de nti al
T he i nf or mati o n pr o vi de d i n t his d oc u me nt is strictl y c o nfi de ntial a n d is i nte n de d s olel y f or t he perf or ma nce of  
t he cli nical i n vesti gati o n. Re pr o d ucti o n or discl os ure of t his d oc u me nt, w het her i n part or i n f ull, t o parties n ot 
ass ociate d wit h t he cli nical i n vesti gati o n or its use f or a n y ot her p ur p ose wit h o ut t he pri or writte n c o nse nt of t he 
s p o ns or is n ot per mitte d.
T hr o u g h o ut t his d oc u me nt, s y m b ols i n dicati n g pr o prietar y na mes ( ®, T M) ma y n ot be dis pla ye d. He nce, t he 
a p peara nce of pr o d uct na mes wit h o ut t hese s y m b ols d oes n ot i m pl y t hat t hese na mes are n ot pr otecte d.
P P D
P P D


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Document History Table 
DOCUMENT HISTORY
Document
Version
Date
Comments (if applicable)
Amendment 4
5.0
06 JAN 2022
Amendment 3
4.0
29 JUL 2021
Amendment 2
3.0
15 OCT 2020
Amendment 1
2.0
12 FEB 2020
Clinical Study Protocol
1.0
24 OCT 2019
Version submitted to the HAs


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Protocol Amendment Summary of Changes Table
Amendment 4 (06 JAN 2022)
This is a global amendment and is considered to be substantial based on the criteria set forth 
in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union.
Overall Rationale for the Amendment:
This amendment was primarily implemented to fulfill the FDA request to add secondary 
endpoints to the study and clarify the algorithm for dose decision. In addition, editorial, 
administrative, and typographical corrections were made that do not affect the overall 
document. These changes are not described in this section. The description of changes and a 
brief rationale for each change are as follows:
Section # 
and Name
Description of Change
Brief Rationale


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Section # 
and Name
Description of Change
Brief Rationale
1.1 Synopsis
3.0 Objectives and Endpoints 
8.1.3 Secondary Endpoints
8.1.3.1 Lesion Visualization 
Parameters
8.1.3.2 Number of lesions
9.4 Statistical Analyses 
9.4.1 Efficacy Analyses 
9.4.1.2.1 Lesion Visualization 
Parameters at 5 min post 
injection 
9.4.1.2.2 Lesion visualization 
parameters (border delineation, 
contrast enhancement, internal 
morphology) on pre-contrast 
and combined pre- and post-
contrast (5 min pi) images
9.4.1.2.3 Number of Lesions
9.4.1.3.2 Number of Enhanced 
Lesions on Post-Contrast 
Images at 5 min Post Injection
The following secondary objective and 
corresponding endpoints were 
implemented: 
Secondary Objective:  

Compare pre- and post-contrast 
images with respect to lesion 
visualization parameters and 
number of lesions
Corresponding Secondary Endpoints: 

Lesion visualization parameters 
(border delineation, 
contrast enhancement, internal 
morphology) on pre-contrast and 
combined pre- and post-contrast
(5 min pi) images

Number of lesions on 
pre-contrast and combined pre-
and post-contrast (5 min pi) 
images
The identified subsections under Sections 
8 and 9 were revised to accommodate the 
analyses of visualization parameters, lesion 
number and statistical variables 
corresponding with the additional 
secondary objective and endpoints.
As per FDA request, the study protocol 
was modified to facilitate a secondary 
analysis comparing lesion visualization 
parameters (border delineation, contrast 
enhancement, and internal morphology) 
and number of lesions between pre-
contrast and combined pre- and 
post-contrast images. 
4.3 Justification of Dose 
9.2 Sample Size Determination 
In case “Prefer gadobutrol” and Prefer
BAY 1747846” are equally balanced in 
favor of both compounds, dose adjustment 
will not be needed.
Clarification for the dose decision 
algorithm (option 2-no dose 
adjustment) to rely solely on the 
primary endpoint
9.5 Interim Analyses
Revised wording to specify that an interim 
analysis is optional and ‘‘may’’ be 
performed (changed from ‘‘is planned’’).
If performed, it will not affect the blinding 
design of the study.
Clarification that the interim analysis is 
not mandatory.
Only participants (and central readers) 
are blinded as per study design and this 
will not be affected by the interim 
analysis, if performed.
6.1 Study Interventions 
Administered
Table 6-1 was revised to remove mention 
of specific country sourcing, packaging, 
and label procedures. Additional text 
indicating that local requirements for the 
applicable countries will be followed as to 
ensure compliance.
Clarification of text to prevent 
confusion of the local country 
requirements used for sourcing, 
packaging and labeling of study 
intervention.


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Table of Contents
Title Page................................................................................................................................... 1
Document History Table.......................................................................................................... 2
Protocol Amendment Summary of Changes Table............................................................... 3
Table of Contents ..................................................................................................................... 5
Table of Tables ......................................................................................................................... 7
Table of Figures........................................................................................................................ 8
1.
Protocol Summary ............................................................................................................ 9
1.1
Synopsis........................................................................................................................... 9
1.2
Schema........................................................................................................................... 10
1.3
Schedule of Activities (SoA) ......................................................................................... 12
2.
Introduction..................................................................................................................... 15
2.1
Study Rationale.............................................................................................................. 15
2.2
Background.................................................................................................................... 15
2.3
Benefit/Risk Assessment ............................................................................................... 20
3.
Objectives and Endpoints............................................................................................... 23
4.
Study Design .................................................................................................................... 23
4.1
Overall Design ............................................................................................................... 23
4.2
Scientific Rationale for Study Design ........................................................................... 24
4.3
Justification for Dose..................................................................................................... 24
4.4
End of Study Definition................................................................................................. 25
5.
Study Population............................................................................................................. 26
5.1
Inclusion Criteria ........................................................................................................... 26
5.2
Exclusion Criteria .......................................................................................................... 27
5.3
Lifestyle Considerations ................................................................................................ 29
5.3.1
Meals and Dietary Restrictions .................................................................................. 29
5.3.2
Activity....................................................................................................................... 29
5.4
Screen Failures............................................................................................................... 29
6.
Study Intervention .......................................................................................................... 29
6.1
Study Interventions Administered ................................................................................. 29
6.2
Preparation/Handling/Storage/Accountability............................................................... 31
6.3
Measures to Minimize Bias: Randomization and Blinding........................................... 31
6.4
Study Intervention Compliance ..................................................................................... 31
6.5
Prior and Concomitant Therapy..................................................................................... 31
6.6
Dose Modification ......................................................................................................... 32
6.7
Intervention after the End of the Study.......................................................................... 32
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal.......................................................................................... 32
7.1
Discontinuation of Study Intervention........................................................................... 32
7.2
Dropout .......................................................................................................................... 32
7.3
Participant Discontinuation/Withdrawal from the Study............................................... 32
7.4
Lost to Follow-up........................................................................................................... 33
8.
Study Assessments and Procedures............................................................................... 33


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8.1
Efficacy Assessments .................................................................................................... 34
8.1.1
MRI Procedure ........................................................................................................... 34
8.1.1.1
MRI Equipment....................................................................................................... 34
8.1.1.2
Sequence Parameters for Brain Imaging................................................................. 34
8.1.1.3
Quality Assurance of Images .................................................................................. 36
8.1.1.4
Image Archiving and Copying ................................................................................ 37
8.1.2
Primary Endpoint........................................................................................................ 37
8.1.3
Secondary Endpoints.................................................................................................. 37
8.1.3.1
Lesion Visualization Parameters............................................................................. 37
8.1.3.2
Number of lesions ................................................................................................... 38
8.1.4
Other Endpoints.......................................................................................................... 38
8.1.4.1
Quantitative Signal Intensity................................................................................... 38
8.1.4.2
Efficacy Evaluation at 10 and 15 min Post Injection.............................................. 38
8.1.4.3
Number of Enhanced Lesions ................................................................................. 39
8.2
Safety Assessments........................................................................................................ 39
8.2.1
Physical Examinations................................................................................................ 39
8.2.2
Vital Signs .................................................................................................................. 39
8.2.3
Electrocardiogram ...................................................................................................... 40
8.2.4
Pulse Oximetry........................................................................................................... 40
8.2.5
Short Mental Status Check ......................................................................................... 40
8.2.6
Clinical Safety Laboratory Assessments .................................................................... 40
8.3
Adverse Events and Serious Adverse Events ................................................................ 41
8.3.1
Time Period and Frequency for Collecting AE and SAE Information....................... 41
8.3.2
Method of Detecting AEs and SAEs.......................................................................... 42
8.3.3
Follow-up of AEs and SAEs ...................................................................................... 42
8.3.4
Regulatory Reporting Requirements for SAEs .......................................................... 42
8.3.5
Pregnancy ................................................................................................................... 43
8.3.6
Adverse Event of Special Safety Interest ................................................................... 43
8.3.7
Expected Adverse Events........................................................................................... 43
8.3.8
Reporting of Medical Device Failures (Japan Only).................................................. 44
8.4
Treatment of Overdose .................................................................................................. 44
8.5
Pharmacokinetics........................................................................................................... 44
8.5.1
Drug Measurements.................................................................................................... 44
8.5.2
Population Pharmacokinetic Evaluation..................................................................... 45
8.6
Pharmacodynamics ........................................................................................................ 46
8.7
Genetics ......................................................................................................................... 46
8.8
Biomarkers..................................................................................................................... 46
8.9
Medical Resource Utilization and Health Economics ................................................... 46
8.10
Population Characteristics ............................................................................................. 46
8.10.1
Demographics............................................................................................................. 46
8.10.2
Medical and Surgical History..................................................................................... 47
9.
Statistical Considerations ............................................................................................... 47
9.1
Statistical Hypotheses.................................................................................................... 47
9.2
Sample Size Determination ........................................................................................... 47
9.3
Populations for Analyses ............................................................................................... 49
9.4
Statistical Analyses........................................................................................................ 49
9.4.1
Efficacy Analyses....................................................................................................... 50


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9.4.1.1
Primary Efficacy Analysis – Overall Diagnostic Preference at 5 min post 
injection................................................................................................................... 51
9.4.1.2
Secondary Efficacy Analysis .................................................................................. 52
9.4.1.3
Other Efficacy Analysis .......................................................................................... 53
9.4.2
Safety Analyses .......................................................................................................... 55
9.4.2.1
Adverse Events........................................................................................................ 55
9.4.2.2
Other Safety Examinations...................................................................................... 55
9.4.2.3
Demographic and Other Baseline Characteristics Analyses................................... 56
9.4.3
Analyses of Gd Plasma Concentration....................................................................... 56
9.5
Interim Analyses............................................................................................................ 56
10. Supporting Documentation and Operational Considerations .................................... 57
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........................ 57
10.1.1
Regulatory and Ethical Considerations ...................................................................... 57
10.1.2
Financial Disclosure ................................................................................................... 58
10.1.3
Informed Consent Process.......................................................................................... 58
10.1.4
Data Protection ........................................................................................................... 58
10.1.5
Committees Structure ................................................................................................. 59
10.1.6
Dissemination of Clinical Study Data ........................................................................ 59
10.1.7
Data Quality Assurance.............................................................................................. 59
10.1.8
Source Documents...................................................................................................... 60
10.1.9
Study and Site Closure ............................................................................................... 61
10.1.10 Publication Policy....................................................................................................... 61
10.2
Appendix 2: Clinical Laboratory Tests.......................................................................... 61
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting.............................................................................................. 63
10.3.1
Definition of AE......................................................................................................... 63
10.3.2
Definition of SAE....................................................................................................... 64
10.3.3
Recording and Follow-Up of AE and/or SAE............................................................ 65
10.3.4
Reporting of SAEs...................................................................................................... 67
10.4
Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information......... 68
10.5
Appendix 5: Abbreviations............................................................................................ 69
10.6
Appendix 6: Protocol Amendment History ................................................................... 72
11. References ........................................................................................................................ 74
Table of Tables
Table 1-1: Study SoA............................................................................................................... 13
Table 2-1: Dose normalized AUC and CL/bw (mean [CV%]) obtained from dose groups 1 – 6 
in the FiH Study 19324 for ascending doses of BAY 1747846 in comparison to
the same parameters reported for gadobutrol and gadoterate meglumine............. 18
Table 6-1: Identity of study intervention.................................................................................. 30
Table 8-1: Recommended MRI sequence parameters.............................................................. 36
Table 8-2: Sampling schedule for sparse PK sampling............................................................ 46
Table 9-1: Analysis sets ........................................................................................................... 49
Table 10-1: Parameters of laboratory analyses ........................................................................ 62


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Table of Figures
Figure 1-1: Overall study design.............................................................................................. 11
Figure 2-1: RSE (% ± SD) determined in the sigmoidal sinus at 5, 10 and 15 min after 
injection of 0.01, 0.03 or 0.06 mmol Gd/kg bw of BAY 1747846 or 
0.1 mmol Gd/kg bw of gadobutrol. ....................................................................... 19


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1.
Protocol Summary
1.1
Synopsis
Protocol Title:
Multicenter, single-blind, adaptive dose finding study of single 
intravenous injections of BAY 1747846 with corresponding blinded 
read in adult participants with known or highly suspected CNS lesions 
referred for contrast-enhanced MRI of the CNS
Short Title:
Adaptive dose finding study
Rationale:
This study is conducted to establish a dose of BAY 1747846 in participants with known or 
highly suspected central nervous system (CNS) pathology which shows similar image quality 
and signal enhancement (at a reduced gadolinium [Gd] dose) to the established comparator 
gadobutrol. Gadobutrol is a macrocyclic gadolinium-based contrast agent (GBCA) approved 
worldwide for various indications and populations (incl. all age groups) with broad utilization 
(more than 50 million administrations [Scott 2018]). Hence, it is well suited to serve as 
comparator and to ensure that similar imaging performance can be achieved with 
BAY 1747846 while relevantly reducing the Gd burden per contrast-enhanced magnetic 
resonance imaging (MRI) examination.
Objectives and Endpoints:
Objectives
Endpoints
Primary

Identify a dose for further development 
that has an overall diagnostic preference 
rate similar to that of the comparator
gadobutrol at 5 min post injection (pi).

Overall diagnostic preference based on a 
randomized paired blinded read using a 5-
point scale (greatly prefer BAY 1747846, 
prefer BAY 1747846, no preference, 
prefer gadobutrol, greatly prefer 
gadobutrol) at 5 min pi
Secondary

Show non-inferiority of BAY 1747846 
compared to gadobutrol at 5 min pi with 
respect to sum of lesion visualization 
parameters

Compare pre- and post-contrast images
with respect to lesion visualization 
parameters and number of lesions

Lesion visualization parameters 
(border delineation, contrast
enhancement, internal morphology) on 
post-contrast images at 5 min pi

Lesion visualization parameters (border 
delineation, contrast enhancement, 
internal morphology) on pre-contrast and 
combined pre- and post-contrast (5 min 
pi) images

Number of lesions on pre-contrast and 
combined pre- and post-contrast (5 min 
pi) images
Overall Design:
This is a multicenter Phase 2 study with a single-blind design with blinded read in participants 
with known or highly suspected CNS pathology. Participants will be enrolled in up to 
3 cohorts. Gadobutrol will serve as active comparator.
Intervention Model:


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Intra-individual comparison, single-blind design
Primary Purpose:
Diagnostic
Number of Arms:
Not applicable.
A maximum of 3 cohorts will be needed for the dose finding of BAY 1747846.
Masking:
Blinded participants, blinded readers
Number of Participants:
Approximately 60 participants per cohort will be assigned to study intervention such that at 
least 50 evaluable participants per cohort complete the study. Enrolment should continue until 
50 participants have completed the MRIs in both study periods and the corresponding 
required images are fully evaluable for efficacy (i.e. central image quality control [QC] by 
General Clinical Imaging Services [GCIS] passed). If the primary endpoint is met in the first 
cohort, there will be the option to investigate another cohort with an adapted lower or higher 
dose level to evaluate the robustness and dose range of that result in a no preference outcome 
for BAY 1747846 and the comparator.
In total, approximately 180 participants (i.e. if all 3 cohorts will be conducted) will be 
assigned to study intervention such that at least 150 evaluable participants complete the study.
Intervention Groups and Duration:
Each participant will be assigned to receive gadobutrol as intervention for contrast-enhanced 
MRI as single intravenous (IV) administration during Period 1 and then a single IV 
administration of BAY 1747846 during Period 2.
There will be a washout period of 3 to 14 days between each study intervention administration
during the study.
The individual study duration will be approximately 2 to 4 weeks including screening and last 
measurements in Period 2, which will be conducted 24 h after the last study MRI. The total 
duration of the study will be approximately 1 year until final clean data base.
Data Monitoring Committee:
No
1.2
Schema
This is a multicenter, single-blind, adaptive dose finding study with corresponding blinded 
read. The first cohort of participants will receive BAY 1747846 at the initial dose of 
0.04 mmol Gd/kg body weight (bw). Up to two dose adjustments (in steps of about 
0.005 mmol Gd/kg bw higher or lower) will be performed depending on the outcome of the 
preceding cohort. The active comparator for this study will be gadobutrol (Gadovist/Gadavist) 
at the approved standard dose for CNS imaging of 0.1 mmol Gd/kg bw. Each cohort will 
consist of at least 50 evaluable participants. The overall study design is shown in Figure 1-1.


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Figure 1-1: Overall study design
bw = Body weight; Gd = Gadolinium; MRI = Magnetic resonance imaging, N = Number of participants
a
Decision on study continuation with a further cohort depends on outcome of previous cohort


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1.3
Schedule of Activities (SoA)
Table 1-1 provides the SoA presenting the study-related measures/actions planned for this 
study. Screening activities might be combined with baseline measurements on the same day. 
In that case, the participant needs to sign the informed consent form (ICF) by documenting 
the time point in addition to the signature date before any baseline activity starts. Baseline 
activities are scheduled within 48 h prior to study intervention administration (see Section 
10.1.3) and need to be done for each study period, including check of inclusion and exclusion 
criteria as relevant changes might occur in between (e.g. eGFR, medical condition).
The reference point (Day 1, relative time: 00d00h00 min) for the time matrix to be used for 
data evaluation will be the administration of study intervention. All measures/actions to be 
performed before this reference point will be assigned to negative time points, all 
subsequent measures/actions will have positive time points.


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Table 1-1: Study SoA
Evaluation/procedure
Scr
Baselinek
MRI and injection phase in
Period 1 and 2
Post injection phase in Period 1 and 2
Time point
≤48 h before 
dosing
Prior 
to injection
Dosing
5 min pi
Immediately after MRI 
(20 – 60 min pi)
2 – 4 h
6 – 8 h
24 ± 4 hm-n
Relative time point
-2d 00h 00min 0d 00h 00min 
(PRE)
0d 00h 
00min
0d 00h 05min
0d 00h 20min
0d 02h 
00min
0d 06h 
00min
1d 00h 00min
Written informed consenta
X
Demographic data
X
Medical/surgical history
X
Prior medication
X
Concomitant medication
X
X
X
X
Urine pregnancy testb
X
X
Determination of eGFRc
X
Body height and weight, BMI
X
Complete physical examination
X
  X
X
In/exclusion criteria
X
X
At-hospitald
X




X
Administration of study intervention
X
Blood pressure, heart rate or pulsee
X
X
X
X
Body temperature
X
X
X
Respiratory rate
X
X
Short physical checkf
X
Examination of injection siteg
X
X
X
Short mental status check
X
X
12-lead ECGe
X
X
X
X
Placement of IV line for dosing
X
MRI phase
Xl

X
X
Pulse oximetryh
X


X
Blood sampling for safety
X
X
X
Blood sampling for PKi
X
X
X
X
X
Blood sampling for centralized serum 
creatininej
X
Urinalysis
X
X
X
AE monitoring
X






X
Table continued


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Table 1-1: Study SoA – continued
AE = Adverse event; BMI = Body mass index; ECG = Electrocardiogram; eGFR = Estimated glomerular filtration rate; IV = Intravenous; MRI = Magnetic resonance imaging; pi 
= post injection; PK = Pharmacokinetics; Scr = Screening
X
Measure/action to be done at the time point indicated.

Measure/action to be done continuously, starting/ending from/at the time point indicated.
a
The informed consent has to be obtained within 8 weeks before any study-related procedures and assessments are conducted. If screening and baseline activities are to 
be performed on the same day, time of signature needs to be documented on the informed consent form in addition to signature date.
b
For women of child-bearing potential only. At the day of study intervention administration, the result must be available prior to administration of contrast media injection.
c
With regards to baseline of period 1, eGFR can be derived from a serum creatinine result obtained within 4 weeks prior to the first study MRI. If a serum creatinine result is 
not available, it will be determined by the study site (creatinine that is part of blood sampling for safety at each baseline can be used to derive eGFR for the respective 
baseline period as long as the result is available prior to administration of the intervention).
d
patient may be hospitalized throughout each period for participant convenience or site operations, based on operational feasibility, participant health condition and 
willingness, after a positive benefit/risk assessment by the Investigator for such hospitalization
e
After 5 min resting phase.
f
Done by observation and asking the participant about his/her physical condition.
g
Before and after placement of IV line as well as after discontinuation of IV line.
h
Continuously monitored, starting prior to the beginning of the first MRI and continuing throughout until completion of the second MRI.
i
A second indwelling cannula will be required for PK sampling. Population PK samples time windows: 20 – 60 min, 2 – 4 h, 6 – 8 h and 24 ± 4 h (together with blood sample 
for safety) after administration of study intervention. Actual sampling times will be documented in the eCRF. The first 3 time windows will be subdivided in 3 sub-windows, 
see Table 8-2.
j
Only performed once.
k
Baseline assessment to be done in Period 1 and 2. All baseline values will be assessed before placement of IV line.
l
MRI prior to study intervention administration is an unenhanced MRI (i.e. without contrast media). Details can be found in Section 8.1.1.
m
In Period 2, this time point will be the follow-up visit. For participants with premature study termination, the same assessments scheduled for follow-up will be conducted 
during an early discontinuation visit.
n
24 ± 4 h procedures for period 1 and/or period 2 may be conducted at hospital, at a local facility or at home based on operational feasibility, local regulations, participant 
health condition and willingness. At hospital procedures are preferred when possible.


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2.
Introduction
BAY 1747846 is a new macrocyclic GBCA with high relaxivity for enhancing magnetic 
resonance (MR) images. The clinical utility of GBCAs in contrast-enhanced MRI is well 
established and demonstrated in various indications and populations for more than 3 decades 
and in over 500 million procedures.
BAY 1747846 is in development as multi-purpose GBCA for contrast-enhanced MRI in 
adults and children of all ages. So far, it has been studied in two Phase 1 trials. The initial 
first-in-human (FiH) study (Study 19324) examined increasing doses of BAY 1747846, 
ranging from 0.025 up to 0.2 mmol Gd/kg bw in healthy men and women, and confirmed 
similar safety and pharmacokinetics (PK) compared to marketed GBCAs. In Study 19325, 
signal enhancement of various selected regions in the head and neck area at increasing dose 
levels (0.01 to 0.06 mmol Gd/kg bw) was evaluated in healthy men and women in comparison 
to gadobutrol at the standard dose of 0.1 mmol Gd/kg bw. Also in this study, the safety profile 
was similar to gadobutrol and the FiH Study 19324. A dose proportional enhancement pattern 
was observed and could be compared quantitatively to gadobutrol.
2.1
Study Rationale
This study is conducted to establish a dose of BAY 1747846 in participants with known or 
highly suspected CNS pathology which shows similar image quality and signal enhancement 
(at a reduced Gd dose) to the established comparator gadobutrol. Gadobutrol is a macrocyclic 
GBCA approved worldwide for various indications and populations (incl. all age groups) with 
broad utilization (more than 50 million administrations [Scott 2018]). Hence, it is well suited 
to serve as comparator and to ensure that similar imaging performance can be achieved with 
BAY 1747846 while relevantly reducing the Gd burden per contrast-enhanced MRI
examination.
2.2
Background
Since their introduction almost 30 years ago and after 500 million administrations worldwide, 
GBCAs have been established as a crucial element in transforming MRI into a high 
performance. GBCAs are complexes of Gd, a paramagnetic metal acting as the signal and 
contrast-enhancing component, with different organic chelators. Depending on the structure 
of the chelator, they are differentiated in linear or macrocyclic compounds. Macrocyclic 
GBCAs are generally more stable than linear GBCAs.
In 2006, the administration of GBCAs was identified as a risk factor for the development of 
Nephrogenic Systemic Fibrosis (NSF) in patients with severe renal impairment (glomerular 
filtration rate [GFR] <30 mL/min) (Grobner 2006). NSF may result in fatal or debilitating 
fibrosis affecting the skin, muscle, and internal organs. The risk for NSF was found to be 
higher for linear compounds with lower stability of the Gd-chelate.
In 2014, increased signal intensity (SI) in the dentate nucleus and the globus pallidus was 
reported on unenhanced T1-weighted (T1w) MR images in patients who had received multiple 
injections of GBCAs before (Kanda et al. 2014). Further non-clinical and clinical 
investigations have shown that traces of Gd may remain in parts of the body, including bone, 
skin, brain, blood, urine, and other areas, for long periods of time after injection of all 


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GBCAs. The less stable linear agents resulted in higher concentrations of Gd than the 
macrocyclic agents. In animals, no histopathological change was detectable in brain tissue 
after repeated high doses of even the least stable agents (Radbruch 2016, Runge 2016).
Although no symptoms or diseases linked to Gd in the brain have been reported, the European 
Medicines Agency (EMA) took a precautionary approach, requesting the lowest Gd doses that 
enhance images sufficiently should be used (EMA 2017).
Health authorities worldwide either requested label updates to reflect the above-mentioned 
findings or requested in the case of the EMA the suspension of the less stable linear 
multipurpose GBCAs as a precautionary measure. In addition, health authorities consistently 
request the lowest dose resulting in diagnostic enhancement. BAY 1747846 addresses this 
request by substantially lowering the Gd burden per administration while maintaining 
sufficient enhancement.
The scientific and medical evidence to date continues to support a favorable benefit-risk 
profile for GBCAs in the vast majority of patients, in accordance with the product 
information.
Gadobutrol
Gadobutrol is a macrocyclic GBCA and is indicated for contrast enhancement in MRI in 
adults and children for MRI of the brain and spine, MR angiography and whole-body MRI. 
Clinical safety, efficacy and PK are well characterized (see local product label for 
gadobutrol). Gadobutrol is approved for various indications in most regions/countries
worldwide including the European Union (EU), USA and Japan.
Preclinical Data of BAY 1747846
The effect of a GBCA on relaxation times in tissues, and consequently enhancement in SI and 
contrast on MR images, depends on its relaxivity and its concentration in the tissue of interest, 
i.e. its PK behavior.
For BAY 1747846, the relaxivities measured in vitro were more than 2-fold higher compared 
to other macrocyclic GBCAs like gadobutrol, when normalized to Gd. MRI studies in rats, 
rabbits, and minipigs confirmed that BAY 1747846 shows similar signal enhancement at less 
than half the Gd dose as other available macrocyclic GBCAs (see Section 4.1.2 of the 
Investigator’s Brochure [IB] and report PH-40545).
The PK profile of BAY 1747846 was investigated in several animal species, including rats, 
rabbits and cynomolgus monkeys. It was found to be identical to that of marketed 
multipurpose/macrocyclic GBCAs with superimposable concentration-time profiles when 
administered at the same dose. Elimination was almost exclusively via the kidneys and at the 
same excretion rates. The elimination rate of BAY 1747846 was similar to the GFR. In vitro
studies showed a negligible protein binding, no uptake into hepatocytes and no potential for 
drug-drug interactions. Further details can be found in Section 4.2 of the IB.
Clinical Data of BAY 1747846
First-in-Human (FiH) Study 19324


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The FiH Study 19324 was a randomized, single-blind, placebo-controlled, escalating single-
dose study on the safety, tolerability, and PK of IV administered BAY 1747846 in healthy 
women and men.
The main objective of this study was to investigate safety, tolerability and PK including 
gender differences, excretion pathways and analysis for potential metabolites. The first 
3 cohorts received single ascending doses of 0.025, 0.05 or 0.1 mmol Gd/kg bw of 
BAY 1747846 or placebo (0.9% sodium chloride) as a 5-min IV infusion; cohorts 4, 5 and 
6 received 0.03, 0.1 or 0.2 mmol Gd/kg bw of BAY 1747846 or placebo (0.9% sodium 
chloride) as IV injection at 2 mL/s. In total, 49 participants were recruited in this study and 
received BAY 1747846 or placebo in Study 19324.
BAY 1747846 was found to be very well tolerated at single IV doses up to 
0.2 mmol Gd/kg bw. The safety assessment based on adverse events (AEs), vital signs, 
electrocardiogram (ECG) parameters, pulse oximetry, and laboratory examinations indicated
that IV administration of BAY 1747846 was very well tolerated. The incidence and severity 
of AEs was independent from the dose administered and similar to placebo. No relevant 
effects on cardiac or respiratory function were observed. Laboratory examinations were 
without clinically relevant observation.
PK results of participants in Study 19324 revealed - as expected - a rapid decline of the 
plasma concentration-time profile shortly after the end of the administration. Main PK 
parameters (AUCnorm and CL/bw) are summarized in Table 2-1.
Maximum concentration (Cmax) was reached shortly after the end of the infusion in most 
cases. Following injection (2 mL/s), Cmax was observed either at 2 or 5 min after injection.
Cmax and area under the concentration versus time curve (AUC) increased dose proportionally 
from 0.025 to 0.2 mmol Gd/kg bw. The total body clearance of drug normalized by bw
(CL/bw), volume of distribution at steady state normalized by bw (Vss/bw), mean residence 
time and effective t1/2 remained constant within the dose range tested. BAY 1747846 showed 
a clearance similar to the GFR and Vss indicated distribution into the extracellular water space 
of the body.
For the main PK parameters, the variability was low (between 8.23 and 22.1%). For Cmax, 
variability was slightly higher (up to 34%) as can be expected during the early time after IV 
administration for a compound with such a rapid distribution phase.
As expected and similar to other marketed macrocyclic GBCAs, the major part of the Gd dose 
was excreted within 12 h pi. On average, about 84 – 101% of the dose was already excreted 
within 12 h via urine, except for the highest dose group, where on average 74% was excreted 
during that time frame. However, in this group, two participants had a low recovery during 
the first 4 h (32 and 57%) post dose which may indicate loss of urine during collection. 
Exemption of these 2 participants from average calculations showed a recovery of 84%.
The PK results of BAY 1747846 were in the expected range based on the preclinical data and 
were very similar to those reported for marketed macrocyclic GBCAs, e.g. gadobutrol and 
gadoterate meglumine, when corrected for dose.
The CL/bw values determined for all dose levels were around 0.09-0.1 L·kg/h and essentially 
the same as determined for gadobutrol (0.09 L·kg/h) and gadoterate meglumine (0.08 L·kg/h). 


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The same holds true for the average dose normalized AUC for all dose groups of 
BAY 1747846, gadobutrol and gadoterate meglumine, as listed in Table 2-1.
Table 2-1: Dose normalized AUC and CL/bw (mean [CV%]) obtained from dose 
groups 1 – 6 in the FiH Study 19324 for ascending doses of BAY 1747846 in 
comparison to the same parameters reported for gadobutrol and gadoterate 
meglumine
Compound / 
administration
Dose
[mmol Gd/kg bw]
AUCnorm
[kg·h/L]
CL/bw
[L·kg/h]
BAY 1747846
5 min infusion
0.025
10.1 [8.23]
0.0985 (8.23]
BAY 1747846
5 min infusion
0.05
9.78 [8.51]
0.102 [8.51]
BAY 1747846
5 min infusion
0.1
10.7 [11.4]
0.0936 [11.4]
BAY 1747846
injection
0.03
9.73 [17.2]
0.103 [17.2]
BAY 1747846
injection
0.1
10.2 [22.1]
0.0984 [22.1]
BAY 1747846
injection
0.2
10.2 [12.0]
0.0978 [12.0]
Gadobutrola
injection
0.1
11.1 [N/A]
0.094 [8.90]
Gadoterate meglumineb
injection
0.1
9.87 [N/A]
0.08 [12.6]
a
Report No. 9746; Report No A44213
b
Le Mignon et al. 1990; Dotarem SmPC
In addition, the amount of BAY 1747846 excreted within 12 to 24 h is matching the amount 
of macrocyclic GBCAs (gadobutrol: 86 – 100% of the administered dose, see Report 
No 9746; gadoterate meglumine: 89 – 95% of the administered dose, see Dotarem Summary 
of Product Characteristics [SmPC]) excreted via the kidneys.
Overall, these results confirm the expected safety and PK of BAY 1747846 that was already 
shown pre-clinically in several animal species. The determined PK profile, with its rapid 
extracellular distribution and elimination (according to GFR) and its similarity to other 
marketed macrocyclic GBCAs, supports the implemented minimum washout period of 3 days 
between the administration of BAY 1747846 and gadobutrol, respectively.
Dose-response Study 19325 in healthy participants
This was a randomized, single-blind, 4 x 4 cross-over, dose-response study of 3 single IV 
injections of increasing doses of BAY 1747846 compared to gadobutrol in healthy 


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participants. The primary objective of the study was to determine relative signal enhancement 
(RSE) of BAY 1747846 in relation to dose and compare it to the RSE achieved with 
gadobutrol at the standard dose (0.1 mmol Gd/kg bw). The secondary objective of the study 
was to investigate the safety of BAY 1747846 in healthy participants.
In this study, 43 participants were treated. 42 participants received 3 doses of BAY 1747846 
(0.01, 0.03 and 0.06 mmol Gd/kg bw) and one dose of gadobutrol (0.1 mmol Gd/kg bw) in a 
randomized order with at least 7 days between injections.
The conduct of the study was completed; preliminary results for safety and dose response are 
available.
The preliminary safety assessment confirmed the good safety profile observed in the FiH 
Study 19324. There were 16 participants with treatment-emergent adverse events (TEAEs), 
12 were of mild and 4 of moderate intensity. There was a balanced distribution among 
treatments. No AE led to discontinuation and no serious adverse events were observed.
To establish a dose response, SI was measured in five enhancing areas of the head and neck 
region before (pre) and at approximately 5, 10 and 15 min after each injection: Sagittal sinus, 
sigmoidal sinus, parotid gland, submandibular gland, and internal carotid artery. MR Images 
were acquired with a T1w 3D gradient echo sequence on a 1.5 T MR Scanner. BAY 1747846 
showed an increase in signal enhancement in relation to Gd dose in all regions of interest for 
each imaging time point. RSE for all treatments and time points for an exemplary area 
(sigmoidal sinus) is shown in Figure 2-1.
Figure 2-1: RSE (% ± SD) determined in the sigmoidal sinus at 5, 10 and 15 min after 
injection of 0.01, 0.03 or 0.06 mmol Gd/kg bw of BAY 1747846 or 0.1 mmol Gd/kg bw 
of gadobutrol.
BAY 1747846: 0.01 mmol Gd/kg bw
BAY 1747846: 0.03 mmol Gd/kg bw
BAY 1747846: 0.06 mmol Gd/kg bw
Gadobutrol: 0.1 mmol Gd/kg bw


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RSE for each area was determined by dividing the difference between pre and post SI by pre 
SI. Based on the RSE values a dose response curve was established for each area by inverse 
regression which was then compared to the RSE determined after injection of gadobutrol. 
Overall, BAY 1747846 leads to the same enhancement as gadobutrol with less than half the 
Gd dose. The estimated dose to reach the same signal enhancement was in the range from 
0.038 to 0.065 mmol Gd/kg bw.
These results are well in line with the T1w relaxivity differences of BAY 1747846 
(11.8 Lmmol-1s-1) and gadobutrol (5.2 Lmmol-1s-1), which is approximately 2.3 and 
underline that signal enhancement is independent of different organs and depends mainly on 
relaxivity of the GBCA and its presence in the area of interest.
2.3
Benefit/Risk Assessment
This study will be performed in male and female participants with known or highly suspected 
CNS pathology. The participants will benefit from the contrast-enhanced MRI examination 
which they will receive based on the underlying clinical need. They will not directly benefit 
from the additional MRI being performed in relation to the study. However, the data obtained 
from this study will contribute to the development of BAY 1747846 for contrast-enhanced 
MRI in adults and children of all ages, with the goal to relevantly reduce the dose of Gd.
The overall safety profile of GBCAs is favorable and well established with more than 
500 million administrations of all GBCAs since 1988. Adverse reactions following their 
administration are usually mild to moderate in severity and transient in nature. The most 
commonly reported adverse reactions following administration of GBCAs are headache, 
nausea and dizziness.
Hypersensitivity/anaphylactoid reactions consisting primarily of cutaneous, respiratory, and 
cardiovascular symptoms have been recognized to occur in association with all GBCAs. The 
mechanism by which anaphylactoid reactions occur is not fully understood but may involve 
release of active mediators, such as histamine and bradykinin. The vast majority of 
hypersensitivity reactions to GBCAs are mild to moderate in nature, and transient, consisting 
of events such as urticaria and usually occur within 30 min after administration (Prince et al. 
2011). As a precaution, hypersensitivity reactions will be monitored narrowly as adverse 
event of special safety interest (AESI) and reported within the same timelines as any serious 
adverse event (SAE).
Post-marketing experience with GBCAs identified rare adverse reactions, such as 
anaphylactoid reactions/anaphylactoid shock, which may be severe or life-threatening, 
seizures, and NSF as further risks (Prince et al. 2011). NSF was observed in patients with
severe renal impairment (GFR <30 mL/min) or with acute renal failure, populations excluded 
from participation in this study (Kanal 2016).
Recently, increased SI was reported in some brain areas on unenhanced scans after repeated 
injections of primarily linear GBCAs (Kanda et al. 2014). However, to date, none of the many 
studies have shown an association between the observed increased SI in the brain after 
repeated GBCA administrations and the occurrence of any clinical AEs. Additionally, no 
causal relationship has been reported between clinical signs and symptoms and the presence 


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of traces of Gd in the body in patients with normal renal function following use of a GBCA 
(see Section 5.3.3.3 of the IB).
The safety and tolerability of BAY 1747846 was assessed in the FiH Study 19324 based on 
the incidence and severity of AEs during a study period of 7 days post dose. This included the 
serial evaluation of cardiac (heart rate, blood pressure [BP], ECG) and respiratory function 
(peripheral hemoglobin oxygen saturation), hematology, biochemistry, and monitoring of 
markers for complement activation and histamine release. In addition, plasma, urine, and 
feces were collected over a period of 72 h post dose to investigate the PK of BAY 1747846, 
including investigation of metabolism and excretion.
No SAE was observed during the study conduct.
The incidence of TEAEs was similar in all dose groups and in placebo participants. Most 
TEAEs were mild, two were of moderate intensity (creatine kinase increase after intense 
physical activity and brief lymphocyte decrease in the context of laboratory evidence of a 
short inflammatory reaction) and none were severe. All AEs were recovered or recovering at 
the end of the study close out visit one week after administration.
The preliminary overall safety assessment based on TEAEs, vital signs, ECG, pulse oximetry, 
and laboratory examinations indicates that IV administration of BAY 1747846 was very well 
tolerated. The incidence and severity of AEs was independent of the dose administered and 
was similar to placebo. No relevant effect on cardiac or respiratory function was observed.
Also, no clinically relevant change in laboratory examinations attributable to treatment with 
BAY 1747846 was observed.
Based on nonclinical data and preliminary data from the FiH Study 19324, the safety and PK 
profiles of BAY 1747846 are assumed to be similar to other GBCAs.
The safety monitoring activities that are part of this clinical study are considered appropriate 
to detect any effect with relevance to the safety of the study participants. The principal 
investigator or his/her delegate will be present at the MRI unit from study intervention 
administration until at least 1 h after administration to promptly and efficiently manage any 
acute reaction, should it occur.
Repeated pregnancy testing and the required use of highly effective contraception will 
minimize the risk of inadvertent administration to a pregnant woman or prenatal exposure in 
this study.
Based on the favorable non-clinical and clinical safety data of BAY 1747846 at the doses 
investigated, it is concluded that female and male participants will not be exposed to any 
relevant health risk in this cross-over study. Therefore, their inclusion in this study is justified 
considering the potential benefit that the development of a low-dose, macrocyclic GBCA may 
provide to patients undergoing contrast-enhanced MRI examinations.
This clinical study does not involve invasive procedures other than single IV administration 
of the test and comparator GBCAs and a very limited number of venous blood samples for 
safety and PK analysis.
The typical contraindications for MRI are reflected in the selection criteria. When properly 
performed, the MRI examination is painless and no harmful effects are currently known.


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In conclusion, the procedure-related risks of study participation are considered to be minimal.
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of BAY 1747846 can be found in the IB and for Gadovist/Gadavist within the 
respective local product label.


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3.
Objectives and Endpoints
Objectives
Endpoints
Primary

Identify a dose for further development 
that has an overall diagnostic preference 
rate similar to that of the comparator
gadobutrol at 5 min pi

Overall diagnostic preference based on a 
randomized paired blinded read using a 5-
point scale (greatly prefer BAY 1747846, 
prefer BAY 1747846, no preference, 
prefer gadobutrol, greatly prefer 
gadobutrol) at 5 min pi
Secondary

Show non-inferiority of BAY 1747846 
compared to gadobutrol at 5 min pi with 
respect to sum of lesion visualization 
parameters

Compare pre- and post-contrast images
with respect to lesion visualization 
parameters and number of lesions

Lesion visualization parameters 
(border delineation, contrast 
enhancement, internal morphology) on 
post-contrast images at 5 min pi

Lesion visualization parameters 
(border delineation, contrast 
enhancement, internal morphology) on 
pre-contrast and combined pre- and post-
contrast (5 min pi) images

Number of lesions on pre-contrast and 
combined pre- and post-contrast (5 min 
pi) images
Other pre-specified

Evaluate SI/enhancement

Evaluate efficacy at 15 min pi

Evaluate efficacy at 10 min pi

Determine plasma concentrations of Gd
following administration of BAY 1747846 
and gadobutrol

Evaluate safety profile of BAY 1747846 
in comparison to gadobutrol

Number of enhanced lesions on 
post-contrast images

Quantitative parameters: SI, contrast to 
noise ratio (CNR), signal to noise ratio 
(SNR)

Lesion visualization parameters at 15 min 
pi

Lesion visualization parameters at 10 min 
pi

Plasma concentrations of Gd within 3 time 
windows on Day 1 and after 24 ± 4 h 
following administration of BAY 1747846 
and gadobutrol

Incidence and severity of TEAEs and 
other parameters

Number of enhanced lesions on post-
contrast images at 5 min pi
4.
Study Design
4.1
Overall Design
This is a multicenter Phase 2 study with a single-blind design with blinded read. The study 
will permit up to two adaptive dose changes (i.e. increase or decrease) to ensure that the dose 
of BAY 1747846 shows similar overall diagnostic preference and enhancement as the 
selected active comparator gadobutrol.


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Each participant will receive an IV gadobutrol administration during Period 1 and an IV 
BAY 1747846 administration during Period 2 followed by recording of a contrast-enhanced 
MRI in each period.
Between each study intervention administration there will be a washout period of 3 – 14 days.
The individual study duration will be approximately 2 to 4 weeks including screening and last 
measurements in Period 2, which will be conducted 24 h after the last study MRI. The total 
duration of the study will be approximately 1 year until final clean data base.
4.2
Scientific Rationale for Study Design
The decision for the study design is primarily based on the following considerations:

The non-randomized design was selected to enable a diagnostic MRI for the study 
participants during Period 1 as the participants are patients with CNS lesions requiring 
a contrast-enhanced MRI, and they need to be provided with standard medical care 
with the first imaging. Therefore, the comparator (gadobutrol)-enhanced MRI will 
always be done in Period 1, whereas the MRI including the injection of BAY 1747846 
will be done during Period 2. Based on the gadobutrol-enhanced MRI, the investigator 
may identify the need for immediate treatment or that the participant has no lesions, 
both may yield in exclusion from further study participation.

The single-blind design is addressing primarily an unbiased assessment of safety 
parameters. The study participants will be blinded to the study intervention. Only the 
investigator and site staff will be unblinded to the study intervention, obeying to the 
need for participants to receive the best medical care as urgently as needed based on 
clinical judgment.

The single-blind design might potentially lead to a bias with regard to safety 
assessment on the investigators side. Safety bias is minimized by the blind in the 
participants and evaluation of images for efficacy. The risk for bias was evaluated vs. 
the benefit for the participants in obtaining a diagnostic MRI in the study Period 1 and 
was regarded acceptable.

The efficacy analysis is done in an independent blinded read which is unaffected by 
the single-blind non-randomized study design.
4.3
Justification for Dose
BAY 17147846
The starting dose of BAY 1747846 of 0.04 mmol Gd/kg bw was selected based on the results 
of the dose response Study 19325. Based on the RSE values determined in five different areas 
of the head and neck, a dose response curve was established for each area by inverse 
regression which was then compared to the RSE determined after injection of gadobutrol. 
Overall, BAY 1747846 led to the same enhancement as gadobutrol with less than half the Gd 
dose. The estimated dose to reach the same signal enhancement was in the range of 
0.038 to 0.065 mmol Gd/kg bw (see Section 2.2). A starting dose was chosen at the lower end 
of the range.


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The primary and secondary endpoints will be based on the images acquired 5 min pi, as this 
time point is representative of steady-state when the GBCA has been distributed in the 
extracellular space. In addition, 5 min pi image acquisition is used broadly in clinical routine 
for CNS contrast-enhanced MRI.
There are 3 possible outcomes from the first cohort of at least 50 evaluable participants (see 
Section 9.2 for determination of sample size):
1) If the confidence intervals (CIs) for the choices “Prefer gadobutrol” and “Prefer 
BAY 1747846” are not overlapping and the proportion expressing “Prefer gadobutrol” 
is greater than the proportion “Prefer BAY 1747846”, then the dose needs to be 
adjusted upward and an additional cohort with a higher dose will be enrolled.
2) In case, the choices “Prefer gadobutrol” and “Prefer BAY 1747846” are equally 
balanced in favor of both compounds, dose adjustment will not be needed. 
3) If the CIs for the choices “Prefer gadobutrol” and “Prefer BAY 1747846” are not 
overlapping and the proportion expressing “Prefer BAY 1747846” is greater than the 
proportion “Prefer gadobutrol”, then the dose needs to be adjusted downward and an 
additional cohort with a lower dose will be enrolled.
For outcome 1, a second participant cohort will be studied with an adjusted dose of
BAY 1747846 which will be about 0.005 mmol Gd/kg bw higher than the initial dose. If that 
cohort does not result in outcome 2 or 3, an additional dose adjustment of about 
0.005 mmol Gd/kg bw will be performed in a third cohort of additional 50 evaluable 
participants.
The starting dose was selected to be unlikely to require more than one upwards dose 
adjustment.
For outcome 2, which means that the primary endpoint is met, there will be no investigation 
of another cohort.
For outcome 3, one downward adjustment of about 0.005 mmol Gd/kg bw with additional 
50 evaluable participants will be performed.
The final determination of the dose will also consider the individual visualization parameters 
which are evaluated as secondary endpoints as well as quantitative SI measurements using 
dedicated software.
Gadobutrol
Gadobutrol will be the active comparator for this study. It will be administered at the 
approved standard dose for CNS imaging of 0.1 mmol Gd/kg bw.
4.4
End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study including completion of the 24 h post MRI measurements in Period 2.
The end of the study is defined as the date when the clean database is available.


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Primary completion
The primary completion event for this study is the availability of the blinded read results for 
all participants.
5.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1. Participant must be at least 18 years of age at the time of signing the informed 
consent.
Type of Participant and Disease Characteristics
2. Known or highly suspected CNS pathology (contrast-enhancing CNS lesion) referred 
for contrast-enhanced MRI of the CNS. The suspicion of a CNS pathology can be
based on current clinical symptoms and/or on a previous imaging procedure. Types of 
CNS lesions and pathologies which could be included are:

Glial tumor (low grade [I/II], high grade [III/IV], grade cannot be 
determined)

Oligodendrogliomas grade II and III (anaplastic/malignant)

Metastases

CNS lymphoma

Meningiomas, anaplastic/malignant meningiomas, meningeal spread of 
meningiomas [dural involvement], swannomas, neurinomas/accusticus 
neurinomas

Craniopharyngiomas

Ependymomas.
Participants who are referred for follow-up MRIs after treatment or for treatment 
planning (e.g. targeted radiosurgery) are eligible if there is a possibility to schedule an 
additional MRI exam.
Sex
3. Male and female.
4. Contraceptive use by men or women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies. 
Sexually active men, who have not been surgically sterilized, and women of child-
bearing potential must agree to use reliable and acceptable methods of contraception. 
This applies for the time period between signing the informed consent form (ICF), 
until 24 h after the last study MRI. Men must not to act as sperm donor. Acceptable 


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methods of contraception include user-independent (e.g. implantable hormonal 
contraception associated with inhibition of ovulation, intrauterine device, intrauterine 
hormone-releasing system, bilateral tubal occlusion) and user-dependent methods 
(e.g., hormonal contraception with inhibition of ovulation, vasectomized partner if 
sole sexual partner, sexual abstinence). Preference should be given to user-
independent methods of contraception (detailed guidance see Section 10.4).
Informed Consent
5. Capable of giving informed consent within 8 weeks before any study-related 
procedures and assessments are conducted as described in Section 10.1.3 which 
includes compliance with the requirements and restrictions listed in the ICF and in this 
protocol.
Other
6. Estimated glomerular filtration rate (eGFR) value ≥60 mL/min/1.73m2 at baseline. 
With regards to baseline of period 1, eGFR value can be derived from a serum 
creatinine result within 4 weeks prior to the first study MRI determined by local 
hospital lab.
7. Ability and willingness to understand and follow study-related instructions, including 
two contrast-enhanced MRI examinations with both BAY 1747846 and gadobutrol.
8. Confirmation of the participant’s health insurance coverage prior to the baseline 
examinations, if required by country (e.g. Germany).
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Considered clinically unstable or has a concomitant/intercurrent condition (e.g.
COVID-19 infection) that would not allow participation for the full planned study 
period (i.e. period 1, 2 or both) in the judgement of the investigator.
2. Severe cardiovascular disease (e.g. known long QT syndrome, acute myocardial 
infarction [<14 days], unstable angina, congestive heart failure New York Heart 
Association class IV or acute stroke [<48 h]).
3. Patients undergoing liver transplantation.
4. Any contraindication to MRI examinations (e.g. metallic implants, pacemaker, 
claustrophobia).
5. History of severe allergic or anaphylactic/anaphylactoid reaction to any allergen 
including drugs and contrast agents, foods, chemicals or other substances.
6. History of allergic asthma and/ or atopic dermatitis.
7. Suspected lesions or suffering from any of the following CNS diseases/lesion types as 
the main indication for MRI. Secondary findings identified by the investigator might 
not lead to exclusion of the participant, e.g. a small venous angioma:


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
Lepto-meningeal disease (e.g. leptomeningeal carcinomatosis). Dural 
lesions (e.g. meningiomas) fulfilling inclusion criteria #2 are not excluded.

Pituitary adenomas (macro and micro)

Tumors of the choroid plexus

Tumors of the pineal gland

Dermoid/epidermoid tumors

Infectious disease (e.g. brain abscess, cisticercosis, etc.)

Venous angiomas

Subacute/chronic ischemia

Encephalitis

Multiple sclerosis (acute and chronic)

Optic neuritis

Chordomas

Von Hippel Lindau syndrome 

Hypertensive leukoencephalopathy.
Prior/Concomitant Therapy
8. Receipt of any contrast agent <72 h prior to the study MRIs, or planned receipt of any 
contrast agent within 72 h after the second study MRI.
9. Planned or expected biopsy in the region of interest or any interventional therapeutic 
procedure from the first study MRI up to 24 h after the second study MRI.
10. Planned or expected change in any treatment or procedure between the two study 
MRIs that may alter image comparability, e.g. corticosteroid and /or chemotherapy 
which is changed between the two MRI procedures.
Prior/Concurrent Clinical Study Experience
11. Has been previously enrolled in this study.
12. Has received any investigational product within 30 days, or within 5 times half-life of 
the investigational product, whichever is shorter, prior to enrolling in this study. Note: 
Participants who have entered the follow-up period of or have been discontinued from 
an investigational study may participate as long as it has been 30 days after the last 
dose of the previous investigational product, or 5 times half-life of that investigational
product, whichever is shorter.
13. Contraindications to the administration of gadobutrol, as specified in the local product 
label (e.g. history of severe hypersensitivity reaction to gadobutrol).
Other Exclusions
14. Women of child-bearing potential with a positive urine test at the day of study 
intervention administration.
15. Breast feeding women.


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5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
Fasting is recommended according to clinical practice.
No water is allowed from 1 h prior to and until 1 h after study intervention administration.
5.3.2
Activity
Participants will abstain from excessive or unusual exercise in the period from signing of the 
ICF until 24 h after the last study MRI.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently receiving study intervention. A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
re-screened. A maximum of 10% of participants may be enrolled in the study after re-
screening. Re-screened participants should be assigned a new participant number. The 
previous participant number of the participant will be documented in the electronic case report 
form (eCRF).
Re-starting the defined set of screening procedures to enable the “screen failure” to participate 
at a later time point is not allowed – with the following exceptions:

The participant had successfully passed the screening procedures but could not start 
subsequent study intervention administration on schedule.

The in-/exclusion criteria preventing the participant’s initial attempt to take part in the 
study have been changed (via protocol amendment).
In any case, the investigator has to ensure that the repeated screening procedures do not 
expose the participant to an unjustifiable health risk. Also, for re-screening, the participant has 
to re-sign the ICF, even if it was not changed after the participant’s previous screening.
6.
Study Intervention
Study intervention is defined as any investigational interventions, marketed products, placebo, 
or medical devices intended to be administered to a study participant according to the study 
protocol.
Note: In this study, study intervention refers to administration of test intervention 
BAY 1747846 and comparator intervention gadobutrol.
6.1
Study Interventions Administered
Regarding the selection of doses in the study, refer to Section 4.3.


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The identity of the study interventions is described in detail in Table 6-1.
Table 6-1: Identity of study intervention
Arm name
Active drug
Active drug
Intervention Name
BAY 1747846
Gadobutrol
Type
Test drug
Comparator drug
Dose formulation
Solution for IV injection
Solution for IV injection
Unit dose strength
193.43 mg BAY 1747846/mL
(equivalent to 0.3 mmol Gd/mL); 
4 ml (773.70 mg) per vial (nominal 
amount)
604.72 mg gadobutrol/mL)
(equivalent to 1.0 mmol Gd/mL)
Dosage level(s)
1. cohort: 0.04 mmol Gd/kg bw
2. cohort: 0.04 + 0.005 or 
0.04 - 0.005 mmol Gd/kg bw
3. cohort: 0.04 + 0.01 or 
0.04 - 0.01 mmol Gd/kg bw
0.1 mmol Gd/kg bw
Route of administration
IV injection
IV injection
IMP and NIMP
IMP
IMP
Sourcing
Provided centrally by the sponsor 
Provided locally by the study site as 
marketed product or provided
centrally by the sponsor (depending 
on local requirements).
Packaging and 
Labeling
Will be supplied in 10 mL vials, 
colorless glass type I for injection 
with stopper. Each glass vial will be 
labeled as required per country 
requirement.
Will be supplied in vials. Study 
intervention will be used as 
unchanged product with market 
authorization or each vial will be 
labeled as required per country 
requirement (depending on local 
requirement).
Current/Former 
Name(s) or Alias(es)
BAY 1747846
Gadovist/Gadavist
bw = body weight; Gd = gadolinium; IMP = investigational medicinal product; IV = intravenous;
NIMP = non-investigational medicinal product
Administration procedure
An IV injection line consisting of a large bore indwelling catheter will be placed in an 
antecubital vein. The location of the IV injection line has to be documented in the eCRF.
The study intervention will be administered as a bolus at the rate of 2 mL/s either using an 
automated MR-compatible injection system or by hand injection via the IV injection line, 
each followed by a 20 mL 0.9% saline flush at the same flow rate. Dose and volume of study 
intervention will be recorded in the eCRF.


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6.2
Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. 
3. All study intervention must be stored in a secure, environmentally controlled, and 
monitored (manual or automated) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff.
4. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (i.e. receipt, reconciliation, and final disposition records).
6.3
Measures to Minimize Bias: Randomization and Blinding
This is a single-blind study. Participants will remain blinded to the sequence of the study 
intervention throughout the course of the study. In order to maintain this blind, the study 
intervention must be prepared without the study participant being able to witness it. 
Furthermore, the investigator’s team has to ensure that the participants remain blinded 
throughout the study.
Blind readers will not be provided with information on study intervention throughout the 
course of the study.
6.4
Study Intervention Compliance
The IV administration of the study intervention will be done by a member of the 
investigator’s team. This person will ascertain and document that the participant receives the 
treatment as planned.
6.5
Prior and Concomitant Therapy
Participants are not to receive any contrast agent <72 h prior to the study MRIs or within 72 h 
after the second study MRI (see Section 5.2).
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving within 4 weeks before signing of 
the ICF or receives during the study must be recorded along with:

Reason for use.

Dates of administration including start and stop dates.

Dosage information including dose and frequency.
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy.
The regular use of contraceptives and the occasional use of paracetamol, aspirin, or ibuprofen 
are permitted prior and during the study.


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Medication other than the study intervention must not be taken during the study without 
consulting the investigator. Participants will be instructed to not use any medication without 
consulting the investigator, unless prescribed by a physician to treat an AE. Participants will 
be instructed to report any used concomitant medication, including herbal remedies or food 
supplements, to the investigator. All concomitant medication is to be recorded in the source 
documentation and the appropriate pages of the eCRF. For concomitant medication 
administered on days of study intervention administration each dose will be documented with 
time of administration.
6.6
Dose Modification
See Section 4.3.
6.7
Intervention after the End of the Study
After the end of this study, no further treatment is planned.
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
7.1
Discontinuation of Study Intervention 
No further participant will be dosed with BAY 1747846 and the study findings will be 
evaluated thoroughly at this point to decide on further progress of the study, if one of the 
following occurs:

Occurrence of any SAE assessed as related to BAY 1747846 which is not in line with 
the safety profile of current macrocyclic GBCAs.

Occurrence of severe AEs related to BAY 1747846 in more than 3 participants. This 
includes changes of laboratory parameters qualifying as severe.

Any relevant information, from this study or from outside of this study, indicating a 
relevant deterioration of the risk-benefit ratio.
See the SoA (Section 1.3) for data to be collected at the time of intervention discontinuation 
and follow-up and for any further evaluations that need to be completed.
7.2
Dropout
A participant who discontinues study participation prematurely for any reason is defined as a 
“screen failure” if the participant has not received any study intervention (Section 5.4).
A participant who at the time of premature withdrawal, has received any study intervention is 
a “drop out”.
7.3
Participant Discontinuation/Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. This is expected to be uncommon.

At the time of discontinuing from the study, if possible, an early discontinuation visit 


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should be conducted. See SoA for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be 
completed.

The participant will be permanently discontinued both from the study intervention and 
from the study at that time.

If the participant withdraws consent for disclosure of future information, the sponsor 
may retain and continue to use any data collected before such a withdrawal of consent.

If, in the investigator’s opinion, continuation of the study which includes start of 
Period 2 would be harmful to the participant’s well-being the participant will be 
permanently discontinued. Participants that suffer a severe hypersensitivity reaction 
related to gadobutrol during Period 1 of the study, must not be advanced into Period 2 
of the study.
7.4
Lost to Follow-up
A participant will be considered lost to follow-up if he/she fails to return for Period 2 and is 
unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as soon 
as possible and counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the participant wishes to and/or should 
continue in the study.

Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing address 
or local equivalent methods). These contact attempts should be documented in the 
participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered lost to 
follow-up.
8.
Study Assessments and Procedures

Study procedures and their timing are summarized in the SoA (see Section 1.3). 
Protocol waivers or exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.


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
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (e.g.
blood count) and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and were 
performed within the time frame defined in the SoA.
8.1
Efficacy Assessments
The independent review and centralized measurements will be planned and conducted by 
GCIS (Bayer). Details on blinded image evaluation and centralized procedures will be 
provided by GCIS in the Image Review Charter. The blinded readers will be experienced 
independent certified radiologists not affiliated with the imaging facilities and not involved in 
the conduct of the study and/or the recruitment of participants. Prior to the conduct of the 
blinded read, the readers will be trained by GCIS on the alignment of the assessment rules for 
image evaluation.
8.1.1
MRI Procedure
8.1.1.1
MRI Equipment
The MRI will be performed at MRI units with readily available emergency and intensive care 
facilities. State of the art 1.5 Tesla MRI scanners that can perform the required pulse 
sequences with a dedicated head or head/neck coil will be used. The same scanner, coil and 
MR techniques per participant must be used for both the gadobutrol and BAY 1747846 
contrast-enhanced MRIs.
8.1.1.2
Sequence Parameters for Brain Imaging
Protocol-defined sequences for CNS MRI will be used to obtain unenhanced and 
contrast-enhanced image presentations.
The same parameter setting must be used for unenhanced T1w images and for contrast-
enhanced T1w images in each participant. The required pulse sequences for BAY 1747846 
and gadobutrol are:

Unenhanced:

Localization sequence for brain according to the study site’s standard

2D T1w images of the whole brain (axial)

3D T1w images of the whole brain (axial or sagittal, consistent across visits 
per participant)

Contrast-enhanced:

3D T1w images of the whole brain (axial or sagittal, consistent to 
unenhanced and across visits per participant), starting 5 min pi.

2D T1w images of the whole brain (axial), starting directly after prior 
sequence at about 10 min pi.


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
3D T1w images of the whole brain (axial or sagittal, consistent across visits 
per participant), starting 15 min pi.

General considerations:

The MRI scanner must NOT be actively retuned after the unenhanced 
sequences.

It is crucial that all imaging parameters are as consistent as possible 
throughout both image visits of each study participant.
Further sequences (e.g. DWI or T2/FLAIR) can be run for local clinical use, as long as no 
active retuning or shimming is ensured between the mandatory study sequences. 
The date and start time of the study intervention injection will be recorded in the eCRF as 
well as any deviation from the specified MRI procedures and the reason for it (scanner-related 
problem or participant-related problem).
The recommended MRI parameters for the mandatory study sequences are displayed in 
Table 8-1 below.


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Table 8-1: Recommended MRI sequence parameters
2D T1w a
3D T1w a
Plane
Axial
Sagittal or axialb
Pulse sequence
Spin echo (SE)
Inversion recovery gradient recall echo
(IR-GRE)c
Patient position
Supine
Supine
Coil
Head/head-neck
Head/head-neck
Slice thickness 
(Gap/spacing)
≤5 mm 
(0 mm)
1 mm (isovoxel)
(0 mm)
Frequency
≥256
≥256
Phase
≥256
≥256
Inplane resolution
1.5 x 1.5 mm
1 x 1 mm
NEX/NSA
≥1
≥1
Parallel imaging
Up to 2x
Up to 2x
TR
According to site’s standard
According to site’s standardd
TE
According to site’s standard
Minimum valued
TI
–
According to site’s standardd
Acquisition
2D
3D
Contrast media
Unenhanced
Starting about 10 min pi (directly after 
prior sequence)
Unenhanced
Starting 5 and 15 min pi
2/3D = 2/3 dimensional, IR-GRE = inversion recovery gradient recall echo, NEX = number of 
excitations, NSA = number of acquisitions, pi = post injection, SE = spin echo, T1w = T1-weighted, 
TE = echo time, TI = inversion time, TR = repetition time.
a 
All parameters must be as consistent as possible across both image visits per participant and 
equivalent for pre- and post-contrast T1w images per image visit.
b 
Either axial or sagittal anatomic orientation can be performed, but must be consistent for both 
image visits and for unenhanced and contrast-enhanced images per study participant.
c 
Equivalent to MPRAGE = magnetization prepared rapid gradient-echo (Siemens & Hitachi), 
inversion recovery spoiled gradient-echo (IR-SPGR or Fast SPGR with inversion activated or 
BRAVO; GE), 3D turbo field echo (TFE; Philips), or 3D fast field echo (3D Fast FE; Toshiba).
d
Recommended TR/TE values based on Ellingson et al.: TR = 2100 msec (Siemens, Hitachi) or 
5 to 15 msec (GE, Philips, Toshiba); TI = 1100 msec (Siemens, Hitachi) or 400 to 450 msec (GE, 
Philips, Toshiba).
8.1.1.3
Quality Assurance of Images
The investigator must assure that the MRI image set is of acceptable diagnostic quality.
All image sets will be de-identified and sent to GCIS. GCIS will conduct QC and quality 
assurance (QA) of the MR images.
Further details and guidance for the sites will be provided in the Imaging Manual by GCIS.


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8.1.1.4
Image Archiving and Copying
Once all the study-related images are acquired, all sets of images and related documents are 
considered to be source data and therefore must be stored on appropriate archival media at the 
site according to local requirements, but at least for 15 years.
8.1.2
Primary Endpoint
To assess the primary study endpoint, 3 blinded readers (i.e. blinded to the treatment 
allocation and any other information on the participant) will independently compare the 
following contrast-enhanced image sets of each study participant in a matched pairs approach:
Contrast-enhanced T1w (BAY 1747846) 5 min pi
Contrast-enhanced T1w (gadobutrol) 5 min pi.
The gadobutrol and BAY 1747846 image sets will be randomly assigned to either the left 
(image L) or right (image R) position in the image visualization system. Qualitative technical 
efficacy is measured by the reviewers overall diagnostic preference based on the randomized 
paired blinded read using the following 5-point scale:
1 = 
greatly prefer image R
2 = 
prefer image R
3 = 
no preference
4 = 
prefer image L
5 = 
greatly prefer image L.
8.1.3
Secondary Endpoints
8.1.3.1
Lesion Visualization Parameters
The following 3 lesion visualization parameters will be scored by the 3 blinded readers for 
assessing the secondary endpoint “lesion visualization parameters” for each enhanced (5 min 
pi) MR image set separately (no matched pairs approach), as well as for assessing the 
secondary endpoint “lesion visualization parameters” for comparison of pre- and post-contrast 
images on pre-contrast and combined pre- and post-contrast images (5 min pi) separately (no 
matched paired approach):

Lesion border delineation (see Section 8.1.3.1.1)

Degree of lesion contrast enhancement (see Section 8.1.3.1.2)

Lesion internal morphology (see Section 8.1.3.1.3).
8.1.3.1.1
Lesion Border Delineation
Up to 5 of the largest lesions will be selected and scored by the blinded readers.
The following 4-point scale will be used for lesion delineation:
1 = 
None
no or unclear delineation of the lesion boundaries
2 = 
Moderate
some aspects of border delineation covered
3 = 
Good
almost clear, but not complete delineation


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4 = 
Excellent
clear and complete delineation.
8.1.3.1.2
Contrast Enhancement
A total of up to the 5 largest lesions will be selected and scored by the blinded readers.
The following 4-point scale will be used for lesion enhancement:
1 = 
No
lesion is not enhanced
2 = 
Moderate
lesion is weakly enhanced
3 = 
Good
lesion is clearly enhanced
4 = 
Excellent
lesion is clearly and brightly enhanced.
8.1.3.1.3
Internal Morphology
Up to 5 of the largest lesions will be selected and scored by the blinded readers.
The following 3-point scale will be used for lesions:
1 = 
Poor
the structure and internal morphology of the lesion is poorly visible
2 = 
Moderate
the structure and internal morphology of the lesion is partially visible
3 = 
Good
the structure and internal morphology of the lesion is sufficiently 
visible.
8.1.3.2
Number of lesions
The 3 blinded readers will record the total number of lesions for each pre-contrast and 
combined pre- and post-contrast (5 min pi) MR image set separately (no matched pairs 
approach). The upper limit of lesions to be counted is 20.
8.1.4
Other Endpoints
8.1.4.1
Quantitative Signal Intensity
For each image set, one additional blinded reader will perform quantitative measurements on 
unenhanced and contrast-enhanced (5 min pi, 10 min pi, and 15 min pi) images of both image 
sets for each study participant. The following quantitative parameters will be calculated (for 
further details see Section 9.4.1.3):

Percentage of lesion enhancement

CNR

SNR.
In addition, an algorithm-based evaluation of weighted mean contrast enhancement may also 
be conducted centrally using dedicated software.
8.1.4.2
Efficacy Evaluation at 10 and 15 min Post Injection
Efficacy evaluation as described in Sections 8.1.3 and 8.1.4 (lesions visualization parameters, 
number of lesions and quantitative SI) will additionally be performed for enhanced images 
10 and 15 min pi.


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8.1.4.3
Number of Enhanced Lesions
The 3 blinded readers will record the total number of enhanced lesions for each enhanced 
(5 min pi) MR image set separately (no matched pairs approach). The upper limit of lesions to 
be counted is 20.
8.2
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 1.3).
8.2.1
Physical Examinations
The complete physical examination (by means of inspection, palpation, auscultation) will be 
performed by a physician, or by another qualified healthcare professional under the 
responsibility of the investigator or physician designee, and cover at least the organs of the 
cardiovascular, respiratory and abdominal systems. Orientating tests of neurological function 
will be included.
The short physical check will be done by a qualified healthcare professional by observation 
and asking the participant about his/her physical condition. Additionally, participants will be 
asked using open questions about any symptoms that they experience, i.e. AEs.
The performance of the physical examination will be documented in the eCRF. Abnormal 
physical examination findings are recorded either as medical history or as AEs (see 
Section 10.3.1).
8.2.2
Vital Signs
The following vital signs will be assessed at the time points specified in the SoA 
(Section 1.3):

BP (systolic and diastolic)

Heart rate or pulse

Body temperature

Respiratory rate.
BP and heart rate or pulse will be assessed by a member of the investigator’s team under the
following conditions:

Position: Supine (small pillow under head allowed), resting period of at least 5 min in 
a quiet setting without distractions (e.g. television, cell phones).

Measuring site: cuff to be placed on the right/left upper arm (if possible, the same arm 
will be used for all measurements in one participant); cuff location will be 
documented. BP will not be measured at the arm used for injection of the study 
intervention.

Method: oscillometric measurement of systolic and diastolic BP by automatic 
measurement device.
Body temperature will be measured by a member of the investigator’s team with an 
appropriate thermometer. The location of temperature measurement will be documented in the 
eCRF.


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8.2.3
Electrocardiogram
Single 12-lead ECGs will be obtained as outlined in the SoA (see Section 1.3) by a member of 
the investigator’s team under the following conditions:

Position: supine (small pillow under head allowed) for at least 5 min

Device: computerized ECG device, representing paper velocity of 25 mm or 50 mm 
per second as preferred by the site, same velocity for all ECGs

Automatic calculation of the following parameters: Heart rate (HR), PR interval (PR), 
QRS duration, QT interval uncorrected (QT) and corrected for HR (QTc).

Safety evaluation of all ECG recordings by a site physician, in a timely manner during 
the timeframe of the visit, providing diagnosis including an overall assessment of the 
findings and the overall clinical relevance (normal, abnormal clinically insignificant or
abnormal clinically significant).

All ECGs recorded during the study at one site will be evaluated by a cardiologist 
from the institutions, including measurements of intervals and a diagnosis. Only these 
ECG measurements will be used for the statistical data evaluation.
8.2.4
Pulse Oximetry
In both study periods, non-invasive monitoring of pulse oximetry will be performed during 
the MRI phase. The continuous assessment will be done while the participant is in the MR
scanner. Results of the pulse oximetry monitoring will not be recorded within the eCRF 
unless the results qualify for an AE.
8.2.5
Short Mental Status Check
A short mental status check will be performed, which is an interview of the participants to do 
a basic assessment of orientation, memory, and cognitive function, for time points see SoA 
(Section 1.3).
8.2.6
Clinical Safety Laboratory Assessments

Blood and urine samples will be collected by a member of the investigator’s team.  
Detailed information about the collection, processing, storage and shipment of 
laboratory samples is provided in the laboratory manual.

See Section 10.2 for the list of clinical laboratory tests to be performed and the SoA 
(Section 1.3) for the timing and frequency.

The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
eCRF. The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected 
for the participant’s condition.


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
Additional safety assessments may be conducted at the discretion of the investigator. 
These may be laboratory examinations at additional time points or additional 
laboratory parameters.

All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 24 h after the last dose of study intervention should 
be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the investigator.

If such values do not return to normal/baseline within a period of time 
judged reasonable by the investigator, the etiology should be identified and 
the sponsor notified.

All protocol-required laboratory assessments, as defined in Section 10.2, 
must be conducted in accordance with the laboratory manual and the SoA.

If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in 
participant management or are considered clinically significant by the 
investigator (e.g. SAE or AE or dose modification), then the results must be 
recorded in the eCRF.

In the event of implausible results, the laboratory may measure additional parameters 
to assess the quality of the sample (e.g. clotted or hemolyzed) and to verify the results.
8.3
Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Section 10.3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative or health care professional not involved in the
study).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE. They remain responsible for 
following up SAEs, or AEs considered related to the study intervention or study procedures, 
or those that caused the participant to discontinue the study. AESIs have to be followed up 
regardless of causality or relationship to study intervention (see Section 8.3.6).
8.3.1
Time Period and Frequency for Collecting AE and SAE Information
All AEs/SAEs will be collected from signing of the ICF until follow-up at the time points 
specified in the SoA (Section 1.3).
Medical occurrences that begin before the start of study intervention but after signing the ICF 
will be recorded on the Medical History/Current Medical Conditions section of the eCRF not 
the AE section, if they:

Are surgical procedures that were planned prior to the start of the study by any physician 
treating the participant.


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
Started before signing the ICF and for which no symptoms or treatments are present until 
signing of ICF (e.g. seasonal allergy without acute complaints).

Started before signing of ICF and for which symptoms or treatment are present after 
signing ICF at an unchanged intensity (e.g. allergic pollinosis).
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstances should this exceed 24 h, as indicated in Section 10.3. The investigator will 
submit any updated SAE data to the sponsor within 24 h of it being available.
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the investigator must 
promptly notify the sponsor.
8.3.2
Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences.
8.3.3
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and non-serious AESIs (as defined in 
Section 8.3.6), will be followed until resolution, stabilization, the event is otherwise 
explained, or the participant is lost to follow-up (as defined in Section 7.4). Further
information on follow-up procedures is given in Section 10.3.
8.3.4
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of an SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators.

Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g. summary or listing of SAEs) from the sponsor will 


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review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements.
8.3.5
Pregnancy

Details of all pregnancies in female participants and, if indicated, female partners of 
male participants will be collected after the start of study intervention and until 24 h
after the second study MRI during Period 2. Any outcome of the mother and the child 
at delivery should be reported.

If a pregnancy is reported, the investigator should inform the sponsor within 24 h of 
learning of the pregnancy and should follow the procedures outlined in Section 10.4.

Abnormal pregnancy outcomes (e.g. spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered as SAEs.

The child’s health should be followed up until 6 to 8 weeks after birth.
8.3.6
Adverse Event of Special Safety Interest
Any AESI is to be reported within 24 h of the investigator’s awareness, independently from 
seriousness and causality assessments.
For the purpose of this study, the following AEs are defined as AESI:

Reactions indicating hypersensitivity, e.g. bronchial asthma, rhinosinusitis, 
anaphylaxis, urticarial, and any type of skin reactions including late cutaneous and 
organ-specific reactions.

All AEs which are “severe” in intensity.
Hypersensitivity/anaphylactoid reactions have been reported to occur rarely for all GBCAs, as 
discussed in Section 2.3. The definition of hypersensitivity/anaphylactoid reactions as AESI is 
intended as a precaution, to assure that the sponsor is informed within short timelines about 
their occurrence and to allow thorough investigation of all circumstances, e.g. concomitant 
medications or environmental factors.
SAEs may represent a stopping criterion for the study (Section 7.1) and, therefore, need to be 
followed closely.
8.3.7
Expected Adverse Events
For this study, the applicable reference document is the current version 2.0 of the IB for 
BAY 1747846 and the SmPC of gadobutrol (available at 
(https://www.medicines.org.uk/emc/product/2876/smpc). If relevant new safety information 
for BAY 1747846 is identified, the information will be integrated into an update of the IB and 
distributed to all participating study centers.
The expectedness of AEs will be determined by the sponsor according to the applicable 
reference document and according to all local regulations.


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Expected Conduct-related Adverse Events
The frequent blood sampling (by single vein puncture and/or indwelling cannula) may be 
accompanied by mild pain, hematoma and, in rare cases, inflammation of the vessel wall or 
injury of a nerve. Awareness should be raised to the possibility of a vasovagal attack or 
syncope (marked by pallor, nausea, sweating, bradycardia, decrease in arterial BP, which, 
when below critical level, results in dizziness and/or loss of consciousness) during the 
sampling procedure.
The use of adhesive electrodes (ECG leads) and/or adhesive dressings may be accompanied 
by mild and transient reddening and/or itching of the skin.
8.3.8
Reporting of Medical Device Failures (Japan Only)
Medical device failure is defined as a medical device event which is related to an SAE or 
could cause health damage to participants or healthcare professionals in a clinical study. The 
investigator must report immediately all non-approved medical device failures. For this 
reporting, the forms provided are to be used and sent to the designated recipient.
8.4
Treatment of Overdose
For this study, any dose of BAY 1747846 greater than 0.2 mmol Gd/kg bw (corresponding to 
the highest dose applied in the FiH Study 19324) and any dose of gadobutrol greater than 
0.3 mmol Gd/kg bw within a 24-h time period will be considered an overdose. This dose is 
below the currently approved maximum dose for GBCAs. It is assumed that overdosing with 
the study intervention is highly unlikely. No signs of intoxication from an overdose of 
gadobutrol have so far been reported during clinical use (see local product label of
gadobutrol). GBCAs like BAY 1747846 and gadobutrol are quickly eliminated via glomerular 
filtration, which is not-dose depended. Patients with impaired renal function will be excluded 
from the study. 
In the event of an overdose, the investigator should:
1.
Contact the Medical Monitor immediately.
2.
Closely monitor the participant for any AE/SAE and laboratory abnormalities 
(cardiovascular monitoring [including ECG] and control of renal function 
recommended as a measure of precaution) until BAY 1747846 or gadobutrol can no 
longer be detected systemically (at least 7 days).
3.
Obtain a plasma sample for PK analysis within 7 days from the date of the last dose of 
study intervention if requested by the Medical Monitor (determined on a case-by-case 
basis).
4.
Document the quantity of the excess dose in the eCRF.
8.5
Pharmacokinetics
8.5.1
Drug Measurements
In total, 5 blood samples will be collected per participant per period for measurement of Gd in 
plasma at the time points specified in the SoA (Section 1.3). Instructions for the collection 


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and handling of biological samples will be provided by the sponsor in the laboratory manual. 
The actual date and time (24-h clock time) of each sample will be recorded in the eCRF.
Plasma concentrations of Gd will be determined using a validated inductively coupled plasma 
mass spectrometry method. Calibration samples and QC samples will be analyzed 
concurrently with study samples. The results of calibration and QC samples will be reported 
in the Bioanalytical Report, which will be included in the Clinical Study Report for this study.
Whenever possible, all efforts should be made to adhere to the sampling time windows in the 
SoA as it is important to have these data thoroughly and accurately documented in the eCRF.
Sampling times outside the suggested time windows will be listed as “other protocol 
deviations” only.
8.5.2
Population Pharmacokinetic Evaluation
Per period, a baseline blood sample will be taken prior to and 4 blood samples will be taken 
after administration of BAY 1747846 or gadobutrol and after the imaging MRI scans are 
complete in all participants. Each blood sample will be drawn during a pre-defined time-
window (20 min – 1 h, 2 – 4 h, 6 – 8 h after study intervention administration) or at 24 ±4 h 
after study intervention administration. The first time window starts after the MRI acquisition 
is completed. The 3 time windows and the late time point on the following day were chosen 
based on the well-established PK profile of GBCAs and the determined similarity of the PK 
profile of BAY 1747846 in the FiH Study 19324.
The 3 time windows on the dosing day will be subdivided into 3 further sub-windows (see 
Table 8-2). In order to achieve an approximately equal distribution of blood samples over the 
whole time window, the time points (sub-windows) at which the samples are taken will be 
randomized. This means that the sampling time point for each participant will be allocated to 
a sub-window. The PK sample scheduled for the next day (24 ± 4 h) can be taken together 
with the safety blood sample.
The PK calculation will be based on the actual sampling and dosing times. Therefore, it is of 
importance to have this data thoroughly documented in the eCRF. Deviations from the 
specified time points will be documented and taken into account when calculating the PK 
parameters. Those deviations do not qualify as protocol violations.
Randomization of the sub-windows will be performed for each participant on the basis of a 
computer-generated randomization list. Each study site will be provided with a randomization 
list for a balanced participant assignment to all sub-windows per time point.


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Table 8-2: Sampling schedule for sparse PK sampling
Time window/time frame for blood sampling
Sampling times points as defined by 
randomization
Immediately pre-injection
Randomization not applicable
20 min – 1 h
20 min to <30 min
30 min to <45 min
45 min to 1 h
2 h – 4 h
2 h to <2 h 40 min
2 h 40 min to <3 h 20 min
3 h 20 min to 4 h
6 h – 8 h
6 h to <6 h 40 min
6 h 40 min to <7 h 20 min
7 h 20 min to 8 h
24 ± 4 h
Randomization not applicable
Gd plasma concentration data for BAY 1747846 collected in the present study will be 
evaluated using non-linear mixed effects models together with data collected from other 
clinical studies investigating BAY 1747846. Mixed effects models, or population-type PK 
models, describe the relationship between dose, time and variables, such as drug plasma 
concentrations. The population PK model to be developed based on PK data from the FiH 
study data will be applied and adjusted, if appropriate. PK of BAY 1747846 will be compared 
to gadobutrol.
The results of this evaluation may be presented in a separate Modelling and Simulation
Evaluation Report.
8.6
Pharmacodynamics
Not applicable.
8.7
Genetics
Not applicable.
8.8
Biomarkers
Not applicable.
8.9
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics parameters will not be evaluated in this 
study.
8.10
Population Characteristics
8.10.1
Demographics
For demographic assessment the following parameters will be recorded: year of birth/age, sex, 
race/ethnicity, weight and height.


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Body weight and height, body mass index
Body weight will be measured by a member of the investigator’s team under the following 
conditions:

Light clothing without shoes after having emptied the bladder.

Electronic physician (column) scale with digital display, measurement units 0.1 kg.
The participant’s height will be measured (without shoes). The body mass index (BMI) will 
be calculated in RAVE, see Section 10.1.7.
8.10.2
Medical and Surgical History
Medical and surgical history findings (i.e. previous diagnoses, diseases or surgeries) meeting 
all criteria listed below will be collected as available to the investigator:

Not pertaining to the study indication,

Starting before signing of the ICF,

Considered relevant for the participant’s study eligibility.
Detailed instructions on the differentiation between medical history and AEs can be found in 
Section 10.3.1.
9.
Statistical Considerations 
9.1
Statistical Hypotheses
The main objective of this study is to identify a BAY 1747846 dose similar to the comparator
gadobutrol in diagnostic preference. Therefore, only point estimators and CIs will be 
considered and no formal hypothesis testing will be performed to compare differences 
between treatments or between individual doses.
9.2
Sample Size Determination
The justification of sample size was based on the proportion of participants for whom “No 
preference”, “Prefer BAY 1747846” and “Prefer gadobutrol” is expressed for each cohort
along with a corresponding two-sided 95% CI.
Number of Participants
For each BAY 1747846 dose cohort, approximately 60 participants will be enrolled. Based on 
the experience from previous studies, it is expected that up to 18% of the participants will 
discontinue prematurely and thus have images with only one of the two study interventions 
available. Therefore, participants will be enrolled on an ongoing basis until 50 participants 
have completed the MRIs in both study periods to ensure 50 evaluable participants per cohort 
for the analysis.
A maximum of two dose adjustments will be used, so that a maximum of approximately 
180 participants (3 cohorts) will be enrolled into the study.


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Dose Finding Algorithm
The decision criteria for dose adjustment will consider both the proportion of participants for 
whom no preference is selected, and the difference between the proportion preferring 
gadobutrol and preferring BAY 1747846.The following algorithm for dose adjustment will be 
used:

If the CIs for the choices “Prefer gadobutrol” and “Prefer BAY 1747846” are not 
overlapping and the proportion expressing “Prefer gadobutrol” is greater than the 
proportion “Prefer BAY 1747846”, then the dose needs to be adjusted upward and an 
additional cohort with a higher dose will be enrolled.

In case, the choices “Prefer gadobutrol” and “Prefer BAY 1747846” are equally 
balanced in favor of both compounds, dose adjustment will not be needed. 

If the CIs for the choices “Prefer gadobutrol” and “Prefer BAY 1747846” are not 
overlapping and the proportion expressing “Prefer BAY 1747846” is greater than the 
proportion “Prefer gadobutrol”, then the dose needs to be adjusted downward and an 
additional cohort with a lower dose will be enrolled.
Simulation
The reads of the blinded readers will be treated as independent confirmations of the results. 
For each cohort, 3 readers will be used as independent replications of the result, therefore the 
number of participants is 50 even though there will be 150 reads available. Having 2 or 
3 readers giving the same result lends confidence to the conclusion. If 2 or 3 readers reach the 
same conclusion on the recommended action (no dose adjustment needed, dose increase 
needed, dose decrease needed), then that will be the recommended action taken.
If all 3 readers reach different conclusions, then no dose adjustment is needed.
If 50% of choices are no preference, with 50 evaluable participants the 95% CI would be 
(36%, 64%). Based on simulations and assuming that the true percentage of no preference 
responses is 50%, and that there are no differences between the proportions preferring 
BAY 1747846 and comparator, with 50 patients the above decision algorithm would conclude 
no dose adjustment greater than 95% of the time. This is equivalent to saying that with 
50 patients and these assumptions there is greater than 95% power to conclude that no dose 
adjustment is needed. If we assume that there is a 30% difference in proportions between 
preferring BAY 1747846 and comparator, there is 77% power to conclude that a dose 
adjustment is needed.


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9.3
Populations for Analyses
For purposes of analysis, the following populations are defined:
Table 9-1: Analysis sets
Population
Description
Enrolled
All participants who sign the ICF.
Full analysis set (FAS)
All participants who have complete MR image datasets that 
qualify for blinded read.
Safety analysis set (SAF)
All participants who receive any dose of study intervention. 
9.4
Statistical Analyses
The statistical analysis plan will be developed and finalized before database lock and will 
describe the participant populations to be included in the analyses, and procedures for 
accounting for missing, unused, and spurious data. This section is a summary of the planned 
statistical analyses of the primary and secondary endpoints.
For the primary objective

The estimand is then the proportion of participants for whom no preference is chosen for 
the image preference in the overall diagnostic preference based on a randomized paired 
blinded read using a 5-point scale (see Section 8.1.2) at 5 min pi in all participants who 
have 2 image sets (gadobutrol and BAY 1747846) available. No imputations or 
adjustments will be made for those participants who have no images or only one image set
as these participants will be excluded from the analysis.

The estimand is then the difference between the proportion of participants for whom the 
BAY 1747846 image sets are preferred and the proportion of participants for whom the 
gadobutrol image sets are preferred in the overall diagnostic preference based on a 
randomized paired blinded read using a 5-point scale (see Section 8.1.2) at 5 min pi in all 
participants who have 2 image sets available. No imputations or adjustments will be made 
for those participants who have no images or only one image as these participants will be 
excluded from the analysis.
For the secondary objectives

The estimand is then the sum of lesion visualization parameters between both image sets
(BAY 1747846 and gadobutrol) in all participants who have 2 image sets available. No 
imputations or adjustments will be made for those participants who have no images or 
only one image set as these participants will be excluded from the analysis.

The estimand is then the mean of lesion visualization parameters between both image sets
(pre-contrast and combined pre- and post-contrast) in all participants who have 2 image
sets available. No imputations or adjustments will be made for those participants who 
have no images or only one image set as these participants will be excluded from the 
analysis.


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For objectives and endpoints see also Section 3.
For the analysis of preference, a participant needs to have two image sets (gadobutrol and 
BAY 1747846) available. No imputations for missing data will be performed. A low number 
of missing values will be expected due to the short duration for each participant and the 
expected high adherence to the study protocol. Imputations might introduce bias due to the 
small sample size and the study design (for drop-outs, the experimental intervention will 
always be missing).
9.4.1
Efficacy Analyses
Endpoint
Statistical Analysis Methods
Primary

Overall diagnostic preference based on a 
randomized paired blinded read using a 5-
point scale (greatly prefer BAY 1747846, 
prefer BAY 1747846, no preference, prefer 
gadobutrol, greatly prefer gadobutrol) at 5 min 
pi

For overall diagnostic preference 95% two-
sided CIs for the proportion of participants for 
whom “No preference” was expressed will be 
calculated.

Treatment difference will be tested with 
McNemar’s test.
Secondary

Lesion visualization parameters (border 
delineation, contrast enhancement, internal 
morphology) on post-contrast images at 5 min 
pi

Lesion visualization parameters (border 
delineation, contrast enhancement, internal 
morphology) on pre-contrast and combined 
pre- and post-contrast (5 min pi) images

Number of lesions on pre-contrast and 
combined pre- and post-contrast (5 min pi)
images

For the sum of lesion visualization parameters, 
95% two-sided CIs for the mean difference 
between BAY 1747846 and gadobutrol will be 
calculated.

For lesion visualization parameters, 95% two-
sided CIs for the mean difference between 
pre-contrast and combined pre- and post-
contrast will be calculated.

The number of lesions will be analyzed 
descriptively.
Other pre-specified

Quantitative parameters: SI, contrast to noise 
ratio (CNR), signal to noise ratio (SNR)

Lesion visualization parameters at 15 min pi

Lesion visualization parameters at 10 min pi

Number of enhanced lesions on post-contrast
images

The percentage of enhancement of the lesion 
post administration of study intervention 
injection in comparison to baseline (i.e. prior to 
administration of study intervention) will be 
calculated.

Sum of lesion visualization parameters at 
15 min pi will be analyzed descriptively.

Sum of lesion visualization parameters at 
10 min pi will be analyzed descriptively.

The number of enhanced lesions will be 
analyzed descriptively.


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9.4.1.1
Primary Efficacy Analysis – Overall Diagnostic Preference at 5 min 
post injection
The blinded readers will evaluate the relative image quality of the BAY 1747846-enhanced
T1w MR images and the gadobutrol-enhanced T1w MR images. The assessment will be based 
on the overall subjective interpretation of the degree of contrast enhancement, border 
delineation, and internal morphology. These images will be presented in a paired fashion in a 
separate reading session. The BAY 1747846 and gadobutrol images will be randomly 
assigned to either the left (image L) or right (image R) positions.
Image quality will be compared on a 5-point scale:
1 = 
greatly prefer image R
2 = 
prefer image R
3 = 
no preference
4 = 
prefer image L
5 = 
greatly prefer image L.
As part of the randomization and blinding process, R and L will represent either the 
BAY 1747846 or gadobutrol image. After the data is unblinded, the above codes will be 
translated into the following scale:
1 = 
greatly prefer BAY 1747846,
2 = 
prefer BAY 1747846,
3 = 
no preference
4 = 
prefer gadobutrol,
5 = 
greatly prefer gadobutrol.
For each cohort, the proportion of participants for whom “No preference”, “Prefer 
BAY 1747846” and “Prefer gadobutrol” is expressed, will be calculated along with a
corresponding two-sided 95% CI. The three categories are collapsed from the 5-point 
preference scale.
Additionally, the distribution of the choices other than “No preference” will be examined 
descriptively using frequency tables and histograms. 
The null and alternative hypotheses for an exploratory analysis of a treatment difference are 
as follows:
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	 	 
   : 	

	   ≠	

	 	,
where π	

	   is the proportion of participants for whom the BAY 1747846-
enhanced image was preferred and π	

	 	 is the proportion of participants for 
whom the gadobutrol-enhanced image was preferred. For this exploratory analysis, a 
McNemar’s test will be used.
A table displaying frequencies and percentages of the results of the 5-point scale will also be 
provided.


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9.4.1.2
Secondary Efficacy Analysis 
For the secondary endpoints, there will be multiple values for each subject (ratings for 
multiple lesions). The average of these ratings will be used for the analyses. To avoid using a 
scoring system that rates the detection of fewer but more well-visualized lesions over the 
detection of more lesions, some of which may be not so well visualized, the analysis will be 
performed using zero-filled averages of the ratings for each subject. A more detailed 
description will be provided in the SAP.
9.4.1.2.1
Lesion Visualization Parameters at 5 min Post Injection on Post-
Contrast Images
The 3 analysis variables are derived from the 3 parameters below using the following 
methodology:
1. Contrast enhancement (measured on an ordinal 4-point scale)
2. Border delineation (measured on an ordinal 4-point scale)
3. Internal morphology (measured on an ordinal 3-point scale).
In order to reduce multiplicity, the 3 variables will be combined by adding them up for each 
participant and each blinded reader, leading to only one variable on an ordinal 11-point scale.
Average reader will be used in addition to the 3 individual readers.
The analysis is based on the data from the blinded readers’ evaluation of the 3 visualization 
parameters, which are evaluated in the MR image sets.
For the combined visualization parameter, the non-inferiority of BAY 1747846 versus 
gadobutrol will also be evaluated using CIs based on the t-distribution. A non-inferiority 
margin of 1 will be used.
The non-inferiority margin was determined by the 95%-95% method described in the FDA 
Guidance “Non-Inferiority Clinical Trials to Establish Effectiveness” and is based on the past 
performance of the comparator in the Gadavist Study 310123. Data from this study were re-
analyzed using the combined approach described above. After combining the visualization 
parameters of Study 310123 and calculating the two-sided 95% CI for the mean difference 
gadobutrol – unenhanced, the observed mean difference was 2.49 and the corresponding 95% 
CI [2.337; 2.651]. As described in the FDA Guidance, the lower bound of the 95% CI was 
selected as the known effect of gadobutrol to the unenhanced imaging ! = 2.337. To retain 
at least half of the effect of the original treatment, the non-inferiority margin is set to
!& = 0.5 ∗ ! = 1.16785. Due to the fact that in Study 310123 the averaged reader was 
used for evaluation, which helped lowering the variability, the non-inferiority margin was 
even further lowered to 1.
This means that a 95% two-sided CI for the mean difference BAY 1747846 score –
gadobutrol score must exclude the value -1 for non-inferiority to be achieved. A one-sided test 
conducted at the 0.025 level of significance would be a statistically equivalent procedure. The 
null and alternative hypotheses for non-inferiority are:
H: μBAY 1747846 − μgadobutrol < −1 vs  H: μBAY 1747846 − μgadobutrol ≥−1,


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where μBAY 1747846 and μgadobutrol are the mean of the score evaluated by blinded readers after 
administration of BAY 1747846 and gadobutrol, respectively.
The analyses of the visualization efficacy variables will be performed on the data from each 
blinded reader, as well as the data obtained by averaging across the 3 blinded readers, 
producing one mean value per participant.
Inter-reader agreement for each of the 3 visualization variables will be assessed using the 
intra-class correlation coefficient. Separate coefficients will be generated by imaging 
modality.
9.4.1.2.2
Lesion Visualization Parameters on Pre-Contrast and Combined Pre-
and Post-Contrast (5 min pi) Images
The analysis is based on the data from the blinded readers’ evaluation of the 3 visualization 
parameters, which are evaluated in the MRI sets.
A comparison of the pre-contrast and combined pre- and post-contrast images will be 
performed for each of the 3 visualization parameters. Summary statistics for absolute values 
and difference of the pre-contrast and combined pre- and post-contrast will be presented for 
each Blinded Reader and the Average Reader along with the 95% two-sided CIs for the 
difference of the pre-contrast and combined pre- and post-contrast.
9.4.1.2.3
Number of Lesions on Pre-Contrast and Combined Pre- and Post-
Contrast (5 min pi) Images
A table displaying frequencies and percentages of different numbers of  lesions detected by 
pre- and combined pre- and post-contrast will be generated. A CI for the difference in number 
of lesions detected in the two image sets will be constructed.
9.4.1.3
Other Efficacy Analysis
9.4.1.3.1
Efficacy Evaluation at 10 and 15 min Post Injection
Summary statistics and frequency table will additionally be provided for contrast-enhanced 
images at 10 and 15 min pi.
9.4.1.3.2
Number of Enhanced Lesions on Post-Contrast Images at 5 min Post 
Injection
A table displaying frequencies and percentages of different numbers of contrast-enhanced 
lesions detected by BAY 1747846 and gadobutrol will be generated. A CI for the difference 
in enhanced lesions detected by the 2 study interventions will be constructed.


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9.4.1.3.3
Signal Intensity Measurements
Quantitative measurements will be done in order to evaluate the percentage of lesion 
enhancement in the T1w sequence after injection of BAY 1747846 or gadobutrol compared to 
the unenhanced T1w sequence. Furthermore, the CNR of the lesions will be determined.
One additional independent blinded reader will perform SI measurements on the image sets. 
The blinded reader will have knowledge if the T1w sequence is pre-injection or post-injection, 
but will be blinded to knowledge of contrast agent (i.e. BAY 1747846 or gadobutrol). The 
images will be evaluated as follows:

Contrast-enhanced T1w MRI: the image giving the best visualization of the lesion will 
be chosen (either BAY 1747846-enhanced or gadobutrol-enhanced sequence). The
region of interest (ROI) will be placed in that area of the lesion that shows best 
enhancement, avoiding necrotic regions. A second ROI will be drawn in normal brain 
tissue on the contralateral white matter or in normal spine tissue. A third ROI will be 
positioned in an area outside the brain or spine to determine the background.

All ROIs of the chosen contrast-enhanced sequence will be copied and pasted into the
corresponding images of the other contrast-enhanced sequence and the unenhanced
sequence in order to assure same location and size of ROIs in all T1w images
(BAY 1747846-enhanced, gadobutrol-enhanced, and unenhanced).
The percentage of enhancement of the lesion will be based on SI measurements obtained from
the combined results of unenhanced MRI – BAY 1747846 and unenhanced MRI –
gadobutrol-enhanced MRI as follows:
SIL,post −SIL,pre
SIL,pre
× 100%,
where SIL,post is the SI of the contrast-enhanced lesion and SIL,pre is the SI of the unenhanced 
lesion. For heterogeneous lesions, multiple ROIs can be placed over different areas, and the 
region that shows the maximum relative enhancement will be used for analysis.
SNR and CNR will be calculated based on SI measurements obtained as follows:
SNR = SIN,post
SDnoise
and
CNR = SIL,post −SIN,post
SDnoise
,
where SIL,post is the SI of the lesion on the contrast-enhanced image, SIN,post is post injection 
SI of normal tissue of the brain or spine, and SDnoise is the standard deviation of the noise 
(background).
The ROI size of the same lesion will be identical in all measurements within a single 
participant. SI measurements will be summarized by MRI modality using descriptive statistics 
and CIs.


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9.4.2
Safety Analyses
Endpoint
Statistical Analysis Methods
Primary

Not applicable

Not applicable
Secondary

Not applicable

Not applicable
Other pre-specified

Incidence and severity of TEAEs and other 
parameters

Determine plasma concentrations of Gd within 
3 time windows on Day 1 and after 24 ± 4 h 
following administration of BAY 1747846 and 
gadobutrol

The number of participants with TEAEs will be 
displayed in a frequency table. Descriptive 
results will be displayed for vital signs, ECG 
and safety laboratory.

Individual concentration versus time curves 
will be provided.
All safety analyses will be performed on the SAF population, unless otherwise stated.
9.4.2.1
Adverse Events
Individual listings of AEs will be provided.
TEAEs
AEs are considered to be treatment-emergent if they have started or worsened after first 
application of study intervention GBCA injection up to 24 h ± 4 h follow-up time point (i.e. 
per period).
The incidence of TEAEs and study intervention-related TEAEs, respectively, will be 
summarized by treatment using System Organ Class (SOC) and Preferred Terms (PTs) 
according to the current Medical Dictionary for Regulatory Activities (MedDRA) version.
SAEs and Deaths
For SAE outcomes, AEs leading to discontinuation and deaths, listings of participants will be 
provided by treatment sequence, participant and/or AE.
9.4.2.2
Other Safety Examinations
Quantitative data (hematology, blood chemistry, vital signs) will be described by the 
following summary statistics: arithmetic mean, standard deviation, minimum, median and 
maximum for quantitative data. These summary statistics will be presented by treatment for 
the original data and for the difference to the respective baseline for quantitative data (i.e. pre-
dose measurements, performed prior to the first administration of the study intervention per 
treatment period). Frequency tables will be provided for qualitative data. Laboratory data 
outside the reference range will be listed and flagged with ‘L’ for low and ‘H’ for high.  
Additional tables with all abnormal (out-of-range) values will be presented.
Graphical displays of individual data and mean values with standard deviations will be 
included.
Data from the standard ECGs will be reported in a descriptive way.


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Pulse oximetry during MRI will only be done for monitoring purposes without documenting 
values within the eCRF. Only time interval and occurrence of AEs will be documented from 
these measurements.
9.4.2.3
Demographic and Other Baseline Characteristics Analyses
Participant Validity and Disposition
Study sample size will be summarized by treatment sequence and total. Participant validity 
with reason for exclusion from analysis sets, participant disposition, end of study medication, 
and important deviations/validity findings will be summarized by total using frequency tables 
over appropriate analysis sets like FAS or ‘All enrolled participants’.
Demographics
Summary statistics (arithmetic mean, standard deviation, median, minimum and maximum for 
quantitative variables) will be presented for all patients in the analysis population being 
summarized. Frequency tables for qualitative data will be provided. If the FAS population 
differs from the SAF population, summary statistics and frequency tables for FAS will be 
provided as well.
Medical/Surgical History
The number of participants with medical history findings will be summarized by classified 
data using frequency tables. The classification will be done according to MedDRA using 
SOC, high level terms and PTs. The most recent MedDRA version will be used.
Prior and Concomitant Medication
The number of participants that used prior or concomitant medication will be analyzed using 
frequency tables based on classified data. The classification will be done according to the 
World Health Organization Drug Dictionary (WHO-DD).
9.4.3
Analyses of Gd Plasma Concentration
Individual Gd plasma concentrations will be listed per study intervention (i.e. BAY 1747846 
and gadobutrol). Individual concentration versus time curves of Gd plasma will be provided 
separately for each treatment, for each participant and for all participants.
9.5
Interim Analyses
A non-binding interim analysis (IA) may be perfomed for this study to facilitate informed 
planning of the next phases of development. 
The IA can be triggered at any time when at least 25 participants have been enrolled in a dose 
cohort and have completed both MRI periods (i.e., at least 50% completion of the dose-
cohort).
Enrollment in the dose-cohort will continue while the IA is ongoing. Independent of the
outcome from the IA, the cohort will be completed. 
The Statistical Analysis Plan (SAP) will describe the planned interim analyses in detail.
In brief, the IA will evaluate the primary efficacy endpoint for the selected dose-cohort. 


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In case a trend of “no-preference” between BAY 1747846 and gadobutrol (or a trend of 
“preference of BAY 174846”) is observed, further efficacy analyses will be performed for the 
secondary endpoint and the number of enhanced lesions. In addition, safety analysis will be 
conducted including the incidence and severity of TEAEs along with other safety parameters 
and Gd plasma concentrations. 
If no trend is observed or if deemed inconclusive, no further analysis will be performed until 
the primary completion of the selected dose-cohort.
Since the assessment of the final dose finding algorithm is not based on a formal hypothesis 
test, the type I error (i.e., the alpha level) will not be adjusted for the IA.
This is a single-blind study and the IA will not affect the blinding design as only participants
are blinded and will remain blinded to the sequence of treatment administration. The central 
independent readers evaluating the primary and secondary endpoints will remain blinded 
during the IA and the results.
Data will be processed and analyzed by the sponsor and there will not be an independent data 
monitoring committee. The analysis will be executed with controlled dissemination to ensure 
the integrity of ongoing data collection while maintaining sufficient blinding in the study. 
10.
Supporting Documentation and Operational Considerations
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines.

Applicable International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines.

Applicable laws and regulations.
The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g.
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC.

Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures.


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
Providing oversight of the conduct of the study at the study center and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations.
10.1.2
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
10.1.3
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions 
regarding the study.

Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act (HIPAA) requirements, where 
applicable, and the IRB/IEC or study center.

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must also 
sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study.

A copy of the ICF(s) must be provided to the participant or their legally authorized 
representative.

Participants who are re-screened are required to sign a new ICF.

If the baseline activities are to be performed on the same day as the ICF is signed, the 
time needs to be documented in addition to the signature date.
10.1.4
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier only; 
participant names or any information which would make the participant identifiable 
will not be transferred.

The participant must be informed that his/her personal study-related data will be used 
by the sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the participant.

The participant must be informed that his/her medical records may be examined by 
Clinical QA auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.


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10.1.5
Committees Structure
Not applicable.
10.1.6
Dissemination of Clinical Study Data
Result summaries of Bayer's sponsored clinical trials in drug development Phases 2, 3 and 4
and Phase 1 studies in participants are provided in the Bayer Trial Finder application after 
marketing authorization approval in line with the position of the global pharmaceutical 
industry associations laid down in the "Joint Position on the Disclosure of Clinical Trial 
Information via Clinical Trial Registries and Databases". In addition, results of clinical drug 
trials will be provided on the publicly funded website www.ClinicalTrials.gov and EU 
Clinical Trials Register in line with the applicable regulations.
Bayer commits to sharing upon request from qualified scientific and medical researchers 
patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials 
in patients for medicines and indications approved in the United States and European Union 
on or after January 01, 2014 as necessary for conducting legitimate research.
All Bayer sponsored clinical trials are considered for publication in the scientific literature
irrespective of whether the results of the clinical trials are positive or negative.
10.1.7
Data Quality Assurance

All participant data relating to the study will be recorded in the eCRF unless 
transmitted to the sponsor or designee electronically (e.g. MRI data). The investigator 
is responsible for verifying that data entries are accurate and correct by electronically 
signing the eCRF.

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.

Data required according to this protocol will be recorded by investigational site 
personnel via data entry into the internet-based validated electronic data capture 
(EDC) software system RAVE, which Bayer has licensed from Medidata Solutions 
Worldwide. RAVE has been validated by Medidata Solutions Worldwide and Bayer 
for use in its clinical studies. RAVE allows for the application of software logic to set-
up data entry screens and data checks to ensure the completeness and accuracy of the 
data entered by the site personnel. Bayer extensively applies the logic to ensure data 
are complete and reflect the clinical data requirements of the study. Data queries 
resulting from the application of the software logic are resolved by the site personnel. 
The data are stored at a secure host facility maintained by Medidata Solutions 
Worldwide and transferred on a periodic basis to Bayer's internal computer system via 
a secure Virtual Private Network.

All access to the RAVE system is through a password-protected security system that is 
part of the RAVE software. All internal Bayer and external investigator site personnel 
seeking access must go through a thorough RAVE training process before they are 
granted access to RAVE for use in Bayer's clinical studies. Training records are 
maintained.


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
All personnel with access to the RAVE system are supported by a Service Desk 
staffed with trained personnel to answer questions and ensure access is maintained 
such that data entry can proceed in a timely manner.

The RAVE System contains a system-generated audit trail that captures any changes 
made to a data field, including who made the change, why the change was made and 
the date and time it was made. This information is available both at the investigator’s 
site and at Bayer. Data entries made in the RAVE EDC screens are supported by 
source documents maintained for all participants enrolled in this study.

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.

Monitoring details describing strategy (e.g. risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-
Based Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.

The sponsor assumes accountability for actions delegated to other individuals (e.g.
Contract Research Organizations).

Study monitors will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements.

Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may 
be destroyed during the retention period without the written approval of the sponsor. 
No records may be transferred to another location or party without written notification 
to the sponsor.
10.1.8
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data entered in the eCRF that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.

Definition of what constitutes source data can be found in the investigator site file.


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10.1.9
Study and Site Closure
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines.

Inadequate recruitment of participants by the investigator.

Discontinuation of further study intervention development.
10.1.10
Publication Policy

The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments.

The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
site data. In this case, a coordinating investigator will be designated by mutual 
agreement.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.
10.2
Appendix 2: Clinical Laboratory Tests

Blood and urine sampling for laboratory analysis will be taken as outlined in the SoA 
(see Section 1.3).

The tests detailed in Table 10-1 will be performed by local laboratories or the central 
laboratory.

Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.

Urine pregnancy testing will be performed before each administration of study 
intervention to evaluate eligibility of female participants (see Section 5.2 criterion 14).


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Table 10-1: Parameters of laboratory analyses
Parameters (by category)
Sample destination
Blood / Plasma / Serum 
Hematology:
Leukocytes, erythrocytes, hemoglobin, hematocrit, mean corpuscular 
volume, mean corpuscular hemoglobin, platelets, neutrophils, eosinophils, 
basophils, lymphocytes, monocytes
Local laboratory
Serum chemistry:
Alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl 
transferase, alkaline phosphatase, total bilirubin, lactate dehydrogenase, 
creatinine, urea, creatine kinase, chloride, potassium, sodium, calcium, 
phosphate, glucose, total protein, albumin, high-sensitivity C-reactive 
protein
Local laboratory
Creatinine
Central laboratory
Plasma concentration:
BAY 1747846
Central laboratory
Urine
Urinalysis – dipstick (spot urine):
pH value, urobilinogen, erythrocytes/hemoglobin, leukocytes, protein, 
ketone, bilirubin, nitrite, glucose
Local laboratory
Sediment (spot urine):
Only in case of abnormal urinalysis results for protein, leukocytes, 
erythrocytes/ hemoglobin, or nitrite
Local laboratory
Pregnancy test (spot urine) before administration of study 
intervention
To be performed at 
study site
Investigators must document their review of each laboratory safety report.


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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study participant, 
after providing written informed consent, whether or not considered related to the 
study intervention. 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) associated 
with the use of study intervention.
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g. ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (e.g. endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.


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10.3.2
Definition of SAE
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening

The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization

In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. Complications that occur during hospitalization are AEs. 
If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.

Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.


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10.3.3
Recording and Follow-Up of AE and/or SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event.

The investigator will then record all relevant AE/SAE information in the eCRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to the sponsor in lieu of completion of the AE/SAE eCRF page.

There may be instances when copies of medical records for certain cases are 
requested by the sponsor. In this case, all participant identifiers, with the exception 
of the participant number, will be redacted on the copies of the medical records 
before submission to the sponsor.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity

The investigator will make an assessment of intensity for each AE and SAE 
reported during the study and assign it to 1 of the following categories:

Mild: An event that is easily tolerated by the participant, causing 
minimal discomfort and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with 
normal everyday activities.

Severe: An event that prevents normal everyday activities. An AE that 
is assessed as severe should not be confused with an SAE. Severe is a 
category utilized for rating the intensity of an event; and both AEs and 
SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence,
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.


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
The investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the sponsor.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Important factors to be considered in assessing the relationship of the AE to study 
intervention include:

The temporal sequence from study intervention administration: The event should 
occur after the study intervention is given. The length of time from study 
intervention exposure to event should be evaluated in the clinical context of the 
event.

Underlying, concomitant, intercurrent diseases: Each event should be evaluated in 
the context of the natural history and course of the disease being treated and any 
other disease the participant may have.

Concomitant medication or treatment: The other drugs the participant is taking or 
the treatment the participant receives should be examined to determine whether 
any of them might have caused the event in question.

Known response pattern for this class of drug: Clinical/preclinical.

Exposure to physical and/or mental stresses: The exposure to stress might induce 
adverse changes in the recipient and provide a logical and better explanation for 
the event.

The assessment is not possible.
Causal relationship to protocol-required procedures
The assessment of a possible causal relationship between the AE and protocol-required 
procedure(s) is based on the question whether there was a ‘reasonable causal relationship’ 
to protocol-required procedure(s).

Possible answers are “yes” or “no”.


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Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
sponsor to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care 
professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide the sponsor with a copy of any post mortem
findings including histopathology.

New or updated information will be recorded in the originally completed eCRF.

The investigator will submit any updated SAE data to the sponsor within 24 h of 
receipt of the information.
10.3.4
Reporting of SAEs
SAE Reporting to the sponsor via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE to the sponsor will be the EDC tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 h.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the EDC tool will be taken off-line to 
prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the EDC tool has been taken off-line, then 
the site can report this information on a paper SAE form (see next section) or to the 
sponsor by telephone.

Contacts for SAE reporting can be found in the investigators site file.
SAE Reporting to the sponsor via Paper CRF

Facsimile transmission of the SAE paper CRF or provision of related PDF scans via 
email is the preferred method to transmit this information to the sponsor.

In rare circumstances and in the absence of facsimile and PDF/email equipment, 
notification by telephone is acceptable with a copy of the SAE data collection tool 
sent by overnight mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in the investigators site file.


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10.4
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information
Contraception Guidance
For the purpose of this guidance, methods that can achieve a failure rate of less than 1% per
year when used consistently and correctly are considered as highly effective birth control
methods. Such methods include:

combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation:
o
oral
o
intravaginal
o
transdermal

progestogen-only hormonal contraception associated with inhibition of ovulation:
o
oral
o
injectable
o
implantable 

intrauterine device (IUD) 

intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion 

vasectomized partner 

sexual abstinence 
In addition, male participants with partners of childbearing potential should use a condom
from screening till end of study participation.
Collection of Pregnancy Information
Male Participants with Partners Who Become Pregnant

The investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is in 
this study. This applies only to male participants who received study intervention.

After obtaining the necessary signed ICF from the pregnant female partner directly, 
the investigator will record pregnancy information on the appropriate form and submit 
it to the sponsor within 24 h of learning of the partner’s pregnancy. The female partner 
will also be followed to determine the outcome of the pregnancy. Information on the 
status of the mother and child will be forwarded to the sponsor. Generally, the follow-
up will be no longer than 6 to 8 weeks following the estimated delivery date. Any 
termination of the pregnancy will be reported regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure.


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Female Participants Who Become Pregnant 

The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on 
the appropriate form and submitted to the sponsor within 24 h of learning of a 
participant's pregnancy.

The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate, after 
obtaining the signed ICF from both parents, unless local law or specific circumstances 
of the respective case allow otherwise, and the information will be forwarded to the 
sponsor. Generally, follow-up will not be required for longer than 6 to 8 weeks beyond 
the estimated delivery date. Any termination of pregnancy will be reported, regardless 
of fetal status (presence or absence of anomalies) or indication for the procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or SAE. 
A spontaneous abortion is always considered to be an SAE and will be reported as 
such. Any post-study pregnancy related SAE considered reasonably related to the 
study intervention by the investigator will be reported to the sponsor as described in 
Section 8.3.4. While the investigator is not obligated to actively seek this information 
in former study participants, he or she may learn of an SAE through spontaneous 
reporting.

Any female participant who becomes pregnant while participating in the study will be 
withdrawn from the study.
10.5
Appendix 5: Abbreviations
2/3D
2/3 dimensional
AE
adverse event
AESI
adverse event of special safety interest
AUC
area under the concentration versus time curve from zero to infinity after 
single (first) dose
AUCnorm
AUC normalized for dose and body weight
BMI
body mass index
BP
blood pressure
bw
body weight
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CL
total body clearance of drug
CL/bw
total body clearance of drug normalized by body weight
Cmax
maximum observed drug concentration in measured matrix after single dose 
administration


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CNR
contrast to noise ratio
CNS
central nervous system
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
coronavirus disease 2019
CV
coefficient of variation
d
day(s)
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
FAS
full analysis set
FDA
U.S. Food and Drug Administration
FiH
first-in-human
FLAIR
Fluid Attenuated Inversion Recovery
GBCA
gadolinium-based contrast agent
GCIS
General Clinical Imaging Services
GCP
Good Clinical Practice
Gd
gadolinium 
GFR
glomerular filtration rate
GRE
gradient recalled echo
HIPAA
Health Insurance Portability and Accountability Act
HR
heart rate
IA
Interim analysis
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committees
IMP
investigational medicinal product
IR
inversion recovery
IRB
Institutional Review Boards
IV
intravenous(ly)
MedDRA
Medical Dictionary for Regulatory Activities
MR
magnetic resonance


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MRI
magnetic resonance imaging
NEX
number of excitations
NIMP
non-investigational medicinal product
NSA
number of acquisitions
NSF
Nephrogenic Systemic Fibrosis
PDF
Portable Document Format
pH
pondus hydrogenii (negative log of the ion concentration)
pi
post injection
PK
pharmacokinetic(s)
PR
PR interval
PT
preferred term
QA
quality assurance
QC
quality control
QRS
QRS interval in ECG
QT
QT interval in ECG, uncorrected
QTc
QT corrected by heart rate
ROI
region of interest
RSE
relative signal enhancement
SAE
serious adverse event
SAF
safety analysis set
SAP
Statistical Analysis Plan
SE
spin echo
SI
signal intensity
SmPC
Summary of Product Characteristics
SNR
signal to noise ratio
SoA
Schedule of Activities
SOC
system organ class
SUSAR
suspected unexpected serious adverse reactions
T1W
T1-weighted
TE
echo time
TEAE
treatment-emergent adverse event
TI
inversion time
TR
repetition time
Vss
volume of distribution at steady state
Vss/bw
Vss normalized by body weight


C O N FI D E N TI A L
I nte grate d Cli nical St u d y Pr ot oc ol
B A Y 1 7 4 7 8 4 6 / 2 0 2 4 1
0 6 J A N 2 0 2 2
Pa ge:  7 2 of 7 5
1 0. 6
A p pe n di x 6: Pr ot oc ol A me n d me nt Hist or y 
T he Pr ot oc ol A me n d me nt S u m mar y  of C ha n ges Ta ble f or t he c urre nt a me n d me nt is l ocate d 
directl y  bef ore t he Ta ble of C o nte nts ( T O C).
A m e n d me nt 3 ( 2 9 J U L 2 0 2 1)
T his a me n d me nt is c o nsi dere d t o be s u bsta ntial base d o n t he criteria set f ort h i n Article 1 0(a) 
of Directi ve 2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n.
O ver all R ati o n ale f or t he A me n d me nt:
T his a me n d me nt was pri maril y i m ple me nte d t o i nc or p orate a n i nteri m a nal ysis t o facilitate 
t he pla n ni n g of f ut ure p hases of de vel o p me nt a n d u pc o mi n g e n d of P hase 2 meeti n gs 
/scie ntific a d vis or y disc ussi o ns wit h Healt h A ut h orities . The descri pti o n of c ha n ge s a n d a 
brief rati o nale f or eac h c ha n ge are as f oll o ws:
S e cti o n # 
a n d N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
Title Pa ge
U p date of me dicall y res p o nsi ble 
pers o n f or t he st u d y.
I n or der t o mai ntai n c o nsiste nc y 
wit h t he u p date d i nter nal cli nical 
pr ot oc ol te m plate. T he rele va nt 
c o ntact na me a n d r ole ( 
 
) f or all rele va nt 
me dicall y relate d q ueries a n d safet y 
re p orti n g re q uire me nts is 
mai ntai ne d.
Title Pa ge
D oc u me nt Hist or y Ta ble
Hea der t hr o u g h o ut
T he v ersi o n n u m ber has bee n a d de d t o 
title pa ge, D oc u me nt Hist or y Ta ble 
has bee n i nc or p orate d as a n 
i n de pe n de nt secti o n, a n d t he d oc u me nt 
hea der has bee n m o difie d t hr o u g h o ut 
t o re m o ve versi o n n u m ber a n d i ncl u de 
t he versi o n date .
U p date d t o reflect c urre nt i nter nal 
pr ocesses a n d pr ot oc ol te m plate 
c o n ve nti o ns.
1. 3 Sc he d ule of Acti vities 
5. 1 I ncl usi o n Criteria
T he S o A a n d i ncl usi o n criteri o n # 6 
were u p date d t o f urt her clarif y t hat 
w hile baseli ne e G F R val ue ≥6 0 
m L/ mi n/ 1. 7 3 m 2 is re q uire d pri or t o 
a d mi nistrati o n of st u d y i nter ve nti o n, 
t he baseli ne e G F R assess me nt f or 
peri o d 1 ca n be deri ve d fr o m a ser u m 
creati ni ne res ult o btai ne d wit hi n 4 
wee ks pri or t o t he first M RI . As ser u m 
creati ni ne is a n i ncl u de d para meter f or 
safet y la b orat or y assess me nts, t he 
safet y bl o o d sa m ple c ollecte d at 
baseli ne ( wit hi n 4 8 h o urs pri or t o 
a d mi nistrati o n of st u d y i nter ve nti o n), 
ca n als o be utilize d f or deter mi nati o n 
of e G F R f or eit her c orres p o n di n g 
peri o d. 
Clarificati o n of pr oce d ures 
pertai ni n g t o ba seli ne e G F R 
assess me nts i n t he S o A a n d 
i ncl usi o n criteri o n # 6.
P P D


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Section # 
and Name
Description of Change
Brief Rationale
5.2 Exclusion Criteria
Exclusion criterion #12 was updated to 
include consideration of the half-life 
of any previous investigational drug 
and clarify eligibility of participants 
that would be in the follow-up period 
of another trial while not receiving 
investigational drug. 
Exclusion criterion #13 was updated to 
clarify that contraindications 
pertaining to the administration of 
gadobutrol will be interpreted based 
on the local product label.
Exclusion criterion #12 was 
updated in order to provide 
additional flexibility with prior 
clinical trial participation and with 
respect to facilitating recruitment of 
participants who are in the follow-
up period of concurrent studies but 
are not receiving investigational 
drug. 
The local product label may vary 
depending on the location of the 
study site.
6.1 Study Interventions 
Administered
Table 6-1 was modified to reflect the 
addition of Bulgaria as a study 
country. 
Study sites are currently being 
established in an additional country 
(Bulgaria), thus Bulgaria has been 
added to the protocol.
8.1.4.3 Number of 
Enhanced Lesions
Revised text to specify that the 3 
blinded readers will record the total 
number of enhanced lesions for each 
enhanced (5 min pi) MR image set 
separately (no matched pairs 
approach). 
Correction of previous error 
indicating  4 to 5 min pi for 
recorded number of enhanced 
lesions per MR image set. 
8.2.6 Clinical Safety 
Laboratory Assessments
8.5.1 Drug Measurements
Specification of laboratory manual as 
primary guidance document for study 
samples. References to the sample 
handling sheets were removed.
Information about the collection, 
processing, storage and shipment of 
laboratory samples is provided in 
the laboratory manual.
9.4.2.2 Other Safety 
Examinations
The text pertaining to standard ECG 
data was revised to remove the 
requirement that they only be listed.
The requirement to only list 
standard ECG data was removed to 
provide greater flexibility with 
respect to the descriptive statistical 
output provided.
9.5 Interim Analyses
10.5 Abbreviations
Addition of an interim analysis.
Abbreviations for interim analysis 
(IA) and Statistical Analysis Plan 
(SAP) were added accordingly.
An interim analysis of the dose 
investigated, as well as some 
selected efficacy and safety data
will facilitate the planning of future 
phases of development and 
upcoming end of Phase 2 meetings
/scientific advice with Health 
Authorities.


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11.
References
Bayer Vital GmbH, Leverkusen. SmPC of Gadovist 1.0 mmol/ml solution for injection. 
November 2017. Available at: https://www.medicines.org.uk/emc/product/2876/smpc
Ellingson BM, Bendszus M, Boxerman J, Barboriak D, Erickson BJ, Smits M, Nelson SJ, 
Gerstner E, Alexander B, Goldmacher G, Wick W, et al. Consensus recommendations for a 
standardized Brain Tumor Imaging Protocol in clinical trials. Neurol Oncol 2015; 17(9):1188-
1198.
European Medicines Agency. PRAC confirms restrictions on the use of linear gadolinium 
agents. EMA/424715/2017. Available at: 
https://www.ema.europa.eu/documents/referral/gadolinium-article-31-referral-prac-confirms-
restrictions-use-linear-gadolinium-agents_en.pdf.
FDA Guidance “Non-Inferiority Clinical Trials to Establish Effectiveness”. November 2016. 
Available at: 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/non-inferiority-
clinical-trials
Grobner T. Gadolinium – a specific trigger for the development of nephrogenic fibrosing 
dermopathy and nephrogenic systemic fibrosis? Nephrology Dialysis Transplantation.
2006;21:1104-8.
Guerbet LLC USA. SmPC of Dotarem. August 2017. Available at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/204781s001lbl.pdf
Investigator’s Brochure of BAY 1747846, version 3.0 (dated 31 Jan 2020).
Kanal, E. Gadolinium based contrast agents (GBCA): safety overview after 3 decades of 
clinical experience. Magnetic Reson Imaging. 2016;34(10):1341–5.
Kanda T, Ishii K, Kawaguchi H, Kitajima K, Takenaka D. High signal intensity in the dentate 
nucleus and globus pallidus on unenhanced T1-weighted MR images: relationship with 
increasing cumulative dose of a gadolinium based contrast material. Radiology. 
2014;270(3):834–41.
Le Mignon MM, Chambon C, Warrington S, Davies R, Bonnemain B. Gd-DOTA: 
Pharmacokinetics and tolerability after intravenous injection into Healthy Volunteers. Invest. 
Radiol. 1990;25:933-937.
Nonclinical Research Report PH-40545 (study number KM17051): Three-phase liver and 
steady-state head MRI with BAY 1747846 in minipigs. 2018.
Prince MR, Zhang H, Zou Z, Staron RB, Brill PW. Incidence of immediate gadolinium 
contrast media reactions. AJR Am J Roentgenol. 2011;196(2):196:W138–43.
Radbruch A. Are some agents less likely to deposit gadolinium in the brain? Magn Reson 
Imaging. 2016;34(10):1351–4.


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Report A44213 (Study No. 13226): Exploratory population pharmacokinetic analysis of 
gadobutrol (Gadovist®), to assess ethnic differences between Japanese and Caucasian healthy 
volunteers. 2008.
Report A47567 (Study No. 310123): A multicenter, randomized, double-blind, crossover, 
phase 3 study to determine the safety and efficacy of gadobutrol 1.0 molar (Gadovist®) in 
patients referred for contrast-enhanced MRI of the central nervous system (CNS). 2010.
Report No. 9746 (Study No. 92001): Tolerability and pharmacokinetics of gadobutrol (SH L 
562 A) after intravenous administration in comparison with placebo (first in man 
administration). 1994.
Runge VM. Safety of the gadolinium-based contrast agents for magnetic resonance imaging, 
focusing in part on their accumulation in the brain and especially the dentate nucleus. Invest 
Radiol. 2016;51(5):273–9.
Scott 2018. Gadobutrol: A Review in Contrast-Enhanced MRI and MRA. Clin Drug Investig.
2018 Aug;38:773-784.

SAP_001.pdf: 
 
Document Type: 
Statistical Analysis Plan 
Official Title: 
Multicenter, single-blind, adaptive dose finding study of 
single intravenous injections of BAY 1747846 with 
corresponding blinded read in adult participants with known 
or highly suspected CNS lesions referred for contrast-
enhanced MRI of the CNS 
NCT Number: 
NCT04307186 
Document Date: 
14-Jan-2022 
 


Statistical Analysis Plan
BAY 1747846/20241
Page: 1 of 20:
Reference Number: RD-SOP-1119
Supplement Version: 10
Title page
Multicenter, single-blind, adaptive dose finding study of single 
intravenous injections of BAY 1747846 with corresponding blinded read 
in adult participants with known or highly suspected CNS lesions referred 
for contrast-enhanced MRI of the CNS
Adaptive dose finding study
Bayer study drug
BAY 1747846
Study purpose:
Dose finding
Clinical study 
phase:
II
Date:
14 JAN 2022
Study No.:
20241
Version:
4.0
Author:
Confidential
The information provided in this document is strictly confidential and is intended solely 
for the guidance of the clinical investigation.  Reproduction or disclosure of this 
document, whether in part or in full, to parties not associated with the clinical 
investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (®, TM) are not displayed.  Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures.
The approval of the Statistical Analysis Plan is documented in a separate Signature Document.
PPD


Statistical Analysis Plan
BAY 1747846/20241
Page: 2 of 20:
Reference Number: RD-SOP-1119
Supplement Version: 10
Table of Contents
Title page................................................................................................................................... 1
Abbreviations............................................................................................................................ 4
1.
Introduction....................................................................................................................... 5
2.
Study Objectives................................................................................................................ 6
3.
Study Design ...................................................................................................................... 6
4.
General Statistical Considerations .................................................................................. 8
4.1
General Principles............................................................................................................ 8
4.2
Handling of Dropouts ...................................................................................................... 8
4.3
Handling of Missing Data................................................................................................ 8
4.4
Interim Analyses and Data Monitoring ........................................................................... 8
4.5
Data Rules........................................................................................................................ 9
4.5.1
Baseline ........................................................................................................................ 9
4.5.2
Repeated Measurements............................................................................................... 9
4.5.3
Laboratory Values Outside the Calibration Range....................................................... 9
4.5.4
Zero-filled Averages..................................................................................................... 9
4.6
Blind Review ................................................................................................................. 10
5.
Analysis Sets .................................................................................................................... 10
5.1
Assignment of analysis sets ........................................................................................... 10
6.
Statistical Methodology .................................................................................................. 10
6.1
Population characteristics .............................................................................................. 11
6.1.1
Participants Validity and Disposition......................................................................... 11
6.1.2
Demographics............................................................................................................. 11
6.1.3
Medical and Surgical History..................................................................................... 11
6.1.4
Prior and Concomitant Medication............................................................................. 12
6.2
Efficacy.......................................................................................................................... 12
6.2.1
Primary Efficacy Analysis – Overall Diagnostic Preference ..................................... 12
6.2.2
Secondary Efficacy Analysis...................................................................................... 14
6.2.2.1
Lesion Visualization Parameters at 5 min post injection on Post-Contrast Images 14
6.2.2.2
Lesion Visualization Parameters on Pre-Contrast and Combined Pre- and Post-
Contrast (5 min pi) Images (correlated lesions)...................................................... 16
6.2.2.3
Lesion Visualization Parameters on Pre-Contrast and Combined Pre- and Post-
Contrast (5 min pi) Images (all lesions).................................................................. 16
6.2.2.4
Number of Lesions on Pre-Contrast and Combined Pre- and Post-Contrast (5 
min pi) Images......................................................................................................... 16
6.2.3
Other Efficacy Analyses............................................................................................. 17
6.2.3.1
Efficacy Evaluation at 10 and 15 min Post injection .............................................. 17
6.2.3.2
Number of Enhanced Lesions on Post-Contrast Images......................................... 17
6.2.3.3
SI Measurements..................................................................................................... 17
6.3
Pharmacokinetics/pharmacodynamics........................................................................... 18
6.3.1
Pharmacokinetics........................................................................................................ 18
6.3.2
Pharmacodynamics..................................................................................................... 18
6.4
Safety ............................................................................................................................. 18
6.4.1
Adverse events (AEs)................................................................................................. 18


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6.4.2
Other Safety Examinations......................................................................................... 19
7.
Document history and changes in the planned statistical analysis............................. 19
8.
References ........................................................................................................................ 20
Table of tables
Table 6–1: Overview of the imaging efficacy variables by imaging sets ................................ 12
Table of figures
Figure 3–1: Overall study design ............................................................................................... 7


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Abbreviations
AE
Adverse event
AESI
Adverse event of special safety interest
BR
Blinded reader
bw
Body weight
CI
Confidence interval
CNR
Contrast to noise ratio
CNS
Central nervous system
ECG
Electrocardiogram
eCRF
Electronic case report form
FAS
Full Analysis Set
FDA
Food and Drug Administration
FiH
first-in-human
GBCA
gadolinium-based contrast agent
Gd
gadolinium
i.e.
id est
IA
Interim analysis
IV
intravenous(ly)
LLOQ
lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
min
minute
MRI
magnetic resonance images
pi
Post injection
ROI
Region of interest
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SAF
Safety analysis set
SI
Signal intensity
SNR
Signal to noise ratio
T1w
T1-weighted
TEAE
Treatment emergent adverse event
WHO-DD
World Health Organization Drug Dictionary


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1.
Introduction
BAY 1747846 is a new macrocyclic gadolinium-based contrast agent (GBCA) with high 
relaxivity for enhancing magnetic resonance images (MRI). The clinical utility of GBCAs in 
contrast-enhanced MRI is well established and demonstrated in various indications and 
populations for more than 3 decades and in over 500 million procedures.
BAY 1747846 is in development as a multi-purpose GBCA for contrast-enhanced MRI in 
adults and children of all ages. So far, it has been studied in four Phase 1 trials. The initial 
first-in-human (FiH) study (Study 19324) examined increasing doses of BAY 1747846, 
ranging from 0.025 up to 0.2 mmol gadolinium (Gd)/kg body weight (bw) in healthy men and 
women, and confirmed similar safety and pharmacokinetics compared to marketed GBCAs. 
In dose-response Study 19325, signal enhancement of various selected regions in the head and 
neck area at increasing dose levels (0.01 to 0.06 mmol Gd/kg bw) was evaluated in healthy 
men and women in comparison to gadobutrol at the standard dose of 0.1 mmol Gd/kg bw. 
Also in this study, the safety profile was similar to gadobutrol and the FiH Study 19324. A 
dose proportional enhancement pattern was observed and could be compared quantitatively to 
gadobutrol. Study 19414 was conducted in adult healthy Japanese young men and Study 
19730 reached LPLV in adult healthy Chinese young men.
This study is conducted to establish a dose of BAY 1747846 in participants with known or 
highly suspected central nervous system (CNS) pathology which shows similar overall 
diagnostic preference (at a reduced Gd dose) to the established comparator gadobutrol. 
Gadobutrol is a macrocyclic GBCA approved worldwide for various indications and 
populations (incl. all age groups) with broad utilization (more than 50 million 
administrations). Hence, it is well suited to serve as comparator and to ensure that similar 
imaging performance can be achieved with BAY 1747846 while relevantly reducing the Gd 
burden per contrast-enhanced MRI examination.
This Statistical Analysis Plan (SAP) is based on the Clinical Study Protocol BAY 1747846 / 
20241, Version 5.0, Approval Date: 06 JAN 2022 [1]. This document describes the interim 
and final analysis of this study. 


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2.
Study Objectives
Objectives
Endpoints
Primary

Identify a dose for further development 
that has an overall diagnostic preference 
rate similar to that of the comparator 
gadobutrol at 5 min post injection (pi)

Overall diagnostic preference based on a 
randomized paired blinded read using a 5-
point scale (greatly prefer BAY 1747846, 
prefer BAY 1747846, no preference, 
prefer gadobutrol, greatly prefer 
gadobutrol) at 5 min pi
Secondary

Show non-inferiority of BAY 1747846 
compared to gadobutrol at 5 min pi with 
respect to sum of lesion visualization 
parameters

Compare pre- and post-contrast images 
with respect to lesion visualization 
parameters and number of lesions

Lesion visualization parameters (border 
delineation, contrast enhancement, 
internal morphology) on post-contrast 
images at 5 min pi

Lesion visualization parameters (border 
delineation, contrast enhancement, 
internal morphology) on pre-contrast and 
combined pre- and post-contrast (5 min 
pi) images

Number of lesions on pre-contrast and 
combined pre- and post-contrast (5 min 
pi) images
Other pre-specified

Evaluate signal intensity 
(SI)/enhancement

Evaluate efficacy at 15 min pi

Evaluate efficacy at 10 min pi

Determine plasma concentrations of Gd 
following administration of BAY 1747846 
and gadobutrol

Evaluate safety profile of BAY 1747846 
in comparison to gadobutrol

Number of enhanced lesions on post-
contrast images

Quantitative parameters: SI, contrast to 
noise ratio (CNR), signal to noise ratio 
(SNR)

Lesion visualization parameters at 15 min 
pi

Lesion visualization parameters at 10 min 
pi

Plasma concentrations of Gd within 3 time 
windows on Day 1 and after 24 ± 4 h 
following administration of BAY 1747846 
and gadobutrol

Incidence and severity of treatment-
emergent adverse events (TEAEs) and 
other parameters

Number of enhanced lesions on post-
contrast images at 5 min pi
3.
Study Design
This is a multicenter Phase 2 study with a single-blind design with blinded read (see Figure 3–
1). The study will permit up to two adaptive dose changes (i.e. increase or decrease) to ensure 
that the dose of BAY 1747846 shows similar overall diagnostic preference and enhancement 
as the selected active comparator gadobutrol. 
Each participant will receive an intravenous (IV) gadobutrol administration during Period 1 
and an IV BAY 1747846 administration during Period 2 followed by recording of a contrast-
enhanced MRI in each period.
Between each study intervention administration there will be a washout period of 3 – 14 days.


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Figure 3–1: Overall study design
bw = Body weight; Gd = Gadolinium; MRI = Magnetic resonance imaging, N = Number of participants
a
Decision on study continuation with a further cohort depends on outcome of previous cohort
The individual study duration will be approximately 2 to 4 weeks including screening and last 
measurements in Period 2, which will be conducted 24 h after the last study MRI. The total 
duration of the study will be approximately 1 year until final clean data base.
Participants will be enrolled in up to 3 cohorts. Taking dropouts and unevaluable image reads 
into account, approximately 60 participants per cohort will be assigned to study intervention 
such that at least 50 evaluable participants per cohort complete the study.


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4.
General Statistical Considerations
4.1
General Principles
The statistical evaluation will be performed by using the software package SAS release 9.2 or 
higher (SAS Institute Inc., Cary, NC, USA). All variables will be analyzed by descriptive 
statistical methods. The number of data available, mean, standard deviation, minimum, 
median, and maximum will be calculated for metric data. Frequency tables will be generated 
for categorical data.
All analyses will be performed separately by cohort. 
4.2
Handling of Dropouts
A participant who discontinues study participation prematurely for any reason is defined as a 
“screen failure” if the participant has not received any study intervention.
A participant who at the time of premature withdrawal has received any study interventions is 
a “drop out”.
Valid participants who drop out will be included in the analysis with the data available.
4.3
Handling of Missing Data
No imputations for missing data will be performed. A low number of missing values is
expected due to the short duration for each participant and the expected high adherence to the 
study protocol. Imputations might introduce bias due to the small sample size and the study 
design (for dropouts, the experimental intervention will always be missing).
All missing or partial data will be presented in the subject data listing as they are recorded on 
the Case Report Form. 
4.4
Interim Analyses and Data Monitoring
A statistical analysis will be performed by the study statistican and the study statistical analyst 
for dose decision meetings. The decision criteria for dose adjustment will consider both the 
proportion of participants for whom no preference is selected, and the difference between the 
proportion preferring gadobutrol and preferring BAY 1747846. The analysis as well as the 
dose finding algorithm is described in Section 6.2.1.
Additionally, a non-binding interim analysis (IA) may be performed for this study to facilitate 
informed planning of the next phases of development.
The IA can be triggered at any time when at least 25 participants have been enrolled in a dose 
cohort and have completed both MRI periods (i.e., at least 50% completion of the dose-
cohort).
Enrollment in the dose-cohort will continue while the IA is ongoing. Independent of the 
outcome from the IA, the cohort will be completed. 
The primary efficacy endpoint for the selected dose-cohort will be evaluated as described in 
Section 6.2.1. Neither a decision about the dose selection nor about stopping a dose step will 
be made based on the results from the IA. 
In case a trend of “no-preference” between BAY 1747846 and gadobutrol (or a trend of  
“preference of BAY 174846”) is observed, further analyses will be performed for secondary 


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endpoints as described in Section 6.2.2 and  number of enhanced lesions as described in 
Section 6.2.3.2. In addition, safety analysis will be conducted including the incidence and 
severity of TEAEs along with other safety parameters as described in Section 6.4 and Gd 
plasma concentrations as described in Section 6.3.1. 
If no trend is observed or if deemed inconclusive, no further analysis will be performed until 
the primary completion of the selected dose-cohort.
Since the assessment of the final dose finding algorithm is not based on a formal hypothesis 
test, the type I error (i.e., the alpha level) will not be adjusted for the IA.
This is a single-blind study and the IA will not affect the blinding design as only participants 
are blinded and will remain blinded to the sequence of treatment administration. The central 
independent readers evaluating the primary and secondary endpoints will remain blinded 
during the IA and the results.
Data will be processed and analyzed by the sponsor and there will not be an independent data 
monitoring committee. The analysis will be executed with controlled dissemination to ensure 
the integrity of ongoing data collection while maintaining sufficient blinding in the study. 
4.5
Data Rules
Summary statistics (minimum and maximum excluded) will be provided if evaluable data of 
≥3 subjects is available. Minimum and maximum if at least one evaluable data point exists. 
4.5.1
Baseline
Baseline is defined as last planned pre-dose assessment before first study intervention 
administration per period.
4.5.2
Repeated Measurements
If control measurements for the screening visit are available, the last value (i.e. of the 
measurement closest to the study intervention administration) will be used for the calculation 
of descriptive statistics. If control measurements for a planned time point except screening are 
available, the first value (i.e. of the planned measurement) will be used for the calculation of 
descriptive statistics. 
4.5.3
Laboratory Values Outside the Calibration Range
Means at any time will only be calculated if at least 2/3 of the individual data were measured 
and were above the lower limit of quantification (LLOQ) and below the upper limit of 
quantification (ULOQ). For the calculation of the mean value a data point below LLOQ will 
be substituted by one half of this limit, a data point above ULOQ will be substituted by 
ULOQ. In tables showing mean values, where values below LLOQ or above ULOQ are 
included in the calculation of mean values, these means will be marked. Differences (e.g. 
changes from baseline) will not be calculated if both measurements are substituted.
4.5.4
Zero-filled Averages
For border delineation, contrast enhancement, and internal morphology up to 5 lesions will be 
selected and scored by the blinded readers. Therefore, there will be multiple values for each 
subject (ratings for multiple lesions). The average of these ratings will be used for the 
analyses. 
The analysis of all lesions, of which some may not be so well visualized, will be performed 
using zero-filled averages of the ratings for each subject to avoid using a scoring system that 


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rates the detection of fewer but more well-visualized lesions over the detection of more 
lesions
In cases where the scans detect different number of lesions, enough zeros will be included 
with the scores for the modalities which detected fewer lesions to make the average for each 
imaging set based on the same number of scores. This zero-filled average will always reward 
the detection of extra lesions. This computation of zero-filled averages means that in cases 
where modalities (by the blinded readers) detect for any of the three parameters a different 
number of lesions in the post-gadobutrol and post-BAY 1747846 image set or pre-contrast 
and combined pre- and post-contrast image set, respectively, enough zeros will be included 
for the scores in the image set in which fewer lesions were detected to make the average for 
each imaging set based on the same number of scores.
The approach will not be used for the analysis of correlated lesions since the same number of 
lesions will be rated in each imaging set.
Example: A reader scores in the post-gadobutrol image of a subject two lesions regarding 
internal morphology and three lesions in the post-BAY 1747846 image. In this case, the 
subject’s total score of the reader will be divided by three for both images sets to guarantee 
comparability for the scores.
4.6
Blind Review
This study is a single blind study. The primary (and some secondary) endpoints of the study 
will be evaluated in an independent blinded read. 
The results of the final data assessment will be documented in the final list of important 
deviations, validity findings and assignment to analysis set(s). Any changes to the statistical 
analysis prompted by the results of the review of study data will be documented in an 
amendment and, if applicable, in a supplement to this SAP.
5.
Analysis Sets
5.1
Assignment of analysis sets
Final decisions regarding the assignment of subjects to analysis sets will be made during the 
review of study data and documented in the final list of important deviations, validity findings 
and assignment to analysis set(s) (see Section 4.6).
All participants who signed the informed consent form will be included in the ‘All enrolled 
participants’ evaluations.
Full analysis set (FAS)
All participants who have complete MR image datasets that qualify for blinded read.
Safety analysis set (SAF)
All participants who received any dose of study intervention. 
6.
Statistical Methodology
All analyses will be performed by cohort. Pooled analyses will be provided where 
appropriate.
For the primary objective the following two estimands are of equal interest: 


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
The estimand is then the proportion of participants for whom no preference is chosen for 
the image preference in the overall diagnostic preference based on a randomized paired 
blinded read using a 5-point scale at 5 min pi in all participants who have 2 image sets 
(gadobutrol and BAY 1747846) available. No imputations or adjustments will be made 
for those participants who have no images or only one image set as these participants will 
be excluded from the analysis.

The estimand is then the difference between the proportion of participants for whom the 
BAY 1747846 image sets are preferred and the proportion of participants for whom the 
gadobutrol image sets are preferred in the overall diagnostic preference based on a 
randomized paired blinded read using a 5-point scale at 5 min pi in all participants who 
have 2 image sets available. No imputations or adjustments will be made for those 
participants who have no images or only one image as these participants will be excluded 
from the analysis.
For the secondary objective

The estimand is then the difference in the sum of lesion visualization parameters between 
both image sets (BAY 1747846 and gadobutrol) in all participants who have 2 image sets 
available. No imputations or adjustments will be made for those participants who have no 
images or only one image set as these participants will be excluded from the analysis.

The estimand is then the mean of lesion visualization parameters between both 
image sets (pre-contrast and combined pre- and post-contrast) in all participants who 
have 2 image sets available. No imputations or adjustments will be made for those 
participants who have no images or only one image set as these participants will be 
excluded from the analysis.
For objectives and endpoints see also Section 2.
6.1
Population characteristics
If not stated otherwise, analyses will be performed on the SAF population.
6.1.1
Participants Validity and Disposition
Study sample size, participant validity with reason for exclusion from analysis sets, 
participant disposition, end of study medication, and important deviations / validity findings 
will be summarized by cohort and total using frequency tables over appropriate analysis sets 
like FAS or ‘All enrolled participants’.
6.1.2
Demographics
Summary statistics (arithmetic mean, standard deviation, median, minimum, and maximum 
for quantitative variables) will be presented for all participants in the analysis population 
being summarized. Frequency tables for qualitative data will be provided. If the FAS 
population differs from the SAF population, summary statistics and frequency tables for FAS 
will be provided as well.
6.1.3
Medical and Surgical History
The number of participants with medical history findings will be summarized by classified 
data using frequency tables. The classification will be done according to the Medical 
Dictionary for Regulatory Activities (MedDRA) coding system using system organ class, 
high level terms and preferred terms. The most recent MedDRA version will be used.


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6.1.4
Prior and Concomitant Medication
The number of participants that used prior or concomitant medication will be analyzed using 
frequency tables based on classified data. The classification will be done according to the 
World Health Organization Drug Dictionary (WHO-DD).
6.2
Efficacy
If not stated otherwise, analyses will be performed on the FAS population. An overview over 
all efficacy variables can be found in Table 6–1.
Table 6–1: Overview of the imaging efficacy variables by imaging sets
Unen-
hanced MRI 
in period 1
Gadobutrol-
enhanced 
MRI
Combined 
unen-
hanced and 
Gadobutrol-
enhanced 
MRI
Unen-
hanced MRI 
in period 2
BAY 
1747846-
enhanced 
MRI
Combined 
unen-
hanced and 
BAY
1747846-
enhanced 
MRI
Paired 
gadobutrol-
enhanced 
T1w and 
BAY 
1747846-
enhanced 
T1w MRI
Variables
BR
BR
BR
BR
BR
BR
BR
Overall 
diagnostic 
preference

Contrast 
enhance-
ment






Border 
delineation






Internal 
morphology






Number of 
lesions






Number of 
contrast-
enhanced 
lesions




Signal 
intensity 
measure-
ment




Abbreviations: BR: Blinded Reader, MRI: Magnetic resonance imaging, T1w: T1 weighted
6.2.1
Primary Efficacy Analysis – Overall Diagnostic Preference
The blinded readers will evaluate the relative image quality of the BAY 1747846-enhanced
T1w MRIs and the gadobutrol-enhanced T1w MRIs. The assessment will be based on the 
overall subjective interpretation of the degree of contrast enhancement, border delineation, 
and internal morphology. These images will be presented in a paired fashion in a separate 
reading session. The BAY 1747846 and gadobutrol images will be randomly assigned to 
either the left (image L) or right (image R) positions.
Image quality will be compared on a 5-point scale:
1 = 
greatly prefer image R
2 = 
prefer image R
3 = 
no preference
4 = 
prefer image L
5 = 
greatly prefer image L.


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As part of the randomization and blinding process, R and L will represent either the BAY 
1747846 or gadobutrol image. After the data is unblinded, the above codes will be translated 
into the following scale:
2 = 
greatly prefer BAY 1747846,
1 = 
prefer BAY 1747846,
0 = 
no preference
-1 = prefer gadobutrol,
-2 = greatly prefer gadobutrol.
The results within each reader will be treated independently, and the conclusions will be 
drawn from the overall distribution of results.
For the first estimand of interest, the proportion of participants for whom “No preference”, 
“Prefer BAY 1747846” and “Prefer gadobutrol” is expressed for each cohort, will be 
calculated along with a corresponding two-sided 95% CI. The three categories are collapsed 
from the 5-point preference scale. The 95% Wald CIs are based on the normal approximation 
to the binomial distribution
̂ ± 	
 
 × ̂(1 −̂)

,
where ̂ is the observed proportion of participants for “No preference”, “Prefer 
BAY 1747846” or “Prefer gadobutrol”,  is the number of participants,  is the level of 
significance and 	
 
 is the 100 1 − 2
 th percentile of the standard normal distribution.
The following algorithm for dose adjustment will be used:

If the 95% confidence intervals (CI) for the choices “Prefer gadobutrol” and “Prefer 
BAY 1747846” are not overlapping and the proportion expressing “Prefer gadobutrol” 
is greater than the proportion “Prefer BAY 1747846”, then the dose needs to be 
adjusted upward and an additional cohort with a higher dose will be enrolled.

In case, the choices “Prefer gadobutrol” and “Prefer BAY 1747846” are equally 
balanced, dose adjustment will not be needed. 

If the 95% CIs for the choices “Prefer gadobutrol” and “Prefer BAY 1747846” are not 
overlapping and the proportion expressing “Prefer BAY 1747846” is greater than the 
proportion “Prefer gadobutrol”, then the dose needs to be adjusted downward and an 
additional cohort with a lower dose will be enrolled.
The reads of the blinded readers will be treated as independent confirmations of the results. 
For each cohort, 3 readers will be used as independent replications of the result, therefore the 
number of participants is 50 even though there will be 150 reads available. Having 2 or 
3 readers giving the same result lends confidence to the conclusion. If 2 or 3 readers reach the 
same conclusion on the recommended action (no dose adjustment needed, dose increase 
needed, dose decrease needed), then that will be the recommended action taken.
If all 3 readers reach different conclusions, then no dose adjustment is needed.
For the second estimand of interest, the null and alternative hypotheses for an exploratory 
analysis of a difference between the proportions of participants fo whom the BAY 1747846 


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image sets are preferred and the proportion of participants for whom the gadobutrol image 
sets are as follows:
:  !"#"! $%& '(')(* =  !"#"! ,-./012!/3 
45   :  !"#"! $%& '(')(* ≠ !"#"! ,-./012!/3,
where π !"#"! $%& '(')(* is the proportion of participants for whom the BAY 1747846-
enhanced image was preferred and π !"#"! ,-./012!/3 is the proportion of participants for 
whom the gadobutrol-enhanced image was preferred. For this exploratory analysis, a 
McNemar’s test will be used.
Example: Assume that for a participants BAY 1747846 was preferred, for b participants 
gadobutrol was preferred and for c participants no preference was given. This would lead to 
the following contingency table, which can be analyzed using McNemar’s test [3]:
Prefer Gadobutrol
Yes
No
Total
Prefer BAY 
1747846
Yes
0
a
a
No
b
c
b+c
Total
b
a+c
N
Additionally, the distribution of the choices other than “No preference” will be examined 
descriptively using frequency tables and histograms. The relative image qualities will be 
tested for equality using a Wilcoxon signed-rank test.
A table displaying frequencies and percentages of the results of the 5-point scale will also be 
provided.
6.2.2
Secondary Efficacy Analysis 
6.2.2.1
Lesion Visualization Parameters at 5 min post injection on Post-
Contrast Images
The 3 analysis variables are derived from the 3 parameters below using the following 
methodology:
1. Contrast enhancement (measured on an ordinal 4-point scale)
2. Border delineation (measured on an ordinal 4-point scale)
3. Internal morphology (measured on an ordinal 3-point scale).
Up to 5 of the largest lesions will be selected and scored by the blinded readers. 
The following 4-point scale will be used for lesion enhancement:
1 = 
No
lesion is not enhanced
2 = 
Moderate
lesion is weakly enhanced
3 = 
Good
lesion is clearly enhanced
4 = 
Excellent
lesion is clearly and brightly enhanced.


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The following 4-point scale will be used for lesion delineation:
1 = 
None
no or unclear delineation of the lesion boundaries
2 = 
Moderate
some aspects of border delineation covered
3 = 
Good
almost clear, but not complete delineation
4 = 
Excellent
clear and complete delineation.
The following 3-point scale will be used for lesions:
1 = 
Poor
the structure and internal morphology of the lesion is poorly visible
2 = 
Moderate
the structure and internal morphology of the lesion is partially visible
3 = 
Good
the structure and internal morphology of the lesion is sufficiently 
visible.
The analysis is based on the data from the blinded readers’ evaluation of the 3 visualization 
parameters, which are evaluated in the MRI sets.
The scores for multiple lesions of a subject will be handled by zero-filled method as specified 
in Section 4.5.4. In order to reduce multiplicity, the zero-filled averages of the scores (see 
Section 4.5.4) of the 3 variables will be combined by adding them up for each timepoint, each 
participant and each blinded reader. Average reader, i.e. the mean of the 3 blinded readers
zero-filled averages of the scores per participant, will be used in addition to the 3 individual 
readers.
The descriptive analyses of the sum of lesion visualization parameters will be performed on 
the data from each blinded reader, as well as the data obtained by averaging across the 
3 blinded readers, producing one mean value per participant and timepoint. Zero-filled 
average scores for frequency tables will be rounded to integers, leading to only one variable 
on an ordinal 11-point scale.
For the combined visualization parameter, the non-inferiority of BAY 1747846 versus 
gadobutrol will also be evaluated using CIs based on the t-distribution. A non-inferiority 
margin of 1 will be used. The analysis will be performed on the data from the average reader.
The non-inferiority margin was determined by the 95%-95% method described in the FDA 
Guidance “Non-Inferiority Clinical Trials to Establish Effectiveness” [2] and is based on the 
past performance of the comparator in the Gadavist Study 310123. Data from this study were 
re-analyzed using the combined approach described above. After combining the visualization 
parameters of Study 310123 and calculating the two-sided 95% CI for the mean difference 
gadobutrol – unenhanced, the observed mean difference was 2.49 and the corresponding 95% 
CI [2.337; 2.651]. As described in the FDA Guidance, the lower bound of the 95% CI was 
selected as the known effect of gadobutrol to the unenhanced imaging 8 = 2.337. To retain 
at least half of the effect of the original treatment, the non-inferiority margin is set to
8 = 0.5 ∗ 8 = 1.16785. Due to the fact that in Study 310123 the averaged reader was 
used for evaluation, which helped lowering the variability, the non-inferiority margin was 
even further lowered to 1.
This means that a 95% two-sided CI for the mean difference BAY 1747846 score –
gadobutrol score must exclude the value -1 for non-inferiority to be achieved. A one-sided 
t-test conducted at the 0.025 level of significance would be a statistically equivalent procedure. 
The null and alternative hypotheses for non-inferiority are:


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H: μBAY 1747846 − μgadobutrol < −1 vs  H: μBAY 1747846 − μgadobutrol ≥−1,
where μBAY 1747846 and μgadobutrol are the mean of the score evaluated by blinded readers after 
administration of BAY 1747846 and gadobutrol, respectively.
In addition to the combined visualization parameter, frequency tables and descriptive statistics 
for the 3 lesion visualization variables will be provided as described above.
Inter-reader agreement for each of the 3 visualization variables and the sum of lesion 
visualization parameters will be assessed using the intra-class correlation coefficient treatment. 
The intra-class correlation coefficient S can be estimated as follows:
ST =
UV
 −UW

UV
 + (Y −1)UW,
Where UV
 denotes the variance between subjects, UW
 denotes the average within subject 
variance and Y is the number of readers.
6.2.2.2
Lesion Visualization Parameters on Pre-Contrast and Combined Pre-
and Post-Contrast (5 min pi) Images (correlated lesions)
The analysis is based on the data from the blinded readers’ evaluation of the 3 visualization 
parameters, which are evaluated in the MR Image sets. Up to 5 lesions will be selected and 
scored by the blinded readers. Only data of lesions that are identified on pre-BAY 1747846 
images will be used for this analysis.
The scores for multiple lesions of a subject will be averaged, i.e. the mean of all correlated 
lesions will be calculated per subject and imaging set. Average reader, i.e. the mean of  the 3 
blinded readers averages of the scores per participant, will be used in addition to the 
3 individual readers. 
A comparison of the pre- contrast and combined pre- and post-contrast images will be 
performed for each of the 3 visualization parameters. Summary statistics for absolute values 
and difference of the pre-contrast and combined pre- and post-contrast will be presented for 
each Blinded Reader and the Average Reader along with the 95% two-sided CIs for the 
difference of the pre-contrast and combined pre- and post-contrast.
6.2.2.3
Lesion Visualization Parameters on Pre-Contrast and Combined Pre-
and Post-Contrast (5 min pi) Images (all lesions)
The analysis is based on the data from the blinded readers’ evaluation of the 3 visualization 
parameters, which are evaluated in the MR image sets. Up to 5 lesions will be selected and 
scored by the blinded readers. Data of all lesions will be analyzed.
The scores for multiple lesions of a subject will be handled by zero-filled method as specified 
in Section 4.5.4. Average reader, i.e. the mean of  the 3 blinded readers zero-filled averages of 
the scores per participant, will be used in addition to the 3 individual readers. 
The analysis will be performed as described in Section Error! Reference source not found..
6.2.2.4
Number of Lesions on Pre-Contrast and Combined Pre- and Post-
Contrast (5 min pi) Images
The 3 blinded readers will record the total number of lesions for each pre-contrast and 
combined pre- and post-contrast (5 min pi) MR image set separately (no matched pairs 
approach). The upper limit of lesions to be counted is 20.


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A table displaying frequencies and percentages of different numbers of lesions detected 
by pre- and combined pre- and post-contrast images will be generated. A CI based on the t-
distribution for the difference in number of lesions detected in the two image sets will be 
constructed.
6.2.3
Other Efficacy Analyses
6.2.3.1
Efficacy Evaluation at 10 and 15 min Post injection
Summary statistics and frequency tables for sum of lesion visualization parameters will 
additionally be provided for contrast-enhanced images at 10 and 15 min pi.
6.2.3.2
Number of Enhanced Lesions on Post-Contrast Images
The 3 blinded readers will record the total number of enhanced lesions for each enhanced 
(5 min pi) MRI set separately. The upper limit of lesions to be counted is 20.
A table displaying frequencies and percentages of different numbers of contrast-enhanced 
lesions detected by BAY 1747846 and gadobutrol will be generated. A CI based on the t-
distribution for the difference in enhanced lesions detected by the 2 study interventions will 
be constructed.
6.2.3.3
SI Measurements
For each image set, one additional blinded reader will perform quantitative measurements on 
unenhanced and contrast-enhanced (5 min pi, 10 min pi, and 15 min pi) images of both image 
sets for each study participant. The following quantitative parameters will be calculated:

Percentage of lesion enhancement

CNR

SNR.
Quantitative measurements will be done in order to evaluate the percentage of lesion 
enhancement in the T1w sequence after injection of BAY 1747846 or gadobutrol compared to 
the unenhanced T1w sequence. Furthermore, the CNR of the lesions will be determined.
One additional independent blinded reader will perform SI measurements on the image sets. 
The blinded reader will have knowledge if the T1w sequence is pre-injection or post-injection, 
but will be blinded to knowledge of contrast agent (i.e. BAY 1747846 or gadobutrol). The 
images will be evaluated as follows:

Contrast-enhanced T1w MRI: the image giving the best visualization of the lesion will 
be chosen (either BAY 1747846-enhanced or gadobutrol-enhanced sequence). The 
region of interest (ROI) will be placed in that area of the lesion that shows best 
enhancement, avoiding necrotic regions. A second ROI will be drawn in normal brain 
tissue on the contralateral white matter or in normal spine tissue. A third ROI will be 
positioned in an area outside the brain or spine to determine the background.

All ROIs of the chosen contrast-enhanced sequence will be copied and pasted into the 
corresponding images of the other contrast-enhanced sequence and the unenhanced 
sequence in order to assure same location and size of ROIs in all T1w images 
(BAY 1747846-enhanced, gadobutrol-enhanced, and unenhanced).
The percentage of enhancement of the lesion will be based on SI measurements obtained from 
the combined results of unenhanced MRI – BAY 1747846 and unenhanced MRI –
gadobutrol-enhanced MRI as follows:


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SIL,post −SIL,pre
SIL,p_`
× 100%,
where SIL,post is the SI of the contrast-enhanced lesion and SIL,pre is the SI of the unenhanced 
lesion. For heterogeneous lesions, multiple ROIs can be placed over different areas, and the 
region that shows the maximum relative enhancement will be used for analysis.
SNR and CNR will be calculated based on SI measurements obtained as follows:
SNR = 
SIN,post
SDnoise
and
CNR = 
SIL,post −SIN,post
SDnoise
,
where SIL,post is the SI of the lesion on the contrast-enhanced image, SIN,post is post injection 
SI of normal tissue of the brain or spine, and SDnoise is the standard deviation of the noise of 
the normal tissue of the brain or spine (background) at the respective post-measurement time 
point.
The ROI size of the same lesion will be identical in all measurements within a single 
participant. SI measurements will be summarized by MRI imaging set using descriptive 
statistics and CIs.
6.3
Pharmacokinetics/pharmacodynamics
6.3.1
Pharmacokinetics
Analyses will be performed on the SAF population. 
Individual Gd plasma concentrations will be listed per study intervention (i.e. BAY 1747846 
and gadobutrol). Individual plasma concentration versus time curves (actual time) of Gd will 
be provided separately for each treatment, for each participant and for all participants.
In addition, dose normalized Gd concentrations will be plotted over time. Both linear and 
semi-logarithmic scales will be used.
Dose normalized Gd concentrations will be calculated as 
Gd concentration
actual dose (mmol Gd/kg).
Concentrations below LLOQ will be set to missing. In case the actual dose is not available, 
the nominal dose will be used for calculation of the dose normalized concentrations.
6.3.2
Pharmacodynamics
Not applicable.
6.4
Safety
Analyses will be provided on the SAF population. 
6.4.1
Adverse events (AEs)
Individual listings of AEs will be provided. 


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Treatment-emergent adverse events 
AEs are considered to be treatment-emergent if they have started or worsened after first 
application of study intervention GBCA injection up to the end of the following day, i.e. 24 h 
± 4 h follow-up time point per period.
An overall summary of the number and percentage of subjects with TEAEs will be presented 
in total and by treatment separately for each cohort. This summary will include the number 
and percentage of subjects with TEAEsworst intensity, TEAEs of special interest (TEAESI), 
serious adverse events (SAEs), related TEAEs, related serious TEAEs, TEAEs leading to 
permanent discontinuation, and TEAEs related to protocol-required procedure.
The number of subjects with AEs will be summarized by treatment and MedDRA terms for 
pre-treatment AES, TEAEs, study intervention-related TEAEs, AESI and SAEs using 
frequency tables. The incidence of TEAEs and study intervention-related TEAEs, 
respectively, will be summarized by treatment using System Organ Class and Preferred Terms 
according to the current MedDRA version.
Deaths, other serious and significant adverse events
For SAE outcomes, AEs leading to discontinuation and deaths, listings of participants will be 
provided by participant and/or AE.
6.4.2
Other Safety Examinations
Laboratory data for the central lab will be described by the following summary statistics: 
arithmetic mean, standard deviation, minimum, median and maximum for quantitative data. 
Frequency tables will be provided for qualitative data. For data from central and local lab, 
laboratory data outside the reference range will be listed and flagged with ‘L’ for low and ‘H’ 
for high.  Additional tables with all abnormal (out-of-range) values will be presented.
Laboratory data from local lab number of subjects with treatment-emergent high and low 
abnormalities will be presented. Treatment-emergent high abnormalities are all post-baseline 
abnormalities above the normal range for which the baseline value was normal or lower than 
normal. Treatment-emergent low abnormalities are all post-baseline abnormalities below the 
normal range for which the baseline value was normal or higher than normal.
Quantitative data for vital signs and ECG will be described by the following summary 
statistics: arithmetic mean, standard deviation, minimum, median and maximum for 
quantitative data. These summary statistics will be presented by treatment for the original data 
and for the difference to the respective baseline for quantitative data (i.e. pre-dose 
measurements, performed prior to the first administration of the study intervention per 
treatment period). 
Graphical displays of individual data and mean values with standard deviations will be 
included.
Qualitative ECG parameters will be summarized by parameter and time point using frequency 
tables.
7.
Document history and changes in the planned statistical analysis

SAP 1.0 dated 27 FEB 2020 final version

SAP Amendment 1 leading to SAP 2.0 dated 02 JUL 2020: Changes reflecting CSP 
2.0 were included.


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!
SAP Amendment 2 leading to SAP 3.0 dated 15 OCT 2021: Changes reflecting CSP 
3.0 and 4.0 were included.
!
SAP Amendment 3 leading to SAP 4.0 dated 14 JAN 2022: Changes reflecting CSP 
5.0 were included
8.
References
[1] Clinical Study Protocol No. BAY 1747846 / 20241, version 5.0, xx JAN 2022
[2] FDA Guidance “Non-Inferiority Clinical Trials to Establish Effectiveness”. November 
2016. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/non-inferiority-clinical-trials
[3] Senn, S. (2002). Crossover Trials In Clinical Research. Wiley.