Conditions: Magnetic Resonance Imaging
Keywords: Gadolinium Contrast enhancement Central nervous system lesion
Allocation: NON_RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 157
Healthy volunteers: no

Brief summary:
The study was conducted to gain knowledge about a new dose of a diagnostic drug that is used for contrast-enhanced Magnetic Resonance Imaging (MRI) of the human central nervous system (CNS). MRI can visualize the anatomy of the body and is used to detect medical conditions. Diagnostic drugs like gadobutrol and gadoterate contain an element called gadolinium that is applied to improve the analysability of MRI-images.

The purpose of this study was to examine if contrast-enhanced MRI using a reduced dose of the gadolinium-based contrast agent gadobutrol delivers images of similar quality to those obtained when a full dose of the gadolinium-based contrast agent gadoterate was used.

Detailed description:
The study was an open-label, multi-center, comparative, cross-over trial in adult patients with known or highly suspected CNS pathology who were referred for imaging of the CNS.

The primary objective of the study was to demonstrate the non-inferiority of gadobutrol (0.075 mmol/ kg body weight) to gadoterate (0.1 mmol/ kg body weight).

Arms:
arm 1: Patients with suspected or confirmed CNS-lesions underwent unenhanced MRI, and contrast-enhanced MRI after gadoterate injection. arm 2: Patients with gadoterate-confirmed CNS-lesions (subgroup of Arm 1) underwent a second unenhanced MRI, and contrast-enhanced MRI after gadobutrol injection.

Interventions: intervention 1: Gadoterate (Dotarem/Clariscan) intervention 2: Gadobutrol (Gadavist/Gadovist, BAY86-4875)
Intervention descriptions: intervention 1: Patients received a single dose of 0.5 molar gadoterate (0.1 mmol per kg body weight) intravenously. intervention 2: Patients received a single dose of 1.0 molar BAY86-4875 (0.075 mmol per kg body weight) intravenously.

Protocol document:
SAP_004.pdf: 
 
 
 
Document Type: 
Statistical Analysis Plan  
Official Title: 
LowEr Administered Dose with highEr Relaxivity: Gadovist vs 
Dotarem (LEADER 75) 
NCT Number: 
NCT03602339 
Document Date: 
18 MAR 2021 (SAP Supplement)  
24 JUL 2020 (SAP Supplement) 
26 MAY 2020 (SAP) 
 
 


Statistical Analysis Plan Supplement 
Version 2.0 
Protocol No.: BAY No. 86-4875/ 19773 
Page: 1 of 7
 
Reference Number: RD-SOP-1119 
Supplement Version: 10 
LowEr Administered Dose with highEr Relaxivity: Gadovist vs Dotarem 
(LEADER 75) 
Bayer study drug BAY No. 86-4875/ Gadobutrol / (GADOVIST) 
 
Study purpose: 
Comparison of Gadovist 75% standard dose to Dotarem at full standard 
dose 
Clinical study 
phase: 
IV 
Date: 
 18 MAR 2021 
Study No.: 
 
IMPACT No. 19773 
Version: Final 2.0 
Bayer Study 
Statistician 
  
 
 
Author: 
 
Biostatistician II 
Covance Clinical Development Services 
206 Carnegie Center 
Princeton, NJ 08540-6233 
 
 
 
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 Supplement is produced on a word-processing system and bears 
no signatures. 
The approval of the Statistical Analysis Plan Supplement is documented in a separate 
Signature Document. 
 
 
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Statistical Analysis Plan Supplement  
Version 2.0 
Protocol No.: BAY No. 86-4875/ 19773 
Page: 2 of 7
 
Reference Number: RD-SOP-1119 
Supplement Version: 10 
 
Table of Contents 
 
Abbreviations ........................................................................................................................ 2 
1. 
Background of supplementary analyses ...................................................................... 3 
2. 
Shells ............................................................................................................................... 4 
2.1 
Table shells .................................................................................................................. 4 
Table 16.4.1/11  
Comparison of degree of lesion contrast enhancement detected by 
blinded readers for combined image sets – Equivalence Test (Full analysis set) .... 5 
Table 16.4.1/12  
Comparison of border delineation detected by blinded readers for 
combined image sets – Equivalence Test (Full analysis set) ................................... 6 
Table 16.4.1/13  
Comparison of internal morphology detected by blinded readers for 
combined image sets – Equivalence Test (Full analysis set) ................................... 6 
3. 
Document history .......................................................................................................... 7 
4. 
References ...................................................................................................................... 7 
 
Abbreviations 
 
BR 
Blinded Reader 
CI 
Confidence interval 
FAS 
Full Analysis Set 
SAP 
Statistical Analysis Plan 
TOST 
Two One -Sided Tests 
 


Statistical Analysis Plan Supplement  
Version 2.0 
Protocol No.: BAY No. 86-4875/ 19773 
Page: 3 of 7
 
Reference Number: RD-SOP-1119 
Supplement Version: 10 
1. 
Background of supplementary analyses 
This Statistical Analysis Plan (SAP) Supplement provides details on the post-hoc 
supplementary analyses. 
Post-hoc 
examination 
of 
the 
Average 
Reader 
mean 
scores 
for 
combined 
(unenhanced/enhanced) gadobutrol and combined gadoterate results revealed that there was 
less than a 1% difference for each primary efficacy parameter. This provided a compelling 
reason to investigate the equivalence of the performance of combined gadobutrol and combined 
gadoterate. A direct comparison of the complete studies (combined image sets) is consistent 
with clinical practice. 
Supplementary Analyses of efficacy data will be performed in the Full analysis set (FAS). 
A comparison of the two combined image sets will be performed. The means, medians and 
standard deviations will be presented for each Blinded Reader (BR) and the Average Reader.  
For each primary visualization parameter, a difference of the two combined image sets will be 
calculated from the values already calculated in the primary analysis as described in SAP v3.0  
Means, medians, standard deviations along with the 95% two-sided CIs and one-sided p-values 
for the difference of the combined gadobutrol minus k* times the combined gadoterate will be 
presented (k represents a constant for each hypothesis). 
For each primary visualization parameter, an equivalence test will be considered, where the 
comparison will relate to a reasonable portion (5% margin) of the difference between the 
combined results of gadoterate and gadobutrol. The goal is to show that performance of 
combined gadobutrol and combined gadoterate is equivalent regarding the three visualization 
parameters. 
Equivalence tests at level α=0.025 will be calculated using the two one-sided t-tests (TOST) 
procedure, see Schuirmann (1987). 
The null hypotheses for equivalence are: 
• H01: (gadobutrol– gadoterate) ≤ -0.05* (gadoterate)  
and  
• H02: (gadobutrol – gadoterate) ≥ +0.05* (gadoterate). 
 
The alternative hypotheses, representing equivalence, are: 
• H11: (gadobutrol– gadoterate) > -0.05* (gadoterate)  
and  
• H12: (gadobutrol – gadoterate) < +0.05* (gadoterate). 
 
Statistical significance would be achieved if both null hypotheses could be rejected with 
p-values ≤ 0.025 for each primary efficacy variable. In each case, the overall p-value will be 
calculated as the maximum of the one-sided p-values of null hypotheses H01 and H02, 
respectively. 
 


Statistical Analysis Plan Supplement  
Version 2.0 
Protocol No.: BAY No. 86-4875/ 19773 
Page: 4 of 7
 
Reference Number: RD-SOP-1119 
Supplement Version: 10 
2. 
Shells 
2.1 
Table shells 
 
 
 


Statistical Analysis Plan Supplement  
Version 2.0 
Protocol No.: BAY No. 86-4875/ 19773 
Page: 5 of 7
 
Reference Number: RD-SOP-1119 
Supplement Version: 10 
Table 16.4.1/11  
Comparison of degree of lesion contrast enhancement detected by blinded 
readers for combined image sets – Equivalence Test (Full analysis set)  
Reader 
Treatment 
Image set 
Subjects Mean Median SD 
Min Max 
95% 
CI 
Lower 
Limit 
95% 
CI 
Upper 
Limit 
 
one -
sided 
p-value 
 
 
p-value 
1 
 
Gadoterate  
0.1 
mmol/kg 
bw 
Combined 
unenhanced/enhanced 
xxx 
xxx 
xxx 
xxx xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gadobutrol 
0.075 
mmol/kg 
bw 
Combined 
unenhanced/enhanced 
xxx 
xxx 
xxx 
xxx xxx 
xxx 
 
 
 
 
 
 
 
Difference (gadobutrol  
–0.95 gadoterate)  
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
 
 
 
Difference (gadobutrol  
–1.05  gadoterate)  
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
 
 
 
Equivalence Test Result 
 
 
 
 
 
 
 
 
 
 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 
 
Gadoterate  
0.1 
mmol/kg 
bw 
Combined 
unenhanced/enhanced 
xxx 
xxx 
xxx 
xxx xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gadobutrol 
0.075 
mmol/kg 
bw 
Combined 
unenhanced/enhanced 
xxx 
xxx 
xxx 
xxx xxx 
xxx 
 
 
 
 
 
 
 
Difference (gadobutrol  
–0.95 gadoterate)  
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
 
 
 
Difference (gadobutrol  
–1.05  gadoterate)  
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
 
 
 
Equivalence Test Result 
 
 
 
 
 
 
 
 
 
 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
3 
 
Gadoterate  
0.1 
mmol/kg 
bw 
Combined 
unenhanced/enhanced 
xxx 
xxx 
xxx 
xxx xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gadobutrol 
0.075 
mmol/kg 
bw 
Combined 
unenhanced/enhanced 
xxx 
xxx 
xxx 
xxx xxx 
xxx 
 
 
 
 
 
 
 
Difference (gadobutrol  
–0.95 gadoterate)  
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
 
 
 
Difference (gadobutrol  
–1.05  gadoterate)  
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
 
 
 
Equivalence Test Result 
 
 
 
 
 
 
 
 
 
 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan Supplement  
Version 2.0 
Protocol No.: BAY No. 86-4875/ 19773 
Page: 6 of 7
 
Reference Number: RD-SOP-1119 
Supplement Version: 10 
Reader 
Treatment 
Image set 
Subjects Mean Median SD 
Min Max 
95% 
CI 
Lower 
Limit 
95% 
CI 
Upper 
Limit 
 
one -
sided 
p-value 
 
 
p-value 
Average 
Reader 
Gadoterate  
0.1 
mmol/kg 
bw 
Combined 
unenhanced/enhanced 
xxx 
xxx 
xxx 
xxx xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gadobutrol 
0.075 
mmol/kg 
bw 
Combined 
unenhanced/enhanced 
xxx 
xxx 
xxx 
xxx xxx 
xxx 
 
 
 
 
 
 
 
Difference (gadobutrol  
–0.95 gadoterate)  
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
 
 
 
Difference (gadobutrol  
–1.05  gadoterate)  
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
 
 
 
Equivalence Test Result 
 
 
 
 
 
 
 
 
 
 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
- The 95% CI is based on a t-distribution. 
- An equivalence test was calculated using the two one-sided t-tests (TOST) procedure with null hypotheses H01: (gadobutrol– 
gadoterate) ≤ -0.05* (gadoterate) and H02: (gadobutrol – gadoterate) ≥ +0.05* (gadoterate). The overall p-value was 
calculated as max(p1,p2) where p1 and p2 are the results of null hypotheses H01 and H02, respectively. 
-The degree of lesion contrast enhancement was evaluated on an ordinal scale of 1 to 4, representing no, moderate, good and 
excellent enhancement respectively. The average score over lesions evaluated for each subject was used in the analysis. 
- Where scans within a reader and treatment detect a different number of lesions, the zero-filled average is calculated so each 
average is based on the maximum number of lesions detected per reader and treatment. For the difference between 
treatments, the zero-filled average uses the maximum number of lesions detected per reader. 
- Gadobutrol in the image set means combined unenhanced/gadobutrol enhanced image set. Gadoterate in the image set 
means combined unenhanced/gadoterate enhanced image set. 
 
Table 16.4.1/12  
Comparison of border delineation detected by blinded readers for 
combined image sets – Equivalence Test (Full analysis set)  
Replace footnotes by: 
- The 95% CI is based on a t-distribution. 
- An equivalence test was calculated using the two one-sided t-tests (TOST) procedure with null hypotheses H01: (gadobutrol– 
gadoterate) ≤ -0.05* (gadoterate) and H02: (gadobutrol – gadoterate) ≥ +0.05* (gadoterate). The overall p-value was 
calculated as max(p1,p2) where p1 and p2 are the results of null hypotheses H01 and H02, respectively. 
-The border delineation was evaluated on an ordinal scale of 1 to 4, representing none, moderate, good and excellent border 
delineation respectively. The average score over lesions evaluated for each subject was used in the analysis. 
-Where scans within a reader and treatment detect a different number of lesions, the zero-filled average is calculated so each 
average is based on the maximum number of lesions detected per reader and treatment. For the difference between 
treatments, the zero-filled average uses the maximum number of lesions detected per reader. 
- Gadobutrol in the image set means combined unenhanced/gadobutrol enhanced image set. Gadoterate in the image set 
means combined unenhanced/gadoterate enhanced image set. 
 
Table 16.4.1/13  
Comparison of internal morphology detected by blinded readers for 
combined image sets – Equivalence Test (Full analysis set) 
Replace footnotes by:  
- The 95% CI is based on a t-distribution. 
- An equivalence test was calculated using the two one-sided t-tests (TOST) procedure with null hypotheses H01: (gadobutrol– 
gadoterate) ≤ 0.05* (gadoterate) and H02: (gadobutrol – gadoterate) ≥ +0.05* (gadoterate). The overall p-value was 
calculated as max(p1,p2) where p1 and p2 are the results of null hypotheses H01 and H02, respectively. 
- The internal morphology was evaluated on an ordinal scale of 1 to 3, representing poor, moderate and good structure and 
internal morphology of the lesion respectively. The average score over lesions evaluated for each subject was used in the 
analysis. 
- Where scans within a reader and treatment detect a different number of lesions, the zero-filled average is calculated so each 
average is based on the maximum number of lesions detected per reader and treatment. For the difference between 
treatments, the zero-filled average uses the maximum number of lesions detected per reader. 
- Gadobutrol in the image set means combined unenhanced/gadobutrol enhanced image set. Gadoterate in the image set 
means combined unenhanced/gadoterate enhanced image set. 
 


Statistical Analysis Plan Supplement  
Version 2.0 
Protocol No.: BAY No. 86-4875/ 19773 
Page: 7 of 7
 
Reference Number: RD-SOP-1119 
Supplement Version: 10 
3. 
Document history  
Not applicable. 
4. 
References 
Schuirmann DJ. A Comparison of the Two One-Sided Tests Procedure and the Power Approach 
for Assessing the Equivalence of Average Bioavailability. J Pharmacokinetics and 
Biopharmaceutics. 1987;15(6):657-81. 
 


Reference Number: RD-SOP-1119 
Supplement Version: 7 
Page 1 of 2 
Statistical Analysis Plan (Supplement)  
Approval Form 
 
Study Number (Bay No./IMP no.)* 
BAY 86-4875/19773 
Statistical Analysis Plan (SAP) 
Version and Date 
Final 2.0, 18 Mar 2021 
 
 
 
 
 
 
 
 
* if no IMPACT number is available, refer to the approved Study Concept 
 
I have read and approve the SAP Supplement referred above.  
 
 
Name 
Signature and Date 
Author: 
Study Statistician 
<plus affiliation, if not Bayer>  
 
Covance, Inc. 
Approved by: 
Project Statistician/Internal  
Study Statistician 
 
Medical Affairs Responsible 
(MAR)/Study Medical Expert)  
 
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Reference Number: RD-SOP-1119 
Supplement Version: 7 
Page 2 of 2 
Study Statistical Analyst 
<plus affiliation, if not Bayer> 
 
Covance, Inc. 
Medical Writer 
<plus affiliation, if not Bayer> 
 
Covance, Inc 
 
  
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Clinical Study Report 
PH-41312 
BAY 86-4875/19773 
Page:  1 of 1 
16.1.9 
Documentation of statistical methods 
List of content: 
Statistical Analysis Plan Supplement Final Version 1.0 dated 24 JUL 2020
Statistical Analysis Plan Final Version 3.0 dated 26 MAY 2020 


Statistical Analysis Plan Supplement 
Protocol No.: BAY No. 86-4875/ 19773 
Page: 1 of 17
Reference Number: RD-SOP-1119 
Supplement Version: 10 
LowEr Administered Dose with highEr Relaxivity: Gadovist vs Dotarem 
(LEADER 75) 
Bayer study drug BAY No. 86-4875/ Gadobutrol / (GADOVIST) 
Study purpose: 
Comparison of Gadovist 75% standard dose to Dotarem at full standard 
dose 
Clinical study 
phase: 
IV 
Date: 
 24 JUL 2020 
Study No.: 
IMPACT No. 19773 
Version: Final 1.0 
Bayer Study 
Statistician 
 
Author: 
 
 
Covance Clinical Development Services 
206 Carnegie Center 
Princeton, NJ 08540-6233 
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 Supplement is produced on a word-processing system and bears 
no signatures. 
The approval of the Statistical Analysis Plan Supplement is documented in a separate 
Signature Document. 
PPD
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Reference Number: RD-SOP-1119 
Supplement Version: 7 
Page 1 of 1 
Statistical Analysis Plan (Supplement)  
Approval Form 
 
Study Number (Bay No./IMP no.)* 
BAY 86-4875/19773 
Statistical Analysis Plan (SAP) 
Version and Date 
Final 1.0, 24 Jul 2020 
 
 
 
 
 
 
 
 
* if no IMPACT number is available, refer to the approved Study Concept 
 
I have read and approve the SAP Supplement referred above.  
 
 
Name 
Signature 
Date 
Author: 
Study Statistician 
<plus affiliation, if not Bayer>  
 
Covance, Inc. 
 
Approved by: 
Project Statistician/Internal  
Study Statistician 
  
 
Medical Affairs Responsible 
(MAR)/Study Medical Expert)  
 
 
 
Study Statistical Analyst 
<plus affiliation, if not Bayer> 
 
Covance, Inc. 
 
 
Medical Writer 
<plus affiliation, if not Bayer> 
 
Covance, Inc 
 
 
 
  
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Reference Number: RD-SOP-1119 
Supplement Version: 7 
Page 1 of 1 
Statistical Analysis Plan (Supplement)  
Approval Form 
 
Study Number (Bay No./IMP no.)* 
BAY 86-4875/19773 
Statistical Analysis Plan (SAP) 
Version and Date 
Final 1.0, 24 Jul 2020 
 
 
 
 
 
 
 
 
* if no IMPACT number is available, refer to the approved Study Concept 
 
I have read and approve the SAP Supplement referred above.  
 
 
Name 
Signature 
Date 
Author: 
Study Statistician 
<plus affiliation, if not Bayer>  
 
Covance, Inc. 
 
 
Approved by: 
Project Statistician/Internal  
Study Statistician 
 
Medical Affairs Responsible 
(MAR)/Study Medical Expert)  
 
Study Statistical Analyst 
<plus affiliation, if not Bayer> 
 
Covance, Inc. 
 
 
Medical Writer 
<plus affiliation, if not Bayer> 
 
 
Covance, Inc 
 
 
 
  
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28Aug2020
Reference Number: RD-SOP-1119 
Supplemert Version. 7 
Statistical Analysis Plan (Supplement) 
Approval Form 
BAY 86-4875/19773 
Study Number (Bay No./lMP no.)* 
Statistical Analysis Plan (SAP) 
Version and Date 
Final 1.0, 24 Jul 2020 
• if no IMPACT number is available, refer to the approved Study Concept 
I have read and approve the SAP Supplement referred above. 
Author: 
Study Statistician 
<plus affiliation, if not Bayer> 
Approved by: 
Project Statistician/Internal 
Study Statistician 
Medical Affairs Responsible 
(MAR)/Study Medical Expertl 
Study Statistical Analyst 
<plus affiliation, if not Bayer> 
Medical Writer 
<plus affiliation, if not Bayer> 
Name 
 
Covance, Inc. 
 
 
 
Covance, Inc. 
 
 
Covance, Inc 
Signature 
Date 
I 
Page 1 of 1 
PPD
PPD
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Statistical Analysis Plan 
 
 
Protocol No.: BAY No. 86-4875/ 19773 
Page: 2 of 17
 
Reference Number: RD-SOP-1119 
Supplement Version: 10 
 
Table of Contents 
 
Abbreviations ........................................................................................................................ 2 
1. 
Background of supplementary analyses ...................................................................... 3 
2. 
Shells ............................................................................................................................... 4 
2.1 
Table shells .................................................................................................................. 4 
Table 16.4/1 
Number of subjects by region  and country (All enrolled subjects) ............ 5 
Table 16.4/2 
Comparison of degree of lesion contrast enhancement detected by blinded 
readers  - Average reader as simple mean over reader results (Full analysis set) ....... 6 
Table 16.4/3 
Comparison of border delineation detected by blinded readers  - Average 
reader as simple mean over reader results (Full analysis set) ...................................... 8 
Table 16.4/4 
Comparison of internal morphology detected by blinded readers  - 
Average reader as simple mean over reader results (Full analysis set) ....................... 9 
Table 16.4/5 
Comparison of degree of lesion contrast enhancement detected by blinded 
readers – compared to mean of both unenhanced image sets (Full analysis set) ....... 10 
Table 16.4/6 
Comparison of border delineation detected by blinded readers – compared 
to mean of both unenhanced image sets (Full analysis set) ....................................... 12 
Table 16.4/7 
Comparison of internal morphology detected by blinded readers – 
compared to mean of both unenhanced image sets ( Full analysis set) ..................... 13 
Table 16.4/8 
Summary of  difference of degree of lesion of contrast enhancement 
between gadobutrol and gadoterate unenhanced images detected by blinded readers 
(Full analysis set) ....................................................................................................... 14 
Table 16.4/9 
Summary of difference of border delineation between gadobutrol and 
gadoterate unenhanced images detected by blinded readers (Full analysis set) ........ 14 
Table 16.4/10 
Summary of difference of internal morphology between gadobutrol and 
gadoterate unenhanced images  detected by blinded readers (Full analysis set) ....... 14 
2.2 
Figure Shells .............................................................................................................. 15 
Figure 16.4/11 
Bar Plot of the mean scores of the three primary efficacy variables for 
the average reader (Full analysis set) ......................................................................... 15 
Figure 16.4/12 
Bar Plot of frequency of comparison of image quality values between 
gadobutrol and gadoterate detected by blinded readers (Full analysis set) ............... 16 
3. 
Document history ........................................................................................................ 17 
4. 
References .................................................................................................................... 17 
 
 
Abbreviations 
 
BR 
Blinded Reader 
CI 
Confidence interval 
FAS 
Full Analysis Set 
SAP 
Statistical Analysis Plan 
 


 
Statistical Analysis Plan 
 
 
Protocol No.: BAY No. 86-4875/ 19773 
Page: 3 of 17
 
Reference Number: RD-SOP-1119 
Supplement Version: 10 
1. 
Background of supplementary analyses 
 
This Statistical Analysis Plan Supplement provides details on the post-hoc supplementary 
analyses and also includes the correction of the formula of the standard error of the difference 
of rates, used for the computation of the asymptotic McNemar’s test-based confidence intervals 
(CIs) as described in section 6.2.3 of the Statistical Analysis Plan (SAP) v3.0. 
Supplementary Analyses of efficacy data will be performed in the Full analysis set (FAS). 
The primary and secondary analysis as described in section 6.2.2 of the SAP v3.0 will be 
repeated with the Average Reader calculated  now as simple mean of the arithmetic means of 
the values of Blinded Readers (BRs) 1, 2 and 3. No additional zero-filling across the BRs will 
be implemented.  
Example: The primary efficacy analyses of the 3 primary efficacy variables (visualization) was 
done using the average (arithmetic mean) of the values of the 3 BRs, zero-filled over all detected 
lesions for a patient across the 3 BRs. The analysis of these variables was also performed on 
the data from the 3 BRs individually using the zero-filled average method. To calculate the 
Average Reader as simple mean, the sum of the  already calculated values described above will 
be used and then divided by 3.  
A comparison of the two unenhanced image sets (paired comparison) will be performed. The 
means, medians, standard deviations along with the  95% two-sided CIs and two sided p-values 
will be presented per for each BR and the Average Reader. As described above the Average 
Reader  will be calculated  as simple mean of the arithmetic means of the differences of 
unenhanced images between gadobutrol and gadorate of Blinded Readers (BRs) 1, 2 and 3 for 
each of the three primary efficacy variables. No additional zero-filling across the BRs will be 
implemented. 
For each parameter, a simple difference of the two unenhanced and the combined unenhanced 
image sets will be calculated from the values already calculated in the primary analysis using 
the average (arithmetic mean) of the values of the 3 BRs. A difference of gadobutrol – gadorate 
will also be calculated. 
Means, medians, standard deviations along with the  95% two-sided CIs and p-values for the 
mean difference of the gadobutrol minus the mean of both unenhanced image set scores and the 
gadoterate minus the  mean of both unenhanced image set scores, the mean difference of 
gadobutrol – gadoterate will be presented.  
For each parameter, a noninferiority hypothesis will be considered, where the comparison will 
relate to a reasonable portion (c = 0.2) of the difference between gadoterate and the mean of 
both unenhanced sets. The goal is to show that the loss in the visualization parameter 
(gadoterate minus mean unenhanced) – (gadobutrol minus mean unenhanced) is lower than 0.2 
times the difference between combined unenhanced/gadoterate and the mean unenhanced.  
The null and alternative hypotheses for noninferiority are: 
• H0: (gadobutrol – mean unenhanced) – (gadoterate –mean  unenhanced)  
≤ - 0.2*(gadoterate – mean unenhanced) vs  
• H1: (gadobutrol – mean unenhanced) – (gadoterate– mean unenhanced)  
> - 0.2*(gadoterate – mean unenhanced). 


 
Statistical Analysis Plan 
 
 
Protocol No.: BAY No. 86-4875/ 19773 
Page: 4 of 17
 
Reference Number: RD-SOP-1119 
Supplement Version: 10 
One-sided p-values will be calculated and compared to a one-sided alpha of 0.025. 
  
The number and percentage of subjects by region, country and treatment group will be 
presented for all enrolled subjects.  
A bar plot of the mean scores for  the the average reader for the thre primary efficacy 
variables will be created. A bar plot of the frequency of comparison of image quality values 
between gadobutrol and gadorate will also be created.  
 
The correction of the formula of the standard error of the difference of rates, used for the 
computation of the asymptotic McNemar’s test-based CIs) as described in section 6.2.3 of the 
Statistical Analysis Plan v3.0, is as follows. 
 
𝑆𝑆𝑆𝑆𝑝𝑝2−𝑝𝑝1 = ඨ൭൬𝑏𝑏+ 𝑐𝑐
𝑛𝑛
൰−(𝑝𝑝2 −𝑝𝑝1)2൱1
𝑛𝑛 
 
 
2. 
Shells 
 
2.1 
Table shells 
 
 


 
Statistical Analysis Plan Supplement 
 
 
Protocol No.: BAY No. 86-4875/ 19773 
Page: 5 of 17
 
Reference Number: RD-SOP-1119 
Supplement Version: 10 
Table 16.4/1 
Number of subjects by region  and country (All enrolled subjects) 
 
Region 
Country  
 
Gadoterate  
0.1 mmol/kg bw 
N = x (100.0%) 
 
Gadobutrol  
0.075 mmol/kg bw 
N = x (100.0%) 
 
Total 
N=x (100.0%) 
All 
Total 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
Asia Pacific 
Total 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
China 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
Taiwan 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
Japan 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
Add as applicable 
 
 
 
 
 
 
 
 
Eastern Europe 
Total 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
Czech Republic 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
Hungary 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
Add as applicable 
 
 
 
 
 
 
 
 
North America 
Total 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
Canada 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
United States of America 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
South America 
Total 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
Argentina 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
Brazil 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
Add as applicable 
 
 
 
 
 
 
 
 
Western Europe and Australia, Israel and South Africa 
Total 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
Australia 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
Belgium 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
Add as applicable 
 
 
 
 
{Program, file pathway, date/time and other details of analysis}. 
 
 
 


 
Statistical Analysis Plan 
 
 
Protocol No.: BAY No. 86-4875/ 19773 
Page: 6 of 17
 
Reference Number: RD-SOP-1119 
Supplement Version: 10 
Table 16.4/2 
Comparison of degree of lesion contrast enhancement detected by blinded readers  - Average reader as simple mean over reader results (Full analysis set) 
Reader 
Treatment 
Image set 
Subjects 
Mean 
Median 
SD 
Min 
Max 
95% CI 
Lower Limit 
95% CI 
Upper Limit 
 
p-value 
 
Non-
inferiority 
achieved 
1 
Gadoterate  
0.1 mmol/kg bw Unenhanced 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
Combined unenhanced/enhanced 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
Difference (superiority test) 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gadobutrol 
0.075 mmol/kg 
bw 
Unenhanced 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
Combined unenhanced/enhanced 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
Difference (superiority test) 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
Difference (gadobutrol minus 
unenhanced) – (gadoterate minus 
unenhanced) (non-inferiority test) 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
<Yes, No> 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 
Gadoterate  
0.1 mmol/kg bw Unenhanced 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
Combined unenhanced/enhanced 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
Difference (superiority test) 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gadobutrol 
0.075 mmol/kg 
bw 
Unenhanced 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
Combined unenhanced/enhanced 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
Difference (superiority test) 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
Difference (gadobutrol minus 
unenhanced) – (gadoterate minus 
unenhanced) (non-inferiority test) 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
<Yes, No> 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3 
Gadoterate  
0.1 mmol/kg bw Unenhanced 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
Combined unenhanced/enhanced 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
Difference (superiority test) 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gadobutrol 
0.075 mmol/kg 
bw 
Unenhanced 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
Combined unenhanced/enhanced 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 


 
Statistical Analysis Plan 
 
 
Protocol No.: BAY No. 86-4875/ 19773 
Page: 7 of 17
 
Reference Number: RD-SOP-1119 
Supplement Version: 10 
Reader 
Treatment 
Image set 
Subjects 
Mean 
Median 
SD 
Min 
Max 
95% CI 
Lower Limit 
95% CI 
Upper Limit 
 
p-value 
 
Non-
inferiority 
achieved 
 
 
Difference (superiority test) 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
Difference (gadobutrol minus 
unenhanced) – (gadoterate minus 
unenhanced) (non-inferiority test) 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
<Yes, No> 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Average 
Gadoterate  
0.1 mmol/kg bw Unenhanced 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
Combined unenhanced/enhanced 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
Difference (superiority test) 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gadobutrol 
0.075 mmol/kg 
bw 
Unenhanced 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
Combined unenhanced/enhanced 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
Difference (superiority test) 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
Difference (gadobutrol minus 
unenhanced) – (gadoterate minus 
unenhanced) (non-inferiority test) 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
<Yes, No> 
 
 
 
 
 
 
 
 
 
 
 
 
 
-The difference for superiority test is defined as the subject-wise scores of (combined unenhanced/ enhanced – unenhanced). The 95% CIs and one-sided p-values are based on a t-distribution. The superiority is 
achieved if the one-sided p-value<0.025.  
-The score to evaluate the non-inferiority is calculated for each subject as (combined unenhanced/ gadobutrol-enhanced  - unenhanced) - 0.8*( combined unenhanced/ gadoterate enhanced – unenhanced). The 95% CI is 
based on a t-distribution. The noninferiority for gadobutrol is achieved if the one-sided p-value for “H0: (gadobutrol minus unenhanced) – 0.8*(gadoterate minus unenhanced)  <= 0” is lower than 0.025. 
-The degree of lesion contrast enhancement was evaluated on an ordinal scale of 1 to 4, representing no, moderate, good and excellent enhancement respectively. The average score over lesions evaluated for each 
subject was used in the analysis. 
- Where scans within a reader and treatment detect a different number of lesions, the zero-filled average is calculated so each average is based on the maximum number of lesions detected per reader and treatment. For 
the difference between treatments, the zero-filled average uses the maximum number of lesions detected per reader. 
- The Average Reader is using the arithmetic mean of the values of the Readers 1, 2 and 3. 
- Gadobutrol in the image set means combined unenhanced/gadobutrol enhanced image set. Gadoterate in the image set means combined unenhanced/gadoterate enhanced image set. 
{Program, file pathway, date/time and other details of analysis}. 


 
Statistical Analysis Plan 
 
 
Protocol No.: BAY No. 86-4875/ 19773 
Page: 8 of 17
 
Reference Number: RD-SOP-1119 
Supplement Version: 10 
Table 16.4/3 
Comparison of border delineation detected by blinded readers  - Average reader as simple mean over reader results (Full analysis set) 
Replace footnotes by: 
-The difference for superiority test is defined as the subject-wise scores of (combined unenhanced/ enhanced – unenhanced). The 95% CIs and one-sided p-values are based on a t-distribution. The superiority is 
achieved if the one-sided p-value<0.025.  
-The score to evaluate the non-inferiority is calculated for each subject as (combined unenhanced/ gadobutrol-enhanced  - unenhanced) - 0.8*( combined unenhanced/ gadoterate enhanced – unenhanced). The 95% CI is 
based on a t-distribution. The noninferiority for gadobutrol is achieved if the one-sided p-value for “H0: (gadobutrol minus unenhanced) – 0.8*(gadoterate minus unenhanced)  <= 0” is lower than 0.025. 
-The border delineation was evaluated on an ordinal scale of 1 to 4, representing none, moderate, good and excellent border delineation respectively. The average score over lesions evaluated for each subject was used 
in the analysis. 
Where scans within a reader and treatment detect a different number of lesions, the zero-filled average is calculated so each average is based on the maximum number of lesions detected per reader and treatment. For 
the difference between treatments, the zero-filled average uses the maximum number of lesions detected per reader. 
- The Average Reader is using the arithmetic mean of the values of the Readers 1, 2 and 3. 
- Gadobutrol in the image set means combined unenhanced/gadobutrol enhanced image set. Gadoterate in the image set means combined unenhanced/gadoterate enhanced image set. 
{Program, file pathway, date/time and other details of analysis}. 


 
Statistical Analysis Plan 
 
 
Protocol No.: BAY No. 86-4875/ 19773 
Page: 9 of 17
 
Reference Number: RD-SOP-1119 
Supplement Version: 10 
Table 16.4/4 
Comparison of internal morphology detected by blinded readers  - Average reader as simple mean over reader results (Full analysis set) 
Replace footnotes by: 
-The difference for superiority test is defined as the subject-wise scores of (combined unenhanced/ enhanced – unenhanced). The 95% CIs and one-sided p-values are based on a t-distribution. The superiority is 
achieved if the one-sided p-value<0.025.  
-The score to evaluate the non-inferiority is calculated for each subject as (combined unenhanced/ gadobutrol-enhanced  - unenhanced) - 0.8*( combined unenhanced/ gadoterate enhanced – unenhanced). The 95% CI is 
based on a t-distribution. The noninferiority for gadobutrol is achieved if the one-sided p-value for “H0: (gadobutrol minus unenhanced) – 0.8*(gadoterate minus unenhanced)  <= 0” is lower than 0.025. 
- The internal morphology was evaluated on an ordinal scale of 1 to 3, representing poor, moderate and good structure and internal morphology of the lesion respectively. The average score over lesions evaluated for 
each subject was used in the analysis.  
- Where scans within a reader and treatment detect a different number of lesions, the zero-filled average is calculated so each average is based on the maximum number of lesions detected per reader and treatment. For 
the difference between treatments, the zero-filled average uses the maximum number of lesions detected per reader. 
- The Average Reader is using the arithmetic mean of the values of the Readers 1, 2 and 3.  
- Gadobutrol in the image set means combined unenhanced/gadobutrol enhanced image set. Gadoterate in the image set means combined unenhanced/gadoterate enhanced image set. 
 
{Program, file pathway, date/time and other details of analysis}. 
 
 


 
Statistical Analysis Plan 
 
 
Protocol No.: BAY No. 86-4875/ 19773 
Page: 10 of 17
 
Reference Number: RD-SOP-1119 
Supplement Version: 10 
Table 16.4/5 Comparison of degree of lesion contrast enhancement detected by blinded readers – compared to mean of both unenhanced image sets (Full analysis set) 
Reader 
Treatment 
Image set 
Subjects 
Mean 
Median 
SD 
Min 
Max 
95% CI 
Lower Limit 
95% CI 
Upper Limit 
 
p-value 
 
Non-
inferiority 
achieved 
1 
Gadoterate  
0.1 mmol/kg 
bw 
Unenhanced 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
Combined unenhanced/enhanced 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
Difference (gadoterate minus 
mean of both unenhanced) 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gadobutrol 
0.075 mmol/kg 
bw 
Unenhanced 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
Combined unenhanced/enhanced 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
Difference (gadobutrol minus 
mean of both unenhanced) 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Difference Unenhanced  
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx  
 
 
 
 
Difference (gadobutrol -gadoterate)  
 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
Difference ((gadobutrol minus mean 
unenhanced) – (gadoterate minus 
mean unenhanced)) (non-inferiority 
test) 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
<Yes, No> 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 
Gadoterate  
0.1 mmol/kg 
bw 
Unenhanced 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
Combined unenhanced/enhanced 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
Difference (gadoterate minus 
mean of both unenhanced 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gadobutrol 
0.075 mmol/kg 
bw 
Unenhanced 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
Combined unenhanced/enhanced 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
Difference (gadobutrol minus 
mean of both unenhanced 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Difference Unenhanced  
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx  
 
 


 
Statistical Analysis Plan 
 
 
Protocol No.: BAY No. 86-4875/ 19773 
Page: 11 of 17
 
Reference Number: RD-SOP-1119 
Supplement Version: 10 
Reader 
Treatment 
Image set 
Subjects 
Mean 
Median 
SD 
Min 
Max 
95% CI 
Lower Limit 
95% CI 
Upper Limit 
 
p-value 
 
Non-
inferiority 
achieved 
 
 
 
Difference (gadobutrol -gadoterate)  
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
 
 
 
 
Difference ((gadobutrol minus mean 
unenhanced) – (gadoterate minus 
mean unenhanced)) (non-inferiority 
test) 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
<Yes, No> 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3 
Gadoterate  
0.1 mmol/kg 
bw 
Unenhanced 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
Combined unenhanced/enhanced 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
Difference (gadoterate minus 
mean of both unenhanced 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gadobutrol 
0.075 mmol/kg 
bw 
Unenhanced 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
Combined unenhanced/enhanced 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Difference (gadobutrol minus mean 
of both unenhanced) 
 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
 
 
Difference Unenhanced  
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx  
 
 
 
 
Difference (gadobutrol -gadoterate) 
 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx  
 
 
 
 
Difference ((gadobutrol minus mean 
unenhanced) – (gadoterate minus 
mean unenhanced)) (non-inferiority 
test) 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
<Yes, No> 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Average 
Gadoterate  
0.1 mmol/kg 
bw 
Unenhanced 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
Combined unenhanced/enhanced 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
Difference (gadoterate minus 
mean of both unenhanced 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 


 
Statistical Analysis Plan 
 
 
Protocol No.: BAY No. 86-4875/ 19773 
Page: 12 of 17
 
Reference Number: RD-SOP-1119 
Supplement Version: 10 
Reader 
Treatment 
Image set 
Subjects 
Mean 
Median 
SD 
Min 
Max 
95% CI 
Lower Limit 
95% CI 
Upper Limit 
 
p-value 
 
Non-
inferiority 
achieved 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gadobutrol 
0.075 mmol/kg 
bw 
Unenhanced 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
Combined unenhanced/enhanced 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
Difference (gadobutrol minus mean 
of both unenhanced) 
 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Difference Unenhanced  
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx  
 
 
 
 
Difference (gadobutrol -gadoterate) 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
Xxx 
 
 
 
 
 
Difference ((gadobutrol minus mean 
unenhanced) – (gadoterate minus 
mean unenhanced)) (non-inferiority 
test) 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
<Yes, No> 
 
 
 
 
 
 
 
 
 
 
 
 
 
- The 95% CIs and two-sided p-values are based on a t-distribution.  
- The score to evaluate the non-inferiority is calculated for each subject as (combined unenhanced/gadobutrol-enhanced – mean unenhanced) - 0.8*(combined unenhanced/gadoterate-enhanced – mean unenhanced). 
-The noninferiority for gadobutrol is achieved if the one-sided p-value for “H0: (gadobutrol minus mean unenhanced) – 0.8*(gadoterate minus mean unenhanced)  <= 0” is lower than 0.025. 
-The degree of lesion contrast enhancement was evaluated on an ordinal scale of 1 to 4, representing no, moderate, good and excellent enhancement respectively. The average score over lesions evaluated for each 
subject was used in the analysis. 
- Where scans within a reader and treatment detect a different number of lesions, the zero-filled average is calculated so each average is based on the maximum number of lesions detected per reader and treatment. For 
the difference between treatments, the zero-filled average uses the maximum number of lesions detected per reader. 
- Gadobutrol in the image set means combined unenhanced/gadobutrol enhanced image set. Gadoterate in the image set means combined unenhanced/gadoterate enhanced image set. 
 
{Program, file pathway, date/time and other details of analysis}. 
Table 16.4/6 Comparison of border delineation detected by blinded readers – compared to mean of both unenhanced image sets (Full analysis set) 
Replace footnotes by: 
The 95% CIs and two-sided p-values are based on a t-distribution.  
The noninferiority for gadobutrol is achieved if the one-sided p-value for “H0: (gadobutrol minus mean unenhanced) – 0.8*(gadoterate minus mean unenhanced)  <= 0” is lower than 0.025. 
-The border delineation was evaluated on an ordinal scale of 1 to 4, representing none, moderate, good and excellent border delineation respectively The average score over lesions evaluated for each subject was used in 
the analysis. 
- Where scans within a reader and treatment detect a different number of lesions, the zero-filled average is calculated so each average is based on the maximum number of lesions detected per reader and treatment. For 
the difference between treatments, the zero-filled average uses the maximum number of lesions detected per reader. 
- Gadobutrol in the image set means combined unenhanced/gadobutrol enhanced image set. Gadoterate in the image set means combined unenhanced/gadoterate enhanced image set. 
 


 
Statistical Analysis Plan 
 
 
Protocol No.: BAY No. 86-4875/ 19773 
Page: 13 of 17
 
Reference Number: RD-SOP-1119 
Supplement Version: 10 
{Program, file pathway, date/time and other details of analysis}. 
 
Table 16.4/7 Comparison of internal morphology detected by blinded readers – compared to mean of both unenhanced image sets ( Full analysis set) 
Replace footnotes by: 
The 95% CIs and two-sided p-values are based on a t-distribution.  
The noninferiority for gadobutrol is achieved if the one-sided p-value for “H0: (gadobutrol minus mean unenhanced) – 0.8*(gadoterate minus mean unenhanced)  <= 0” is lower than 0.025. 
- The internal morphology was evaluated on an ordinal scale of 1 to 3, representing poor, moderate and good structure and internal morphology of the lesion respectively. The average score over lesions evaluated for 
each subject was used in the analysis. 
- Where scans within a reader and treatment detect a different number of lesions, the zero-filled average is calculated so each average is based on the maximum number of lesions detected per reader and treatment. For 
the difference between treatments, the zero-filled average uses the maximum number of lesions detected per reader. 
- Gadobutrol in the image set means combined unenhanced/gadobutrol enhanced image set. Gadoterate in the image set means combined unenhanced/gadoterate enhanced image set. 
 
{Program, file pathway, date/time and other details of analysis}. 
 
 


 
Statistical Analysis Plan 
 
 
Protocol No.: BAY No. 86-4875/ 19773 
Page: 14 of 17
 
Reference Number: RD-SOP-1119 
Supplement Version: 10 
Table 16.4/8 Summary of  difference of degree of lesion of contrast enhancement between gadobutrol and gadoterate unenhanced images detected by blinded readers (Full analysis set) 
Reader 
Subjects 
mean 
median 
SD 
Min 
Max 
95% CI Lower Limit 
95% CI Upper Limit 
p-value 
1 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
2 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
3 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
Average 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The 95% CIs and two-sided p-values are based on a t-distribution.  
-The degree of lesion contrast enhancement was evaluated on an ordinal scale of 1 to 4, representing no, moderate, good and excellent enhancement respectively. The average score of the two unenhanced images over 
lesions evaluated for each subject was used in the analysis. 
- The Average Reader is using the arithmetic mean of the values of the Readers 1, 2 and 3.  
 
{Program, file pathway, date/time and other details of analysis}. 
 
Repeat for the following table(s) : 
 
Table 16.4/9 Summary of difference of border delineation between gadobutrol and gadoterate unenhanced images detected by blinded readers (Full analysis set) 
Replace footnotes by: 
The 95% CIs and two-sided p-values are based on a t-distribution.  
- The border delineation was evaluated on an ordinal scale of 1 to 4, representing none, moderate, good and excellent border delineation respectively.. The average score of the two unenhanced images over lesions 
evaluated for each subject was used in the analysis. 
- The Average Reader is using the arithmetic mean of the values of the Readers 1, 2 and 3. 
 
{Program, file pathway, date/time and other details of analysis}. 
 
Table 16.4/10 Summary of difference of internal morphology between gadobutrol and gadoterate unenhanced images  detected by blinded readers (Full analysis set) 
Replace footnotes by: 
The 95% CIs and two-sided p-values are based on a t-distribution.  
- The internal morphology was evaluated on an ordinal scale of 1 to 3, representing poor, moderate and good structure and internal morphology of the lesion respectively The average score of the two unenhanced 
images over lesions evaluated for each subject was used in the analysis. 
- The Average Reader is using the arithmetic mean of the values of the Readers 1, 2 and 3. 
 
{Program, file pathway, date/time and other details of analysis}. 
 
 


 
Statistical Analysis Plan 
 
 
Protocol No.: BAY No. 86-4875/ 19773 
Page: 15 of 17
 
Reference Number: RD-SOP-1119 
Supplement Version: 10 
 
2.2 
Figure Shells 
Figure 16.4/11 Bar Plot of the mean scores of the three primary efficacy variables for the average reader (Full analysis set) 
 
 
 


 
Statistical Analysis Plan 
 
 
Protocol No.: BAY No. 86-4875/ 19773 
Page: 16 of 17
 
Reference Number: RD-SOP-1119 
Supplement Version: 10 
Figure 16.4/12 Bar Plot of frequency of comparison of image quality values between gadobutrol and gadoterate detected by blinded readers (Full analysis set) 
 
 
 


 
Statistical Analysis Plan Supplement 
 
 
Protocol No.: BAY No. 86-4875/ 19773 
Page: 17 of 17
 
Reference Number: RD-SOP-1119 
Supplement Version: 10 
 
3. 
Document history  
Not applicable. 
4. 
References 
None 
 


Statistical Analysis Plan 
Protocol No.: BAY No. 86-4875/ 19773 
Page: 1 of 29
Reference Number: RD-OI-0119 
Supplement Version: 8 
LowEr Administered Dose with highEr Relaxivity: Gadovist vs Dotarem 
(LEADER 75) 
Bayer study 
drug 
BAY No. 86-4875/ Gadobutrol / (GADOVIST) 
Study purpose: 
Comparison of Gadovist 75% standard dose to Dotarem at full standard 
dose 
Clinical study 
phase: 
IV 
Date: 
26 MAY 2020 
Study No.: 
IMPACT No. 19773 
Version: 
Final 3.0 
Bayer Study 
Statistician 
 
Author: 
 
 
Covance Clinical Development Services 
206 Carnegie Center 
Princeton, NJ 08540-6233 
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
PPD
PPD


Reference Number: RD-SOP-1119 
Supplement Version: 7 
Statistical Analysis Plan (Amendment) 
Approval Form 
Study Number (Bay No./lMP no.)* 
Statistical Analysis Plan (SAP) 
Version and Date 
BAY 86-4875/19773 
Final 3.0, 26 May 2020 
* if no IMPACT number is available, refer to the approved Study Concept 
I have read and approve the SAP/SAP Amendment referred above. 
Name 
Signature 
Author: 
Study Statistician 
<plus affiliation, if not Bayer> 
Covance, Inc. 
Approved by: 
Project Statistician/Internal 
Study Statistician1> 
Medical Affairs Responsible 
(MAR)/Study Medical Expert 
Study Statistical Analyst 
 
<plus affiliation, if not Bayer> 
Covance, Inc. 
Medical Writer 
Date 
<plus affiliation, if not Bayer> 
Covance, Inc 
Page 1 of1 
PPD
PPD
PPD
PPD
PPD
PPD
PPD


 
Statistical Analysis Plan 
 
 
Protocol No.: BAY No. 86-4875/ 19773 
Page: 2 of 29
 
Reference Number: RD-OI-0119 
Supplement Version: 8 
Table of Contents 
Abbreviations ......................................................................................................................... 4 
1. 
Introduction ..................................................................................................................... 5 
2. 
Study Objectives ............................................................................................................. 5 
2.1 
Primary Objectives ........................................................................................................ 5 
2.2 
Secondary Objectives .................................................................................................... 5 
3. 
Study Design .................................................................................................................... 6 
3.1 
Overall Design ............................................................................................................... 6 
3.2 
Determination of Sample Size ....................................................................................... 9 
4. 
General Statistical Considerations .............................................................................. 10 
4.1 
General Principles ....................................................................................................... 10 
4.2 
Handling of Dropouts .................................................................................................. 11 
4.3 
Handling of Missing Data ........................................................................................... 11 
4.4 
Handling of Nonassessable (uninterpretable) Images ................................................. 11 
4.5 
Interim Analyses and Data Monitoring ....................................................................... 12 
4.6 
Data Rules ................................................................................................................... 12 
4.7 
Validity Review ........................................................................................................... 12 
5. 
Analysis Sets .................................................................................................................. 12 
6. 
Statistical Methodology ................................................................................................ 14 
6.1 
Population Characteristics ........................................................................................... 14 
6.1.1 
Subject disposition ................................................................................................... 14 
6.1.2 
Protocol deviations ................................................................................................... 15 
6.1.3 
Demographics .......................................................................................................... 15 
6.1.4 
Referral and final diagnosis ..................................................................................... 15 
6.1.5 
Medical history ......................................................................................................... 15 
6.1.6 
Prior and concomitant medications .......................................................................... 16 
6.1.7 
Study drug dosage and administration ..................................................................... 16 
6.2 
Efficacy ........................................................................................................................ 16 
6.2.1 
Primary efficacy variables ........................................................................................ 17 
6.2.2 
Analysis of primary efficacy variables .................................................................... 18 
6.2.3 
Secondary efficacy variables .................................................................................... 20 
6.2.4 
MRI field strengh ..................................................................................................... 26 
6.3 
Pharmacokinetics/pharmacodynamics ........................................................................ 26 
6.4 
Safety ........................................................................................................................... 26 
6.4.1 
Baseline findings ...................................................................................................... 26 
6.4.2 
Adverse events ......................................................................................................... 26 
6.4.3 
Other Safety Variables ............................................................................................. 28 
7. 
Document History and Changes in the Planned Statistical Analysis ....................... 28 
8. 
References ...................................................................................................................... 29 
 


Statistical Analysis Plan 
Protocol No.: BAY No. 86-4875/ 19773 
Page: 3 of 29
Reference Number: RD-OI-0119 
Supplement Version: 8 
List of Tables 
Table 3-1 Schedule of study events ........................................................................................... 7 
Table 3–2 Results for average reader derived from study 310123 ............................................ 9 
Table 6–1: Overview of the imaging efficacy variables .......................................................... 17 
Table 6–2: Final clinical diagnosis of CNS lesions ................................................................. 22 
Table 6–3: Components of the definitions for sensitivity, specificity, and accuracy .............. 23 
Table 6–4: Components of confidence interval ....................................................................... 24 


 
Statistical Analysis Plan 
 
 
Protocol No.: BAY No. 86-4875/ 19773 
Page: 4 of 29
 
Reference Number: RD-OI-0119 
Supplement Version: 8 
Abbreviations 
AE 
adverse event 
BR 
blinded reader 
BW 
body weight 
CI 
confidence interval 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration equation 
CNS 
central nervous system 
eCRF 
electronic case report form 
FAS 
full analysis set 
FLAIR 
Fluid Attenuated Inversion Recovery 
FN 
false negative 
FP 
false positive 
GBCA 
Gadolinium-Based Contrast Agent 
GCIS 
General Clinical Imaging Service 
eGFR 
estimated glomerular filtration rate 
IV 
intravenous 
MDRD 
Modification of Diet in Renal Disease Study equation 
MedDRA 
Medical Dictionary for Regulatory Activities 
MR 
magnetic resonance 
MRI 
magnetic resonance imaging 
NAN 
not assessed negative 
NAP 
not assessed positive  
PPS 
per protocol analysis set 
PT 
preferred term 
SAE 
serious adverse event 
SAF 
safety analysis set 
SAP 
statistical analysis plan 
SOC 
System organ class 
SOT 
standard of truth 
T1 
longitudinal relaxation time 
T1w 
T1-weighted 
T2 
transversal relaxation time 
T2w 
T2-weighted 
TE 
treatment-emergent 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
TN 
true negative 
TP 
true positive 
 
 
 


 
Statistical Analysis Plan 
 
 
Protocol No.: BAY No. 86-4875/ 19773 
Page: 5 of 29
 
Reference Number: RD-OI-0119 
Supplement Version: 8 
1. 
Introduction 
Gadolinium-Based Contrast Agents (GBCA) are intravenous (IV) drugs used in diagnostic 
imaging procedures to enhance the quality of magnetic resonance imaging (MRI). Macrocyclic 
GBCAs, such as gadobutrol, gadoteridol, and gadoterate meglumine, have higher in-vitro and 
in-vivo stability and longer dissociation half-lives. The standard dose for all marketed GBCAs, 
including gadobutrol and gadoterate, is 0.1 mmol/kg body weight (BW) regardless of each 
agent’s relaxivity.  
This study is designed to examine if a 75% dose of gadobutrol (0.075 mmol/kg), which has a 
high relaxivity, is noninferior to a 100% dose of gadoterate (Dotarem) (0.1 mmol/kg) for steady 
state central nervous system (CNS) imaging. 
Below is a list of documents this statistical analysis plan (SAP) is based on: 
• Protocol Amendment 1.0, dated on 26 MAR 2018 
• eCRF Final 2.0, dated on 06 Mar 2018. 
2. 
Study Objectives 
2.1 
Primary Objectives 
The primary objective of this study is to demonstrate noninferiority of gadobutrol-enhanced 
CNS imaging (at a dose of 0.075 mmol/kg BW) compared to gadoterate (0.1 mmol/kg 
BW) -enhanced CNS imaging (at a dose of 0.1 mmol/kg BW) for 3 lesion visualization 
parameters (degree of contrast enhancement, assessment of border delineation, and internal 
morphology of lesions) based on a blinded read. 
2.2 
Secondary Objectives 
The secondary objectives of this study are to: 
• Demonstrate noninferiority for number of lesions based on a blinded read 
• Evaluate confidence in diagnosis 
• Compare the 0.075 mmol/kg BW dose of gadobutrol to standard dose gadoterate for: 
• T1 (longitudinal relaxation time)-weighted (T1w) MRI image quality in a 
paired blinded comparison 
• Sensitivity/Specificity for presence of malignant disease based on a blinded 
read 
• Compare the overall contrast enhancement of gadobutrol (0.075 mmol/kg BW) to the 
standard dose of gadoterate (0.1 mmol/kg BW) for steady-state CNS imaging. 
Quantitative contrast enhancement will be performed using an exploratory Overall 
Contrast Enhancement Estimation Algorithm. 
• Assess the safety profile of the reduced dose of 0.075 mmol/kg BW of gadobutrol and 
standard dose gadoterate after IV administration. 


 
Statistical Analysis Plan 
 
 
Protocol No.: BAY No. 86-4875/ 19773 
Page: 6 of 29
 
Reference Number: RD-OI-0119 
Supplement Version: 8 
3. 
Study Design 
3.1 
Overall Design 
This study is a Phase 4, multicenter, controlled, cross-over study with corresponding blinded 
image evaluations in male and female subjects at least 18 years of age, who are referred for a 
contrast-enhanced MRI of the CNS based on a known or highly suspected lesion of the CNS. 
Subjects will undergo an unenhanced and contrast-enhanced MRI of the CNS using gadoterate 
at the standard dose of 0.1 mmol/kg BW. If the investigator does not identify an enhancing 
lesion of the CNS, then this subject will be considered a screening failure. If an enhancing 
lesion is identified, then the subject will undergo a second unenhanced and contrast-enhanced 
MRI of the CNS using gadobutrol at a dose of 0.075 mmol/kg BW. 
Safety will be assessed from the first administration of gadoterate through 24 hours after the 
second administration of gadobutrol. Adverse events (AEs) will be collected from the signing 
of informed consent through the end of the follow-up period. Serious AEs (SAEs) will be 
followed through resolution. Subjects who receive only the first MRI scan (considered 
screening failures) will be followed for SAEs only. 
Gadobutrol will be administered at the dose of 0.075 mmol/kg BW by single IV injection at a 
rate of 2 mL/sec, followed by 20-mL 0.9% saline flush at the same rate. Gadoterate will be 
administered at the approved standard dose of 0.1 mmol/kg BW by single IV injection at 
2 mL/sec, followed by 20-mL 0.9% saline flush at the same rate. The 2 injections will be 
separated by at least 24 hours, but not more than 15 days.  
During the course of the study, 2 MRIs will be obtained from each subject as follows: before 
the administration of each of the contrast agent (unenhanced MRI) consisting of steady-state 
sequences (T1w, T2 [transfersal relaxation time]-weighted [T2w], and Fluid Attenuated 
Inversion Recovery [FLAIR]), following the gadoterate injection (gadoterate-enhanced MRI) 
consisting of steady-state sequences of T1; and following the gadobutrol injection 
(gadobutrol-enhanced MRI) consisting of steady-state sequences (T1w).  
The unenhanced magnetic resonance (MR) image set, combined unenhanced and 
gadobutrol-enhanced MR image sets, and the unenhanced and combined unenhanced and 
gadoterate-enhanced MR image sets will be evaluated by 3 independent blinded readers (BRs). 
The BRs will also evaluate the gadobutrol-enhanced T1w images compared to the 
gadoterate-enhanced T1w images in a paired read for image quality.  
The final clinical diagnosis will be determined by the site investigator using all available 
clinical information up to 30 days post the first MRI. This final clinical diagnosis will be 
utilized as the standard of truth (SOT) for the blinded assessment of diagnostic performance 
(sensitivity/specificity for malignant disease).  
The safety of the subjects will be assessed by monitoring of AEs and treatment-emergent AEs 
(TEAEs).  
An overview of the schedule of study evaluations and procedures is presented in Table 3-1. 
 


 
Statistical Analysis Plan 
 
 
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Reference Number: RD-OI-0119 
Supplement Version: 8 
Table 3-1 Schedule of study events 
 
 
Study Period 1a 
 
Study Period 2a 
Final Diagnosis 
up to 30 days 
Phone Call 
 
Evaluation/Procedure 
Baselineb 
MRI 
Post  
injection 
Phone 
Contact C 
Baselinec 
MRI 
Post 
injection 
Phone 
ContactC 
 
Time Point 
Up to 72 hours 
prior to the 1st 
MRI 
Unenhanced 
Enhanced 
24 h ± 4 h 
Within  
24 h  
of the 2nd 
MRI 
Unenhanced 
Enhanced 
24 h  
(± 4 h) 
Sign informed consent 
X 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
 
 
 
Baseline findings 
X 
 
 
 
 
 
 
 
 
Referral diagnosis 
X 
 
 
 
 
 
 
 
 
Previous/concomitant  
medicationsd 
X 
 
 
X 
X 
 
 
X 
 
Weighte 
Xi 
 
 
 
Xi 
 
 
 
 
Urine pregnancy testf 
Xi 
 
 
 
 
 
 
 
 
Creatinine valueg 
X 
 
 
 
 
 
 
 
 
Gadoterate administration 
 
 
X 
 
 
 
 
 
 
Gadobutrol administration 
 
 
 
 
 
 
X 
 
 
Adverse event monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
 
Final clinical diagnosis up to  
30 days post first MRIh 
 
 
 
 
 
 
 
 
X 
Abbreviations: CKD-EPI = Chronic Kidney Disease Epidemiology Collaboration equation; eCRF = electronic Case Report Form; eGFR = estimated glomerular 
filtration rate; h = hour(s); MDRD = Modification of Diet in Renal Disease Study equation; MRI = magnetic resonance imaging; TEAE = 


 
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Reference Number: RD-OI-0119 
Supplement Version: 8 
treatment-emergent adverse event; TESAE = treatment-emergent serious adverse event. 
a A period of 24 hours up to 15 days is required between the contrast agent injections. 
b Baseline for Study Period 1 is from after signing informed consent up to 72 hours for gadoterate administration. 
c Baseline for Study Period 2 is within the 24 hours prior to administration of gadobutrol. At least 2 hours is required between the 24-hour follow-up evaluations 
from Study Period 1 and the baseline evaluations for Study Period 2. The subject will be contacted by phone after 24-hour (± 4 hours) after each contrast 
agent injection. The two MRI contrast agents will be separated by at least 24 hours, but not more than 15 days. Any TEAEs or TESAEs and/or concomitant 
medications reported during this period will be recorded in the eCRF. 
d All concomitant medication will be collected. 
e Weight will be obtained at baseline and reconfirmed prior to the second MRI. 
f Urine pregnancy test (if applicable) to be done at the site, according to the standard of the institution, and the results must be available prior to the gadoterate 
MRI.  
g Serum creatinine (eGFR value calculated using either MDRD or the CKD-EPI Creatinine Equation, 2009) derived up to 4 weeks prior to the first study MRI 
value and date obtained and method used needs to be recorded at Screening. 
h The final clinical diagnosis will be recorded by the investigator within 30 days of the first study MRI.  
i Within 1 hour of injection.  
 
 


 
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Reference Number: RD-OI-0119 
Supplement Version: 8 
3.2 
Determination of Sample Size  
The determination of the sample size was based on the primary noninferiority test for 
comparing 
the 
difference 
between 
unenhanced 
means 
and 
combined 
unenhanced/gadobutrol-enhanced means with the difference between unenhanced means and 
combined unenhanced/gadoterate-enhanced means.  
It considers all three primary efficacy visualization parameters:  
1. The contrast enhancement  
2. The border delineation  
3. The internal morphology.  
For each parameter, a noninferiority hypothesis was considered, where the comparison was 
related to a reasonable portion of the difference between gadoterate and unenhanced. The goal 
is to show that the loss in the visualization parameter (gadoterate vs gadobutrol) is lower than 
a constant times the combined gadoterate and unenhanced to unenhanced. 
In the Gadovist CNS pivotal study (study 310123) submitted to and agreed by the US Food 
and Drug Administration for the initial approval, the fixed noninferiority margin of 0.35 for the 
three visualization parameters (contrast enhancement, border delineation, internal 
morphology) for comparison of gadobutrol and gadoteridol (ProHance) was used for the 
secondary objective in that study. 
In this study, a modified noninferiority margin for the primary efficacy variables will be used, 
which is 0.2*(gadoterate – unenhanced), separately for each variable. In the concept planning 
of the study, the constant c = 0.2 was considered reasonable as this means that it would be 
shown that the loss in image quality with gadobutrol at lower dose is less than 20% of the gain 
the comparator (gadoterate) achieves over unenhanced. The rationale for the choice of c = 0.2 
is also based on the results derived from the pivotal study (study 310123) as seen in the 
following Table 3–2. The GBCAs like gadobutrol and gadoteridol behave similar in 
comparison to unenhanced within one parameter, but not across parameters. 
 
Table 3–2 Results for average reader derived from study 310123 
 
Gadobutrol - unenhanced 
Gadoteridol - unenhanced 
 
n 
mean (std) 
0.2*mean 
n 
mean (std) 
0.2*mean 
Contrast 
enhancement 
316 
1.29 (0.56) 
0.26 
315 
1.24 (0.53) 
0.25 
Border 
delineation 
316 
0.60 (0.53) 
0.12 
315 
0.56 (0.48) 
0.11 
Internal 
morphology 
316 
0.61 (0.42) 
0.12 
315 
0.58 (0.41) 
0.12 
Abbreviations: n = number; std = standard error. 
 
 


 
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Reference Number: RD-OI-0119 
Supplement Version: 8 
The mean differences of combined gadobutrol and unenhanced to unenhanced 
“(gadobutrol-unenhanced)” observed in the pivotal study 310123 for these parameters were 
used for power calculation (1.29, 0.60, 0.61).  
The related statistical hypotheses read as follows:  
• H0: (gadobutrol – unenhanced gadobutrol) – (gadoterate – unenhanced gadoterate)  
≤- 0.2*(gadoterate – unenhanced gadoterate) vs  
• H1: (gadobutrol – unenhanced gadobutrol) – (gadoterate– unenhanced gadoterate)  
> - 0.2*(gadoterate – unenhanced gadoterate).  
The study is considered successful if all 3 hypotheses related with these co-primary target 
variables can be rejected at a one-sided alpha of 0.025 or equivalently at a two-sided alpha of 
0.05. Appropriate paired t-tests will be used.  
Rejection of such a hypothesis means that it is demonstrated that gadobutrol (at reduced dose) 
preserves at least 80% of the effect gadoterate/Dotarem has compared to unenhanced images.  
Enrolling 180 subjects allows for approximately 25% nonevaluable subjects and guarantees 
90% power for border delineation. For the remaining two variables, the power will be close to 
100% with this sample size. Hence, the overall power of this study will be 90%.  
No type I error adjustment for multiple comparisons is needed because tests on all 3 variables 
must be significant to demonstrate primary efficacy. 
4. 
General Statistical Considerations 
4.1 
General Principles 
The primary efficacy analyses of the 3 primary efficacy variables (visualization) will be done 
using the average (arithmetic mean) of the values of the 3 BRs. The analysis of these variables 
and the analyses of the secondary efficacy variables will also be performed on the data from 
the 3 BRs individually. 
For border delineation, contrast enhancement, and internal morphology, there will be multiple 
values for each subject (ratings for multiple lesions). The average (arithmetic mean) of these 
ratings will be used for the primary and secondary 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. 
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 
modality 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 BRs) detect for any of the three parameters a different number of lesions in 
the unenhanced and enhanced image set, enough zeros will be included for the scores in the 
image set in which fewer lesions were detected to make the average for each modality based 
on the same number of scores. 


 
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Reference Number: RD-OI-0119 
Supplement Version: 8 
Example: A reader scores in the unenhanced image of a subject two lesions regarding internal 
morphology and three lesions in the combined unenhanced/enhanced images. Therefore, the 
subject’s total score of the reader will be divided by three for both images sets. 
For the comparison of gadobutrol to gadoterate, the zero-filled method will be used across 
contrast agents. 
Example: For gadobutrol, a reader scores in the unenhanced image of a subject two lesions 
regarding internal morphology and three lesions in the combined unenhanced/enhanced 
images. For gadoterate, a reader scores in the unenhanced image of a subject two lesions 
regarding internal morphology and five lesions in the combined unenhanced/enhanced images. 
Therefore, the subject’s total score of the reader will be divided by five for all image sets. 
Demographic variables (age, race, sex, etc.) will be summarized using frequency tables and 
descriptive statistics. 
Safety variables will be summarized using descriptive statistics and frequency tables.  
All confidence intervals (CIs) will be 2-sided, 95% intervals. 
Any statistical tests used for noninferiority will be one-sided tests using the 0.025 level of 
significance.  
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 and mean, standard deviation, minimum, 
median, and maximum will be calculated for continuous data. Frequency tables will be 
generated for categorical data. 
4.2 
Handling of Dropouts 
A subject who satisfies all eligibility criteria and discontinues study participation prior to the 
second MRI not due to an AE is defined as a “dropout” if the subject has already been submitted 
to the first study MRI. 
Subjects who fail to complete both the gadoterate and gadobutrol administration as described 
in Section 3 will not be evaluated for the full analysis set (FAS) analyses. 
Data from subjects enrolled who do not complete the study will be included in all safety 
analysis set (SAF) analyses. 
4.3 
Handling of Missing Data 
No imputations will be made for missing data resulting from early termination, missed 
evaluations, or any other unforeseen reason. 
4.4 
Handling of Nonassessable (uninterpretable) Images 
For the 3 primary visualization variables, the BRs must provide a numerical score for each 
image set; an option for uninterpretable is not available. 


 
Statistical Analysis Plan 
 
 
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Reference Number: RD-OI-0119 
Supplement Version: 8 
For evaluation of diagnoses, the readers are given the option of “not assessable,” which 
essentially means that the image was uninterpretable for diagnostic purposes. If this evaluation 
occurs for the final diagnosis, the case will be excluded from the analysis of diagnoses as no 
SOT is available. The rare instance of a blinded-read evaluation of “not assessable” for a 
diagnosis based on MRI images will be considered incorrect (not a match to final diagnosis) if 
a final diagnosis is available for that subject. 
When the BR chooses “not assessable” for diagnosis, by definition the confidence level is 1 
(not confident). 
4.5 
Interim Analyses and Data Monitoring 
No interim analyses were planned for the study. 
4.6 
Data Rules 
Not applicable. 
4.7 
Validity Review 
The validity of subjects to the FAS, the Per Protocol analysis set (PPS), and the SAF will be 
reviewed and determined before database lock. The definition for FAS, PPS, and SAF is 
provided in Section 5. Any changes to the statistical analysis prompted by the results of the 
Validity Review (or other process equivalent) will be documented in a supplement to this SAP, 
if applicable, or in the Clinical Study Report.  
5. 
Analysis Sets 
Full analysis set (FAS) 
Analyses of efficacy data will be performed using data from all subjects for whom electronic 
case report form (eCRF) entries and images are available for unenhanced MRI, combined 
unenhanced 
and 
gadobutrol-enhanced 
MRI, 
and 
combined 
unenhanced 
and 
gadoterate-enhanced MRI. This population will be the FAS. 
Per protocol set (PPS) 
Efficacy analyses will also be performed using data from those subjects from the FAS who also 
fulfill all major provisions of this protocol. This set will be the PPS. 
A subject will be excluded from the PPS for any one of the following reasons: 
1. The subject received a dose of gadobutrol that was less than 90% or greater than 110% 
of the assigned dose. 
2. The subject received a dose of gadoterate that was less than 90% or greater than 110% 
of the assigned dose. 
3. An obvious error in the MRI procedure occurred either during the gadobutrol period or 
during the gadoterate period. 
4. Pertinent images for the subject are damaged or lost. 


 
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Final decision regarding the assignment of subjects to analysis sets will be made during the 
Validity Review (see Section 4.7). 
Safety analysis set (SAF) 
The SAF will consist of all enrolled subjects (i.e., those who have signed informed consent and 
completed end of screening). Analysis of safety data will be performed using all available data 
from the SAF. 
 


 
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6. 
Statistical Methodology 
For this crossover study, the study period will be divided into 3 segments: 
• The pre-treatment period is the period after the informed consent date and before the 
first administration of study drug in the study. 
• Two treatment-emergent periods (TE periods) will be defined to attribute the AEs or 
concomitant medications to the corresponding treatment group: 
• TE period for Study Period 1 is from the first study drug administration in 
Study Period 1 to 24 ± 4 hours post-injection; 
• TE period for Study Period 2 is from the first study drug administration in 
Study Period 2 to 24 ± 4 hours post-injection. 
• The post-treatment period is the period after the last date of TE period for Treatment 
Period 2 to the date of the last study record in the clinical database or the period between 
the end of TE period for Treatment Period 1 and the start of TE period for Treatment 
Period 2. 
• The baseline value is defined as the most recent nonmissing assessment (scheduled or 
unscheduled) collected up to 72 hours prior to first administration of study drugs in the 
whole study. This will include values collected at baseline visit with regard to the 
gadoterate scan but before signing informed consent. 
6.1 
Population Characteristics 
6.1.1 
Subject disposition 
The number and percentage of total subjects in the following categories will be presented using 
SAF: 
• Enrolled subjects 
• Study drug administered in Study Period 1 
• Completed Study Period 1 
• Prematurely discontinued the Study Period 1 
• Discontinued after Study Period 1 and before Study Period 2 
• Study drug administered in Study Period 2 
• Completed Study Period 2 
• Prematurely discontinued the Study Period 2 
• Completed study (defined as that the final clinical diagnosis is obtained, up to 30 days 
post the first study MRI). 


 
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Subject validity and primary reasons for exclusions from analysis sets will be presented by 
treatment group. The sample sizes in SAF, FAS, and PPS will also be presented by site and 
treatment group.  
6.1.2 
Protocol deviations 
The number and percentage of subjects with important protocol deviations will be presented 
by treatment group and deviation category for all enrolled subjects. 
The MRI procedure-specified protocol deviations will be summarized by treatment group and 
type of deviations (scanner-related or subject-related) in the SAF. 
6.1.3 
Demographics 
Demographic and baseline characteristics will be summarized for total subjects in FAS and 
PPS, and by treatment group for SAF if applicable. Demographic data will include but not 
limited to the following: 
• Age at screening 
• Categorized age group at screening (< 45, ≥ 45 to 64, and ≥ 65 years)  
• Sex (male, female) 
• Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, and not reported) 
• Ethnicity (not Hispanic or Latino, Hispanic or Latino, not reported) 
• Baseline height (cm) 
• Baseline weight (kg) 
• Baseline body mass index (kg/m2) 
• Categorized baseline body mass index (< 25, ≥ 25 to < 30, ≥ 30 kg/m2) 
• Baseline creatinine (mg/dL) 
• Baseline estimated glomerular filtration rate (eGFR; in mL/min/1.73m2) 
The creatinine does not require collection – Investigator must determine if eGFR is 
> 60 mL/min/1.73m2. 
6.1.4 
Referral and final diagnosis 
The number and percentage of subjects in each category of the referral and final diagnosis 
will be presented for overall subjects in the FAS, SAF, and PPS.  
6.1.5 
Medical history 
Medical history will be coded using the latest version of Medical Dictionary for Regulatory 
Activities (MedDRA) during the study. Medical history will be summarized descriptively by 


 
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system organ class (SOC) and preferred term (PT) for total subjects in the SAF and total in 
FAS.  
6.1.6 
Prior and concomitant medications 
Medications taken during the study will be coded using the World Health Organization Drug 
Dictionary Enhanced and categorized as follows: 
• Prior medication: any medication that started prior to the first study drug administration, 
regardless of when it ended. 
• Concomitant medication: medication continued or newly received during the TE period 
for Study Period 1 or Study Period 2. If a subject took a medication during a specific 
TE period, this medication will be attributed to the study drug the subject received 
during this study period. One medication may be attributable to more than 1 study drug 
for an individual subject. 
• Post-treatment medication: medication continued or newly received after the TE period 
for Study Period 2, or between the TE periods for Study Period 1 and for Study Period 2, 
or after the TE period for Study Period 1 for subjects who do not have Study Period 2. 
A given medication can be classified as a prior medication, a concomitant medication, or a 
post-treatment medication; both prior and concomitant; both concomitant and post-treatment; 
or prior, concomitant, and post-treatment.  
For medications with partial start dates, a missing month will be imputed with January and a 
missing day will be imputed with 1. For medications with partial stop dates, a missing month 
will be imputed with December and a missing day will be imputed with the last day of the 
month. If a medication has a missing or partial missing start/end date or time and it cannot be 
determined whether the medication was taken before initial dosing, concomitantly, or 
post-treatment, it will be considered as prior, concomitant, and post-treatment.  
Prior medication summary (for medication that ended before the first study drug 
administration) will be presented by Anatomical Therapeutic Chemical class level 1 
(anatomical class) and class level 3 (chemical level) for total subjects, and concomitant 
medication summary will be presented by treatment group, anatomical class, and chemical 
level. Both summaries of prior and concomitant medication will be based on FAS and SAF.  
6.1.7 
Study drug dosage and administration 
The summary of drug dose and administration will be based on FAS and SAF. The actual 
volume (mL) and dose (mL/kg) of gadobutrol and gadoterate administered and injection rate 
(mL/sec) will be summarized by treatment group. The drug dose will also be presented by 
categories: < 90%, 90% to 110%, and > 110% relative to the assigned dose. 
6.2 
Efficacy 
An overview of the imaging efficacy variables is provided in Table 6–1. 


 
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Table 6–1: Overview of the imaging efficacy variables 
 
Unenhanced 
MRI 1 
Combined 
unenhanced 
and 
gadoterate-
enhanced MR 
Unenhanced 
MRI 2 
Combined 
unenhanced 
and 
gadobutrol-
enhanced 
MRI 
Paired 
gadobutrol-
enhanced 
T1w and 
gadoterate-
enhanced 
T1w MRI 
Variables 
BR 
BR 
BR 
BR 
BR 
Degree of contrast 
enhancement (lesions) 
✓ 
✓ 
✓ 
✓ 
 
Assessment of border 
delineation (lesions) 
✓ 
✓ 
✓ 
✓ 
 
Internal morphology 
(lesions) 
✓ 
✓ 
✓ 
✓ 
 
Overall contrast 
enhancement (Core Lab) 
✓ 
✓ 
✓ 
✓ 
 
Total number of lesions 
detected  
✓ 
✓ 
✓ 
✓ 
 
Malignant Disease 
 
✓ 
 
✓ 
 
Confidence in diagnosis 
 
✓ 
 
✓ 
 
Image quality 
 
 
 
 
✓ 
Abbreviations: BR = blinded reader, MRI = magnetic resonance imaging. 
6.2.1 
Primary efficacy variables 
The following 3 lesion visualization parameters scored by three independent BRs constitute the 
primary efficacy variables:  
• Degree of lesion contrast enhancement  
• Lesion Border delineation  
• Lesion Internal morphology.  
As shown in Table 6–1, the independent BRs will evaluate the 3 primary variables 
(visualization parameters) for up to the 5 largest lesions in each of the following images/image 
sets separately:  
• Unenhanced and combined unenhanced (T1w, T2w, FLAIR) and gadoterate-enhanced 
(T1w) MR image sets. 
• Unenhanced and combined unenhanced (T1w, T2w, FLAIR) and 
gadobutrol-enhanced (T1w) MR image sets. 
The 2 image sets will be evaluated separately in 2 blinded read sessions, with 2 weeks apart 
between the 2 sessions to prevent reader recall. 
For the evaluation of the degree of contrast enhancement, border delineation, and internal 
morphology, the BRs will score the lesion using the image sequence which best depicts each 
variable. The scores for multiple lesions of a subject will be handled by zero-filled average 
method as specified in Section 4.1.  


 
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6.2.1.1 
Degree of contrast enhancement 
A total of up to the 5 largest lesions will be selected and scored by the BRs.  
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 
The score will be evaluated according to Table 6–1. 
6.2.1.2 
Border delineation 
Up to 5 of the largest lesions will be selected and scored by the BRs.  
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 score will be evaluated according to Table 6–1.  
6.2.1.3 
Internal morphology 
Up to 5 of the largest lesions will be selected and scored by the BRs.  
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 score will be evaluated according to Table 6–1. 
6.2.2 
Analysis of primary efficacy variables 
Analyses of efficacy data will be performed in Full analysis analysis set and Per Protocol 
analysis set. 
The 3 primary analysis variables are derived from the 3 primary visualization parameters below 
using the following methodology: 
1. The contrast enhancement (measured on an ordinal 4-point scale) 
2. The border delineation (measured on an ordinal 4-point scale) 


 
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3. The internal morphology (measured on an ordinal 3-point scale) 
For the 3 variables, the arithmetic mean lesion score will be calculated for each subject and 
each BR based on the scores for each individual lesion in a given subject. This average will be 
the “overall average” for each subject and each BR, and this value will be used for the primary 
analysis. 
For example, BR 1 scores two lesions for subject X. Using border delineation as the example, 
he scores one lesion as a 3 and the other lesion as a 4. This reader’s average lesion border 
delineation score for subject X will be 3.5 ((3+4)/2). This process is repeated for all 3 BRs. The 
average of the 3 BR overall averages for subject X is then used for the primary analysis. 
The primary efficacy analysis is based on the data from the BRs’ evaluation of 3 visualization 
parameters, which are evaluated in unenhanced and combined unenhanced and enhanced MR 
image sets. 
A successful primary analysis is a demonstration of noninferiority for the difference between 
the improvement of combined unenhanced/gadobutrol in contrast to the unenhanced vs the 
improvement of combined unenhanced/gadoterate in contrast to the unenhanced, compared to 
a reasonable proportion (c = 0.2) of unenhanced vs combined gadoterate for the first 3 primary 
visualization parameters. 
1. The contrast enhancement (measured on an ordinal 4-point scale) 
2. The border delineation (measured on an ordinal 4-point scale) 
3. The internal morphology (measured on an ordinal 3-point scale) 
The analysis for the 3 parameters (1, 2, and 3) will be performed on the mean of the values for 
the 3 BRs (BR average). This analysis will be performed on the dataset including the subject 
average ratings for lesions. 
For each parameter, a noninferiority hypothesis will be considered, where the comparison will 
relate to a reasonable portion (c = 0.2) of the difference between combined 
unenhanced/gadoterate mean and the unenhanced. The goal is to show that the loss in the 
visualization parameter (gadoterate minus unenhanced) – (gadobutrol minus unenhanced) is 
lower than 0.2 times the difference between combined unenhanced/gadoterate and the 
unenhanced mean. “Mean” is the mean of the BR averages. 
The null and alternative hypotheses for noninferiority are: 
• H0: (gadobutrol – unenhanced gadobutrol) – (gadoterate – unenhanced gadoterate)  
≤ - 0.2*(gadoterate – unenhanced gadoterate) vs  
• H1: (gadobutrol – unenhanced gadobutrol) – (gadoterate– unenhanced gadoterate)  
> - 0.2*(gadoterate – unenhanced gadoterate).  
The expression “(gadoterate – unenhanced gadoterate)” indicates the difference between 
combined unenhanced and gadoterate-enhanced mean vs the unenhanced mean. 
The study is considered successful if all 3 hypotheses related to these co-primary target 
variables can be rejected each at a one-sided alpha of 0.025 or equivalently at a two-sided alpha 
of 0.05. Appropriate paired t-tests will be used as follows 


 
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The comparisons require calculations of zero-filled averages for each co-primary target 
variable and each subject for 
• (gadobutrol minus unenhanced gadobutrol) 
• (gadoterate minus unenhanced gadoterate)   
Then, for each subject and each co-primary target variable, a score is derived representing 
(gadobutrol minus unenhanced gadobutrol) – 0.8*(gadoterate minus unenhanced gadoterate)   
For these scores, means and standard deviations will be calculated. Appropriate t-tests will be 
applied. For demonstration of noninferiority, p-values will be calculated for the t-test of the 
working hypotheses 
• H0: (gadobutrol –unenhanced gadobutrol) – 0.8*(gadoterate – unenhanced gadoterate)  
≤ 0   
• H1: (gadobutrol–unenhanced gadobutrol) – 0.8*(gadoterate– unenhanced gadoterate)  
> 0 
One-sided p-values will be calculated and compared to a one-sided alpha of 0.025. 
No type I error adjustment for multiple comparisons is needed because tests on all 3 variables 
must be significant to demonstrate primary efficacy. 
In addition, 95% two-sided CIs for the mean difference of the gadobutrol minus unenhanced 
score and the gadoterate minus unenhanced score will be calculated. 
The other set of analysis will compare the combined enhanced and unenhanced image set to 
corresponding unenhanced image for both gadoterate and gadobutrol to demonstrate the 
superiority of the combined assessment in these 3 variables. One-sided p-values will be 
calculated and compared to a one-sided alpha of 0.025. This will be considered as a secondary 
analysis. Boxplots will be created for visualization. 
Subgroup analysis will also be performed to descriptively summarize the improvement of 
combined unenhanced and enhanced MR image set in contrast to the unenhanced in each of the 
3 primary variables (contrast enhancement, border delineation and internal morphology) by the 
field strength of the MRI device (1.5 or 3.0 Tesla) for gadoterate and gadobutrol groups. 
6.2.3 
Secondary efficacy variables 
The secondary efficacy variables will be the number of lesions identified, the evaluation of the 
detection of malignant disease and the confidence in diagnosis. The evaluation of quantitative 
parameters will be performed by General Clinical Imaging Service and image quality will be 
evaluated by the BR(s).  
The secondary efficacy variables are the: 
• Comparison of contrast enhancement utilizing an Overall Contrast Enhancement 
Estimation Algorithm; 
• Number of lesions identified (up to 10); 


 
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• Identification of benign or malignant disease; 
• Confidence in diagnosis; 
• Image quality. 
6.2.3.1 
Overall Contrast Enhancement Estimation Algorithm 
Quantitative contrast enhancement estimation will be performed using an exploratory Overall 
Contrast Enhancement Estimation Algorithm (Relative Contrast Enhancement Score, Full 
Image Contrast Enhancement Score and Dice Score). The  Dice Coefficient is 2 * the Area of 
Overlap divided by the total number of pixels in both images.  The pre-contrast and post-
contrast center of mass values will be calculated by the algorithm only for T1w images. The 
contrast enhancement will be quantified in terms of the relative difference of the centers of 
masses of ordinary histograms of the unenhanced and enhanced image sets. These results of 
the algorithm will be summarized by MRI modality using descriptive statistics and 95% CIs. 
Subgroup analysis will also be performed to descriptively summarize the estimation scores by 
the field strength of the MRI device (1.5 or 3.0 Tesla) for gadoterate and gadobutrol groups. 
Negative values of Relative and Full Image scores will be set to zero for analyses purposes.  
6.2.3.2 
Number of lesions able to be identified 
For each image set, the BR is to record the total number of lesions, up to 10. 
The number of lesions will be set to 11 for analysis purposes if > 10 lesions are reported. 
For the number of lesions detected the noninferiority of gadobutrol vs gadoterate will be 
evaluated using tests or CIs based on the t-distribution. A noninferiority margin of 0.35 will be 
used in each case. This means that a 95% 2-sided CI for the mean difference gadobutrol 
score – gadoterate score must exceed the value -0.35 for noninferiority to be achieved. 
The null and alternative hypothesis for noninferiority are: 
H0: combined unenhanced and gadobutrol MRI mean - combined unenhanced and gadoterate 
MRI mean ≤ -0.35, vs 
H1: combined unenhanced and gadobutrol MRI mean - combined unenhanced and gadoterate 
MRI mean > -0.35, 
where “mean” is the mean of the BR averages. 
6.2.3.3 
Identification of benign or malignant disease 
Up to 30 days post first MRI the site investigator will record in the eCRF his final clinical 
diagnosis, see Table 6–2 and if it confirms that the subject has malignant disease. This will 
serve as SOT for malignancy. A summary of final clinical diagnosis will be presented for total 
subjects in FAS and PPS. 
The BRs will evaluate the presence of malignant lesions for each subject for the combined 
unenhanced and gadobutrol-enhanced MR image sets, and the combined unenhanced and 
gadoterate-enhanced MR image sets separately. 


 
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The SOT will be compared to the blinded read evaluations individually and per majority of 
BRs (at least 2 out of 3 readers). 
Table 6–2: Final clinical diagnosis of CNS lesions 
• 
Meningioma 
• 
Chordomas 
• 
Anaplastic/malignant meningioma 
• 
Primary lymphoma 
• 
Glial tumor, low grade (I/II) 
• 
Dermoid/Epidermoid tumors 
• 
Glial tumor, high grade (III/IV) 
• 
Infectious disease (e.g., brain abscess, 
cisticercosis, etc.) 
• 
Glial tumor, tumor grade cannot be 
determined 
• 
Venous angiomas 
• 
Metastases 
• 
Meningeal spread of meningiomas (dural 
involvement) 
• 
Multiple sclerosis (acute and chronic) 
• 
Cerebellopontine angle tumors 
• 
Optic neuritis 
• 
Von Hippel Lindau syndrome 
• 
Meningeal disease (focal enhancement) 
• 
Hypertensive leukoencephalopathy 
• 
Pituitary adenomas (macro and micro) 
• 
Subacute/chronic ischemia 
• 
Craniopharyngiomas 
• 
Encephalitis 
• 
Tumors of the choroid plexus 
• 
Others, specify 
• 
Tumors of the pineal gland 
• 
Not assessable 
• 
Meningeal carcinomatosis 
 
• 
Oligodendrogliomas grade II 
 
• 
Oligodendrogliomas grade III 
(anaplastic/malignant) 
 
 
Abbreviations: CNS = central nervous system 
Diagnoses of the presence or absence of malignant tumors in each subject will be evaluated for 
consistency with the final diagnosis. Proportions of diagnoses consistent with the final 
diagnosis regarding malignancy will be calculated for gadobutrol and gadoterate, and a CI 
based on McNemar’s test for the difference of these proportions will be given. The 
noninferiority of gadoterate to gadobutrol will be claimed using a noninferiority margin of 10%. 
These analyses will be performed for sensitivity, specificity, and overall accuracy. 
Table 6–3 displays the components of the definitions for sensitivity, specificity, and accuracy. 


 
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Table 6–3: Components of the definitions for sensitivity, specificity, and accuracy 
Reader Response for MRI 
Final clinical diagnosis 
(Standard of truth) 
Malignant 
Not Malignant 
Malignant 
True positive (TP) 
False positive (FP) 
Not Assessable 
Not assessed positive (NAP) Not assessed negative (NAN) 
Not Malignant 
False negative (FN) 
True negative (TN) 
 
Sensitivity will be calculated as the number of subjects identified by MRI to have malignant 
lesions divided by the total number of subjects with malignant lesions according to the truth 
standard. Specificity will be calculated as the number of subjects identified by MRI to have no 
malignant lesion divided by the total number of subjects with no malignant lesion according to 
the truth standard. Accuracy will be calculated as the number of subjects correctly identified 
by MRI as having or not having malignant lesions, divided by the total number of subjects. For 
this analysis, a response of Benign will be considered as Not Malignant. When a response is 
neither benign nor malignant, then this will be considered as Not Assessable.  
Using the notation of the above table, 
Sensitivity = TP/(TP + NAP + FN);  
Specificity = TN/(TN + NAN + FP);  
Accuracy = (TP + TN)/(TP + TN + NAP + NAN + FP + FN). 
Note that these calculations consider nonassessable segments as incorrect. 
For the computation of the asymptotic CIs, McNemar’s test-based CIs for the difference of 
rates between both MRI sets, the definitions in Table 6–4 are needed. With this, the standard 
error of the difference between p2 and p1 is defined as 
(
)
(
)n
p
p
p
p
SE
p
p
1
2
2
1
2
1
1
2
−
−
+
=
−
 
Then, the 95% asymptotic CI of the difference between p2 and p1 can be computed as
(
)
(
) (
)
(
)


1
2
1
2
p
p
975
.
0
1
2
p
p
975
.
0
1
2
SE
z
p
p
;
SE
z
p
p
−
−

+
−

−
−
, 
with 
z0.975 = 1.96 
as 
the 
corresponding quantile of the standard normal distribution. 


 
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Table 6–4: Components of confidence interval 
Combined 
unenhanced/gad
oterate-
enhanced 
diagnoses agree 
with final 
diagnoses 
Combined unenhanced/gadobutrol enhanced 
diagnoses agree with final diagnoses 
 
Yes 
No 
 
Yes 
Number of subjects 
with matches to final 
diagnosis for both MRI 
sets: 
 
a 
Number of subjects 
with a match for 
gadoterate MRI set but 
not for gadobutrol MRI 
set: 
b 
Proportion of 
subjects with a 
match in 
gadoterate MRI 
set: 
p1 = (a+b)/n   
No 
Number of subjects 
with a match for 
gadobutrol MRI set but 
not for gadoterate MRI 
set: 
c 
The number of subjects 
without a match for 
either MRI set: 
 
 
d 
 
 
Proportion of subjects 
with a match in 
gadobutrol MRI set: 
p2 = (a+c)/n  
 
 
 
 
n = a+b+c+d 
Abbreviations: MRI = magnetic resonance imaging. 
 
The match to final diagnosis will be always considered regarding presence or absence of 
malignancy. 
For comparing sensitivity between modalities, the match to final clinical diagnosis refers to 
malignancy = yes, so n in Table 6–4 will be the total number of subjects with malignant final 
clinical diagnosis by the investigator (SOT). 
For comparing specificity between modalities, the match to final clinical diagnosis refers to 
malignancy = no, so n in Table 6–4 will be the total number of subjects with benign final 
clinical diagnosis by the investigator (SOT). 
For accuracy, the match to final clinical diagnosis refers to true positive (TP) and true negative 
(TN) regarding malignancy, so n will be the total number of subjects with any final clinical 
diagnosis by the investigator (SOT); this will be sum of the entries for each field of the tables 
above for sensitivity and specificity. 
These tables will be produced for each reader and for the majority reader. Majority reader is 
defined as the value of at least two out of three readers.  
Note that truth panel diagnoses of other and not assessable will be excluded from McNemar’s 
test or calculation of McNemar’s test-based CIs. 


 
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6.2.3.4 
Diagnostic confidence 
The BRs will record in the eCRF his/her confidence in diagnosis for each subject for the 
combined unenhanced and gadobutrol-enhanced MR image sets, and the combined unenhanced 
and gadoterate-enhanced MR image sets separately. 
Diagnostic confidence will be evaluated to determine the level of certainty that the BRs assign 
to a diagnosis. This is defined as the degree of confidence that the information on the images 
represents the true and complete clinical picture of a subject. The degree of confidence will be 
rated on a 4-point scale: 
1 = Not confident 
2 = Somewhat confident 
3 = Confident 
4 = Very confident 
When the BR chooses “not assessable” for diagnosis, by definition the confidence level is 1 
(not confident). 
Frequency tables for confidence responses (1-4) for subjects will be constructed for combined 
unenhanced 
and 
gadoterate-enhanced 
MRI, 
and 
combined 
unenhanced 
and 
gadobutrol-enhanced 
MRI. 
Descriptive 
statistics 
for 
the 
combined 
unenhanced/gadobutrol-enhanced MRI and the combined unenhanced/gadoterate-enhanced 
MRI will be generated. The 95% CIs for the differences based on a t-distribution will be 
generated. 
6.2.3.5 
Image quality 
The BRs will evaluate the relative image quality of the gadobutrol-enhanced T1w MR images 
and the gadoterate-enhanced T1w MR images in a third read session different from the 
2 sessions mentioned in Section 6.2.1. 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 gadobutrol and gadoterate 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 = Image R is worse 
2 = Image R is slightly worse 
3 = Image R is same 
4 = Image R is slightly better 
5 = Image R is better 


 
Statistical Analysis Plan 
 
 
Protocol No.: BAY No. 86-4875/ 19773 
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Reference Number: RD-OI-0119 
Supplement Version: 8 
After the data are unblinded, the above codes will be translated into the following scale: 
-2 = Gadobutrol image set is worse 
-1 = Gadobutrol image set is slightly worse 
0 = Image sets are the same 
1 = Gadobutrol image set is slightly better 
2 = Gadobutrol image set is better 
Frequency tables and descriptive statistics will be generated on these values and the combined 
values (Gadobutrol is better/slightly better) and (Gadobutrol is worse/slightly worse) yielding 
a 3 point scale Gadobutrol is better, same, or worse. The relative image qualities will be tested 
for equality using a Wilcoxon signed-rank test. 
6.2.4 
MRI field strengh 
Field strength used in the MRI scan (1.5 Tesla, 3.0 Tesla)  will be summarized for total subjects 
in FAS and PPS. 
6.3 
Pharmacokinetics/pharmacodynamics 
Not applicable. 
6.4 
Safety 
6.4.1 
Baseline findings 
A baseline finding is defined as any untoward medical condition in a study subject who has 
signed the informed consent form but has not received the first dose of the study drug. 
Conditions that started before signature of informed consent and for which no symptoms or 
treatment are present until the first administration of study drug (e.g., seasonal allergy without 
acute complaints) are recorded as medical/surgical history. 
Conditions (e.g., abnormal physical examination findings, symptoms, diseases, or laboratory 
test results) present between signature of informed consent and the first administration of study 
drug will be documented as baseline findings and analyzed as pretreatment AEs. 
Baseline findings will be regarded as serious if they meet the criteria used for defining SAEs 
and they will be reported on the SAE form. 
6.4.2 
Adverse events 
The AE monitoring will begin with the administration of the contrast agent in Study Period 1 
and will end after the last follow-up evaluation. Safety will be assessed using data from TEAEs. 
A TEAE is defined as any AE that increases in intensity or that is newly developed during the 
TE period for Study Period 1 or Study Period 2. If an AE starts (or increases in severity) during 
the TE period for a specific study period, this AE will be attributed to the treatment the subject 
received during the study period.  


 
Statistical Analysis Plan 
 
 
Protocol No.: BAY No. 86-4875/ 19773 
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Reference Number: RD-OI-0119 
Supplement Version: 8 
A post-treatment AE is defined as an AE that increase in severity or that is newly developed 
in post-treatment period as defined in Section 6.  
The AEs are to be coded using the current MedDRA version. 
Frequencies of AEs will be tabulated by contrast agent and the proportions of subjects 
exhibiting each AE will be displayed.  
 
6.4.2.1 
Overview of AEs 
The number and percentage of subjects experiencing AEs will be summarized. Overall 
summary tables will be provided for all AEs, TEAEs and pretreatment AEs with following 
categories: 
• Any such AEs 
• Drug-related AEs  
• AEs related to procedures required by the protocol 
• AEs by intensity (mild, moderate, severe) 
• Drug-related AEs by intensity 
• Serious AEs (SAEs) 
• Drug-related SAEs 
• SAEs related to procedures required by the protocol 
• AEs leading to discontinuation of study drug 
• SAEs leading to discontinuation of study drug 
• AEs leading to death. 
The overall summary table will also be presented on AEs of subjects only receiving gadoterate 
but not included in the SAF. 
The number and percentage of subjects with TEAEs will be summarized for the following: 
• TEAEs and treatment-emergent SAEs (TESAEs) by SOC and PT 
• Drug-related TEAEs and TESAEs by SOC and PT 
• Nonserious TEAE by SOC and PT 
• TEAEs and TESAEs resulting in discontinuation of study drug by SOC and PT 
• TEAEs and TESAEs by maximum intensity, SOC, and PT 
• Drug-related TEAEs and TESAEs by maximum intensity, SOC, and PT 
• TEAEs and TESAEs by worst outcome, SOC, and PT 
• Drug-related TEAEs and TESAEs by worst outcome, SOC, and PT 


 
Statistical Analysis Plan 
 
 
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Reference Number: RD-OI-0119 
Supplement Version: 8 
• Common TEAEs, TESAEs, drug-related TEAEs, and drug-related TESAEs with 
frequency ≥ 1% by SOC and PT.  
Tables will be sorted alphabetically by SOC and PT. 
Subject listings of all AEs as well as subset listings of AEs leading to death and AEs resulting 
in discontinuation of study drug will be created. 
6.4.3 
Other Safety Variables  
No additional safety variables will be collected. 
7. 
Document History and Changes in the Planned Statistical Analysis 
• Approval of the SAP version 3.0 dated 26 MAY 2020. 
1. Section 6 – Baseline definition has been updated and is defined as the most recent 
nonmissing assessment (scheduled or unscheduled) collected up to 72 hours prior to 
first administration of study drugs in the whole study. This will include values collected 
at baseline visit with regard to the gadoterate scan but before signing informed consent. 
2. Section 5.1 – The SAF has been updated and will consist of all enrolled subjects (i.e., 
those who have signed informed consent and completed end of screening) 
3. Section 6.1.2 Protocol deviations – The number and percentage of subjects with 
important protocol deviations presented by treatment group and deviation category for 
all enrolled subjects table was added. 
4. Section 6.2.4 MRI field strength – Field strength used in the MRI scan (1.5 Tesla, 3.0 
Tesla)  will be summarized for total subjects in FAS and PPS was added. 
5. Section 6.2.3.1 Overall Contrast Enhancement Estimation Algorithm –  Relative 
Contrast Enhancement Score, Full Image Contrast Enhancement Score and Dice Score 
were added. 
 
• Approval of the SAP version 2.0 dated 10 JUN 2019. 
The following changes have been made onto SAP version 1.0: 
1. Section 6.1.3 Demographics – A baseline characteristic summary on the number 
and percentage of subjects who have used 1.5 Tesla or 3.0 Tesla MRI device was 
added. 
2. Section 6.2.2 Primary efficacy variables – A subgroup analysis of 3 primary 
variables by the field strength of MRI device used (1.5T and 3.0T) was added. 
3. Section 6.2.3 Secondary efficacy variables – A subgroup analysis of contrast 
enhancement utilizing an Overall Contrast Enhancement Estimation Algorithm by 
the field strength of MRI device used (1.5T and 3.0T) was added. 
4. Section 6.4.2 Adverse events – This section was changed to remove the McNemar’s 
test and related CIs for incidence rates of AEs as this is not Bayer standard.  


Statistical Analysis Plan 
Protocol No.: BAY No. 86-4875/ 19773 
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Reference Number: RD-OI-0119 
Supplement Version: 8 
•
Approval of the SAP version 1.0 dated 29 AUG 2018.
8.
References 
None. 

Prot_002.pdf: 
 
 
 
Document Type: 
Protocol 
Official Title: 
LowEr Administered Dose with highEr Relaxivity: Gadovist vs 
Dotarem (LEADER 75) 
NCT Number: 
NCT03602339 
Document Date: 
26 MAR 2019 
 


Clinical Study Protocol
No. BAY No. 86-4875 / IMPACT no.19773
26 March 2019   
Version no. 2.0
Page: 1 of 60
Cover page of the integrated protocol
LowEr Administered Dose with highEr Relaxivity: Gadovist vs Dotarem (LEADER 75)
This protocol version is an integration of the following documents / sections:

Original protocol, Version 1.0, dated 23 JAN 2018

Amendment no. 1 (described in Section 15) forming integrated protocol Version 
2.0, dated 26 MAR 2019
Amendments not included in the consecutive numbering of amendments are local 
amendments not forming part of this integrated global protocol


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1.
Title page (AMENDED)
LowEr Administered Dose with highEr Relaxivity: Gadovist vs Dotarem (LEADER 75)
Test drug:
BAY No. 86-4875/ Gadobutrol / (GADOVIST)
Study purpose:
Comparison of Gadovist 75% standard dose to Dotarem at full 
standard dose
Clinical study phase:
4
Date:
26 MAR 2019
Registration:
EudraCT:  2018-000690-78 
Version no.: 2.0
Sponsor’s study no.:
IMPACT no. 19773
Sponsor:
a) Sponsor (Non-US): Bayer AG, D-51368 Leverkusen, 
Germany
b) Sponsor (US territory): Bayer HealthCare 
Pharmaceuticals Inc., 100 Bayer Boulevard, 
P.O. Box 915, Whippany NJ 07981-0915, USA
Sponsor’s medical 
expert:
MRI Special Indications & Support
Bayer HealthCare Pharmaceuticals Inc., 100 Bayer Boulevard, 
P.O. Box 915, Whippany NJ 07981-0915, USA
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable 
regulatory requirements.
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) may not be displayed. 
Hence, the appearance of product names without these symbols does not imply that these names 
are not protected.
PPD
PPD


Clinical Study Protocol 
No. BAY No. 86-4875/ IMPACT no. 19773 
26 MAR 2019 
Version no. 2 
Pagc:3ol'61 
Signature of the sponsor's medically responsible person 
The signatory agrees to the content of the final clinical study protocol as presented. 
Name: 
 
Role: 
Signature: 
 
PPD
PPD


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Signature of principal investigator
The signatory agrees to the content of the final clinical study protocol as presented.
Name:
__________________________________________                      
Affiliation: __________________________________________
Date:
Signature:
Signed copies of this signature page are stored in the sponsor’s study file and in the respective 
center’s investigator site file.
In the protocol document, this page may remain unsigned.


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2.
Synopsis
Title
LowEr Administered Dose with highEr Relaxivity: Gadovist vs Dotarem 
Acronym
LEADER 75
Clinical study phase
Phase 4
Study objective(s)
The primary objectives of this study are to demonstrate:
Noninferiority of gadobutrol (0.075 mmol/kg BW) compared to gadoterate 
(0.1 mmol/kg BW) based on a blinded read for: 

Degree of contrast enhancement 

Assessment of border delineation 

Internal morphology of lesions
The secondary objectives of this study are to:  

Demonstrate non-inferiority for number of lesions

Confidence in diagnosis

Compare the 0.075 mmol/kg BW dose of gadobutrol to standard 
dose gadoterate (Dotarem) for:
o
T1w MRI image quality in a paired comparison
o
Sensitivity/Specificity for presence of malignant disease
versus the final clinical diagnosis.

Compare the overall contrast enhancement of gadobutrol 
(0.075 mmol/kg BW) to the standard dose of gadoterate 
0.1 mmol/kg) for steady-state CNS imaging. Quantitative contrast 
enhancement will be performed using an exploratory Overall 
Contrast Enhancement Estimation Algorithm. 

Assess the safety profile of the reduced dose of 0.075 mmol/kg 
BW of gadobutrol and standard dose gadoterate after IV 
administration
Test drug(s)
gadobutrol (Gadovist®/Gadavist®) 1.0 molar
Name of active ingredient
gadobutrol
Dose(s)
0.075 mmol/kg
Route of administration
IV
Duration of treatment
single dose
Reference drug(s)
gadoterate (Dotarem®/Clariscan™) 0.5 molar
Name of active ingredient
gadoterate
Dose(s)
0.1 mmol/kg
Route of administration
IV
Duration of treatment
single dose


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Indication
Contrast-enhancement in MRI of the central nervous system (CNS) for the 
detection/visualization of areas with normal and disrupted blood brain 
barrier (BBB) and/or abnormal vascularity
Diagnosis and main criteria for 
inclusion /exclusion
Adult patients with known or highly suspected CNS pathology referred for
contrast-enhanced MRI of the CNS based on current clinical symptoms or 
on a previous imaging procedure.
Study design
Open label multi-center comparative, cross-over trial open to adult patients 
with known or highly suspected of having CNS pathology referred for 
imaging of the CNS. 
Methodology
Two CNS MRIs will be obtained for each enrolled patient:  

Unenhanced MRI consisting of steady-state sequences 
(T1-weighted, T2-weighted, and FLAIR) and gadoterate-enhanced 
MRI consisting of steady-state sequence (T1-weighted)

Unenhanced MRI consisting of steady-state sequences 
(T1-weighted, T2-weighted, and FLAIR) and gadobutrol-enhanced 
MRI consisting of steady-state sequence (T1-weighted)
The unenhanced MRI, combined unenhanced and gadoterate-enhanced 
MRI, and the unenhanced, and the combined unenhanced and gadobutrol-
enhanced MRI will be evaluated by 3 independent blinded readers for the 
primary efficacy endpoints. 
The investigator will note the referring diagnosis, and identify the size and 
location of the enhancing lesion which makes the subject eligible for study 
inclusion. The investigator will also provide the final clinical diagnosis and 
whether this represents malignant disease. The final clinical diagnosis will 
be based on all available clinical information up to 30 days after the first 
MRI.
All AEs from the signing of informed consent will be recorded. Safety will 
be assessed using data from treatment emergent adverse events (TEAEs). 
Type of control
Gadoterate-enhanced MRI
Number of patients
Total:
180 enrolled patients
Minimum per center: N/A    Maximum per center:~ 20
Primary variable(s)
The 3 primary efficacy variables (visualization parameters) are:

the degree of lesion contrast enhancement, 

assessment of lesion border delineation, and 

internal morphology of lesions
Time point/frame of 
measurement for primary 
variable(s)
The primary variable requires completion of a blinded read, done in three
sessions


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Plan for statistical analysis
Co-primary target variable(s):

Lesion contrast enhancement

Lesion border delineation

Lesion internal morphology
Up to 5 of the largest lesions will be selected and scored using a 
pre-specified scale by the blinded readers.
The related statistical hypotheses read as follows:

H0: (gadobutrol - gadoterate) ≤ -0.2*(gadoterate – unenhanced) 
vs. 
K0 H1: (gadobutrol – gadoterate) > -0.2*(gadoterate –
unenhanced)
The study is considered successful if all 3 hypotheses related to these co-
primary target variables can be rejected at a one-sided alpha of 0.025, 
which will be equivalent to a two-sided alpha of 0.05.
Rejection of such a hypothesis means that it is demonstrated that gadobutrol 
(Gadovist) at reduced dose preserves at least 80% of the effect gadoterate 
(Dotarem) as compared to unenhanced images.
Enrolling 180 subjects allows for approximately 25% of non-evaluable 
patients, and guarantees 90% power for border delineation. For the 
remaining two variables the power will be close to 100% with this sample 
size. Hence, the overall power of this study will be at least 90%.


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Table of contents
1.
Title page (AMENDED).................................................................................................... 2
Signature of the sponsor’s medically responsible person ..................................................... 3
Signature of principal investigator ......................................................................................... 4
2.
Synopsis.............................................................................................................................. 5
Table of tables......................................................................................................................... 10
Table of figures....................................................................................................................... 10
List of abbreviations and Definitions of terms .................................................................... 11
3.
Introduction ..................................................................................................................... 13
4.
Study objectives............................................................................................................... 13
4.1
Primary objectives ......................................................................................................... 13
4.2
Secondary objectives ..................................................................................................... 13
5.
Study design..................................................................................................................... 14
5.1
Design overview ............................................................................................................ 14
5.2
Primary variable(s)......................................................................................................... 15
5.3
Secondary efficacy variables ......................................................................................... 15
5.4
Justification of the design .............................................................................................. 15
5.5
End of study ................................................................................................................... 16
5.6
Primary objectives ......................................................................................................... 16
5.7
Primary completion........................................................................................................ 16
6.
Study population ............................................................................................................. 16
6.1
Eligibility ....................................................................................................................... 16
6.2
Inclusion criteria ............................................................................................................ 17
6.3
Exclusion criteria ........................................................................................................... 17
6.4
Justification of selection criteria .................................................................................... 18
6.5
Recruitment.................................................................................................................... 18
6.6
Withdrawal of patients from study ................................................................................ 19
6.6.1
Withdrawal ................................................................................................................. 19
6.6.2
Replacement ............................................................................................................... 20
6.7
Patient identification ...................................................................................................... 20
7.
Treatments ....................................................................................................................... 20
7.1
Treatments to be administered....................................................................................... 20
7.1.1
Gadobutrol.................................................................................................................. 20
7.1.2
Gadoterate treatment................................................................................................... 21
7.2
Dosage and administration............................................................................................. 21
7.3
Identity of study treatment............................................................................................. 21
7.4
Blinding.......................................................................................................................... 22


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7.5
Drug logistics and accountability................................................................................... 22
7.6
Treatment compliance.................................................................................................... 22
8.
Non-study therapy........................................................................................................... 22
8.1
Prior and concomitant therapy....................................................................................... 22
8.2
Post-study therapy.......................................................................................................... 23
9.
Procedures and variables................................................................................................ 23
9.1
Tabular schedule of evaluations..................................................................................... 23
9.2
Study periods ................................................................................................................. 26
9.2.1
Baseline study period 1............................................................................................... 26
9.2.2
Study period 1............................................................................................................. 26
9.2.3
Baseline study period 2............................................................................................... 27
9.2.4
Study period 2............................................................................................................. 27
9.2.5
Post-Injection phone contact....................................................................................... 27
9.2.6
Final clinical diagnosis ............................................................................................... 28
10. Procedures and variables................................................................................................ 28
10.1
Population characteristics .............................................................................................. 28
10.1.1
Demographic............................................................................................................... 28
10.1.2
Medical history........................................................................................................... 29
10.1.3
Prior and concomitant medications ............................................................................ 29
10.2
Efficacy.......................................................................................................................... 29
10.2.1
MRI procedures .......................................................................................................... 29
10.3
Pharmacokinetics ........................................................................................................... 34
10.4
Safety ............................................................................................................................. 34
10.4.1
Adverse events............................................................................................................ 34
10.5
Prospective blinded image evaluation and centralized procedures................................ 39
10.5.1
Image handling and preparation ................................................................................. 39
10.5.2
Blinded reading evaluations ....................................................................................... 40
10.5.3
Technical prerequisites for blinded readings.............................................................. 41
10.5.4
Randomization of image material............................................................................... 42
10.6
Appropriateness of procedures and measurements........................................................ 43
11. Statistical methods and determination of sample size ................................................. 43
11.1
General considerations................................................................................................... 43
11.2
Statistical and analytical plans....................................................................................... 43
11.2.1
General considerations................................................................................................ 43
11.3
Analysis sets................................................................................................................... 44
11.3.1
Definition of efficacy analysis set .............................................................................. 44
11.4
Variables and planned statistical analyses ..................................................................... 44
11.4.1
Primary efficacy variables.......................................................................................... 44
11.4.2
Secondary efficacy variables...................................................................................... 46
11.5
Determination of sample size......................................................................................... 47
12. Data handling and quality assurance ............................................................................ 48
12.1
Data recording................................................................................................................ 48


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12.2
Monitoring ..................................................................................................................... 49
12.3
Data processing.............................................................................................................. 50
12.4
Missing data................................................................................................................... 50
12.5
Audit and inspection ...................................................................................................... 50
12.6
Archiving ....................................................................................................................... 51
13. Ethical and legal aspects................................................................................................. 51
13.1
Investigator(s) and other study personnel...................................................................... 51
13.2
Funding and financial disclosure ................................................................................... 51
13.3
Ethical and legal conduct of the study........................................................................... 52
13.4
Patient information and consent..................................................................................... 52
13.5
Publication policy and use of data ................................................................................. 53
13.6
Compensation for health damage of patients / insurance .............................................. 54
13.7
Confidentiality ............................................................................................................... 54
14. Reference list.................................................................................................................... 54
15. Protocol amendments...................................................................................................... 55
15.1
Amendment 1 — 26 MAR 2019.................................................................................... 55
15.1.1
Overview of changes to the study............................................................................... 55
15.1.2
Modification 1:  Section 10.2.1.1  MRI equipment.................................................... 56
15.1.3
Modification 2:  Section 10.2.1.2. Pulse Sequences................................................... 56
15.1.4
Modification 3: Section 10.2.1.2.1  Sequence parameters for brain imaging ............ 56
15.1.5
Modification 4: Section 10.2.1.6.1  Quantitative contrast enhancement estimation.. 57
15.1.6
Modification 5:  Section 11.4.2.4   Confidence in diagnosis...................................... 57
15.1.7
Modification 6:  Section 11.4.2.6  Analysis of safety variables................................. 58
16. Appendices ....................................................................................................................... 58
Table of tables
Table 9-1:  Schedule of Study Events ...................................................................................... 24
Table 10-1:  Referral Diagnosis of CNS Lesions..................................................................... 28
Table 10-2:   Orientation parallel to the planum sphenoidale (only for axial) — AMENDED30
Table 10-3:  Overview of the imaging efficacy variables........................................................ 31
Table of figures
Figure 7-1:  Structural Formula of Gadobutrol ........................................................................ 20


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List of abbreviations and Definitions of terms
AE
adverse event
ADR
adverse drug reaction
BBB
blood brain barrier
BR
blinded reader
BW
body weight
CNR
contrast to noise ratio
CNS
central nervous system
CRA
clinical research assistant/associate
CRO
clinical research organization
CSF 
cerebrospinal fluid
DICOM
digital images and communications in medicine
GBCA
gadolinium-based contrast agent
GCIS
General Clinical Imaging Service 
ECCM
extracellular contrast medium/media
ECG
electrocardiogram
eCRF
electronic case report form
EudraCT
EU data repository for clinical trials
FAS
full analysis set
FDA 
Food and Drug Administration
FLAIR
Fluid Attenuated Inversion Recovery
FSE
fast spin echo
GCP
Good clinical practice
Gd/Gd3+
gadolinium
GFR
glomerular filtration rate 
GMP
Good manufacturing practice
HIPAA
Health Insurance Portability and Accountability Act 
IB
Investigator’s Brochure
ICH
International Conference on Harmonization
IEC
independent ethics committee
IND
Investigational New Drug
Inv
investigator
IRB
institutional review board
ITF
investigator's trial file 
IV
intravenous
IVRS  
Interactive Voice Response System 
MedDRA
Medical Dictionary for Regulatory Activities
MR
magnetic resonance
MRI
magnetic resonance imaging
NFD
Nephrogenic Fibrosing Dermopathy 
nos.
numbers


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NSF
Nephrogenic Systemic Fibrosis
PID
patient identification number
PPS
per protocol analysis set
SAE
serious adverse event
SDMB
study data management book
SH
sponsor’s formulation code numbering system
SI
signal intensity
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event
T1
longitudinal relaxation time
T1w
T1-weighted
T2
transversal relaxation time
T2w
T2-weighted
TMF
trial master file
WHODD
World Health Organization Drug Dictionary


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3.
Introduction
The constant evolution of magnetic resonance (MR) systems with faster sequences, functional 
imaging, and multichannel technology necessitates a contrast agent with the potential to 
benefit from these technical advances. 
Gadobutrol (Gadovist) was first developed for the indication “contrast enhancement in cranial 
and spinal MRI” in doses of up to 0.3 mmol/kg BW. 
First approved in Switzerland in 1998, gadobutrol has since been approved in more than 
100 countries worldwide (including the European Union countries, USA, Japan, Canada, 
Australia, South Africa, Mexico, New Zealand, Turkey, and several Eastern European and 
Asian countries). In addition, gadobutrol has proven to be an effective contrast medium for all 
of its approved indications (CNS, MR angiography, liver and kidney, other body regions) and 
has exhibited an excellent safety profile, comparable to that of other marketed extracellular 
gadolinium based contrast agents.
The ideal extracellular gadolinium-based contrast agent (GBCA) for MRI would have a 
favorable safety profile and a low risk of potential long-term deposition within normal tissue. 
In this regard, macrocyclic agents GBCA (e.g. gadobutrol, gadoteridol, or gadoterate 
meglumine) that have higher in-vitro and in-vivo stability and longer dissociation half-lives 
are reasonable alternatives. The standard dose for all marketed GBCAs, including gadobutrol 
and gadoterate, is 0.1 mmol/kg BW regardless of each agent’s relaxivity.
This study is designed to examine if a 75 percent dose of gadobutrol (0.075 mmol/kg), which 
has a high relaxivity, is noninferior to a 100% dose of gadoterate (Dotarem) (0.1 mmol/kg) for 
steady state CNS imaging. 
4.
Study objectives
4.1
Primary objectives
The primary objective of this study is to demonstrate noninferiority of gadobutrol-enhanced 
CNS imaging (at a dose of 0.075 mmol/kg) compared to gadoterate (0.1 mmol/kg BW) -
enhanced CNS imaging (at a dose of 0.1 mmol/kg) for 3 lesion visualization parameters 
(degree of contrast enhancement, assessment of border delineation, and internal morphology
of lesions) based on a blinded read.
4.2
Secondary objectives
The secondary objectives of this study are to:

Demonstrate noninferiority for number of lesions based on a blinded read

Confidence in diagnosis

Compare the 0.075 mmol/kg BW dose of gadobutrol to standard dose gadoterate for:
o
T1w MRI image quality in a paired blinded comparison


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o
Sensitivity/Specificity for presence of malignant disease based on a blinded read

Compare the overall contrast enhancement of gadobutrol (0.075 mmol/kg BW) to the 
standard dose of gadoterate (0.1 mmol/kg) for steady-state CNS imaging. Quantitative 
contrast enhancement will be performed using an exploratory Overall Contrast 
Enhancement Estimation Algorithm.

Assess the safety profile of the reduced dose of 0.075 mmol/kg BW of gadobutrol and 
standard dose gadoterate after intravenous (IV) administration.
5.
Study design
5.1
Design overview
This study is a Phase 4, multicenter, controlled, cross-over study with corresponding blinded 
image evaluations in male and female patients at least 18 years of age, who are referred for a 
contrast-enhanced MRI of the CNS based on a known or highly suspected lesion of the CNS. 
Patients will undergo an unenhanced and contrast-enhanced MRI of the CNS using gadoterate 
at the standard dose of 0.1 mmol/kg BW. If the investigator does not identify an enhancing 
lesion of the CNS, then this patient will be considered a screening failure. If an enhancing 
lesion is identified, then the patient will undergo a second unenhanced and contrast-enhanced 
MRI of the CNS using gadobutrol at a dose of 0.075 mmol/kg BW. 
Safety will be assessed from the first administration of gadoterate through 24 hours after the 
second administration of gadobutrol. Adverse events will be collected from the signing of 
informed consent through the end of the follow-up period. Serious adverse events (SAEs) will 
be followed through resolution. Patients who receive only the first MRI scan (considered 
screening failures) will be followed for SAEs only. 
Gadobutrol will be administered at the dose of 0.075 mmol/kg body weight by single IV 
injection at a rate of 2 mL/sec, followed by 20-mL 0.9% saline flush at the same rate. 
Gadoterate will be administered at the approved standard dose of 0.1 mmol/kg body weight by 
single IV injection at 2 mL/sec, followed by 20-mL 0.9% saline flush at the same rate. 
The 2 injections will be separated by at least 24 hours, but not more than 15 days. 
During the course of the study, 2 MRIs will be obtained from each patient as follows:  before 
the administration of each of the contrast agent (unenhanced MRI) consisting of steady-state 
sequences (T1w, T2w, and FLAIR), following the gadoterate injection (gadoterate-enhanced 
MRI) consisting of steady-state sequences T1; and following the gadobutrol injection 
(gadobutrol-enhanced MRI) consisting of steady-state sequences (T1w).
The unenhanced MR image set, combined unenhanced and gadobutrol-enhanced MR image 
sets, and the unenhanced and combined unenhanced and gadoterate-enhanced MR image sets 
will be evaluated by 3 independent blinded readers. The blinded readers will also evaluate the 


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gadobutrol-enhanced T1w images compared to the gadoterate-enhanced T1w images in a 
paired read for image quality. 
The final clinical diagnosis will be determined by the site investigator using all available 
clinical information up to 30 days post the first MRI. This final clinical diagnosis will be 
utilized as the standard of truth for the blinded assessment of diagnostic performance 
(sensitivity/specificity for malignant disease).
The safety of the patients will be assessed by monitoring of adverse events and treatment 
emergent adverse events (TEAEs). 
5.2
Primary variable(s)
The 3 primary efficacy variables will be lesion visualization parameters based on a blinded 
read (see Section 10.2.1.5 for details):  

Degree of lesion contrast enhancement

Lesion border delineation

Lesion internal morphology
5.3
Secondary efficacy variables
The secondary efficacy variables are the:

Number of lesions identified (up to 10) based on a blinded read

Identification of benign or malignant disease based on blinded read

Confidence in diagnosis based on a blinded read

Image quality based on a blinded read

Contrast enhancement utilizing an exploratory Overall Contrast Enhancement 
Estimation Algorithm.
5.4
Justification of the design
Gadoterate is an approved macrocyclic contrast agent for steady-state CNS imaging. It has the 
lowest relaxivity among all approved gadolinium contrast agents and was therefore chosen as 
the comparator. Gadoterate belongs to the same chemical class as gadobutrol, which is also a 
macrocyclic contrast agent. Macrocyclic contrast agents may be considered preferable to 
linear agents in certain situations, for example, in light of Nephrogenic Systemic Fibrosis 
(NSF), which has been rarely observed in renally impaired patients who received multiple 
and/or high doses of primarily linear GBCAs, and in the accumulation of gadolinium in 
tissues, also thought to occur to a lesser extent with macrocyclic agents. In addition, as both 
of these conditions appear to be dose-related, the lowest dose of gadolinium is recommended. 


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The purpose of this study is to demonstrate that the higher relaxivity of gadobutrol compared 
to gadoterate will permit a dose reduction by 25% for gadobutrol and still provide noninferior 
efficacy to a full dose of gadoterate.
The patient population for this study will be those with known or highly suspected lesions of 
the CNS referred for a contrast-enhanced MRI of the CNS.
The multicenter design is used to gain a wide range of experience and to reduce bias. 
A prospective planned blinded image evaluation by independent readers will be performed in 
order to facilitate an independent evaluation and permit randomization of the image 
evaluation. The blinded readers will be experienced radiologists who will not have been 
involved in the clinical portion of the study and are considered independent from the study. 
Selecting experienced readers and performing adequate and extensive reader training prior to 
the evaluation of the images is expected to sufficiently address standardization issues and to 
minimize inter-reader variability. All quantitative measurements and qualitative evaluations of 
the MRI data will be performed in a core laboratory in a standardized fashion using validated 
software. 
5.5
End of study
The end of the patients’ participation in the study will be reached at the last patient last visit, 
defined as when the final clinical diagnosis is obtained for the last patient enrolled. The end of 
the study will be considered the end of the blinded read, approximately 30 days after the 
LPLV. 
5.6
Primary objectives
The primary objective of this study is to demonstrate noninferiority of gadobutrol-enhanced 
CNS imaging (at a three-quarter dose of 0.075 mmol/kg) compared to gadoterate -enhanced 
CNS imaging (at a full dose of 0.1 mmol/kg) for 3 lesion visualization parameters (degree of 
enhancement, border delineation, internal morphology) based on a blinded read.
5.7
Primary completion
The primary completion event for this study is completion of the blinded read for all patients.
The primary completion date for this study according to the FDA Amendment Act is specified 
in a separate document (not part of this study protocol).
6.
Study population
6.1
Eligibility
Male and female patients (≥ 18 years of age) of any ethnic group, who meet the inclusion 
criteria and none of the exclusion criteria, and who give written informed consent will be 
eligible for enrollment into the study.


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6.2
Inclusion criteria
To be included in the study a patient must:
1. Have known or highly suspected CNS pathology referred for contrast-enhanced MRI of 
the CNS based on current clinical symptoms or on a previous procedure.
2. If female and of child bearing potential, have a negative urine pregnancy test within 
1 hour prior to the administration of gadoterate (the first MRI).
3. Have an estimated glomerular filtration rate (eGFR) value ≥ 60 mL/min/1.73m2 derived 
from a serum creatinine result within four (4) weeks prior to the first study MRI.
4. Be fully informed about the study, including provisions of the Health Insurance Portability 
and Accountability Act (HIPAA) as applicable, and consent to participate
6.3
Exclusion criteria
A patient will be excluded from the study if he/she:
1. Has no enhancing lesion visible on the gadoterate-enhanced MRI scan.
2. Is pregnant or breast feeding
3. Has received any investigational product or has participated in any other clinical trial 
within 30 days prior to enrolling in this study
4. Has any contraindication to the MRI examinations or the use of gadolinium-containing 
contrast agents
5. Has a history of severe allergic or anaphylactic/anaphylactoid reaction to any allergen 
including drugs and contrast agents
6. Has received any gadolinium-based contrast agent < 24 hours prior to the study MRIs, or 
is scheduled to receive any contrast agent within 24 hours after the second study MRI
7. Is considered clinically unstable
8. Has severe cardiovascular disease (eg, known long QT syndrome, acute myocardial 
infarction [< 14 days], unstable angina, congestive heart failure New York Heart 
Association class IV or acute stroke (< 48 hours) 
9. Is expected or is scheduled to have a change in any treatment or procedure between the 
gadoterate and gadobutrol MRIs that may alter image comparability
10. Is scheduled or is likely to require a biopsy or any interventional therapeutic procedure 
from the first study MRI up to 24 hours after the second study MRI


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6.4
Justification of selection criteria
The following is the FDA class warning for gadolinium-based contrast agents:
WARNING: NEPHROGENIC SYSTEMIC FIBROSIS
Gadolinium-based contrast agents increase the risk for Nephrogenic Systemic Fibrosis (NSF) in patients with:
acute or chronic severe renal insufficiency (glomerular filtration rate < 30 mL/min/1.73m2), or acute renal 
insufficiency of any severity due to hepato-renal syndrome or in the perioperative liver transplantation period.
In these patients, avoid use of gadolinium-based contrast agents unless the diagnostic information is essential and 
not available with non-contrast-enhanced MRI. NSF may result in fatal or debilitating systemic fibrosis affecting 
the skin, muscle and internal organs. Screen all patients for renal dysfunction by obtaining a history and/or 
laboratory tests. 
When administering a gadolinium-based contrast agent, do not exceed the recommended dose and allow a 
sufficient period of time for elimination of the agent from the body prior to any readministration.
It must be ensured that each patient is suitable for the technical requirements of a MRI 
examination, and especially that each patient has no metallic implants that would be affected 
by magnetic fields (Exclusion criterion 4). 
In order to prevent interference with the investigational product and to ensure that the cause 
of TEAEs can be easily traced, no other contrast agents are to be administered (Exclusion 
criteria 6 and 7). 
The physical condition of each patient must be stable and must not be significantly influenced 
by other therapies so that the patient does not have the potential for demonstrating unrelated
TEAEs after contrast agent administration (Exclusion criterion 6). 
To ensure that the patient’s clinical picture is the same during gadobutrol-enhanced MRI and 
the gadoterate-enhanced MRI and there is no change due to external influences, no local or 
systemic therapy or biopsy/interventional therapeutic procedure should occur between the 
2 MRI examinations (Exclusion criteria 10 and 11). 
6.5
Recruitment
Patient recruitment will be from the patient populations at the investigative study centers who 
are referred for a contrast-enhanced CNS MRI. 


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6.6
Withdrawal of patients from study
6.6.1
Withdrawal
Withdrawal criteria
Patients must be withdrawn from the study if any of the following occurs:

At their own request or at the request of their legally acceptable representative. At any 
time during the study and without giving reasons, a patient may decline to participate 
further. The patient will not suffer any disadvantage as a result.
Patients may be withdrawn from the study if any of the following occurs:

If, in the investigator's opinion, continuation of the study would be harmful to the 
patient's well-being

At the specific request of the sponsor and in liaison with the investigator (e.g. obvious
non-compliance, safety concerns).
Depending on the time point of withdrawal, a withdrawn patient is referred to as either 
“screening failure” or “dropout” as specified in the following:
Screening failure
A patient who for any reason (e.g. failure to satisfy the inclusion/exclusion criteria), 
terminates the study before the time point used for the definition of “dropout” (see below) is 
regarded a “screening failure”. 
Dropout
A patient who satisfies all eligibility criteria, and discontinues study participation prior to the 
second MRI not due to an adverse event is defined as a “dropout” if the patient has already 
been submitted to the first study MRI.
General procedures
In all cases, the reason for withdrawal must be recorded in the CRF and in the patient's 
medical records. 
The patient may object to the generation and processing of post-withdrawal data as specified 
in Section 13.4.
Any patient removed from the trial will remain under medical supervision until discharge or 
transfer is medically acceptable.
Details for the premature termination of the study as a whole (or components thereof) are 
provided in Section 13.


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6.6.2
Replacement
Patients who have undergone a gadoterate-enhanced MRI but have no enhancing lesions 
identified will not be enrolled. Recruitment will, therefore, continue until at least 180 patients 
have completed both the gadoterate and gadobutrol studies.
6.7
Patient identification
The patient number is a 9-digit number consisting of:
Digits 1 to 5 = Unique center number
Digits 6 to 9 = Current patient number within the center
After patients have signed an informed consent form, they will be identified by a unique 
9 digit patient identification number (PID). The PID will identify the patient throughout the 
study. The first 2 digits represent the country number, the second 3 digits represent the center 
number, and the third 4 digits represent a sequential number in the order in which the patient 
signed the informed consent at the study center. For example, the third patient 
enrolled 
at center number 
 in the 
 (14) would be PID 
7.
Treatments
7.1
Treatments to be administered
7.1.1
Gadobutrol
Gadobutrol injection (Gadovist/Gadavist) is the gadolinium complex of 10-[2,3-dihydroxy-1-
(hydroxymethyl) propyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetate (see Figure 7-1). 
This is a neutral chelated, racemic complex of the rare earth element gadolinium (Gd3+). 
Gadobutrol injection is a white to off-white, highly water soluble substance that is an 
injectable contrast medium for MRI. Gadobutrol is to be administered by IV injection. 
Figure 7-1:  Structural Formula of Gadobutrol
Molecular weight:  604.72 g/mol
N
N
N
N
OH
OH
H H
OH
Gd
O-
-O
-O
O
O
O
3+
(Racemate)
PPD
PPD
PPD
PPD


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Each milliliter of 1.0 molar gadobutrol injection (SH L 562 BB) contains 604.72 mg of pure 
gadobutrol, 0.513 mg calcium sodium butrol, 1.211 mg tromethamine, 0.1N hydrochloric acid 
and water for injection. Gadobutrol injection contains no antimicrobial preservative. For a 
description of the product characteristics, including pertinent physicochemical data, see the 
Investigator’s Brochure. 
7.1.2 Gadoterate treatment
The comparator contrast agent is gadoterate (Dotarem®/ Clariscan™), which is approved for 
steady-state CNS imaging. (See www.guerbet.com for Dotarem package insert, GE 
Healthcare for Clariscan.)
7.2
Dosage and administration
Patients will receive a single dose of gadoterate at the approved dose, 0.1 mmol/kg BW
(± 10 percent), via IV bolus administration using a power injector via a peripheral vein (the 
antecubital vein is preferred). Gadoterate will be injected at a rate of 2 mL/second followed by 
a 20-mL 0.9% saline flush at the same rate. If the patient is eligible for inclusion in the study, 
the patient will undergo a second contrast-enhanced MRI using a single dose of gadobutrol 
0.075 mmol/kg BW via IV bolus administration using a power injector via a peripheral vein 
(the antecubital vein is preferred). Gadobutrol will be injected at a rate of 2 mL/second 
followed by a 20-mL 0.9% saline flush at the same rate. 
The administration of gadoterate and gadobutrol is not randomized. During the 24-hour 
follow-up period after the gadoterate injection and during the 24-hour follow-up period after 
the gadobutrol injection, no other contrast agent should be given. 
7.3
Identity of study treatment
Marketed drugs will be used for this study. If required at country level, the study drugs will be 
labeled according to the requirements of local law and legislation. Label text will be approved 
according to the sponsor’s agreed procedures, and a copy of the labels will be made available 
to the study site upon request.
A complete record of batch numbers and expiry dates of all study treatment as well as the 
labels will be maintained in the sponsor’s study file.


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7.4
Blinding
The study is formally unblinded, however, all primary and most secondary efficacy endpoints 
(except for the open-label site investigator assessments) are blinded. 
For the off-site blinded read, study images for each subject will be reviewed both unpaired 
and paired. The gadoterate and gadobutrol image sets from the same patient will be 
randomized. For the paired reading, the gadoterate and gadobutrol images will be shown
randomly on either the right or left monitor.   
Three experienced radiologists who are not involved with the conduct of the study, the 
evaluation of local study images at the site, and/or the recruitment of patients will be selected 
to perform the independent blinded image evaluations. Each blinded reading session will have 
sufficient separation (at least 2 weeks) between the unenhanced and combined unenhanced 
and enhanced MRI for each contrast agent to minimize recall bias (see Section 11.4). The 
images used for blinded evaluation sessions will not contain any information regarding the 
patient’s privacy or clinical data. Information on study center, scanner manufacturer, or 
imaging times will not be provided to the blinded reviewers. 
7.5
Drug logistics and accountability
The investigator will use the study drug only within the framework of this clinical study and 
in accordance with this study protocol. A record of the volume received will be recorded in 
the patients’ eCRFs. Receipt and return of the study drugs must be properly documented on 
the forms provided by the sponsor.
7.6
Treatment compliance
The study drugs are administered by study center personnel who will record:

Location of injection  

Study drug start date and time

Study drug volume and rate of injection  
The injection volume and rate of injection of the saline flush will be recorded in the eCRF.
8.
Non-study therapy
8.1
Prior and concomitant therapy
Patients are not to receive any contrast agent within 24 hours prior to the first study MRI or 
24 hours after the second study MRI. Patients may receive other concomitant medications, 
including sedation for the MRI examination, during the study. A patient’s current medication 
regimen and/or any additional medication taken from baseline up to 24 hours after the second 
study MRI will be recorded in the eCRF. 


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8.2
Post-study therapy
Not applicable as this is a diagnostic-imaging study.
9.
Procedures and variables
9.1
Tabular schedule of evaluations
Table 9-1 displays the schedule of evaluations and procedures for the study.


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Table 9-1:  Schedule of Study Events
Study Period 1a
Study Period 2a
Final Diagnosis 
up to 30 days 
Phone call
Evaluation/Procedure
Baselineb
MRI
Post 
Injection
Phone 
Contactc
Baselinec
MRI
Post 
Injection
Phone 
Contactc
Time Point
Up to 72 hours 
prior to the 
1st MRI
Unenhanced
Enhanced
24h±4h
Within
24 h
of the 
2nd MRI
Unenhanced
Enhanced
24h 
(±4 h)
Sign informed consent
X
Demographic data
X
Medical/surgical history
X
Baseline findings
X
Referral diagnosis
X
Previous/concomitant
medicationsd
X
X
X
X
Weight e
X i
X i
Urine pregnancy test f
X i
Creatinine valueg
X
Gadoterate administration
X
Gadobutrol administration
X
Adverse event monitoring
X
X
X
X
X
X
X
X
Final clinical diagnosis up to 
30 day post first MRIh
X


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Abbreviations: h = hour(s); immed = immediately; inj = injection; min = minutes
Notes;
a A period of 24 h up to 15 days is required between the contrast agent injections;
b Baseline for study period 1 is from after signing informed consent up to 72 hours for gadoterate administration; 
c Baseline for study period 2 is within the 24 h prior to administration of gadobutrol. At least 2 h is required between the 24-h follow-up evaluations from study period 1 and the baseline 
evaluations for study period 2. The patient will be contacted by phone after 24-hour (± 4 hours) after each contrast agent injection. The two MRI contrast agents will be separated by at least 
24 hours, but not more than 15 days. Any TEAEs or TESAEs and/or concomitant medications reported during this period will be recorded in the eCRF.
d All concomitant medication will be collected 
e Weight will be obtained at baseline and reconfirmed prior to the second MRI
f Urine pregnancy test (if applicable) to be done at the site, according to the standard of the institution, and the results must be available prior to the gadoterate MRI.
g Serum creatinine (eGFR value calculated using either MDRD or the CKD-EPI Creatinine Equation, 2009) derived up to 4 weeks prior to the first study MRI value and date obtained and 
method used needs to be recorded at Screening.
h The final clinical diagnosis will be recorded by the investigator within 30 days of the first study MRI. 
i Within 1h of injection


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9.2
Study periods
9.2.1
Baseline study period 1
Baseline is the up to 72 hour period from signing informed consent to administration of 
gadoterate (including saline flush). 
Prior to administration of gadoterate the following will be performed: placement of IV injection 
line, urine pregnancy test (in women of child bearing potential the date and time of the pregnancy 
test sample and the result of the pregnancy test will be recorded in the eCRF). Results of the 
pregnancy test must be negative prior to the administration of any contrast agent.
The IV injection line will consist of a large bore indwelling catheter (at least 18 gauge) preferably
placed in an antecubital vein. The location of the IV injection line must be documented in the 
eCRF. 
9.2.2 Study period 1
The administration of gadoterate is study period 1 and the administration of the gadobutrol is 
study period 2. 
The following procedures will be performed during study period 1:
1. An unenhanced MRI of the brain will be performed according to the standards of the 
institution. 
2. The appropriate volume corresponding to 0.1 mmol/kg of gadoterate will be administered 
IV as a bolus injection at the rate of 2 mL/sec using a power injector via a peripheral vein 
(the antecubital vein is preferred) followed by a 20-mL 0.9% saline flush using a power 
injector at the same flow rate. The dose and volume of the contrast agent will be recorded. 
3. AE monitoring will begin at baseline. All TEAEs will be monitored for 24 hours after the 
administration of each contrast agent. However, if no enhancing lesion is identified in the first 
imaging study, the patient will not be included in the safety database and only SAEs for that 
patient would be reported. 
4. Conventional steady-state contrast-enhanced imaging with a T1w sequence according to 
the parameters listed in Section 10.2.1.2 will start 4 to 10 minutes following the injection of 
the contrast agent. 
5. The patient will be asked about his/her physical condition. Any clinically significant changes 
in the patient's physical condition from the baseline values are to be recorded in the eCRF, 
and the TEAE section is to be completed accordingly. 


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According to the internal clock of the MR device, the date and start time of the first MR 
sequence, date and start time of the contrast injection and the end time of the complete MR 
examination will be recorded in the eCRF. Any deviation from the specified MRI procedures and 
the reason for it (scanner-related problem or patient-related problem) will be recorded in the 
eCRF. 
9.2.3 Baseline study period 2
Any changes in concomitant diseases and concomitant medication will be recorded in the eCRF. 
The IV injection line will consist of a large bore indwelling catheter (at least 18 gauge) preferably 
placed in an antecubital vein. The location of the IV injection line must be documented in the 
eCRF. 
9.2.4 Study period 2
The following procedures will be performed:
1. An unenhanced MRI will be performed exactly as done in Study Period 1. 
2. The appropriate volume of 75% of the standard gadobutrol dose (0.075 mmol/kg BW) will be 
administered IV as a bolus injection at the rate of 2 mL/sec using a power injector via a 
peripheral vein (the antecubital vein is preferred) followed by a 20-mL 0.9% saline flush 
using a power injector at the same flow rate. The dose and volume of the contrast agent will 
be recorded. 
3. Conventional steady-state contrast-enhanced imaging with a T1w sequence according to the 
parameters listed in Section 10.2.1.2 will start 4 to 10 minutes following the injection of the 
contrast agent.
4. The patient will be asked about his/her physical condition. Any clinically significant changes 
in the patient's physical condition from the baseline values are to be recorded in the eCRF, 
and the TEAE section is to be completed accordingly.
The date and start time of the first MR sequence, date and start time of the contrast injection and 
the end time of the complete MR examination will be recorded in the eCRF. Any deviation from 
the specified MRI procedures and the reason for it (scanner-related problem or patient-related 
problem) will be recorded in the eCRF. 
9.2.5 Post-Injection phone contact
The patient must be contacted by phone after 24-hour (± 4 hours) after each contrast injection. 
The two MRI contrast agents will be separated by at least 24 hours, but not more than 15 days. 


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Any TEAEs or TESAEs and/or concomitant medications reported during this period will be 
recorded in the eCRF. 
The end of Study Period 2 is after the 24 hour post injection AE follow-up phone call.
9.2.6 Final clinical diagnosis
The final clinical diagnosis and whether this represents malignant disease will be determined by 
the investigator using all available clinical information available up to 30 days post-first MRI. 
10. Procedures and variables
10.1
Population characteristics
Male and female patients of any ethnic group, who meet the inclusion criteria and none of the 
exclusion criteria, will be eligible for enrollment into the study.
10.1.1
Demographic
Demographic data (year of birth, age, sex, ethnic group), height, weight, baseline findings, and 
the suspected or known referral diagnosis according to Table 10-1 will be obtained at baseline.
Table 10-1:  Referral Diagnosis of CNS Lesions

Meningioma 

Anaplastic/malignant meningioma

Glial tumor, low grade (I/II)

Glial tumor, high grade (III/IV)

Glial tumor, tumor grade cannot be determined 

Metastases

Multiple sclerosis (acute and chronic)

Optic neuritis

Meningeal disease (focal enhancement)

Pituitary adenomas (macro and micro)

Craniopharyngiomas

Tumors of the choroidal plexus

Tumors of the pineal gland

Meningeal carcinomatosis

Oligodendrogliomas grade II

Oligodendrogliomas grade III 
(anaplastic/malignant)

Chordomas

Primary lymphoma

Dermoid/Epidermoid tumors

Infectious disease (eg, brain abscess, cisticercosis, etc)

Venous angiomas

Meningeal spread of meningiomas (dural involvement)

Cerebelopontine angle tumors

Von Hippel Lindau syndrome

Hypertensive leukoencephalopathy

Subacute/chronic ischemia

Encephalitis

Others, specify

Not assessable


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10.1.2
Medical history
Medical history findings (i.e. previous diagnoses, diseases or surgeries) meeting all criteria listed 
below will be collected as available to the investigator:

Start before signing of the informed consent 

Considered relevant for the patient’s study eligibility.
Detailed instructions on the differentiation between (i) medical history and (ii) adverse events can 
be found in Section 10.4.1.1.
10.1.3
Prior and concomitant medications
Any medication received within 72 hours prior to the first contrast agent through 24 hours after 
the second contrast agent will be recorded in the eCRF, including the drug name (brand name is 
preferred), indication, total daily dose, route of administration, and start and stop dates. Any 
changes in concomitant medication will also be recorded. 
No contrast agent is allowed to be administered within 24 hours prior to the study MRIs or during 
the study period.
10.2
Efficacy
10.2.1
MRI procedures
10.2.1.1
MRI equipment — AMENDED
The procedure will be performed using either a 1.5 or a 3.0 Tesla MRI scanner that can perform 
the required pulse sequences (see Section 10.2.1.2) with a dedicated head coil. The manufacturer, 
model, software version, and field strength of the MRI device will be recorded in the eCRF. The 
same scanner and required pulse sequences must be used for both the gadoterate and gadobutrol 
enhanced MRI’s.
The same field strength (either 1.5 or 3.0) must be used for both scans. Mixed field strength scans 
are not permitted. 
In addition, T1w enhanced sequences must be performed at or near the same post-dose timepoint 
(4-10 mins) for each study drug (gadoterate and gadobutrol).
10.2.1.2
Pulse sequences — AMENDED
The same parameter setting must be used for unenhanced T1w images and for contrast-enhanced 
T1w images in each patient.T1w spin echo/FSE acquisition should be performed in 2D mode.
The required pulse sequences for gadobutrol and gadoterate are:  

Unenhanced (axial and sagittal image presentation for brain)
o
T1w spin-echo/FSE images of the whole brain - axial
o
Fluid Attenuated Inversion Recovery (FLAIR) of the whole brain – axial


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o
Optional: T2w spin-echo images of the whole brain – sagittal or axial

Contrast-enhanced (axial and coronal image presentation for brain)
o
T1w spin echo/ FSE images of the whole brain

General considerations
o
The MR scanner should NOT be actively retuned after the unenhanced sequences  
Deviations from the specified MRI procedure will be recorded in the eCRF. 
10.2.1.2.1
Sequence parameters for brain imaging — AMENDED
The recommended sequence parameters for brain imaging is displayed below in Table 10-2.
Table 10-2:   Orientation parallel to the planum sphenoidale (only for axial) — AMENDED
T2
SE/FSE T1
FLAIR
Plane
Sagittal or Axial
Axial or Coronal
Axial
Pulse Sequence
Spin echo/FSE
Spin echo/FSE
IR
Patient position
Supine
Supine
Supine
Coil
Head
Head
Head
Slice thick/spacing
3-5 skip 0-1.5
3-5 skip 0-1.5
3-5 skip 0-1.5
Frequency
≥256
≥256
≥256
Phase
≥256
≥256
≥128
Nex
≥2
≥2
≥1
10.2.1.3
Quality assurance of images
The investigator must assure that the unenhanced MRI image set (T1w, FLAIR and T2w) is of 
acceptable diagnostic quality. It is known that in CNS imaging, motion artifacts, aliasing artifacts, 
and/or other disturbing artifacts (e.g. metal implants or dental brace) can, in rare instances impact 
the ability to interpret images of the brain. In such cases, the enhanced images will also be 
similarly impacted. The investigator must insure that the unenhanced images are interpretable, or 
document why the technical quality impacts the evaluation. 
All image sets will be sent to the imaging core lab (the Bayer internal General Clinical Imaging 
Service, GCIS). 
Quality control and quality assurance of the MR images and conduct of the blinded readings will 
be done at the image core laboratory, GCIS in Berlin, Germany.


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10.2.1.4
Image archiving and copying
Once all the study-related images are acquired, both sets of unenhanced images and all contrast-
enhanced MRI images must be stored on appropriate archival media at the site. Study images 
should be uploaded to GCIS without time delay (max. 5 business days). 
The images must not include the patient’s privacy data such as name or initials or other personal 
identifier, sex and birth date, but his/her patient number and the study number must be included. 
No further information needs to be given. Further details and guidance for the sites will be 
provided in the Imaging Manual by GCIS. An overview of the imaging efficacy variables is 
provided in Table 10-3. 
Table 10-3:  Overview of the imaging efficacy variables
Unenhanced
MRI 1
Combined 
unenhanced 
and gadoterate-
enhanced MR
Unenhanced
MRI 2
Combined 
unenhanced 
and gadobutrol-
enhanced MRI
Paired 
Gadobutrol-
enhanced T1w 
and Gadoterate-
enhanced T1w 
MRI
Variables
BR
BR
BR
BR
BR
Degree of contrast 
enhancement (lesions)




Assessment of border 
delineation (lesions)




Internal morphology 
(lesions)




Overall contrast 
enhancement (Core Lab)




Total number of lesions 
detected 




Malignant Disease


Confidence in diagnosis


Image quality

10.2.1.5
Primary efficacy variables
The following 3 lesion visualization parameters scored by the blinded readers constitute the 
primary efficacy variables:  

Degree of lesion contrast enhancement

Lesion Border delineation


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
Lesion Internal morphology
The independent blinded readers will evaluate the 3 primary variables (visualization parameters) 
for up to the 5 largest lesions in each of the following images/image sets separately:  

Unenhanced and Combined unenhanced (T1w, T2w, FLAIR) and gadoterate-
enhanced (T1w) MR image sets

Unenhanced and Combined unenhanced (T1w, T2w, FLAIR) and gadobutrol-
enhanced (T1w) MR image sets
For the evaluation of the degree of contrast enhancement, border delineation, and internal 
morphology the blinded readers will score the lesion using the image sequence which best depicts 
each variable.
10.2.1.5.1
Degree of 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
The score for each lesion will be recorded in the eCRF. This will be evaluated according to Table
10-3. 
10.2.1.5.2
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
4 =
Excellent
clear and complete delineation
The internal morphology score will be recorded into eCRF. This will be evaluated according to 
Table 10-3.


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10.2.1.5.3
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  
The internal morphology score will be recorded into eCRF. This will be evaluated according to 
Table 10-3.
10.2.1.6
Secondary efficacy variables
10.2.1.6.1
Quantitative contrast enhancement estimation - AMENDED
Quantitative contrast enhancement estimation will be performed using an exploratory Overall 
Contrast Enhancement Estimation Algorithm. Descriptive statistics will be presented for each 
study drug (gadoterate and gadobutrol). 
10.2.1.6.2
Diagnosis of Malignancy/Confidence in Diagnosis
The blinded readers will determine if the pathology detected in the combined image sets is benign 
or malignant. These scores will be matched with the final diagnosis of malignant or benign 
disease based on the final diagnosis provided by the Investigator.
The blinded readers will record in the eCRF his/her confidence in diagnosis for each patient for 
the combined unenhanced and gadobutrol-enhanced MR image sets, and the combined 
unenhanced and gadoterate-enhanced MR image sets separately. 
Diagnostic confidence will be evaluated to determine the level of certainty that the blinded 
readers assign to a diagnosis. This is defined as the degree of confidence that the information on 
the images represents the true and complete clinical picture of a patient. The degree of confidence 
will be rated on a 4-point scale:  
1 = Not confident
2 = Some what confident
3 = Confident
4 = Very confident


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10.2.1.6.3
Image quality
The blinded readers will evaluate the relative image quality of the gadobutrol-enhanced T1w MR 
images and the gadoterate-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 gadobutrol and gadoterate 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 = Image R is worse
2 = Image R is slightly worse
3 = Image R is same
4 = Image R is slightly better
5 = Image R is better
10.2.1.6.4
Total number of lesions
For each image set, the blinded reader is to record the total number of lesions up to a maximum 
of 10 lesions.
10.3
Pharmacokinetics
Not applicable.
10.4
Safety
10.4.1
Adverse events
10.4.1.1
Definitions
Definition of adverse event (AE) and treatment emergent AEs
In this study, adverse events (AEs), defined as any untoward medical occurrence (i.e. any 
unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) 
in a patient or clinical investigation patient after signing informed consent will be recorded. 
A treatment emergent AE is defined as any AE that is reported after the patient has received at 
least one dose of study drug. Therefore, a TEAE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product.
Pathology identified on the MRI will not be considered a TEAE. 


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A surgical procedure that was planned prior to the start of the study by any physician treating the 
patient should not be recorded as a TEAE (however, the condition for which the surgery is 
required may be a TEAE).
In the following differentiation between medical history and TEAEs, the term “condition” may 
include abnormal e.g. physical examination findings, symptoms, diseases, laboratory results, 
ECG.

Conditions that started before signing of informed consent and for which no symptoms or 
treatment are present until signing of informed consent are recorded as medical history
(e.g. seasonal allergy without acute complaints).

Conditions that started before signing of informed consent and for which symptoms or 
treatment are present after signing of informed consent, at unchanged intensity, are 
recorded as medical history (e.g. allergic pollinosis).

Conditions that started or deteriorated after signing of informed consent will be 
documented as adverse events. This includes intercurrent illnesses.
Definition of serious AE (SAE) and treatment emergent serious (TESAE)
A SAE is classified as any untoward medical occurrence that, at any dose, meets any of the 
following criteria (a – f) and a TESAE is any SAE that is reported after the patient has received at 
least one dose of study drug. 
The criteria for both an SAE and a TESAE are:
a.
Results in death
b. Is life-threatening
The term ‘life-threatening’ in the definition refers to an event in which the patient was at 
risk of death at the time of the event, it does not refer to an event which hypothetically 
might have caused death if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
A hospitalization or prolongation of hospitalization will not be regarded as a SAE or 
TESAE if at least one of the following exceptions is met:
- The admission results in a hospital stay of less than 12 hours
- The admission is pre-planned
(e.g. elective or scheduled surgery arranged prior to the start of the study; admission is 
part of the study procedures as described in Section 9.2)
- The admission is not associated with an AE 
(e.g. social hospitalization for purposes of respite care).
However, it should be noted that invasive treatment during any hospitalization may fulfill 
the criterion of ‘medically important’ and as such may be reportable as a SAE / TESAE 


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dependent on clinical judgment. In addition, where local regulatory authorities 
specifically require a more stringent definition, the local regulation takes precedence.
d. Results in persistent or significant disability / incapacity
Disability means a substantial disruption of a person’s ability to conduct normal life’s 
functions.
e.
Is a congenital anomaly / birth defect
f.
Is another serious or important medical event as judged by the investigator
10.4.1.2
Classifications for adverse event assessment
All AEs /TEAEs will be assessed and documented by the investigator according to the categories 
detailed below. 
10.4.1.2.1
  Seriousness
For each AE / TEAE, the seriousness must be determined according to the criteria given in 
Section 10.4.1.1.
10.4.1.2.2
Intensity
The intensity of an AE / TEAE is classified according to the following categories:
-
Mild
-
Moderate
- Severe
10.4.1.2.3
Causal relationship 
The assessment of the causal relationship between an AE / TEAE and the administration of 
treatment is a decision to be made by the investigator, who is a qualified physician, based on all 
information available at the time of the completion of the CRF.
Causality should be assessed separately for each study treatment as detailed in the CRF. If the 
investigator feels that the event cannot be firmly attributed to one of the study treatments 
(e.g. owing to a suspected underlying interaction), the same assessment will be documented for 
each study treatment.
The assessment is based on the question whether there was a “reasonable causal relationship” to 
the study treatment in question.
Possible answers are “yes” or “no”


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An assessment of “no” would include:
1. The existence of a highly likely alternative explanation, e.g. mechanical bleeding at 
surgical site.
or
2. Non-plausibility, e.g. the patient is struck by an automobile when there is no indication 
that the drug caused disorientation that may have caused the event; cancer developing a 
few days after the first drug administration.
An assessment of “yes” indicates that that the TEAE is reasonably associated with the use of the 
study treatment.
10.4.1.2.4
Other specific treatment(s) of AEs / TEAEs
- None
- Remedial drug therapy
- Other
10.4.1.2.5
Outcome
The outcome of the AEs / TEAEs is to be documented as follows: 
- Recovered/resolved
- Recovering/resolving
- Recovered/resolved with sequelae
- Not recovered/not resolved
- Fatal
- Unknown
10.4.1.3
Assessments and documentation of adverse events
The investigator must record on the respective CRF pages all adverse events occurring in the 
period between the signing of the informed consent and the end of the follow-up phase; all 
SAEs/TESAEs must be followed to resolution. After the end of the follow-up phase there is no 
requirement to actively collect TEAEs including deaths. The type of information that should be 
assessed and recorded by the investigator for each TEAE is listed in Section 10.4.1.2. 
10.4.1.4
Expected TEAEs
Known TEAEs of radiographic or MRI contrast media may occur following administration of 
gadobutrol. The majority of TEAEs occur within 30 minutes of administration; this is the 
minimum period during which the patient should be under continuous supervision. The most 
common TEAEs after administration of gadobutrol are nausea, headache and dizziness. Other 
TEAEs that may occur include (but are not limited to) taste perversion, paresthesia, vomiting, 


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hypersensitivity reactions, dyspnea, erythema, pruritus, rash, injection site reactions and feeling 
hot. 
For IV injection of gadobutrol, the routine precautions and supervision should be used as with 
any other radiographic or MRI contrast medium. In very rare cases, severe anaphylactoid 
reactions or shock may occur. Familiarity with the practice of emergency procedures is essential 
for prompt, efficient action in the event of post injection TEAEs. Appropriate emergency staff, 
drugs, and instruments (eg, endotracheal tube and ventilator) must be readily available. 
Symptoms such as itching skin, or a coughing fit may be the first signs of an anaphylactoid 
reaction. Administration of the contrast medium must be discontinued immediately, and any 
complications treated according to generally accepted clinical guidelines. 
The adverse event rate and general safety profile of gadobutrol is comparable to other Gd-based, 
approved MRI contrast agents (eg, gadoterate).
10.4.1.5
Reporting of serious adverse events
The definitions of SAEs /TESAEs are given in Section 10.4.1.1. Each SAE /TESAE must be 
followed up until resolution or stabilization by submission of updated reports to the designated 
recipient.
“Death” should not be recorded as a SAE /TESAE on the SAE /TEAE page. Instead, “death” is 
the outcome of underlying SAE /TESAE (s).
For all SAEs the sponsor has to carry out a separate assessment for expectedness, seriousness and 
causal relationship to study drug.
Investigator’s notification of the sponsor
All investigators will be thoroughly instructed and trained on all relevant aspects of the 
investigator’s reporting obligations for SAEs / TESAEs. This information, including all relevant 
contact details, is summarized in the investigator site file. This information will be updated as 
needed.
The investigator must report immediately (within 24 hours of the investigator’s awareness) all 
SAEs / TESAEs occurring during the observation period defined in Section 10.4.1.3 to the 
recipient detailed in the instructions for SAE / TESAE reporting included in the Investigator File. 
For this, a SAE / TEAE page in the CRF as well as the complementary pages provided in the 
Investigator File must be completed for each SAE /TESAE. 
All SAEs occurring after the protocol-defined observation period will be processed by the 
sponsor according to all applicable regulations.


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Notification of the IECs / IRBs
Notification of the IECs / IRBs about all relevant events (e.g. TESAE s, suspected, unexpected, 
serious adverse reactions [SUSARs]) will be performed by the sponsor/CRO and/or by the 
investigator according to all applicable regulations.
Notification of the authorities
The processing and reporting of all relevant events (e.g. TESAE s, SUSARs) to the authorities
will be done by the sponsor according to all applicable regulations.
Sponsor’s notification of the investigational site
The sponsor/CRO will inform all investigational sites about reported relevant events (e.g. 
SUSARs) according to all applicable regulations.
10.4.1.6
Expected adverse events
For this study, the applicable reference documents are the current versions of the package 
insert/SmPC for each imaging agent.
The expectedness of TEAEs will be determined by the sponsor according to the applicable 
reference document and according to all local regulations.
10.5
Prospective blinded image evaluation and centralized procedures
Diagnostic efficacy will be evaluated by prospective evaluations of the blinded images in a 
centralized manner. The blinded readers will be independent radiologists who have not been 
involved in the clinical study. They will be blinded to all patient history and will not have any 
information about the study center, detailed information about the sequence parameters, the 
application of the contrast agent, or the study protocol. Further details on blinded image 
evaluation and centralized procedures will be provided in the Image Review Charter by GCIS.
10.5.1
Image handling and preparation
All image sets that are required in this protocol will be provided electronically in DICOM format 
by the centers.
The images will be sent to the image core laboratory GCIS, Berlin, where the images will be 
prepared for evaluation. Received images will be reviewed by the core laboratory for quality 
control with regard to clinical appropriateness and protocol adherence. If an issue is found, the 
core laboratory or its representative will contact the investigator and attempt to correct it for 
future patients.
An audit trail will be maintained.
All software for the image processing is standardized.


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10.5.2
Blinded reading evaluations
The blinded image evaluations will be performed centrally at the image core laboratory by 
independent radiologists experienced in CNS imaging who are not involved in the clinical portion 
of the study. A core-lab generated blinded read eCRF will be used to ensure that the images and 
the diagnostic findings are properly aligned and to ensure that all questions are answered by the 
blinded readers. 
The blinded read will be in three sessions. The first session will score the lesion variables for 
unenhanced and combined Agent 1 and a determination of malignant disease and confidence.
Two weeks later – the same blinded read procedure will be followed for Agent 2. 
At a third session, the blinded readers will score a paired presentation of the t1w enhanced 
images for image preference. 
Additional details will be provided in the Image Review Charter by GCIS.
In case one of the readers cannot continue the reading (e.g. illness), a new reader will be selected 
and trained. A separate blinded reading manual contains the details. 
Training will be provided for the reader before the blinded image evaluation in the completion of 
the eCRF, in the operation of the imaging work station (eg, window and leveling controls), and in 
the specific protocol language, such as the definition of the scores used for the imaging variables 
and image quality. A refresher training session may be provided prior to each reading session. 
Refresher training sessions may be provided as applicable. Reading sessions will be usually 
conducted in a remote setting (web based) with each reviewer separated from each other In case 
reading sessions will be conducted at centralized facilities it will be ensured that readers are 
monitored by GCIS staff or qualified external personnel.
A core lab representative might be present at the time of the blinded read to answer technical 
questions initiated by the readers such as use of equipment or completion of eCRFs. All 
interactions will be documented. All personnel present during a reading session will be blinded to 
image modality assignment and other clinical data and will be subject to the applicable financial 
disclosure. The identity and the relationship to the sponsor of such personnel will be recorded.
Exceptionally a case may be re-opened and re-evaluated due to any circumstance that is 
significantly impacting the correct reading process or interpretation of study images, e.g., 
erroneous completion of a case, any non-compliance issues, and additional site information 
delivered after the time of the original reading or technical issues. The responsible Imaging 
Clinician will review such cases before authorizing a re-evaluation of the case, and only data that 
is directly affected by the respective error or circumstances should be subject to a reassessment 
by the Independent Central Reader. A thorough explanation and documentation will be provided 
within the Image Evaluation Summary Report.
Complete re-reads of all images and cases may only be permitted prior to the primary analysis 
when a reader has to be replaced due to non-compliance or systematic errors.


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If cases have to be re-assessed it will be documented in the audit trail. This documentation is 
enforced by the image evaluation module (IEM) system.
The blinded image evaluations may take place in parallel with the conduct of the clinical trial. 
10.5.3
Technical prerequisites for blinded readings
10.5.3.1
Blinded image evaluation system
Blinded image evaluations will be conducted using full fidelity digital images. The system type 
and workstation details will be documented in an Imaging Review Charter provided by the core 
laboratory and maintained in the sponsor’s TMF. 
The number of screens needed for the blinded image evaluation will be adapted to the different 
reading parts.
Standard functions at the image visualization system will be available to the reader during the 
review sessions, eg.:

Ability to change the image brightness and contrast (level/window) of all image material 
and screens

Ability to move through the images of one set 

Ability of image zoom and move
10.5.3.2
Electronic CRF design
An eCRF will be used for the electronic data capture of the evaluation results by the blinded 
readers during the reading sessions as discussed in Section 10.5.2. The eCRF application allows 
for a logical progression design with a built-in plausibility check according to the user 
requirements document, forcing the readers to answer the appropriate questions and auto-
checking for missing data. Once the blinded reader has completed a case, no further changes can 
be made by the blinded reader. This process facilitates the efficient and timely completion of the 
digital based image review. 
Each eCRF is developed based on the annotated CRF created by the sponsor following the 
requirements of the central destination database. 
Adequate data transfer to the sponsor’s database is guaranteed and will be tested prior to the start 
of the blinded image evaluation.
The plausibility check built into the eCRF will guarantee that:  

All entries will be made and checked according to logical plausibility  

The next case to be evaluated can only be started after the entries for the current case have 
been finished.


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All data required by the protocol are to be entered into the eCRF. A trained monitor from the core 
laboratory may be available to assist the reader in entering his/her appropriate answers into the 
eCRF fields. 
Once the reader has completed the appropriate section of the eCRF, he or she will be asked to 
enter a password in order to approve the eCRF case record. After approval, the entry pages are 
locked and no further changes can be made. The eCRF will be signed by the blinded reader 
immediately after each case. 
All evaluations will be stored in the sponsor’s central study destination database for analysis. 
10.5.4
Randomization of image material
Each image set from a single patient will be assigned separate randomization numbers for each 
session.   
10.5.4.1
Independent blinded reader training
All readers will undergo training prior to the start of the blinded image evaluations. Training will 
be provided by the core laboratory, GCIS. The training sessions will include a review of the 
appropriate study guidelines, a review of the image display software, a review of the eCRF, and a 
review of teaching and training cases. A record of the training sessions will be maintained, with 
signatures and dates of the blinded readers and the personnel performing the training. The 
training session data and images will be archived along with the images from the blinded 
evaluations. 
Teaching cases comprised of images not included in the actual image evaluation sessions will be 
reviewed with the readers, noting presentation of various radiologic findings. Additionally, the 
blinded readers will conduct a “mock” blinded image evaluation on training cases that will not be 
part of the study data. The training image evaluations will be identical to the actual image 
evaluations in process and will allow the blinded readers to work with the image review software 
and the eCRF. The training session will be conducted prior to the start of the actual blinded image 
evaluations. Results of the training sessions will be conjointly reviewed with the readers prior to 
the start of the actual blinded image evaluations. 
10.5.4.2
Blinded image evaluation of the MRI
The blinded image evaluations are described in detail in the IRC.
All readers will be completely blinded with regard to patient data, clinical information, center-
related and imaging-related information as well as details of the study protocol. 
10.5.4.3
Quantitative contrast enhancement
Quantitative contrast enhancement estimation will be performed using an exploratory Overall 
Contrast Enhancement Estimation Algorithm. Results will be summarized by MRI modality 
using descriptive statistics and confidence intervals.


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10.6 Appropriateness of procedures and measurements
The efficacy and safety measurements described above are widely used and generally accepted as 
reliable, accurate, and relevant. 
The comparison of the study drug (gadobutrol) with an approved comparator product for 
noninferiority reflects a reliable clinical and scientific technique to determine efficacy and safety. 
The blinded MRI reading procedure with independent radiologists is planned to minimize bias 
from the clinical study, because clinical investigators’ diagnoses might be influenced by other 
clinical information they might have received about the patients. 
The safety parameters evaluated in this study are routine clinical parameters and allow risk 
assessment of the investigational drug. 
11.
Statistical methods and determination of sample size
11.1
General considerations
11.2
  Statistical and analytical plans
11.2.1
General considerations
The primary efficacy analyses of the 3 primary efficacy variables (visualization) will be done 
using the average (arithmetic mean) of the values of the 3 blinded readers. The analysis of these 
variables and the analyses of the secondary efficacy variables will also be performed on the data 
from the 3 blinded readers individually. 
For border delineation, contrast enhancement, and internal morphology, there will be multiple 
values for each patient (ratings for multiple lesions). The average (arithmetic mean) of these 
ratings will be used for the primary and secondary 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 patient. 
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 modality 
based on the same number of scores. This zero-filled average will always reward the detection of 
extra lesions.
Demographic variables (age, race, sex, etc.) will be summarized using frequency tables and 
descriptive statistics. 
Safety variables will be summarized using descriptive statistics and frequency tables.
All confidence intervals will be 2-sided, 95% intervals. 


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Statistical tests for superiority will be 2-tailed, using the 0.05 level of significance. Any statistical 
tests used for noninferiority will be one sided tests using the 0.025 level of significance. 
11.3
Analysis sets
11.3.1
Definition of efficacy analysis set
Analyses of efficacy data will be performed using data from all patients for whom eCRF entries 
and images are available for unenhanced MRI, combined unenhanced and gadobutrol-enhanced 
MRI, and combined unenhanced and gadoterate-enhanced MRI. This population will be the full 
analysis set (FAS).
Efficacy analyses will also be performed using data from those patients from the FAS who also 
fulfill all major provisions of this protocol. This set will be the per protocol analysis set (PPS). 
A patient will be excluded from the PPS for any one of the following reasons:
1. The patient received a dose of gadobutrol that was less than 90% or greater than 110% of the 
assigned dose.
2. The patient received a dose of gadoterate that was less than 90% or greater than 110% of the 
assigned dose.
3. An obvious error in the MRI procedure occurred either during the gadobutrol period or during 
the gadoterate period.
4. Pertinent images for the patient are damaged or lost.
11.3.1.1
Definition of safety analysis set
Analysis of safety data will be performed using all available data from all enrolled patients. 
11.4
Variables and planned statistical analyses
11.4.1
Primary efficacy variables
The 3 primary analysis variables are:  

Lesion border delineation

Degree of lesion contrast enhancement

Lesion internal morphology
For the 3 variables, the average (arithmetic mean) lesion score will be calculated for each patient 
based on the scores for each individual lesions in a given patient. 


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11.4.1.1
  Primary efficacy analysis - visualization parameters
The primary efficacy analysis is based on the data from the blinded readers’ evaluation of
3 visualization parameters, which are evaluated in unenhanced and combined unenhanced and 
enhanced MR image sets. 
A successful primary analysis is a demonstration of noninferiority for the difference between 
unenhanced and combined gadobutrol and unenhanced and combined gadoterate enhanced and 
unenhanced MRI to unenhanced MRI for the first 3 primary visualization parameters. 
1. the contrast enhancement (measured on an ordinal 4-point scale);
2. the border delineation (measured on an ordinal 4-point scale); 
3. the internal morphology (measured on an ordinal 3-point scale)
The analysis for three of these parameters (1, 2, and 3) will be performed on the mean of the 
values for the 3 blinded readers (blinded reader average). This analysis will be performed on the 
dataset including the patient average ratings for lesions.
For each parameter a noninferiority hypothesis will be considered, where the comparison will 
relate to a reasonable portion (c=0.2) of the difference between combined unenhanced and 
gadoterate mean to unenhanced. The goal is to show, that the loss in the visualization parameter 
(gadoterate - gadobutrol) is lower than a 0.2 times the combined gadoterate and unenhanced to 
unenhanced mean, which is equivalent to (gadobutrol – gadoterate) is greater than -0.2 times the 
combined gadoterate and unenhanced to unenhanced mean. “Mean” is the mean of the blinded 
reader averages.
The null and alternative hypotheses for noninferiority are: 
H0: (gadobutrol – gadoterate)  ≤- 0.2*(gadoterate – unenhanced), versus 
K0 H1: (gadobutrol – gadoterate)  > - 0.2*(gadoterate – unenhanced), 
where “(gadobutrol – gadoterate)” indicates the difference between combined unenhanced and 
gadobutrol mean to unenhanced mean minus the difference of combined unenhanced and 
gadoterate mean to unenhanced mean. The expression “(gadoterate – unenhanced)” indicates the 
difference between combined unenhanced and gadoterate mean to unenhanced mean.
The study is considered successful if all 3 hypotheses related with these co-primary target 
variables can be rejected each at a one-sided alpha of 0.025 or equivalently at a two-sided alpha 
of 0.05. Appropriate paired t-tests will be used.
No type I error adjustment for multiple comparisons is needed because tests on all 3 variables 
must be significant to demonstrate primary efficacy. 
In addition 95% two-sided confidence intervals for the mean difference of the gadobutrol score 
and the gadoterate score will be calculated.
The primary analysis will be performed using data from evaluations from lesions.


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11.4.2
Secondary efficacy variables
The secondary efficacy variables will be the evaluation of the detection of malignant disease. The 
evaluation of quantitative parameters will be performed by GCIS and image quality will be 
evaluated only by the blinded reader(s). 
The secondary efficacy variables are the:

Comparison of contrast enhancement utilizing an exploratory Overall Contrast 
Enhancement Estimation Algorithm.

Number of lesions identified (up to 10)

Identification of benign or malignant disease 

Confidence in diagnosis 

Image quality
11.4.2.1
Overall Contrast Enhancement Estimation Algorithm
Quantitative contrast enhancement estimation will be performed using an exploratory Overall 
Contrast Enhancement Estimation Algorithm. Results will be summarized by MRI modality 
using descriptive statistics and confidence intervals.
11.4.2.2
Number of lesions able to be identified
A confidence interval for the difference in the number of lesions detected by the 2 contrast agents 
will be constructed. Noninferiority of number of lesions detected will be demonstrated using 
confidence intervals based on the t-distribution with a noninferiority margin of 0.35. 
11.4.2.3
Identification of benign or malignant disease
The investigator determines if the patient has benign or malignant disease. 
The presence or absence of malignant disease in each patient for both contrast agents will be 
determined by the blinded readers, as well as the majority blinded reader (at least 2 of 3 readers), 
and compared to the investigators’ assessment to calculate sensitivity and specificity for each 
drug. 
Sensitivity, specificity, and accuracy for each drug will be compared using a McNemar’s test 
with a noninferiority margin of 10 percent. 
11.4.2.4
Confidence in diagnosis — AMENDED
Frequency tables for confidence responses (1-4) for patients will be constructed for combined 
unenhanced and gadoterate-enhanced MRI, and combined unenhanced and gadobutrol-enhanced 
MRI. Descriptive statistics for the combined unenhanced and gadobutrol and gadoterate enhanced 


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MRI and their difference will be generated. Confidence intervals for the differences will be 
generated.
11.4.2.5
Image quality
The blinded readers will evaluate relative image quality of gadobutrol and gadoterate as 
described in Section 10.2.1.6.3. 
After the data are unblinded, the 5-point scale used by the blinded readers will be translated into 
the following scale: 
-2 = Gadobutrol image is worse
-1 = Gadobutrol image is slightly worse
0 = Images are the same
1 = Gadobutrol image is slightly better
2 = Gadobutrol image is better
Frequency tables and descriptive statistics will be generated on these values, and the relative 
image qualities will be tested for equality using a Wilcoxon signed-rank test.
11.4.2.6
Analysis of safety variables — AMENDED
Frequencies of TEAE s will be tabulated by contrast agent and the proportions of patients 
exhibiting each TEAE will be displayed. Tabulations will also be made for the body system, 
intensity, and attribution corresponding to each TEAE. Separate tabulations will be made for 
serious TEAEs.
11.5
Determination of sample size
The determination of the sample size was based on the primary noninferiority test for the 
difference between unenhanced means and combined gadobutrol-enhanced and unenhanced 
means and combined gadobutrol-enhanced and unenhanced means to unenhanced means.
It considers all three primary efficacy visualization parameters. 
1. the contrast enhancement
2. the border delineation 
3. the internal morphology 
For each parameter a non-inferiority hypothesis will be considered, where the comparison will 
relate to a reasonable portion of the difference between gadoterate and unenhanced. The goal is to 
show, that the loss in the visualization parameter (gadoterate - gadobutrol) is lower than a 
constant times the combined gadoterate and unenhanced to unenhanced.
The mean differences of combined gadobutrol and unenhanced to unenhanced, “(gadobutrol-
unenhanced)”, observed in the pivotal study 310123 for these parameters will be used for power 
calculation (1.29, 0.60, 0.61).


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The related statistical hypotheses read as follows:

H0: (gadobutrol - gadoterate) ≤ - 0.2*(gadoterate – unenhanced) 
vs. 

K0 H1: (gadobutrol – gadoterate) > - 0.2*(gadoterate – unenhanced)
The study is considered successful if all 3 hypotheses related with these co-primary target 
variables can be rejected at a one-sided alpha of 0.025 or equivalently at a two-sided alpha of 
0.05. Appropriate paired t-tests will be used.
Rejection of such a hypothesis means that it is demonstrated that gadobutrol (at reduced dose) 
preserves at least 80% of the effect gadoterate /Dotarem has compared to unenhanced images.
Enrolling 180 subjects allows for approximately 25% non-evaluable patients and guarantees 90% 
power for border delineation. For the remaining two variables the power will be close to 100% 
with this sample size. Hence also the overall power of this study will be 90%.
No type I error adjustment for multiple comparisons is needed because tests on all 3 variables 
must be significant to demonstrate primary efficacy. 
12.
Data handling and quality assurance
12.1
Data recording
The data collection tool for this study will be a validated electronic data capture system called 
RAVE. Subject data necessary for analysis and reporting will be entered/ transmitted into a 
validated database or data system (SAS). 
Data required according to this protocol will be recorded by investigational site personnel via 
data entry into the internet based electronic data capture (EDC) software system RAVE, which 
has been licensed from Medidata Solutions Worldwide. RAVE has been validated by Medidata 
Solutions Worldwide for use in Bayer’s 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. The logic has been extensively applied 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 
by the CRO to Bayer’s internal computers via secure lines. 
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 as well as the CRO 
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 subjects 
enrolled in this study.
Source documentation
The site must implement processes to ensure availability of all required source documentation. 
A source document checklist (not part of this protocol) will be used at the site to identify the 
source data for key data points collected and the monitor will work with the site to complete this.
It is the expectation of the sponsor that all data entered into the eCRF has source documentation 
available at the site. 
Data recorded from screening failures
At minimum, the following data should be recorded in the CRF:

Demographic information (patient number; year of birth / age; sex; if applicable race / 
ethnicity)

Date of informed consent

Relevant inclusion/exclusion criteria

Reason for premature discontinuation

Date of last visit. 
These data will be transferred to the respective database.
For screening failures with a SAE / TESAE, the following data should be collected in the CRF in 
addition to the data specified above:

All information related to the SAE / TESAE such as: 
- The SAE / TESAE itself
- Concomitant medication
- Medical history
- Other information needed for SAE / TESAE complementary page
12.2
Monitoring
In accordance with applicable regulations, GCP, and sponsor’s/CRO’s procedures, monitors will 
contact the site prior to the start of the study to review with the site staff the protocol, study 


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requirements, and their responsibilities to satisfy regulatory, ethical, and sponsor’s requirements. 
When reviewing data collection procedures, the discussion will also include identification and 
documentation of source data items.
The sponsor/designee will monitor the site activity to verify that the:

Data are authentic, accurate and complete. 
Supporting data may be requested (example: blood glucose readings to support a 
diagnosis of diabetes). 

Safety and rights of patients are being protected

Study is conducted in accordance with the currently approved protocol 
(including study treatment being used in accordance with the protocol)

Any other study agreements, GCP, and all applicable regulatory requirements are met.
The investigator and the head of the medical institution (where applicable) agrees to allow the 
monitor direct access to all relevant documents. Details will be provided in the Monitoring Plan.
12.3
Data processing
Data will be collected as described in Section 12.1. Clinical data management will be performed 
in accordance with applicable sponsor’s / CRO’s standards and data cleaning procedures. This is 
applicable for data recorded on CRF as well as for data from other sources.
For data coding (e.g. AEs /TEAEs, medication), internationally recognized and accepted 
dictionaries will be used.
12.4
Missing data 
Not applicable
12.5
Audit and inspection
To ensure compliance with GCP and regulatory requirements, a member of the sponsor’s (or a 
designated CRO’s) quality assurance unit may arrange to conduct an audit to assess the 
performance of the study at the study site and of the study documents originating there. The 
investigator/institution will be informed of the audit outcome.
In addition, inspections by regulatory health authority representatives and IEC(s)/IRB(s) are 
possible. The investigator should notify the sponsor immediately of any such inspection.
The investigator/institution agrees to allow the auditor or inspector direct access to all relevant 
documents and allocate his/her time and the time of his/her staff to the auditor/inspector to 
discuss findings and any issues. Audits and inspections may occur at any time during or after 
completion of the study.


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12.6
Archiving
Essential documents shall be archived safely and securely in such a way that ensures that they are 
readily available upon authorities’ request.
Patient (hospital) files will be archived according to local regulations and in accordance with the 
maximum period of time permitted by the hospital, institution or private practice. Where the 
archiving procedures do not meet the minimum timelines required by the sponsor (i.e.15 years 
after the end of study), alternative arrangements must be made to ensure the availability of the 
source documents for the required period.
The investigator/institution notifies the sponsor if the archival arrangements change 
(e.g. relocation or transfer of ownership).
The investigator site file is not to be destroyed without the sponsor’s approval.
The contract with the investigator/institution will contain all regulations relevant for the study 
center.
13.
Ethical and legal aspects
13.1
Investigator(s) and other study personnel
All other study personnel not included in this section are identified in a separate personnel list 
(not part of this clinical study protocol) as appropriate. This list will be updated as needed; an 
abbreviated version with personnel relevant for the centers will be available in each center’s 
investigator site file.
Whenever the term ‘investigator’ is noted in the protocol text, it may refer to either the principal 
investigator at the site, or an appropriately qualified, trained and delegated individual of the 
investigational site.
The principal investigator of each center must sign the protocol signature page and must receive 
all required external approvals (e.g. health authority, ethics committee, sponsor) before patient
recruitment may start at the respective center. Likewise, all amendments to the protocol must be 
signed by the principal investigator and must have received all required external approvals before 
coming into effect at the respective center.
A complete list of all participating centers and their investigators, as well as all required signature 
documents, will be maintained in the sponsor’s study file.
The global sponsor of this study is identified on the title page of this protocol. If required by local 
law, local co-sponsors will be nominated; they will be identified on the respective country-
specific signature pages.
13.2
Funding and financial disclosure
Funding


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This study will be funded by its sponsor.
Financial disclosure 
Each investigator (including principal and/or any sub investigators) who is directly involved in 
the treatment or evaluation of research patients has to provide a financial disclosure according to 
all applicable legal requirements. All relevant documentation will be filed in the trial master file.
13.3
Ethical and legal conduct of the study
The procedures set out in this protocol, pertaining to the conduct, evaluation, and documentation 
of this study, are designed to ensure that the sponsor and investigator abide by Good Clinical 
Practice (GCP) guidelines and the guiding principles detailed in the Declaration of Helsinki. 
The study will also be carried out in keeping with applicable local law(s) and regulation(s).
Documented approval from appropriate IEC(s)/IRBs will be obtained for all participating 
centers/countries before start of the study, according to GCP, local laws, regulations and 
organizations. When necessary, an extension, amendment or renewal of the IEC/IRB approval 
must be obtained and also forwarded to the sponsor. The responsible unit (e.g. IEC/IRB, head of 
the study center/medical institution) must supply to the sponsor, upon request, a list of the 
IEC/IRB members involved in the vote and a statement to confirm that the IEC/IRB is organized 
and operates according to GCP and applicable laws and regulations.
Strict adherence to all specifications laid down in this protocol is required for all aspects of study 
conduct; the investigator may not modify or alter the procedures described in this protocol. 
Modifications to the study protocol will not be implemented by either the sponsor or the 
investigator without agreement by both parties. However, the investigator or the sponsor may 
implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) to 
the trial patients without prior IEC/IRB/sponsor approval/favorable opinion. As soon as possible, 
the implemented deviation or change, the reasons for it and if appropriate the proposed protocol 
amendment should be submitted to the IEC/IRB/head of medical institution/sponsor. Any 
deviations from the protocol must be explained and documented by the investigator.
13.4
Patient information and consent
All relevant information on the study will be summarized in an integrated patient information 
sheet and informed consent form provided by the sponsor or the study center. A sample patient
information and informed consent form is provided as a document separate to this protocol.
Based on this patient information sheet, the investigator or designee will explain all relevant 
aspects of the study to each patient, prior to his/her entry into the study (i.e. before any 
examinations and procedures associated with the selection for the study are performed or any 
study-specific data is recorded on study-specific forms).
The investigator will also mention that written approval of the IRB/IEC has been obtained.


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Each patient will be informed about the following aspects of premature withdrawal:
Each patient has the right to withdraw from the study at any time without any disadvantage 
and without having to provide reasons for this decision. 
The patient’s data that have been collected until the time of withdrawal will be retained and 
statistically analyzed in accordance with the statistical analysis plan. 
Patient-specific data on the basis of material obtained before withdrawal may be generated 
after withdrawal (e.g. image reading, analysis of biological specimen such as blood, urine or 
tissues); these data would also be retained and statistically analyzed in accordance with the 
statistical analysis plan. The patient has the right to object to the generation and processing of 
this post-withdrawal data. The patient’s oral objection may be documented in the patient’s 
source data.
Each patient will have ample time and opportunity to ask questions.
Only if the patient voluntarily agrees to sign the informed consent form and has done so, may 
he/she enter the study. Additionally, the investigator will personally sign and date the form. The 
patient / legal representative or proxy consenter will receive a copy of the signed and dated form.
The signed informed consent statement is to remain in the investigator site file or, if locally 
required, in the patient’s note/file of the medical institution.
In the event that informed consent is obtained on the date that baseline study procedures are 
performed, the study record or patient´s clinical record must clearly show that informed consent 
was obtained prior to these procedures.
The informed consent form and any other written information provided to patients will be revised 
whenever important new information becomes available that may be relevant to the patient’s 
consent, or there is an amendment to the protocol that necessitates a change to the content of the 
patient information and / or the written informed consent form. The investigator will inform the 
patient of changes in a timely manner and will ask the patient to confirm his/her participation in 
the study by signing the revised informed consent form. Any revised written informed consent 
form and written information must receive the IEC/IRB`s approval / favorable opinion in advance 
of use.
13.5
Publication policy and use of data
The sponsor has made the information regarding the study protocol publicly available on the 
internet at www.clinicaltrials.gov. 
All data and results and all intellectual property rights in the data and results derived from the 
study will be the property of the sponsor who may utilize them in various ways, such as for 
submission to government regulatory authorities or disclosure to other investigators.
Regarding public disclosure of study results, the sponsor will fulfill its obligations according to 
all applicable laws and regulations. The sponsor is interested in the publication of the results of 
every study it performs. 


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The sponsor recognizes the right of the investigator to publish the results upon completion of the 
study. However, the investigator, whilst free to utilize study data derived from his/her center for 
scientific purposes, must obtain written consent of the sponsor on the intended publication 
manuscript before its submission. To this end, the investigator must send a draft of the 
publication manuscript to the sponsor within a time period specified in the contract. The sponsor 
will review the manuscript promptly and will discuss its content with the investigator to reach a 
mutually agreeable final manuscript. 
13.6
Compensation for health damage of patients / insurance
The sponsor maintains clinical trial insurance coverage for this study in accordance with the laws 
and regulations of the country in which the study is performed.
13.7
Confidentiality
All records identifying the patient will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available.
Patient names will not be supplied to the sponsor. Only the patient number will be recorded in the 
CRF, and if the patient name appears on any other document (e.g. pathologist report), it must be 
obliterated before a copy of the document is supplied to the sponsor. Study findings stored on a 
computer will be stored in accordance with local data protection laws. As part of the informed 
consent process, the patients will be informed in writing that representatives of the sponsor, 
IEC/IRB, or regulatory authorities may inspect their medical records to verify the information 
collected, and that all personal information made available for inspection will be handled in 
strictest confidence and in accordance with local data protection laws.
If the results of the study are published, the patient’s identity will remain confidential.
The investigator will maintain a list to enable patients to be identified.
14.
Reference list 
Not applicable


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15.
Protocol amendments
15.1
Amendment 1 — 26 MAR 2019
Editorial note
In the sections on changes to the protocol text, all protocol sections affected by the respective 
amendment are detailed; the sequence of the sections follows the structure of the most recent 
previous protocol version. As applicable, changes to the protocol text are highlighted as follows:

Editing of an existing portion: Comparative presentation of “old text” versus “new text”, 
with “old text” referring to the most recent previous protocol version. Deletions are 
crossed out in the “old text”. Additions are underlined in the “new text”.
In general, correction of typos or omissions are not highlighted. However, throughout the 
protocol, the designation of the alternative hypothesis has been changed from K0 to H1 to align 
the protocol with the terminology used in the SAP and with the general standard for designation
of the alternative hypothesis. It is not considered to be a protocol change but is a correction. 
15.1.1
Overview of changes to the study

Section 10.2.1.1 MRI Equipment —This section was changed to reflect changes in MRI 
field strength in common use and to permit either the previously specified 1.5 and the 
newer 3.0 field strength and to provide greater flexibility based on the study center’s 
available MRI equipment. 

Section 10.2.1.2  Pulse sequences — This section was changed to recommend that 
T1w spin echo/FSE acquisition should be performed in 2D mode.

Section 10.2.1.6.1 Quantitative contrast enhancement estimation — Up to 10 lesions” 
has to be removed because the quantitative contrast enhancement estimation algorithm 
will not be applied to a single lesion or up to 10 lesions, because it is a software 
evaluation result for a complete image. 

Section 11.4.2.4 Confidence in diagnosis — This section has been modified to clarify 
that frequency tables for confidence responses will not be constructed for unenhanced 
MRI alone. 

Section 11.4.2.6  Analysis of safety variables — This section was changed to remove 
the reference to McNemar's tests and/or related confidence intervals, reflecting a changed 
analysis plan. 


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15.1.2
Modification 1: Section 10.2.1.1  MRI equipment
The modified text is:
The procedure will be performed using either a 1.5 or a 3.0 Tesla MRI scanner that can perform 
the required pulse sequences (see Section 10.2.1.2) with a dedicated head coil. The manufacturer, 
model, software version, and field strength of the MRI device will be recorded in the eCRF. The 
same scanner and required pulse sequences must be used for both the gadoterate and gadobutrol 
enhanced MRI’s. 
The same field strength (either 1.5 or 3.0) must be used for both scans. Mixed field strength scans 
are not permitted. 
In addition, T1w enhanced sequences must be performed at or near the same post-dose time point 
(4-10 mins) for each study drug (gadoterate and gadobutrol).
Affected sections: No other sections.
15.1.3
Modification 2:  Section 10.2.1.2. Pulse Sequences
The modified text is:
The same parameter setting must be used for unenhanced T1w images and for contrast-enhanced 
T1w images in each patient. T1w spin echo/FSE acquisition should be performed in 2D mode.
The required pulse sequences for gadobutrol and gadoterate are:  

Unenhanced (axial and sagittal image presentation for brain)
o
T1w spin-echo/FSE images of the whole brain - axial
o
Fluid Attenuated Inversion Recovery (FLAIR) of the whole brain – axial
o
Optional: T2w spin-echo images of the whole brain – sagittal or axial

Contrast-enhanced (axial and coronal image presentation for brain)
o
T1w spin echo/ FSE images of the whole brain

General considerations
o
The MR scanner should NOT be actively retuned after the unenhanced sequences  
Deviations from the specified MRI procedure will be recorded in the eCRF. 
Affected sections: No other sections.
15.1.4
Modification 3: Section 10.2.1.2.1  Sequence parameters for brain imaging
The modified text is:
The recommended sequence parameters for brain imaging is displayed below in Table: 10-2.


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Table 10-2:     Orientation parallel to the planum sphenoidale (only for axial)
T2
SE/FSE T1
FLAIR
Plane
Sagittal or Axial
Axial or Coronal
Axial
Pulse Sequence
Spin echo/FSE
Spin echo/FSE
IR
Patient position
Supine
Supine
Supine
Coil
Head
Head
Head
Slice thick/spacing
3-5 skip 0-1.5
3-5 skip 0-1.5
3-5 skip 0-1.5
Frequency
≥256
≥256
≥256
Phase
≥256
≥256
≥128
Nex
≥2
≥2
≥1
Affected sections: No other sections.
15.1.5
Modification 4: Section 10.2.1.6.1  Quantitative contrast enhancement
estimation
The modified text is:
Quantitative contrast enhancement estimation will be performed using an exploratory Overall 
Contrast Enhancement Estimation Algorithm. Descriptive statistics will be presented for each 
study drug (gadoterate and gadobutrol). Results will be summarized by MRI modality using. Up 
to 10 lesions will be identified. 
Affected sections: No other sections.
15.1.6
Modification 5:  Section 11.4.2.4  Confidence in diagnosis
The modified text is:
Frequency tables for confidence responses (1-4) for patients will be constructed for unenhanced 
MRI, combined unenhanced and gadoterate-enhanced MRI, and combined unenhanced and 
gadobutrol-enhanced MRI. Descriptive statistics for the combined unenhanced and gadobutrol 
and gadoterate enhanced MRI and their difference from unenhanced MRI will be generated. 
Confidence intervals for the differences will be generated.
Affected sections: No other sections.


Clinical Study Protocol
No. BAY No. 86-4875/ IMPACT no. 19773  
26 MAR 2019
Version no. 2.0   
Page: 58 of 60
15.1.7
Modification 6:  Section 11.4.2.6  Analysis of safety variables
The modified text is:
Frequencies of TEAE s will be tabulated by contrast agent and the proportions of patients 
exhibiting each TEAE will be displayed. Tabulations will also be made for the body system, 
intensity, and attribution corresponding to each TEAE. Separate tabulations will be made for 
serious TEAE s. McNemar's tests and/or related confidence intervals will be used to assess the 
significance of the differences in incidence rates between the agents. 
Affected sections: No other sections.
16.
Appendices
Appendix 1:  Volume of Gadobutrol 0.075 mmol/kg by Body Weight
Appendix 2:  Volume of Gadoterate 0.1 mmol/kg by Body Weight


Clinical Study Protocol
No. BAY No. 86-4875/ IMPACT no. 19773  
26 MAR 2019
Version no. 2.0   
Page: 59 of 60
Appendix 1:  Volume of Gadobutrol 0.075 mmol/kg by Body Weight
Body Weight (kg)
Volume of Gadobutrol 
(mL)
Body Weight (kg)
Volume of Gadobutrol 
(mL)
45
3.4
79
5.9
46
3.5
80
6
47
3.5
81
6.1
48
3.6
82
6.2
49
3.7
83
6.2
50
3.8
84
6.3
51
3.8
85
6.4
52
3.9
86
6.5
53
4
87
6.5
54
4.1
88
6.6
55
4.1
89
6.7
56
4.2
90
6.8
57
4.3
91
6.8
58
4.4
92
6.9
59
4.4
93
7
60
4.5
94
7.1
61
4.6
95
7.1
62
4.7
96
7.2
63
4.7
97
7.3
64
4.8
98
7.4
65
4.9
99
7.4
66
5
100
7.5
67
5
101
7.6
68
5.1
102
7.7
69
5.2
103
7.7
70
5.3
104
7.8
71
5.3
105
7.9
72
5.4
106
8
73
5.5
107
8
74
5.6
108
8.1
75
5.6
109
8.2
76
5.7
110
8.3
77
5.8
115
8.6
78
5.9
120
9


Clinical Study Protocol
No. BAY No. 86-4875 / IMPACT no.19773   
26 MAR 2019   
Version no. 2.0
Page: 60 of 60
Appendix 2:  Volume of Gadoterate 0.1 mmol/kg by Body Weight
Body Weight (kg)
Volume of Gadoterate 
(mL)
Body Weight (kg)
Volume of Gadoterate 
(mL)
45
9.0
79
15.8
46
9.2
80
16.0
47
9.4
81
16.2
48
9.6
82
16.4
49
9.8
83
16.6
50
10.0
84
16.8
51
10.2
85
17.0
52
10.4
86
17.2
53
10.6
87
17.4
54
10.8
88
17.6
55
11.0
89
17.8
56
11.2
90
18.0
57
11.4
91
18.2
58
11.6
92
18.4
59
11.8
93
18.6
60
12.0
94
18.8
61
12.2
95
19.0
62
12.4
96
19.2
63
12.6
97
19.4
64
12.8
98
19.6
65
13.0
99
19.8
66
13.2
100
20.0
67
13.4
101
20.2
68
13.6
102
20.4
69
13.8
103
20.6
70
14.0
104
20.8
71
14.2
105
21.0
72
14.4
106
21.2
73
14.6
107
21.4
74
14.8
108
21.6
75
15.0
109
21.8
76
15.2
110
22.0
77
15.4
115
23.0
78
15.6
120
24.0