Performance of Elucirem (Gadopiclenol) in Dynamic Susceptibility Contrast Magnetic Resonance Imaging (DSC-MRI) Perfusion of Brain Gliomas Phase IIIb Clinical Trial
Phase: PHASE3
Conditions: Brain Tumor, Primary, Brain Tumor, Recurrent
Sponsor: Guerbet

 
 
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Confidentiality clause 
This document and the information therein are GUERBET's proprietary and confidential information. They shall 
not be disclosed, disseminated or reproduced, in whole or in part, to any third party, without the prior written 
consent of GUERBET. 
Performance of Elucirem® (gadopiclenol) in Dynamic Susceptibility Contrast Magnetic 
Resonance Imaging (DSC-MRI) perfusion of brain gliomas 
Phase IIIb Clinical Trial 
 
 
EudraCT No.: 2022-002720-12 
 
COORDINATING INVESTIGATOR or International coordinator (if not a participating site) 
NOT APPLICABLE 
 
SPONSOR 
GUERBET, B.P. 57400, 95943 Roissy CdG Cedex, FRANCE 
GUERBET MEDICAL EXPERT 
 
Phone: 
 / fax: 
 e-mail: 
 
GUERBET PHARMACOVIGILANCE 
Fax + 33 1 45 91 67 70 
E-mail: pharmacovigilance.headquarters@guerbet.com 
 
Ref. No.: 4_23_00007 
 
PPD
PPD
PPD
PPD

 
 
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PROTOCOL SYNOPSIS 
Trial Title: Performance of Elucirem® (gadopiclenol) in Dynamic Susceptibility Contrast Magnetic 
Resonance Imaging (DSC-MRI) perfusion of brain gliomas 
Phase IIIb Clinical Trial 
Trial Product(s): Elucirem® (G03277) 
Active Ingredient(s): gadopiclenol  
EudraCT No.: 2022-002720-12 
Potential Participating countries (Potential Number of sites): Trial involving approximately 10 sites 
in 3-4 countries 
Trial Objectives 
Primary objective: 
To demonstrate the non-inferiority of DSC-MRI perfusion using Elucirem® (gadopiclenol) at 0.05 
mmol/kg compared to DSC-MRI perfusion using Dotarem® (gadoterate meglumine) at 0.1 mmol/kg 
in terms of diagnostic quality of Cerebral Blood Volume (CBV) perfusion map (off-site assessment) 
Secondary objectives: 
 
To evaluate the diagnostic quality of CBV perfusion map for Elucirem® and Dotarem® (on-
site assessment) 
 
 
To compare the performance of DSC-MRI perfusion using Elucirem® at 0.05 mmol/kg to 
DSC-MRI using Dotarem® at 0.1 mmol/kg in differentiating glioma grade through the 
quantification of the relative CBV (rCBV) (off-site assessment) 
 
 
To assess the reliability of the T2* signal intensity time curve in terms of confidence in 
diagnosis in DSC-MRI perfusion using Elucirem® at 0.05 mmol/kg (on-site and off-site 
assessments) 
 
 
To expand the previously established safety profile of Elucirem® at 0.05 mmol/kg in terms 
of incidence of adverse events 
Trial design and methodology 
The trial is designed as a prospective, multi-center, randomized, controlled and parallel group 
comparison. 
The Investigational Medicinal Products (IMP) used for the trial are Elucirem® and Dotarem®. 
Once informed consent form (ICF) signed, the patients will perform a screening visit (V1) to confirm 
trial eligibility. The eligible patients will be randomized by Interactive Web Response System (IWRS) 
to determine the IMP to be injected. They will undergo a DSC-MRI perfusion using Elucirem® or 
Dotarem® (MRI visit - V2). A safety visit (V3) will be performed 1 day after the MRI visit by phone. 
Confirmation of tumor grade diagnosis, if available, will be collected up to 30 days after visit 2. 
The randomization scheme will allocate patients in a 1:1 ratio to the two parallel arms. Stratification 
by glioma grades (low grades versus high grades) between the two arms will be managed by IWRS 
based on the diagnosis collected at screening. 
Images will be evaluated by both on-site and off-site readers. 

 
 
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For on-site reads, at least one experienced neuroradiologist will be appointed in each investigational 
site at the start of the trial to read perfusion images of patients included at the site. 
For off-site reads, all images will be sent to an imaging laboratory which will prepare the images for 
evaluation. The off-site images evaluation will be performed by two independent blinded radiologists 
(IBR) experienced in perfusion MRI and brain tumors. In case of discordance, a consensus meeting 
will be organised in order to reach an agreement. 
An imaging electronic Case Report Form (eCRF) will be used to ensure that the images are properly 
aligned and to ensure that all necessary data for the trial purpose are documented by the independent 
blinded readers. 
For this study, only off-site readers will be blinded to the nature of the IMP injected.  
During the trial, the safety of the patients will be monitored and assessed based on the reporting of 
adverse events (AE). 
Number of patients 
138 patients to be enrolled, in order to have 124 evaluable patients 
Eligibility criteria 
Inclusion criteria: 
To be included in the trial, the patient must meet all the inclusion criteria. 
1. Female or male adult patient (patient having reached legal majority age). 
2. Patient with naive or recurrent primary glial tumor detected at a previous Computed 
Tomography (CT) or MR imaging, and scheduled for a follow-up contrast-enhanced 
MRI. Tumor grade (confirmed or highly suspected) should be available in patients’ 
medical records. 
3. Patient or, if the patient is unable to provide informed consent, the patient's legally 
acceptable representative and/or impartial witness, having read the information and 
having provided patient’s consent to participate in writing by dating and signing the 
informed consent prior to any trial related procedure being conducted. 
4. Patient affiliated to national health insurance according to local regulatory requirements. 
 
Non-inclusion criteria: 
Patient presenting with one or more of the non-inclusion criteria must not be included in the trial. 
1. Patient with known contra-indication(s) to the use or with known sensitivity to one of the 
products under investigation or to other Gadolinium-Based Contrast Agents (GBCA) 
(such as hypersensitivity, post-contrast acute kidney injury). 
2. Patient presenting with any contraindication to MRI examinations. 

 
 
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3. Post treatment patient presenting with pseudo-progression instead of tumor recurrency. 
4. Patient presenting with severe renal insufficiency, defined as an estimated Glomerular 
Filtration Rate (eGFR) < 30 mL/min/1.73 m² assessed within 1 week prior to contrast 
agent injection. 
5. Patient having received any contrast agent (for MRI or CT) within 3 days prior to IMP 
administration or scheduled to receive any contrast agent within 24 hours after IMP 
administration. 
6. Pregnant female patient (a female patient of childbearing potential or with amenorrhea 
for less than 12 months must have a negative pregnancy test within 1 day prior to trial 
MRI and must be using medically approved contraception method until the last trial visit). 
7. Patient having received any investigational medicinal product within 7 days prior to trial 
entry or scheduled to receive any investigational treatment in the course of the trial. 
8. Patient previously randomized in this trial. 
9. Patient with anticipated, current or past condition (medical, psychological, social or 
geographical) that would compromise the patient’s safety or her/his ability to participate 
in the trial. 
10. Patient unlikely to comply with the protocol, e.g., uncooperative attitude, inability to 
return for follow-up visits and/or unlikelihood of completing the trial. 
11. Patient related to the investigator or any other trial staff or relative directly involved in 
the trial conduct. 
The diagnosis obtained from previous (qualifying) imaging examinations will be considered as 
medical history to assess inclusion criteria. All the trial analyses will be only based on the images 
obtained through the trial MRI. 
Investigational Medicinal Products administration 
Investigational Medicinal Product (IMP) 1: 
Name: Elucirem® (gadopiclenol) (formulation G03277) 
Pharmaceutical form: 20-mL vial containing 15 mL of solution presented as a sterile, clear, ready-to-
use aqueous solution for injection. 
Concentration: 0.5 M  
Route and method of administration: 
Elucirem® will be intravenously (IV) administered at 0.05 mmol/kg using a power injector at the 
injection rate of minimum 4 mL/second, followed by a 20-mL 0.9% saline flush at the same injection 
rate.  
Preload bolus is allowed. If applied, the total dose (preload bolus + main bolus) of Elucirem® should 
not exceed 0.05 mmol/kg. 
Investigational Medicinal Product (IMP) 2: 
Name: Dotarem® (gadoterate meglumine) 
Pharmaceutical form: 20-ml vial containing 20 mL of solution presented as a sterile, clear, ready-to-
use aqueous solution for injection. 
Concentration: 0.5 M  
 

 
 
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Route and method of administration: 
Dotarem® will be intravenously (IV) administered at 0.1 mmol/kg using a power injector at the 
injection rate of minimum 4 mL/second, followed by a 20-mL 0.9% saline flush at the same injection 
rate. 
Preload bolus is allowed. If applied, the total dose (preload bolus + main bolus) of Dotarem® should 
not exceed 0.1 mmol/kg. 
Trial duration for patients: 
Minimum trial duration for patients: 2 days, if V1 and V2 are done on the same day. 
Maximum trial duration for patients: 9 days, if the screening period lasts 7 days. 
Maximum trial duration for collection of data: 37 days, if the screening period lasts 7 days and a 
biopsy or surgery is done 30 days after the MRI. 
The trial is considered as completed once all the images collected for all the patients have been 
reviewed by all independent blinded readers and the histopathology results (if any) have been 
obtained. The patient’s participation is defined as the period from the screening visit (ICF signature) 
to the last visit. 
Imaging Protocol 
The imaging procedures will be performed using a 1.5T or a 3T MRI scanner, equipped with echo-
planar imaging (EPI) capabilities, that can perform the required sequences.  
Brain imaging protocol will include: 
Unenhanced sequences:  
 
Axial 3D T1WI GRE 
 
Axial 2D T2WI T(F)SE 
 
Axial 2D FLAIR 
 
Contrast-enhanced sequences:  
 
Perfusion imaging: Axial DSC T2* EPI 
 
Axial 3D T1WI GRE  
Perfusion DSC sequences will be post processed with a dedicated software, which will generate CBV 
map. 
Imaging protocol will be fully described in an imaging manual that will be provided to investigational 
sites. 
Evaluation criteria 
CBV map will be generated through post-processing software for each DSC-MRI perfusion. 
Technical adequacy of CBV map will be determined by on-site and off-site readers using a  
4-point scale with the following grades: non-diagnostic, poor, fair, good. Images are to be considered 
technically adequate if evaluation is possible despite any artifacts that might partially compromise 
image quality. Images are considered technically non-diagnostic if artifacts completely compromise 
image interpretability. 

 
 
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The major artifact according to the list below will be recorded: 
1 = Movement artifacts   
2 = T2* artifacts 
3 = EPI distortion 
4 = Other, to be specified 
 
Only for images considered technically adequate, the following evaluations will be performed: 
 
Primary evaluation criterion:  
Diagnostic quality of the CBV map will be assessed by off-site readers using a  
4-point scale with the grades: poor, fair, good or excellent as defined below: 
1: Poor: IC; EC; BG not distinguishable & CGM; SCWM; DWM not distinguishable 
2: Fair: IC; EC; BG partially distinguishable on AS & CGM; SCWM; DWM partially distinguishable 
on 2S 
3: Good: IC; EC; BG well distinguishable on 2S & CGM; SCWM; DWM well distinguishable on 2S 
4: Excellent: IC; EC; BG well distinguishable on AS & CGM; SCWM; DWM well distinguishable 
on 2S 
IC=Internal Capsule; EC=External Capsule; BG=Basal Ganglia; CGM=Cortical normal appearing 
Gray Matter; SCWM=Sub-Cortical normal appearing White Matter; DWM=Deep normal appearing 
White Matter; AS=all slices; 2S=not more than 2 slices. 
 
Secondary evaluation criteria: 
 
The following assessments will be performed with Elucirem® and Dotarem®: 
 
o Diagnostic quality of the CBV map will be assessed by on-site readers using the 
same 4-point scale as the one used for primary evaluation criterion 
o Assessment of rCBV and T2* signal intensity time curve 
 
Quantification of the relative CBV for differentiating tumor grade (off-site 
assessment) 
The rCBV will be calculated on the CBV perfusion maps generated for each 
DSC-MRI perfusion. The regions of interest (ROIs) will be placed by off-site 
readers on the tumor for providing tumor CBV and also on normal tissue 
(contralateral normal-appearing white matter) for providing referenced CBV. 
To be sure that the imaged tumor is the same as the tumor biopsied, results will 
be matched with the standard of truth for diagnosis of glioma grade. This 
standard of truth will be histopathological results collected on site (diagnosis 
based on 2021 WHO classification of Central Nervous System (CNS) tumors). 
 
Evaluation of the T2* signal intensity time curve and assessment (on-site 
and off-site assessments) 
T2* signal intensity time curve will be visually assessed by on-site and off-site 
readers for the reliability of the curve in providing sufficient information for 
diagnosis purpose. The Full-Width at Half-Maximum (FWHM) and the 
maximum signal drop will be measured by off-site readers only. 

 
 
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Readers will record their confidence in diagnosis based on the reliability of the 
curve using a 5-point scale: 
1 = nil: very uncertain 
2 = poor: uncertain 
3 = moderate: moderately certain 
4 = high: good certainty  
5 = excellent: very certain 
 
 
The following safety parameters will be assessed: 
 
o Adverse events, serious or not, related to IMP or not, that occur from the beginning 
of patient’s participation in the trial (Informed Consent Form signature) until the end 
of the participation. 
Statistical methods 
Sample size: 
The primary objective of the trial is to demonstrate the non-inferiority of DSC MRI perfusion using 
Elucirem® at 0.05 mmol/kg compared to Dotarem® at 0.1 mmol/kg in terms of diagnostic quality of 
the CBV perfusion map based on off-site evaluations. 
A 12% non-inferiority margin was considered clinically as an unimportant difference and therefore 
relevant to establish acceptable diagnostic quality of Elucirem® relative to Dotarem®. 
Statistical hypotheses 
- H0: p(excellent+good for Elucirem® ) – p(excellent+good for Dotarem®) ≤ - 0.12 
- H1: p(excellent+good for Elucirem®) – p(excellent+good for Dotarem®) > - 0.12 
Sample sizes of 62 in each arm achieve 80% power to detect a difference of 0 when the non-inferiority 
difference is -0.12. The reference group proportion is 94%. The treatment group proportion is 
assumed to be 82% under the null hypothesis. The power was computed for the case when the actual 
treatment group proportion is 94%. The test statistic used is the one-sided Z test (unpooled). The 
significance level of the test is 2.5% (unilateral, 5% bilateral). 
Assuming a 10% drop-out rate, the sample size increases to 138 patients to test that the proportion of 
patients presenting with images of excellent and good quality in the Elucirem® arm is not inferior to 
the proportion of patients presenting with images of excellent and good quality in the Dotarem® arm. 
Main analyses: 
For the diagnostic quality of the CBV perfusion map: non-inferiority will be evaluated by testing 
whether the lower bound of the two-sided 95.2% Confidence Interval (CI) for difference of 
“Elucirem®– Dotarem®”, in proportion of patients presenting with images of excellent and good 
quality according to off-site readers, excludes a 12% difference. 
In particular, at the final analysis, for both arms the associated two-sided 95.2% CI for the difference 
will be estimated. 
Non-inferiority of Elucirem® over Dotarem® will be demonstrated, at the final analysis, if the lower 
bound of the two-sided 95.2% CI around the estimated differences in the primary endpoint, 
proportion of patients presenting with images of excellent and good quality, lies above -12%. 

 
 
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In case of conclusion of non-inferiority of Elucirem® compared to Dotarem®, the superiority of 
Elucirem® compared to Dotarem® will then be tested in the same way as described above for the non-
inferiority. 
The same analysis (and only at the final one) will be performed for on-site evaluations. 
An interim analysis will be performed when 50% of the patients will be assessed in terms of 
diagnostic quality of the CBV perfusion map. 
Non-inferiority of Elucirem® over Dotarem® will be evaluated by testing whether the lower bound of 
the two-sided 99.8% CI for difference of “Elucirem®– Dotarem®”, in proportion of patients 
presenting with images of excellent and good quality according to off-site readers, excludes a 12% 
difference. 
Again, if non-inferiority of Elucirem® is concluded at the interim analysis, the superiority of 
Elucirem® compared to Dotarem® will be tested in the same way as described above. 
For rCBV evaluated off-site, the Mann-Whitney U-test will be used to compare the two trial arms 
by tumor grade categorization (high grade on one hand and low grade on the other hand). 
The Mann-Whitney U-test will also be used to test the difference in rCBV between patients with high-
grade and low-grade gliomas, within each of the two study arms.  
These analyses will be performed according to the tumor grade categorization as per stratification 
(high grades versus low grades) and according to tumor grade categorization as per histological 
results. 
Categorization as per histological results will be the following: 
- 
Grade 1 and Grade 2 = Low grade, 
- 
Grade 3 and Grade 4 = High grade. 
For the assessment and evaluation of the T2* signal intensity time curve, off-site FWHM and the 
maximum signal drop will be compared between the trial arms using a Mann-Whitney U-test. 
Moreover, confidence in diagnosis based on the reliability of the curve will be presented for the two 
trial arms, for on-site and off-site read. 
Regarding safety, occurrence rates of AEs will be tabulated by trial arms and according to the causal 
relationship to the IMPs and the procedure itself. 

 
 
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TRIAL FLOW CHART 
Table 1: Trial flow chart 
 
Time points Evaluation/procedures 
Screening 
(V1) (1) 
MRI/Randomization (V2) 
Contrast injection  
Safety follow-
up (V3) (5) 
Record of histopathology 
results (Biopsy or surgery) 
≤7 days 
Prior to MRI 
MRI 
1 day after V2 
Within 30 days of V2 
Informed consent signature 
X 
 
 
 
 
Eligibility criteria 
X 
X 
 
 
 
Demographic data 
X 
 
 
 
 
Medical history 
X 
 
 
 
 
Patient Imaging history 
X 
 
 
 
 
Body weight 
 
X 
 
 
 
Concomitant treatments 
X 
 
Pregnancy test (2) 
X 
X 
 
 
 
Local creatinine and eGFR evaluation (3) 
X 
 
 
 
 
IMP injection 
 
 
X 
 
 
Imaging acquisition 
 
 
X 
 
 
Tumor grade diagnosis collection 
X 
 
 
 
X 
IWRS connection 
X 
X 
 
 
 
Adverse events collection (4) 
X 
Procedures/Therapeutic measures 
X 
 
(1) 
V1 can be performed on the same day as V2.  
(2) 
Urine pregnancy test (if applicable) is to be done on site. Results must be available and negative prior to IWRS connection and administration of IMP. In case V1 
and V2 are performed on the same day, only one pregnancy test is required. 
(3) 
eGFR is to be evaluated locally within 1 week before IMP administration. Results must be available prior to administration of IMP and must fulfill the 
corresponding inclusion criterion. 
(4) 
AEs occurring during the time of the patient’s participation in the trial, must be reported and followed as described in Table 3.  
(5) 
Visit 3 will be performed by phone 

 
 
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TRIAL DIAGRAM 
Figure 1: Trial diagram 
 
 

 
 
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ABBREVIATIONS 
 
AE 
 
Adverse Event 
AESI  
Adverse Event of Special Interest 
AR 
 
Adverse Reaction 
ARPS  
All Randomized Patients Set 
AS 
 
All slices 
ATC 
 
Anatomical Therapeutic Chemical 
BG 
 
Basal Ganglia 
BW 
 
Body Weight 
CBV 
 
Cerebral Blood Volume 
CGM  
Cortical normal appearing Gray Matter 
CI 
 
Confidence Interval 
CNS 
 
Central Nervous System 
CRA 
 
Clinical Research Associate 
CT 
 
Computed Tomography 
EC 
 
External Capsule 
eCRF  
electronic Case Report Form 
CRO 
 
Contract Research Organization 
CT 
 
Computerized Tomography 
DICOM 
Digital Imaging and Communication in Medicine 
DSC 
 
Dynamic Susceptibility Contrast 
DWM  
Deep normal appearing White Matter 
EPI 
 
Echo Planar Imaging 
FAS 
 
Full Analysis Set 
FLAIR  
Fluid Attenuated Inversion Recovery 
FWHM  
Full-Width at Half Maximum 
GBCA  
Gadolinium Based Contrast Agent 
GCP 
 
Good Clinical Practice 
eGFR  
estimated Glomerular Filtration Rate 
GRE 
 
Gradient Recalled Echo 
IBR 
 
Independent Blinded Reader 
IC 
 
Internal Capsule 
ICH 
 
International Conference on Harmonization 

 
 
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ICF 
 
Informed Consent Form 
ICL 
 
Imaging Core Lab 
ID 
 
Identification 
IEC 
 
Independent Ethics Committee 
IMP 
 
Investigational Medicinal Product 
INV 
 
Investigator 
IRB 
 
Institutional Review Board 
ISF 
 
Investigator Site File 
IUD 
 
Intra Uterine Device 
IUS 
 
Intra Uterine System 
IWRS  
Interactive Web Response System 
IV 
 
Intravenously 
LAM  
Lactational Amenorrhoea Method 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
 
Magnetic Resonance Imaging 
mL 
 
Milliliter 
NSF 
 
Nephrogenic Systemic Fibrosis 
PPS 
 
Per Protocol Set 
PT 
 
Preferred Term 
rCBV  
Relative CBV 
ROI 
 
Region Of Interest 
2S 
 
Not more than 2 slices 
SAE 
 
Serious Adverse Event 
SAR 
 
Serious Adverse Reaction 
SD 
 
Standard Deviation 
SCWM  
Sub-Cortical normal appearing White Matter 
SOC 
 
System Organ Class 
SS 
 
Safety Set 
SPS 
 
Screened Patient Set  
TEAE  
Treatment Emergent Adverse Event 
T(F)SE  
Transient (Fast) Spin Echo 
V 
 
Visit 
WHO  
World Health Organization 
 
 

 
 
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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ........................................................................................................................ 2 
TRIAL FLOW CHART .......................................................................................................................... 9 
TRIAL DIAGRAM ............................................................................................................................... 10 
SIGNATURE PAGE ............................................................................................................................. 11 
ABBREVIATIONS ............................................................................................................................... 12 
LIST OF TABLES ................................................................................................................................ 18 
LIST OF FIGURES ............................................................................................................................... 18 
1 
INTRODUCTION ........................................................................................................................ 19 
1.1 
Trial Rationale ....................................................................................................................... 19 
1.2 
Background ........................................................................................................................... 20 
1.3 
Benefit/Risk Assessment ....................................................................................................... 20 
2 
TRIAL OBJECTIVES .................................................................................................................. 20 
2.1 
Primary Objective .................................................................................................................. 20 
2.2 
Secondary Objectives ............................................................................................................ 20 
3 
TRIAL DESCRIPTION................................................................................................................ 21 
3.1 
Protocol Design ..................................................................................................................... 21 
3.2 
Justification for dose ............................................................................................................. 21 
3.3 
Trial Duration ........................................................................................................................ 22 
 
Duration of patients’ participation ................................................................................. 22 
 
End of trial ..................................................................................................................... 22 
3.4 
Interim Analysis .................................................................................................................... 22 
3.5 
Trial Committee(s) ................................................................................................................ 22 
4 
PATIENT SELECTION ............................................................................................................... 22 
4.1 
Inclusion Criteria ................................................................................................................... 22 
4.2 
Non-Inclusion Criteria ........................................................................................................... 23 
4.3 
Patient Identification ............................................................................................................. 24 
5 
INVESTIGATIONAL MEDICINAL PRODUCTS ..................................................................... 24 
5.1 
Investigational Medicinal Product(s) Description ................................................................. 24 
 
Investigational Medicinal Product 1 .............................................................................. 24 
 
Investigational Medicinal Product 2 .............................................................................. 25 
 
Precautions for use for both Investigational Medicinal Products .................................. 25 
5.2 
Packaging, Labeling, Storage ................................................................................................ 26 
5.3 
Condition of Investigational Medicinal Product Allocation .................................................. 26 
 
Investigational Product(s) Allocation / Randomization ................................................ 26 
 
Double-Blind Conditions ............................................................................................... 27 

 
 
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Individual Trial Treatment Unblinding ......................................................................... 27 
5.4 
Investigational Medicinal Product Management ................................................................... 27 
5.5 
Auxiliary Medicinal Product(s) and Other Trial Products .................................................... 27 
5.6 
Trial Product(s) Compliance and Accountability .................................................................. 27 
6 
CONCOMITANT MEDICATIONS / PROCEDURES ............................................................... 28 
6.1 
Concomitant Medications ...................................................................................................... 28 
 
Concomitant Medications of Special Attention ............................................................. 28 
 
Prohibited Concomitant Medications ............................................................................ 28 
6.2 
Concomitant Procedures ........................................................................................................ 28 
7 
EVALUATION CRITERIA ......................................................................................................... 29 
7.1 
Primary Criterion ................................................................................................................... 29 
7.2 
Secondary Criteria ................................................................................................................. 29 
 
Diagnostic quality of CBV map .................................................................................... 29 
 
Assessment of rCBV and T2* signal intensity time curve ............................................ 29 
 
Recording of Adverse events ......................................................................................... 30 
8 
TRIAL SCHEDULE AND PROCEDURES ................................................................................ 31 
8.1 
Trial Schedule ........................................................................................................................ 31 
 
Screening Visit – Visit 1 – Day (- 7) to Day 1 .............................................................. 31 
 
MRI/Randomization Visit – Visit 2 – Day 1 ................................................................. 32 
 
Safety Visit – Visit 3 – 1 day post visit 2 ...................................................................... 32 
 
Record of histopathology results – Within 30 days of V2............................................. 32 
8.2 
Imaging Characteristics ......................................................................................................... 33 
 
Equipment ..................................................................................................................... 33 
 
Imaging protocol ........................................................................................................... 33 
8.3 
On-Site Reading of Images ................................................................................................... 33 
8.4 
Off-Site Reading of Images ................................................................................................... 33 
 
Manuals and Supplies .................................................................................................... 34 
 
Site Qualification ........................................................................................................... 34 
 
Receipt and Tracking of Images .................................................................................... 34 
 
Perfusion post processing software ............................................................................... 34 
 
Image Processing and Quality Check ............................................................................ 35 
 
Independent Blinded Readers Training ......................................................................... 35 
 
Image Randomization .................................................................................................... 35 
 
Blinded Assessment of Images ...................................................................................... 35 
 
Inter & Intra-reader Variability Assessment ................................................................. 36 
 
Lesion tracking/Matching .............................................................................................. 36 

 
 
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Image Archive and Final Deliverables .......................................................................... 36 
9 
SAFETY REPORTING ................................................................................................................ 36 
9.1 
Adverse Event ....................................................................................................................... 36 
 
Definition of Adverse Event .......................................................................................... 36 
 
Collection and recording of Adverse Events ................................................................. 37 
 
Description of Adverse Events ...................................................................................... 38 
9.2 
Serious Adverse Event .......................................................................................................... 39 
 
Definition of Serious Adverse Event ............................................................................. 39 
 
Reporting Serious Adverse Events (SAE) ..................................................................... 40 
9.3 
Special situations ................................................................................................................... 41 
 
Cases of overdose, lack of efficacy, interaction with drug or device, medication errors or 
misuses 41 
 
Pregnancy ...................................................................................................................... 41 
 
Adverse Events of Special Interest ................................................................................ 42 
 
Any suspicion of transmission of an infectious agent via an IMP ................................ 42 
9.4 
Other important safety issue / new fact ................................................................................. 42 
9.5 
Unblinding Procedures .......................................................................................................... 43 
10 
SCREEN FAILURE AND PREMATURE DISCONTINUATION............................................. 43 
10.1 
Screen failure ......................................................................................................................... 43 
10.2 
Premature Discontinuation of the trial per Guerbet Decision ............................................... 43 
10.3 
Premature discontinuation of the patient ............................................................................... 43 
10.4 
Reasons for patient’s screening failure and premature discontinuation ................................ 43 
10.5 
Enrolment of additional patient/ healthy volunteer/subject: .................................................. 44 
11 
STATISTICAL CONSIDERATIONS ......................................................................................... 44 
11.1 
Statistical Method .................................................................................................................. 44 
11.2 
Sample Size ........................................................................................................................... 45 
11.3 
Planned Analysis ................................................................................................................... 45 
 
Disposition of patients/ healthy volunteers/subjects ..................................................... 45 
 
Data Sets Analyzed........................................................................................................ 46 
 
Protocol Deviations ....................................................................................................... 46 
 
Demographics and Baseline Characteristics .................................................................. 46 
 
Compliance .................................................................................................................... 47 
 
Efficacy Analysis........................................................................................................... 47 
 
Adverse Event ............................................................................................................... 49 
 
Laboratory data .............................................................................................................. 50 
 
Other safety observations .............................................................................................. 50 

 
 
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11.4 
Specific Statistical Analytical considerations (not applicable for trial including only 
descriptive analysis) .......................................................................................................................... 51 
 
Adjustments for Covariates ........................................................................................... 51 
 
Handling of Dropouts or Missing Data ......................................................................... 51 
 
Interim Analyses ............................................................................................................ 51 
 
Multicentre Trial ............................................................................................................ 51 
 
Multiple Comparisons/Multiplicity ............................................................................... 51 
 
Use of an "Efficacy Subset" of patients/ healthy volunteers/subjects ........................... 52 
 
Examination of Subgroups ............................................................................................ 52 
12 
TRIAL COMMITTEES................................................................................................................ 52 
13 
ETHICAL AND REGULATORY CONSIDERATIONS ............................................................ 52 
13.1 
References ............................................................................................................................. 52 
13.2 
Institutional Review Board/Independent Ethics Committee and Regulatory/Competent 
Authorities ......................................................................................................................................... 53 
13.3 
Patient Informed Consent ...................................................................................................... 54 
13.4 
Trial Records and Archiving ................................................................................................. 54 
14 
QUALITY CONTROL / QUALITY ASSURANCE ................................................................... 55 
14.1 
Direct Access to Source Data/Documents ............................................................................. 55 
14.2 
Clinical Monitoring ............................................................................................................... 55 
14.3 
Clinical Data Handling .......................................................................................................... 56 
 
Data Reported in the eCRF ............................................................................................ 56 
 
Data Reported in the eCRF according to patient Status ................................................ 56 
 
Data Management System ............................................................................................. 56 
14.4 
Audits and Inspections .......................................................................................................... 56 
15 
PUBLICATIONS RULES ............................................................................................................ 57 
16 
REFERENCES ............................................................................................................................. 57 
17 
COMPANY LIABILITY INSURANCE ...................................................................................... 59 
18 
APPENDICES .............................................................................................................................. 59 
 
 
 

 
 
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LIST OF TABLES 
Table 1: Trial flow chart 
Table 2: Allocation of imaging evaluation criteria assessment per type of reader 
Table 3: Collection and reporting of AEs throughout and after the trial 
Table 4: Agreement according to Cohen kappa (κ) statistics 
 
LIST OF FIGURES 
Figure 1: Trial diagram 
 

 
 
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1 
INTRODUCTION  
1.1 
Trial Rationale 
Gliomas are the most common primary intracranial tumors, representing 81% of malignant brain tumors 
[1]. They are considered the most rapidly growing malignancies of the central nervous system, with 
glioblastoma comprising more than 50% of all gliomas. Early and accurate tumor diagnosis and 
classification is essential for patient care management, as treatment modalities will significantly differ 
according to the glioma grade. 
 
Perfusion MRI provides additional information to conventional MRI [2]. This MRI technique can be 
used to image neovascularization, a hallmark of tumor progression. In this way, perfusion MRI helps to 
characterize brain gliomas [3]. Perfusion MRI sequence is implemented in the standard imaging protocol 
of a large number of sites in USA and in Europe [4; 5]. Among MRI perfusion techniques, Dynamic 
Susceptibility Contrast MRI is the most used perfusion method. 
 
DSC-MRI is a technique in which the first pass of a bolus of GBCA through brain tissue is monitored 
by a series of T2- or T2*-weighted MR images [6]. The susceptibility effect of the paramagnetic contrast 
agent leads to a signal loss in the signal intensity-time curve. Using a signal model for susceptibility 
contrast, the signal information can be converted into a contrast medium concentration -time curve on a 
voxel-by-voxel basis. Various hemodynamic parameters can be calculated from the concentration-time 
curve. Among them, relative CBV (rCBV) is the most used parameters. The ratio of rCBV in lesions 
and in contralateral normal-appearing white matter is often calculated for quantification. It is commonly 
accepted that CBV reflects tumor neoangiogenesis and correlates with glioma grade [7]. Glioblastoma 
presents with elevated rCBV due to increased cellular proliferation. 
 
Most DSC perfusion studies are performed using GBCA at 0.1 mmol/kg. Yet there are several reasons 
for considering reduction of GBCA dose for brain DSC perfusion. The main reasons are safety concerns 
such as the development of Nephrogenic Systemic Fibrosis (NSF) in at-risk subjects with impaired renal 
function [8; 9] and the potential retention of gadolinium in tissues even in subjects with normal renal 
function [10-15]. 
In the context of the necessity to perform multiple contrast-enhanced MR imaging applications, the use 
of half dose of gadolinium is to be considered. 
 
Some studies with other GBCA have shown that reduced-contrast-dose (0.05 mmol/kg) DSC perfusion 
of the brain is comparable with those of the full-dose protocol in terms of diagnostic quality of perfusion 
CBV maps [16; 17]. In addition, no significant difference in CBV mean value was found. 
 
Elucirem® (gadopiclenol) is a new chemical entity discovered and developed by Guerbet. It is a non-
ionic macrocyclic gadolinium complex, of high kinetic stability, intended to be used in human, by 
intravenous administration, as a contrast agent for MRI with variable indications. Its safety and efficacy 
when used at the dose of 0.05 mmol/kg body weight (BW) in adults and in children of 2 years and older 
have been proven through the global clinical development program of gadopiclenol. 
 
The present clinical trial aims to study the performance of Elucirem® at 0.05 mmol/kg in DSC-MRI 
perfusion of brain gliomas and to demonstrate that it is as efficient as Dotarem® at 0.1 mmol/kg for 
qualitative and quantitative CBV perfusion evaluation. 
 

 
 
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1.2 
Background 
During the global clinical development program of Elucirem® nine studies were conducted since 2013. 
In total more than 1 065 patients/healthy volunteers were exposed to Elucirem® at different doses (up to 
0.3 mmol/kg). A Phase IIb trial has been conducted in 280 adults with CNS diseases. This was a dose-
response trial with a cross-over design allowing the comparison of contrast quality provided by each of 
the 4 tested gadopiclenol doses (0.025, 0.05, 0.1 and 0.2 mmol/kg) towards gadobenate dimeglumine at 
the dose of 0.1 mmol/kg. Elucirem® at 0.05 mmol/kg was identified as the lowest dose showing efficacy 
similar to the reference product [18]. In a randomized phase III trial including 256 randomized CNS 
patients, the non-inferiority of gadopiclenol at 0.05 mmol/kg compared to gadobutrol at 0.1 mmol/kg in 
terms of lesion visualization was demonstrated and a good safety profile was observed. 
 
1.3 
Benefit/Risk Assessment 
Patient may not receive direct benefit for participating in this research. 
 
The following potential safety concerns were identified for surveillance based on currently available 
nonclinical and clinical study data and therapeutic class effects for both trial products: 
- 
Injection site tolerance 
- 
Nephrogenic Systemic Fibrosis 
- 
Hypersensitivity 
- 
Seizures 
- 
Nephrotoxicity 
- 
Gadolinium deposition in brain and other organs/tissues 
Minimization measures have been implemented in this protocol for any of those concerns (section 
5.1.3). 
 
2 
TRIAL OBJECTIVES 
2.1 
Primary Objective 
To demonstrate the non-inferiority of DSC-MRI perfusion using Elucirem® at 0.05 mmol/kg compared 
to DSC-MRI perfusion using Dotarem® at 0.1 mmol/kg in terms of diagnostic quality of CBV perfusion 
map (off-site assessment). 
 
2.2 
Secondary Objectives 
 
To evaluate the diagnostic quality of CBV perfusion map for Elucirem® and Dotarem® (on-site 
assessment) 
 
 
To compare the performance of DSC-MRI perfusion using Elucirem® at 0.05 mmol/kg to DSC-
MRI using Dotarem® at 0.1 mmol/kg in differentiating glioma grade through the quantification 
of the relative CBV (off-site assessment) 
 
 
To assess the reliability of the T2* signal intensity time curve in terms of confidence in diagnosis 
in DSC-MRI perfusion using Elucirem® at 0.05 mmol/kg (on-site and off-site assessments) 
 

 
 
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 
To expand the previously established safety profile of Elucirem® at 0.05 mmol/kg in terms of 
incidence of adverse events 
 
 
3 
TRIAL DESCRIPTION 
3.1 
Protocol Design 
The trial is designed as a prospective, multi-center, randomized, controlled and parallel group 
comparison. 
Once informed consent form (ICF) signed, the patients will perform a screening visit (V1) to confirm 
trial eligibility. The eligible patients will be randomized by Interactive Web Response System (IWRS) 
to determine the IMP to be injected. They will undergo a DSC-MRI perfusion using Elucirem® or 
Dotarem® (MRI visit - V2). A safety visit (V3) will be performed 1 day after the MRI visit by phone. 
Confirmation of tumor grade diagnosis, if available, will be collected up to 30 days after visit 2. 
The randomization scheme will allocate patients in a 1:1 ratio to the two parallel arms. Stratification by 
glioma grades (low grades versus high grades) between the two arms will be managed by IWRS based 
on the diagnosis collected at screening. 
Images will be evaluated by both on-site and off-site readers.  
For on-site reads, at least one experienced neuroradiologist will be appointed in each investigational site 
at the start of the trial to read perfusion images of patients included at the site. 
For off-site reads, all images will be sent to an Imaging Core Laboratory (ICL) which will prepare the 
images for evaluation. The off-site images evaluation will be performed by two IBR experienced in 
perfusion MRI and brain tumors. In case of discordance, a consensus meeting will be organised in order 
to reach an agreement. 
An imaging eCRF will be used to ensure that the images are properly aligned and to ensure that all 
necessary data for the trial purpose are documented by the independent blinded readers. 
For this study, only off-site readers will be blinded to the nature of the IMP injected.  
The diagnosis obtained from previous (qualifying) imaging examinations will be considered as medical 
history to assess inclusion criteria. All the trial analyses will be only based on the images obtained 
through the trial MRI. 
During the trial, the safety of the patients will be monitored and assessed based on the reporting of 
adverse events (AE). 
This trial will be an international trial conducted in several European countries. 
 
3.2 
Justification for dose 
The safe and lowest effective clinical dose of gadopiclenol identified in phase IIb trial and confirmed 
by the results of the two phase III trials is 0.05 mmol/kg body weight. This dose will be used for 
gadopiclenol for this trial. 
Dotarem® will be used, as an active comparator, at its standard approved dose of 0.1 mmol/kg BW. 
 

 
 
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3.3 
Trial Duration 
 Duration of patients’ participation 
Minimum trial duration for patients: 2 days, if V1 and V2 are done on the same day. 
Maximum trial duration for patients: 9 days, if the screening period lasts 7 days. 
Maximum trial duration for collection of data: 37 days, if the screening period lasts 7 days and a biopsy 
or surgery is done 30 days after the MRI. 
The trial includes a maximum of 3 visits and the record of histopathology results: 
 
Screening visit (V1): up to 7 days prior to inclusion (V1 could be done on the same day as the 
imaging visit (V2) if all the inclusion/non-inclusion criteria are met). 
 
 
MRI/Randomization visit (V2): the visit will consist of Elucirem® or Dotarem® injection and 
MRI procedure 
 
 
Safety visit (V3): 1 day after MRI examination 
Record of histopathology results from a biopsy or a surgery will be done up to 30 days after the MRI 
examination. 
 
 End of trial  
The trial is considered as completed once all the images collected for all the patients have been reviewed 
by all independent blinded readers and the histopathology results (if any) have been obtained. The 
patient’s participation is defined as the period from the screening visit (ICF signature) to the last visit. 
 
3.4 
Interim Analysis 
An interim analysis will be performed when 50% of the patients will be assessed in terms of diagnostic 
quality of images by the off-site readers. 
 
3.5 
Trial Committee(s) 
An internal committee will assess efficacy results when the results of the interim analysis will be 
available. See section 12 for details. 
 
4 
PATIENT SELECTION 
Prospective approval of any types of protocol deviations, also known as protocol waivers or exemptions, 
is not permitted. 
 
4.1 
Inclusion Criteria 
To be included in the trial, the patient must meet all these inclusion criteria. 
1. 
Female or male adult patient (patient having reached legal majority age). 

 
 
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2. 
Patient with naive or recurrent primary glial tumor detected at a previous CT or MR imaging, and 
scheduled for a follow-up contrast-enhanced MRI. Tumor grade (confirmed or highly suspected) 
should be available in patients’ medical records. 
3. 
Patient or, if the patient is unable to provide informed consent, the patient’s legally acceptable 
representative, having read the information and having provided patient’s consent to participate in 
writing by dating and signing the informed consent prior to any trial related procedure being 
conducted. 
4. 
Patient affiliated to national health insurance according to local regulatory requirements. 
 
4.2 
Non-Inclusion Criteria 
Patient presenting with one or more of the following non-inclusion criteria must not be included in the 
trial: 
1. 
Patient with known contra-indication(s) to the use or with known sensitivity to one of the products 
under investigation or to other GBCAs (such as hypersensitivity, post-contrast acute kidney injury). 
  
2. 
Patient presenting with any contraindication to MRI examinations. 
 
3. 
Post treatment patient presenting with pseudo-progression instead of tumor recurrency. 
 
4. 
Patient presenting with severe renal insufficiency, defined as an estimated Glomerular Filtration 
Rate (eGFR) < 30 mL/min/1.73 m² assessed within 1 week prior to contrast agent injection. 
 
5. 
Patient having received any contrast agent (MRI or CT) within 3 days prior to IMP administration 
or scheduled to receive any contrast agent within 24 hours after IMP administration. 
 
6. 
Pregnant female patient (a female patient of childbearing potential or with amenorrhea for less than 
12 months must have a negative pregnancy test within 1 day prior to trial MRI and must be using 
medically approved contraception method* until the last trial visit). 
 
7. 
Patient having received any investigational medicinal product within 7 days prior to trial entry or 
scheduled to receive any investigational treatment in the course of the trial. 
 
8. 
Patient previously randomized in this trial. 
 
9. 
Patient with anticipated, current or past condition (medical, psychological, social or geographical) 
that would compromise the patient’s safety or her/his ability to participate in the trial. 
 
10. Patient unlikely to comply with the protocol, e.g., uncooperative attitude, inability to return for 
follow-up visits and/or unlikelihood of completing the trial. 
 
11. Patient related to the investigator or any other trial staff or relative directly involved in the trial 
conduct. 
 
*Highly effective birth controlled method includes: abstinence (defined as refraining from heterosexual 
intercourse during the entire trial participation), female sterilization (sterilization methods include 
hysterectomy, bilateral salpingectomy and bilateral oophorectomy),  combined (estrogen and 
progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, 
intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of 
ovulation (oral, injectable, implantable), intrauterine device (IUD), intrauterine hormone-releasing 
system (IUS), bilateral tubal occlusion, vasectomized partner (vasectomized partner is a highly effective 

 
 
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birth control method provided that partner is the sole sexual partner of the female patient and that the 
vasectomized partner has received medical assessment of the surgical success.). Periodic abstinence 
(calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, 
and lactational amenorrhoea method (LAM) are not acceptable methods of contraception. Female 
condom and male condom should not be used together. 
 
4.3 
Patient Identification 
After having signed the written informed consent, patients will be allocated a unique Identification 
Number (patient ID). 
Any patient who has signed an informed consent will be considered as a ‘screened’ patient. 
This patient ID will contain 8 digits: the first three digits corresponding to the country number (code 
ISO 3166-1 numeric) the following two digits corresponding to the site number, which are attributed at 
the beginning of the trial, and the last three digits being chronologically implemented depending on 
patient screening. The lowest screening number will correspond to the first patient screened at this site 
and the highest number to the last patient screened. 
 
5 
INVESTIGATIONAL MEDICINAL PRODUCTS 
Investigational Medicinal Product(s) (IMP) will be manufactured, labeled, packaged and released in 
accordance with: 
- European Directive 2003/94/EC laying down the principles and guidelines of good 
manufacturing practice in respect of medicinal products for human use and investigational 
medicinal products for human use 
- EudraLex, The Rules Governing Medicinal Products in the European Union, Volume 4, EU 
Guidelines to Good Manufacturing Practice - Medicinal Products for Human and Veterinary 
Use, Annex 13 Investigational Medicinal Products 
- US Food and Drug Administration, Title 21 Code of Federal Regulations Part 211 on Current 
Good Manufacturing Practice for Finished Pharmaceuticals 
In addition, the IMP manufacturing, packaging, labeling and release will comply with any local 
applicable regulatory requirement. 
The IMP will consist of 1 vial packaged in a carton box with a single use detachable label that will allow 
ensuring accuracy of IMP allocation per patient. 
 
5.1 
Investigational Medicinal Product(s) Description 
 Investigational Medicinal Product 1 
Name: Elucirem® (formulation G03277) 
Pharmaceutical form: 20-mL vial containing 15 mL of solution presented as a sterile, clear, ready-to-
use aqueous solution for injection. 
Concentration: 0.5 M  
Route and method of administration: 

 
 
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Elucirem® will be intravenously (IV) administered at 0.05 mmol/kg using a power injector at the 
injection rate of minimum 4 mL/second followed by a 20-mL 0.9% saline flush at the same injection 
rate. 
Preload bolus is allowed. If applied, the total dose (preload bolus + main bolus) of Elucirem® should not 
exceed 0.05 mmol/kg. The volume of the preload bolus, if any, should be collected in eCRF. Sufficient 
IMP must be allocated to one patient by IWRS. 
Please refer to the Investigator Brochure for more information on Elucirem®. 
 
 Investigational Medicinal Product 2 
Name: Dotarem® (gadoterate meglumine) 
Pharmaceutical form: 20-mL vial containing 20 mL of solution presented as a sterile, clear, ready-to-
use aqueous solution for injection. 
Concentration: 0.5 M  
Route and method of administration: 
Dotarem® will be intravenously (IV) administered at 0.1 mmol/kg using a power injector at an injection 
rate of minimum 4 mL/second followed by a 20-mL 0.9% saline flush at the same injection rate. 
Preload bolus is allowed. If applied, the total dose (preload bolus + main bolus) of Dotarem® should not 
exceed 0.1 mmol/kg. 
Sufficient IMP must be allocated to one patient by IWRS. 
Please refer to the SmPC for more information on Dotarem®. 
 
 Precautions for use for both Investigational Medicinal Products 
Injection site tolerance 
Caution during administration is necessary to avoid any extravasation. In case of extravasation, the 
injection must be stopped immediately. In case of local reactions, evaluation and treatment should be 
carried out as necessary. 
 
Hypersensitivity 
As with other GBCAs, hypersensitivity reactions may occur with Elucirem® and could be life-
threatening. Hypersensitivity reactions may be either allergic (described as anaphylactic reactions when 
serious) or non-allergic. They can be either immediate (less than 60 minutes) or delayed (up to 7 days). 
Anaphylactic reactions occur immediately and can be fatal. They are independent of the dose, can occur 
after even the first dose of the product, and are often unpredictable. 
During the examination, supervision by a physician is necessary. If hypersensitivity reactions occur, 
administration of the contrast medium must be discontinued immediately and – if necessary - specific 
therapy instituted. A venous access should thus be kept during the entire examination. In order to permit 
immediate emergency countermeasures, appropriate drugs (e.g. epinephrine and antihistamines), an 
endotracheal tube and a respirator should be ready at hand. 
The risk of hypersensitivity reactions may be higher in patients with history of: 
- Previous reaction to a GBCA. 
- Bronchial asthma 
- Allergy 

 
 
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As with other GBCAs, there is a possibility that the injection of Elucirem® or Dotarem® may aggravate 
symptoms of an existing asthma. In patients with asthma unbalanced by the treatment, the decision to 
use Elucirem® must be made after careful evaluation of the benefit/risk ratio. 
 
Seizures 
As with other GBCAs, special caution is necessary in patients with a lowered threshold for seizures. All 
equipment and drugs necessary to counter any convulsion which may occur must be made ready for use 
beforehand. 
 
5.2 
Packaging, Labeling, Storage 
Packaging and labeling will be performed in strict accordance with the local regulatory specifications 
and requirements. 
The packaging and labeling of Elucirem® and Dotarem® will be performed by Guerbet (or its designee).  
In addition to the usual and regulatory labeling for clinical studies, each IMP will have a white 
detachable sticker indicating the protocol number, IMP number, batch number, patient number as well 
as locally required information. This label will be stuck on the patient file or trial documentation. 
IMP will consist in a box that contains one 20-mL vial containing 15 mL of Elucirem® or 20 mL of 
Dotarem®. 
All IMPs will be stored in a secure place, under the responsibility of the Investigator or other authorized 
individuals. The IMPs should be stored at a temperature of 30°C or below. It should not be frozen. 
At the time of the trial completion, all used (including empty vials) and unused IMPs should have been 
returned to Guerbet or to the predefined location for storage before destruction. 
 
5.3 
Condition of Investigational Medicinal Product Allocation 
 Investigational Product(s) Allocation / Randomization 
At visit 2, the patients will be randomly assigned to one of the two arms. One arm consists of the use of 
Elucirem® as contrast agent, the other arm consists in the use of Dotarem® as contrast agent (see Figure 
1). 
The randomization scheme will allocate patients in a 1:1 ratio to the two parallel arms. Stratification by 
glioma grades (low grades versus high grades) between the two arms will be managed by IWRS based 
on the diagnosis collected at screening. 
At visit 2, once all the inclusion /non-inclusion criteria have been checked, the site should log onto the 
IWRS which will allocate IMP(s) number available at the site. This/these IMP(s) will correspond to the 
contrast medium allocated for the enhanced MRI procedure. 
In case of problem of IMP allocation (e.g. wrong IMP administered to a patient), the site must 
immediately report the incident into IWRS and to Guerbet’s representative in order to ensure that all 
corrective actions are taken. Corrective actions may include transferring the IMP to quarantine to 
prevent further IMP allocation by the site until the situation is under control again. Detailed instructions 
can be found in the IWRS manual provided to the sites. 
 

 
 
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 Double-Blind Conditions 
Off-site image readings of all patients will be evaluated in blinded conditions regarding the contrast 
agent injected as described in Section 8.4. This is to ensure that there is no bias in the evaluation of the 
primary criterion. 
Except off-site readers, all parties will be open. 
 
 Individual Trial Treatment Unblinding 
Not applicable 
 
5.4 
Investigational Medicinal Product Management 
The investigator, the hospital pharmacist, or other personnel allowed to store and dispense IMP(s) is 
responsible for ensuring that the IMP used in the clinical trial is securely maintained as specified by 
Guerbet and in accordance with the applicable regulatory requirements. 
Any quality issue noticed with the receipt or use of an IMP (deficient IMP in condition, appearance, 
pertaining documentation, labeling, expiry date, etc.) should be promptly notified to Guerbet, who will 
initiate a complaint procedure. 
Under no circumstances shall the investigator supply IMP to a third party, allows the IMP to be used 
other than as directed by this clinical trial protocol, or dispose of IMP in any other manner. 
 
5.5 
Auxiliary Medicinal Product(s) and Other Trial Products 
Not applicable 
 
5.6 
Trial Product(s) Compliance and Accountability 
The investigator, the hospital pharmacist, or other allowed personnel, designated by the investigator, 
will keep accurate records of IMPs accountability at site level as well as accurate records of the batch 
numbers and quantities of the IMP given to each patient. 
The dosing information will be recorded in individual patient’s records. When protocol required IMP 
administration conditions are not followed, reason(s) will be given and recorded by the investigator in 
patient’s source document and eCRF. 
The volume (mL) of IMP to be injected to the patients will be rounded as per the following rule: 
 
If decimal is <0.5, volume is rounded to the inferior value (e.g.: from 15.4 mL to 15 
mL) 
 
If decimal is ≥ 0.5, volume is rounded to the superior value (e.g.: from 15.8 mL to 16 
mL) 

 
 
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6 
CONCOMITANT MEDICATIONS / PROCEDURES 
6.1 
Concomitant Medications 
Any medication, including homeopathic products, premedication, over-the-counter medications, as well 
as prescription drugs, on-going at the time of patient’s informed consent signed or administered during 
the trial will be recorded in the patient’s eCRF. The following information must be provided:  
- 
Drug (brand name or generic name)  
- 
Route of administration 
- 
Purpose (medical history/trial disease/AE/pre-medication/contraception/prophylaxis) 
- 
Indication  
- 
Start/end period: before administration, after administration, ongoing at the end of the trial. 
 
 Concomitant Medications of Special Attention 
Currently, no treatment has been identified that is capable of preventing an allergic reaction with any 
GBCA. Thus, no pre-treatment of any nature will be recommended before contrast-enhanced MRI. 
Nevertheless, if the investigator decides to premedicate a patient, the treatment must be documented in 
the medical file and then in the clinical eCRF. 
Beta-blockers, vasoactive substances, angiotensin-converting enzyme inhibitors, angiotensin II receptor 
antagonists: these medicinal products decrease the efficacy of the mechanisms of cardiovascular 
compensation for blood pressure disorders: the radiologist must be informed before injection of 
gadolinium complexes, and resuscitation equipment must be at hand. 
 
According to current knowledge, there is no other concomitant treatment of special attention in that trial. 
However, warnings and precautions for use of the concomitant treatments taken by the patient should 
be considered. 
 
 Prohibited Concomitant Medications 
Any contrast agent (MRI or CT) within 3 days prior to trial products administration and during the 
course of the trial or within 24 hours after the trial product administration are prohibited. 
 
6.2 
Concomitant Procedures 
Not applicable 
 
 
 

 
 
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7 
EVALUATION CRITERIA 
CBV map will be generated through post-processing software for each DSC-MRI perfusion.  
Technical adequacy of images will be determined by on-site and off-site readers using a 4-point scale 
with the following grades: non-diagnostic, poor, fair, good. Images are to be considered technically 
adequate if evaluation is possible despite any artifacts that might partially compromise image quality. 
Images are considered technically non diagnostic if artifacts completely compromise image 
interpretability. 
The major artifact according to the list below will be recorded: 
1 = Movement artifacts  
2 = T2* artifacts 
3 = EPI distortion 
4 = Other, to be specified 
 
Only for images considered technically adequate, the evaluations of primary and secondary criteria will 
be performed. 
 
7.1 
Primary Criterion 
Diagnostic quality of CBV map generated will be assessed by off-site readers according to the following 
4-point scale: 
1: Poor: IC; EC; BG not distinguishable & CGM; SCWM; DWM not distinguishable 
2: Fair: IC; EC; BG partially distinguishable on AS & CGM; SCWM; DWM partially 
distinguishable on 2S 
3: Good: IC; EC; BG well distinguishable on 2S & CGM; SCWM; DWM well distinguishable 
on 2S 
4: Excellent: IC; EC; BG well distinguishable on AS & CGM; SCWM; DWM well 
distinguishable on 2S 
IC=Internal Capsule; EC=External Capsule; BG=Basal Ganglia; CGM=Cortical Normal Appearing 
Gray Matter; SCWM=Sub-Cortical Normal Appearing White Matter; DWM=Deep Normal Appearing 
White Matter; AS=all slices; 2S=not more than 2 slices. 
 
7.2 
Secondary Criteria 
 Diagnostic quality of CBV map  
Diagnostic quality of CBV map will be assessed by on-site readers according to the 4-point scale 
poor/fair/good/excellent as described in section 7.1. 
 
 Assessment of rCBV and T2* signal intensity time curve 
7.2.2.1 Quantification of the relative CBV for differentiating tumor grade (off-site 
assessment) 
For each DSC-MRI perfusion, the rCBV will be calculated on the generated CBV perfusion map. The 
regions of interest (ROIs) will be placed by off-site readers on the tumor for providing tumor CBV and 
also on normal tissue (contralateral normal-appearing white matter) for providing referenced CBV. 

 
 
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To be sure that the imaged tumor is the same as the tumor biopsied, localization and size of the tumor 
assessed by the off-site readers will be matched with the standard of truth for grading gliomas. Standard 
of truth will be histopathological results collected on site (diagnosis based on 2021 WHO classification 
of CNS tumors). 
 
7.2.2.2 Evaluation of the T2* signal intensity time curve and assessment (on-site and off-site 
assessment) 
T2* signal intensity time curve will be visually assessed by on-site and off-site readers for the reliability 
of the curve in providing sufficient information for diagnosis purpose. If the curve is assessed as reliable, 
the full-width at half-maximum (FWHM) and the maximum signal drop will be measured by off-site 
readers only. 
Readers will record their confidence in diagnosis based on the reliability of the curve using a 5-point 
scale: 
1 = nil: very uncertain 
2 = poor: uncertain 
3 = moderate: moderately certain 
4 = high: good certainty  
5 = excellent: very certain 
 
An overview of the imaging evaluation criteria to be assessed by the on-site reader (investigator (INV)) 
and the Independent Blinded Readers (IBR) is provided in the table below: 
Table 2: Allocation of imaging evaluation criteria assessment per type of reader 
Evaluation criteria 
Readers 
Technical adequacy of CBV map 
IBR/INV 
Diagnostic quality of CBV map 
IBR/INV 
r-CBV quantification 
IBR 
Visual assessment of T2* signal 
intensity time curve  
IBR/INV 
Maximum signal drop and FWHM 
T2* signal intensity time curve 
assessment  
IBR 
 
 
 Recording of Adverse events 
Adverse events (AE), serious or not, related to IMP or not, that occur from the beginning of patient’s 
participation in the trial (Informed Consent Form signature) will be recorded until the end of the 
participation (see section 9.1.2). 
In case of AE, the investigator should closely monitor patient safety for example through clinical 
laboratory parameters obtained locally as per site standard practice. 

 
 
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No vital signs and no lab parameters measurements (other than eGFR) are requested per the trial 
protocol, but investigators are encouraged to perform those measurements so that baseline values are 
available in case of adverse event occurrence. 
 
8 
TRIAL SCHEDULE AND PROCEDURES 
The schedule of time and events to be performed is given in Table 1. 
8.1 
Trial Schedule 
 Screening Visit – Visit 1 – Day (- 7) to Day 1 
During this visit, the following tasks or assessments will be performed: 
 Written informed consent will be obtained from the patient as described in section 13.3; 
 An Identification Number will be attributed to the patient via IWRS; 
 Checking of all eligibility criteria; 
 Demographic data (sex, self-reported race/ethnic data, age) will be collected; 
 Documentation of relevant medical history/current medical condition present before signing the 
informed consent including trial disease (naive/recurrent tumor, localization, tumor grade: low grade 
or high grade); 
 Documentation of the last CT or MRI detecting the trial disease; 
 Patient imaging history related to GBCA (previous examination(s), number of examinations, adverse 
reaction ); 
 Review and recording of concomitant treatments; 
 Blood sample collection for local dosage of serum creatinine and checking that eGFR is ≥ 30 
mL/min/1.73 m2. Can be done within 1 week prior to MRI. Results should be obtained prior to 
randomization. 
 A urine pregnancy test should be performed for all women of childbearing potential and must be 
negative. Results will be recorded on source documentation and reported in eCRF. 
 IWRS connection for recording the patient screening visit. 
 Trial MRI visit needs to be scheduled within 7 days (or can be performed on the same day if all the 
inclusion/non-inclusion criteria are met). 
 
If a patient is screen failed, this new patient status should be recorded in the IWRS. 
 

 
 
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 MRI/Randomization Visit – Visit 2 – Day 1 
During this visit, the following assessments or tasks will be performed: 
Procedures to be performed prior to IMP administration: 
 Checking of all the eligibility criteria; 
 Measurement of body weight; 
 Any changes in concomitant treatments/procedures/therapeutic measures since the last visit will be 
documented; 
 A urine pregnancy test should be performed for all women of childbearing potential and must be 
negative. Results will be recorded on source documentation and reported in eCRF. If V2 is done the 
same day as V1, only one test will be performed.  
 Assessment of AEs will be documented (see section 9); 
 IWRS connection will be done to randomize the patient and to obtain the IMPs box number. 
Unenhanced and contrast-enhanced MRI examinations: 
 Unenhanced and contrast-enhanced MRI will be performed according to the required sequences 
specified in section 8.2.2). 
 IMP (Elucirem® or Dotarem®) will be injected intravenously (IV) at the appropriate dose using a 
power injector with a flow rate of minimum 4 mL/second. This will be followed by a saline flush of 
a 20 mL bolus of 0.9% saline delivered at the same flow rate. Preload bolus is allowed. If applied, 
the total dose (preload bolus + main bolus) of IMP (Elucirem® or Dotarem®) should not exceed 0.05 
mmol/kg or 0.1 mmol/kg, respectively. 
 
 The following information will be documented in the source document and recorded in eCRF 
 
 : date and time of contrast agent injection, actual volume administered (documentation of difference 
from theoretical volume), actual injection rate, overdose (if any), number of vials dispensed, IMP 
box number(s), injection of saline flush (yes/no, volume), preload bolus (yes/no, volume). 
 
 Safety Visit – Visit 3 – 1 day post visit 2 
The safety visit (V3) will be performed by phone. During this visit, the following assessments or tasks 
will be performed: 
 
 
Use/change of concomitant treatments / procedures / therapeutic measures will be documented; 
 
 
Assessment of AEs will be documented. 
 
 Record of histopathology results – Within 30 days of V2 
For patients undergoing biopsy or surgery within 30 days of visit 2, the result of histopathology will be 
recorded. The date and type of exam (surgery, biopsy) as well as the tumor grade diagnosis are to be 
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8.2 
Imaging Characteristics 
 Equipment 
The imaging procedures will be performed using a MRI scanner, equipped with echo-planar imaging 
capabilities, that can perform the required sequences. 
MRI units with 1.5T or 3T magnetic field will be used regardless of the manufacturer. The following 
information must be recorded: the manufacturer and field strength of the MRI device. 
 
 Imaging protocol 
The same parameters setting for the same sequence should be used for unenhanced images and for 
contrast-enhanced images in each patient. 
The required sequences and parameters per patient for Elucirem® and Dotarem® should be as similar as 
possible. Details on required sequence and parameters will be provided in the Imaging Manual. 
Brain imaging protocol will include: 
Unenhanced sequences:  
 
Axial 3D T1WI GRE  
 
Axial 2D T2WI T(F)SE  
 
Axial 2D FLAIR 
 
Contrast-enhanced sequences:  
 
Perfusion imaging: Axial DSC T2* EPI  
 
Axial 3D T1WI GRE 
It is not allowed to add any sequence between contrast agent injection and perfusion imaging. 
 
8.3 
On-Site Reading of Images 
On-site image evaluations are image evaluations performed by investigators involved in the conduct of 
the protocol or in the care of the patients. 
For each investigational site, one neuroradiologist experienced in MRI perfusion and brain tumors will 
be appointed at the start of the trial to read images of patients included at the site. 
 
8.4 
Off-Site Reading of Images 
Off-site image evaluations are image evaluations performed at sites that have not otherwise been 
involved in the conduct of the trial and by readers who have not had contact with patients, investigators, 
or other individuals involved in the trial. 
Images will be evaluated by prospective evaluation of the blinded images in a centralized manner. All 
images will be sent to an imaging core laboratory (ICL), which will prepare the images for evaluation. 
The file headers of all the images transmitted in DICOM format are to be edited to remove patient or 
site identification. For all images, any sequence information will be removed. Scalar information in the 
MR images will be preserved. A complete audit trail of any changes to the file headers will be 
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The blinded image evaluations will be performed by 2 independent blinded readers experienced in brain 
tumor and perfusion imaging. In case of discordance, a consensus meeting will be organised in order to 
reach an agreement. The following criterion will be concerned by the consensus in case of discordance: 
- 
The localization of the lesion 
- 
The diagnostic quality of the CBV map (primary criterion). 
- 
rCBV quantification (consensus in the glioma grade, not in the rCBV value) 
- 
Visual evaluation of the T2* signal intensity time curve, including the confidence in the 
diagnosis. 
 
An imaging eCRF will be used to ensure that the images and the diagnostic findings are properly aligned 
and to ensure that all data necessary for the trial purpose are documented by the independent blinded 
readers. 
 
 Manuals and Supplies 
Guerbet (or the ICL) will document the imaging tasks and obligations of the investigational site in an 
Imaging Manual. As defined in section 8.2, the standardized image acquisition guidelines or imaging 
protocol will be provided to the sites as part of the Imaging Manual. 
In addition, the Imaging Manual will detail the steps required for masking confidential patient 
information and transferring images to the ICL (if applicable).  
Guerbet (or the ICL) will document the central imaging process in a Blinded Imaging Evaluation 
Charter. 
 
 Site Qualification 
Guerbet’s agent (Clinical Research Organization (CRO), ICL or monitors) will perform pre-trial site 
selection. This selection will allow to ensure that the imaging protocol can be performed by the site, are 
programmed and prepared prior to enrolment of the first patient and that the Imaging Manual will be 
accurately followed by the site. 
 
 Receipt and Tracking of Images 
Guerbet (or the ICL) will request that sites submit anonymous images to the ICL in a format that will 
be agreed prior to trial start. Images will be tracked in the database of the ICL. 
 
 Perfusion post processing software 
Perfusion sequences will be post processed by an adequate software, which allows CBV perfusion maps 
generation. Off-site evaluation will be performed using the same perfusion post processing software for 
the two IBR. 
Regarding the on-site evaluation, each investigating site will use its own perfusion post processing 
software. 
 

 
 
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 Image Processing and Quality Check 
Images received by the ICL as digital data will be translated to a standard format. This data translation 
step enables capturing direct digital data. Patient identifiers are confirmed as removed, and the original 
digital data from the site is archived and stored. 
The ICL will ensure that all imaging protocol requirements have been followed. In the event that a 
problem with an image is identified (e.g.: inappropriate anatomical coverage, inconsistency of images 
parameters with the imaging protocol, poor quality images), the investigational site will be notified 
concerning the nature of the problems and the steps required for corrective action. The ICL will follow-
up on all cases requiring remedial action by the sites. Guerbet (or the ICL) may conduct site training for 
investigator sites with recurring image quality issues. 
 
 Independent Blinded Readers Training 
Two independent readers with expertise in MRI perfusion of brain gliomas, with no participation in the 
trial and no affiliation with any institution where the trial will be conducted, will be selected for the off-
site reading. 
The independent readers will be trained to the trial and reading specifications. Before the readers start 
the readings, they will have to successfully complete training sessions (refer to “Blinded Imaging 
Evaluation Charter” for details). 
Independent readers are readers that are completely unaware of findings of other readers (including 
findings of other blinded readers and on-site investigators) and are readers who are not otherwise 
influenced by the findings of other readers. 
The term “independent” means that the readers involved in centralized review do not participate in 
image acquisition and images are read outside the image acquisition site. 
 
 Image Randomization 
When sufficient images are available for readings, a batch of images will be presented to the blinded 
readers. 
The patients within each batch will be ordered at random without stratification into groups of patients.  
 
 Blinded Assessment of Images 
Imaging database including all evaluable images will be assessed by the independent readers. The 
reading will be performed in a strictly fully blinded manner. 
No communication on patient specific image findings will be allowed between the independent readers 
once the blinded reviews begin. 
To ensure that the centralized reading evaluations remain independent, each individual reader evaluation 
will be locked as they occur (i.e., it will not be possible to alter the evaluation locked). 
In case of discordance between the two readers, a consensus meeting will be organized in order to reach 
an agreement. The process will be described in the blinded Imaging Evaluation Charter. 
 

 
 
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 Inter & Intra-reader Variability Assessment 
The assessments of inter- and intra-reader variability will be done for the primary evaluation criteria in 
the final analysis. 
Inter-reader variability will be evaluated on the whole set of trial patients, since each patient will be read 
by two different readers. 
Intra-reader variability: individual readers will perform repeat image evaluations of 10% of cases 
randomly determined. The cases used for intra-reader variability assessment will be re-introduced 
randomly and re-read during the course of the reading. To minimize recall bias, intra-reader variability 
will be assessed after an enough number of cases are reviewed and no sooner than two weeks from the 
original reviews of these patients. Results of the original reviews for these cases will not be available to 
the reader. Only the first evaluation of a given image set will be included in the efficacy analysis. 
 
 Lesion tracking/Matching 
Lesion matching will be performed as an independent off-site procedure. The purpose is to guarantee an 
unambiguous assignment (matching) of the lesions between histopathology and consensus reads for 
rCBV quantitative evaluations. It will be carried out by a third IBR in blinded condition based on the 
consensus read results and histopathological data lesion identification (size, location). Once the 
concordance process is done, a correspondence/tracking lesion table should be obtained, so that lesions 
could be compared for the analysis. 
 
 Image Archive and Final Deliverables 
All imaging data will be maintained in a secure environment. The Imaging Core Laboratory will 
maintain a centralized image archive that will contain every imaging examination received from the 
clinical investigators for the trial. Measurements will also be stored so that these data may be audited if 
necessary. A copy of images transferred by the investigators to Imaging Core Laboratory will be 
transferred to Guerbet after database lock for archiving. 
 
9 
SAFETY REPORTING 
The Investigator will report to Guerbet any adverse event whether related or not to the investigational 
medicinal products, serious or not, that occurred in a trial patient during its participation to the trial. 
Special situations such as treatment errors, misuses, suspicion of transmission of an infectious agent via 
an IMP, unusual failure in efficacy, overdose (symptomatic or not), drug exposure during pregnancy or 
breastfeeding even if uneventful, suspected drug-drug interaction with another product (symptomatic or 
not) will also be reported to Guerbet. 
The definition, modalities of collection and reporting are provided below. 
 
9.1 
Adverse Event 
 Definition of Adverse Event 
An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment.  

 
 
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An AE can therefore be: 
- any unfavorable and unintended sign, including an abnormal finding from an examination (lab tests, 
X-ray, ECG…) deemed clinically significant by the investigator; 
- any symptom or intercurrent disease; 
- any worsening during the trial of a symptom or a disease already present when the patient entered 
the trial (increase in frequency and/or intensity). 
Any disease identified and diagnosed by trial imaging examination with contrast agent will not be 
considered as AE. It may be collected in eCRF in medical history section. 
The patient’s disease under investigation and part of inclusion criteria or any pre-existing disease is not 
reported as AE, nevertheless, any worsening of such pathologies during the course of the trial has to be 
considered as an AE. 
 
 Collection and recording of Adverse Events 
The Investigator or his/her designee will invite the patient to report any experienced abnormality as part 
of the usual clinical follow-up. In addition, any abnormal finding assessed as medically significant in 
the context of the trial by the Investigator (see section 9.1.1) should be considered as AE and reported 
in the AE section of the eCRF. 
All AEs, whether considered as related or not to the IMP and/or any protocol procedures including 
imaging procedures, and whether serious or not, should be reported and documented in the medical file 
and the appropriate section of the eCRF according to the table below. 
 
Table 3: Collection and reporting of AEs throughout and after the trial 
 
Periods and types of 
AEs to be reported 
Screening 
(V1) 
From 
MRI/Randomiza
tion (V2) to 
Safety follow-up 
visit (V3) 
From follow-up 
visit (V3) to 
biopsy or 
surgery (within 
30 days of V2) 
After biopsy 
or surgery 
Not related Non-serious 
AEs  
X** 
X 
 
 
Not related SAEs 
X 
X 
X 
 
Adverse 
Event 
of 
Special Interest 
X 
X 
X 
 
Related* AEs (serious or 
not)  
X 
X 
X 
X 
Pregnancy cases 
NA 
X 
X*** 
X*** 
* related to the IMP and/or any protocol procedures including imaging procedures 
** The events which occur before the first IMP administration, and which are not serious and not related to the 
trial procedures, might be recorded as medical history upon the investigator’s judgement. 
*** see the period of collection described in section 9.3.2 
As reminder the patient’s participation is defined as the period from the screening visit (ICF signature) 
to the last trial visit in the general case and defined in section 10 in case of premature discontinuation. 

 
 
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Any AE is followed-up from its onset to recovery or stabilization of sequelae. If no follow-up is 
performed, the investigator must provide a justification in the medical file and eCRF. 
Any lab results available in medical records could be asked to site for AE assessment. 
 
 Description of Adverse Events 
The following guidelines and definitions should be used by the investigator for the description of an AE 
when reporting information in eCRF and any specific AE report forms: 
 
Nature (diagnosis) of AE: preferably an overall diagnosis or syndrome, rather than individual 
symptoms or signs. The investigator must report AE using standard medical terminology. The same 
terms should be used in the source documentation and in the eCRF. 
 
Date and time of onset: date and clock time of the AE start. 
 
Intensity: 
o Mild: the patient is aware of the sign or symptom, but it does not interfere with her/his 
usual daily activities and/or it is of no clinical consequence. 
 
o Moderate: the AE interferes with the usual daily activities of the patient or it is of some 
clinical consequence. 
o Severe: the patient is unable to work normally or to carry out his/her usual daily 
activities, and/or AE is of definite clinical consequence. 
 
Date of the event end (or consolidation): This date is the date when the event has come to its 
ends or to its initial intensity (for the events that had been an aggravation of a pre-existing disorder). If 
the AE is still ongoing by the time of end of trial follow-up for the patient (i.e.: last trial visit), the patient 
should be followed-up until AE resolution or a justification should be provided by the Investigator (i.e.: 
chronic disease) in the medical file. 
 
Causal relationship to the IMP: 
o Related: the definition of adverse reaction (AR) implies a reasonable possibility of a 
causal relationship between the event and the IMP. This means that there are facts 
(evidence) or arguments to suggest a causal relationship. 
o Not related: applicable when no IMP has been administered (pre-administration period) 
or when no causal relationship exists between the trial drug and the event, but an 
obvious alternative cause exists (e.g. the patient’s underlying medical condition or 
concomitant therapy). 
 
Causal relationship to a trial procedure (blood test, imaging procedure itself, etc…): 
o Related: the definition of adverse reaction implies a reasonable possibility of a causal 
relationship between the event and the procedure. This means that there are facts (evidence) 
or arguments to suggest a causal relationship. 
o Not related: applicable when no procedure was performed yet or when no causal 
relationship exists between the trial procedure and the event, but an obvious alternative 
cause exists (e.g.: the patient’s underlying medical condition or concomitant therapy). 
 
Outcome: 
o Recovered/resolved: the AE is no longer present at any intensity or return to baseline 
intensity (for pre-existing disorders) or values for biological data. 
o Recovered/resolved with sequelae: the AE is resolved but residual effects are still 
present (to be specified on the AE form).  

 
 
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o Not recovered/not resolved: the AE is still present at the last contact with the patient. 
o Fatal: this AE caused or directly contributed to the patient’s death. 
 
Action taken with regard to administration of the IMP: 
o No action: for AE occurring during the pre-treatment/procedure after the post-
treatment/procedure period, or if the IMP dosing/administration would not change in 
spite of the occurrence of the AE.  
o IMP interrupted: the IMP administration is interrupted during the administration (e. g. 
extravasation…) or the patient is withdrawn from any other IMP administration planned 
during the trial but without known contra-indication to the drug. 
 
Other action taken:  
o AE-targeted medication: the patient took a medication (either prescription or non-
prescription) specifically for this AE. The drug(s) should be reported in the appropriate 
section of the eCRF (“concomitant medication” section). 
o Other AE-targeted action: therapeutic measures other than corrective drug 
administration (e.g. ice, heating pad, brace, cast…) or patient underwent a procedure 
(surgery, physiotherapy, additional laboratory test…) for this AE. The therapeutic 
measure(s) should be reported in the appropriate section of the eCRF 
(“procedures/therapeutic measures” section). 
o Trial discontinuation: the AE leads to a trial discontinuation, 
 
Adverse event of special interest (AESI) should be indicated (see section 9.3.3 for AESI 
definition). 
 
Assessment of the seriousness of the AE: see section 9.2 for SAE definition. 
 
9.2 
Serious Adverse Event 
 Definition of Serious Adverse Event 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose (ICH E2A):  
- 
Results in death 
- 
Is life-threatening 
- 
Requires in patient hospitalization or prolongation of existing hospitalization 
- 
Results in persistent or significant disability / incapacity 
- 
Is a congenital anomaly / birth defect 
- 
Is an important medical event 
 
Important medical event: medical and scientific judgement should be exercised in deciding 
whether expedited reporting is appropriate in situations, such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may jeopardize 
the patient or may require intervention to prevent one of the other outcomes listed in the 
definition above. These should also usually be considered serious.  
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse.  
 
Life-threatening in the definition of a serious adverse event 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.  

 
 
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 
Hospitalization refers to an admission and overnight stay at the hospital due to the adverse 
event. Emergency room visits that do not result in admission to the hospital should be evaluated 
for one of the other serious outcomes. 
In case of a SAE, the investigator is responsible for the measures to be taken to ensure the safety of the 
trial patients. 
Severe / Serious: the term “severe” is used to describe the intensity (severity) of a specific event (within 
the scale mild, moderate, severe). This is not the same as “serious”, which is based on patient event 
outcome or action criteria. The event itself may be severe but of relatively minor medical significance.  
In this protocol, the following situations will not be considered as SAE, providing that they are clearly 
documented as such in the patient’s source data:  
- Any hospitalization that had been planned before the trial and that will take place during the 
trial, provided there is no aggravation of the disease to which it is related. 
- Hospitalizations, which are not associated to an adverse event (such as hospitalization for 
check-up). 
 
  Reporting Serious Adverse Events (SAE) 
All SAEs must be reported immediately by the investigator to Guerbet. Therefore, the investigator 
must immediately forward to Guerbet Pharmacovigilance department a duly completed report form for 
SAE, AESI or pregnancy (F001406) provided by Guerbet with trial documents, even if it is obvious that 
more data will be needed in order to draw any conclusion: 
 
By e-mail to: pharmacovigilance.headquarters@guerbet.com  
 
Or by Fax #: + 33 (0)1 45 91 67 70 
In case of emergency, Guerbet Pharmacovigilance department may be contacted at:  
+ 33 (0)1 45 91 50 00 
SAEs occurring at any time during the patient’s participation to the trial have to be reported also in 
medical file and in the appropriate section of the eCRF (see section 9.1.2) 
In order to allow the assessment and eventual subsequent regulatory reporting of the case, the following 
minimum information should be filled in:  
- 
Patient’s details including age, sex and patient’s trial identification number 
- 
Patient’s medical history relevant to the assessment of the event 
- 
Type of event by reporting a diagnosis or if not available, symptoms 
- 
Date and time to onset of the event 
- 
End date of the event (will be reported in a follow-up report if the event is still ongoing 
at the time of initial notification) 
- 
Date and time of investigational drug administration 
- 
Seriousness criterion 
- 
Causal relationship to the investigational drug or procedure (mandatory) 
- 
Outcome at the time of reporting 
If the investigator is aware of any new relevant information concerning a SAE (e.g.: outcome or any 
information that can have an impact on the assessment of the seriousness or the causal relationship 
between the SAE and the IMP), he has to send immediately to Guerbet Pharmacovigilance department 
the report form for SAE, AESI or pregnancy duly completed (F001406). 

 
 
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In order to comply with current regulations as well as for comprehensive assessment purposes, 
additional information (e.g., autopsy results, biological values…) or clarifications may be required by 
Guerbet in a timely fashion to ensure accurate follow-up and assessment of each case and should be 
transmitted, anonymized, with a specific form (F018362) as soon as they are available. 
SAEs should be followed up by the investigators until complete recovery of the patient or, if not possible, 
until stabilization of sequelae.  
SAEs associated with trial procedures are to be notified using the same reporting procedure as described 
above. 
According to local requirements, Guerbet or its representatives will communicate relevant safety 
information to the appropriate Agency(ies), Independent Ethics Committee (IEC) and/or all active 
investigators, as it becomes available. 
The transmission of the information to Guerbet does not release the investigator from his responsibility 
to inform the regulatory authorities and or Independent Ethics Committee/ Institutional Review Board 
(IEC/IRB), if applicable. 
 
9.3 
Special situations  
 Cases of overdose, lack of efficacy, interaction with drug or device, medication errors 
or misuses 
The safety information regarding the following special situations has to be collected and reported by the 
investigator with the same procedure as for AE, even if uneventful:  
 Medication error: an unintended failure in the drug treatment process that leads to, or has the 
potential to lead to, harm to the patient (e.g.: wrong route of administration). A failure in the 
drug treatment process does not refer to lack of efficacy of the drug, rather to human or 
process mediated failures. 
 Misuse: where the medicinal product is intentionally used not in accordance with the 
protocol. 
 Occupational exposure to an IMP: an exposure to a medicinal product as a result of one’s 
professional or non-professional occupation. 
 Suspected drug-drug or drug device interaction with another product. 
 Unusual Lack of efficacy: for Guerbet imaging products, lack of efficacy is mainly 
represented by cases of "lack of contrast " or " poor iconographic quality " or "no contrast" 
or "poor contrast" for MRI examinations. 
 Overdose: administration of a quantity of a medicinal product given per administration or 
cumulatively which is above the maximum recommended dose, which is above 0,3 mmol/kg 
for the Elucirem® and Dotarem®. 
 
 Pregnancy 
Any participating patient who becomes pregnant or, for a male patient, is aware of the pregnancy of his 
partner during the trial participation should inform immediately the investigational site. The female 
patient should immediately withdraw from the trial and must not receive any IMP. 

 
 
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Any pregnancy (with or without an Adverse Event) of a woman participating in the trial that is 
discovered after the ICF signature must be reported to Guerbet Pharmacovigilance via the report form 
for SAE, AESI or pregnancy (F001406) (see section 9.2.2) unless the conception date is over 1 week 
after the last IMP administration. In this case, there is no need to report the pregnancy to Guerbet except 
in case of noxious effect related to the trial drug according to investigator’s opinion. 
Pregnancy will be monitored until delivery (health of infant up to 8 weeks of age) or early termination. 
Specific forms “history and start of pregnancy” (F006030) and “course and outcome of pregnancy” 
(F006033) will be provided to the investigational sites by Guerbet Pharmacovigilance department. These 
forms will be used to collect information on the medical history of the pregnant woman and any risk 
factor of pregnancy complication, and on the follow-up and outcome of the pregnancy. 
Any complication of pregnancy will be reported as an AE or SAE, as appropriate. 
 
 Adverse Events of Special Interest 
An Adverse Event of Special Interest (AESI), serious or non-serious, is one of scientific and medical 
concern specific to the sponsor’s product or programme, for which ongoing monitoring and rapid 
communication by the investigator to the sponsor can be appropriate. Such an event might warrant 
further investigation in order to characterize and understand it. 
For Guerbet, the transmission of an AESI to the Guerbet Pharmacovigilance Department respects the 
same time frame as an SAE and should be reported using the report form for SAE, AESI or pregnancy 
(F001406). 
The AESI for this protocol is the following: Nephrogenic Systemic Fibrosis (NSF).  
This disease affects the whole body (including kidney) but has its most prominent and visible effects in 
the skin, and mostly occurs in case of preexisting renal deficiency. NSF has been observed with 
gadolinium-based contrast agents, more frequently with the linear ones. The NSF has not been observed 
with Elucirem®, that is not a linear GBCA. In case of any suspicion of NSF, complementary 
investigation should be performed. 
 
 Any suspicion of transmission of an infectious agent via an IMP 
Any suspicion of transmission of an infectious agent via an IMP should be considered as serious and 
processed as an SAE. 
9.4 
Other important safety issue / new fact 
Any new data which may lead to a reassessment of the benefits / risks balance of the research or product 
being studied, changes in the use of that product, the conduct of the research or documents relating to 
the trial, or to suspend or interrupt or modify the protocol of the trial, or similar searches have to be 
evaluated by Guerbet. 
It may include any new event likely to affect the safety of the patient’s and that may be related to the 
conduct of the trial or the development of the trial drug such as: 
 A SAE which could lead to the modification of the conduct of the trial (ex: SAE associated 
with the trial procedures), 
 A new major finding from an animal study, 
 A temporary halt of a trial for safety reasons if the trial is conducted with the same IMP in 
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 Recommendations of the Safety Committee, where relevant for the safety of patients, 
 Increase in the frequency of an expected event considered as clinically significant. 
According to local requirements, Guerbet or its representatives will communicate relevant safety 
information to the appropriate Agency(ies), IEC/IRB and/or all active investigators, as it becomes 
available. 
Consequently, this type of important safety issue might lead also to:  
 Urgent safety measures and their notification 
 Substantial trial documents modifications 
 Premature discontinuation of the trial 
 Premature discontinuation of the patient 
 
9.5 
Unblinding Procedures 
Not applicable 
 
10 SCREEN FAILURE AND PREMATURE DISCONTINUATION  
10.1 Screen failure 
Screen failed patients are defined as patients who consent to participate in the clinical trial but are not 
subsequently randomized. For this trial, a patient who has signed ICF can be re-screened if he/she has 
not been randomized. 
Data to be collected for screen failure patients: refer to section 14.3.2. 
 
10.2 Premature Discontinuation of the trial per Guerbet Decision 
Guerbet reserves the right to discontinue the trial at any time for medical, administrative or other reasons. 
Guerbet will inform the relevant authorities in each country, the ethics committees, the trial site 
investigators, pharmacists and hospital authorities according to the regulatory texts in force. 
 
10.3 Premature discontinuation of the patient 
Premature discontinued patients are defined as patients who consent to participate in the clinical trial 
and are discontinued from the trial after randomization. 
Data collected for premature discontinued patients: refer to section 14.3.2. 
 
10.4 Reasons for patient’s screening failure and premature discontinuation  
Criteria for screen failure and premature discontinuation of patients are: 
- 
Inclusion criteria not met /Non-inclusion criteria met; 

 
 
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- 
Adverse Event (according to the investigator’s judgement); 
- 
Adverse Event of Special Interest (AESI); 
- 
Withdrawal of patient’s consent:  
o If the patient withdraws consent for disclosure of future information, Guerbet may retain 
and continue to use any data collected before such a withdrawal of consent. 
o If a patient withdraws from the trial, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site’s records. 
- 
Patient lost to follow-up (date of last contact will be documented in the medical file and the eCRF). 
Any effort will be undertaken to know the reason for this loss to follow-up and/or to exclude any 
adverse reaction as this reason. This will be documented in the patient’s medical file; 
- 
Discovery of an unexpected, significant, or unacceptable risk to the patient enrolled in the trial; 
- 
At the discretion of the investigator if the patient safety or well-being is not compatible with trial 
continuation; 
- 
Screen failure or premature discontinuation of patient due to Covid-19; 
- 
Other reason (to be specified in eCRF). 
 
10.5 Enrolment of additional patient/ healthy volunteer/subject: 
Patients prematurely discontinuing the trial will not be replaced. In the event of premature 
discontinuation, patients will receive adequate follow-up from on-site investigators. 
 
11 STATISTICAL CONSIDERATIONS 
The following sections summarize the statistical considerations, which are fully described in the 
Statistical Analysis Plan. 
11.1  Statistical Method 
Tabulations of quantitative parameters will include the following summary statistics: Number of 
Patients / Mean / Standard Deviation (SD) / Minimum / Median / Maximum. The mean and median will 
be reported to 1 decimal more than the data; SD to 2 more decimals than the data; and minimum and 
maximum to the same number of decimals as the data. 
Tabulations of frequencies for categorical data will include all possible categories and will display the 
number of observations in a category as well as the percentage (%) relative to the respective group. 
Percentages will be rounded to one decimal place. 
The primary objective of the trial is to demonstrate the non-inferiority of DSC MRI perfusion using 
Elucirem® at 0.05 mmol/kg compared to DSC-MRI perfusion using Dotarem® at 0.1 mmol/kg in terms 
of diagnostic quality of the Cerebral Blood Volume (CBV) perfusion map. 
From a clinical perspective, a 12% non-inferiority margin was not considered importantly different on 
diagnostic quality of contrast agents, therefore it is relevant to establish acceptable diagnostic quality of 
Elucirem® relative to Dotarem®. 
 
 

 
 
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The statistical hypotheses are the followings: 
- H0: p(excellent+good for Elucirem®) – p(excellent+good for Dotarem®) ≤ - 0.12 
- H1: p(excellent+good for Elucirem®) – p(excellent+good for Dotarem®) > - 0.12 
Non-inferiority will be evaluated by testing whether the lower bound of the two-sided Confidence 
Interval (CI) for the difference of “Elucirem®– Dotarem®”, in proportion of patients presenting with 
images of excellent and good quality according to off-site readers, excludes a 12% difference. 
In case of conclusion of non-inferiority of Elucirem® compared to Dotarem®, the superiority of 
Elucirem® compared to Dotarem® will then be tested in the same way as described above for the non-
inferiority. No adjustment for multiplicity is needed as it is a simple closed testing procedure. 
An interim analysis, on the primary evaluation criterion, is planned. It will be performed when 50% of 
the patients will be assessed, by the off-site readers, in terms of diagnostic quality of images. 
 
11.2 Sample Size 
Sample sizes of 62 in each arm achieve 80% power to detect a difference of 0 when the non-inferiority 
difference is -0,12. The reference group proportion is 94% [17]. The treatment group proportion is 
assumed to be 82% under the null hypothesis. The power was computed for the case when the actual 
treatment group proportion is 94%. The test statistic used is the one-sided Z test (unpooled). The 
significance level of the test is 2.5% (unilateral, 5% bilateral). 
Assuming a 10% drop-out rate is expected, the sample size increases to 138 patients to test that the 
proportion of patients presenting with images of excellent and good quality in the Elucirem® arm is not 
inferior to the proportion of patients presenting with images of excellent and good quality in the 
Dotarem® arm. 
The calculations for determine the sample size were performed using the PASS statistical software. 
 
11.3 Planned Analysis  
 Disposition of patients/ healthy volunteers/subjects 
Patient disposition will be based on all patients who have signed their informed consent form (ICF) and 
tabulated, by arm and overall for the following categories: 
 
Number of patients in each Data Set (see section 11.3.2), 
 
Total number of patients screened (only overall), 
 
Number (percentage) of patients randomized, 
 
Number (percentage) of injected patients, 
 
Number (percentage) of patients completing the trial, 
 
Number (percentage) of patients by trial visit, 
 
Number (percentage) of patients by country and by site, 
 
Number (percentage) of patients screen failed (only overall) and prematurely discontinued from 
the trial, 
 
Reason for screen failure (only overall) and premature discontinuation. 
 

 
 
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 Data Sets Analyzed 
The patient sets for this trial, will be presented by arm and overall, and are defined below:  
 
Screened Patients Set (SPS) will include all patients having signed the inform consent form, 
 
All Randomized Patients Set (ARPS) will include all patients having signed the inform consent 
form and randomized in the trial, 
 
Full Analysis Set (FAS) will include all patients who have a valid primary criterion assessment, 
that is to say images available and considered as technically adequate. Patients will be analysed 
according to the treatment arm assigned at randomization, 
 
Per-Protocol Set (PPS) will include all patients from the FAS who have no major protocol 
deviations and who have complied with the treatment allocated at randomization, 
 
Safety Set (SS) will include all patients having received at least one injection of IMP regardless 
of the quantity. Patients will be analysed according to the treatment really received. 
 Protocol Deviations 
As per International Conference on Harmonization (ICH) E3 guideline, a protocol deviation is any 
change, divergence or departure from the trial design or procedures defined in the protocol, with or 
without impact to the subject safety or the efficacy assessments. 
Protocol deviations will be gathered from monitoring files, clinical database, and external vendors of 
off-site data (imaging). 
Protocol deviations will be split in major and non-major deviations. A major deviation is defined as a 
deviation having an impact on the primary criterion. 
Examples of protocol deviations to be stated as major are following: 
 
Patient not presenting, at the time of inclusion, naive or recurrent primary glial tumor and/or 
tumor grade are not available in patients’ medical records. 
 
Imaging protocol not respected with major impact on primary criterion 
Other deviations can be specified during the course of the trial and the exhaustive list of major and non-
major deviations will be provided in the SAP. 
 
 Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be displayed by arm and overall, on the PPS and the 
FAS unless otherwise specify. 
Demographic parameters are age, sex, race, ethnic origin, result of the urinary pregnancy test for women 
with childbearing potential and body weight. 
Baseline characteristics are type of image procedure to detect the glioma (CT, MRI, Other), primary 
glial tumor type (naïve, recurrent), grade of the primary glial tumor (low grade, high grade) according 
to the IWRS data and e-CRF, localization of the tumor, the medical patient's history including current 
medical conditions, imaging history related to GBCA, concomitant procedures / therapeutic measures 
and the concomitant treatments. 
Summary statistics (number [n], mean, standard deviation [SD], median, minimum, and maximum) will 
be calculated for age and body weight. Frequency and percentages will be calculated for sex, result of 
the urinary pregnancy test, patient’s medical history characteristics, imaging history related to GBCA, 
concomitant procedures / therapeutic measures and concomitant treatments. 

 
 
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Patient's medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and tabulated by System Organ Class (SOC), Preferred Term (PT) and status (concomitant 
or not). 
Patient's concomitant procedures / therapeutic measures will be coded using the MedDRA. 
Patient's concomitant treatments will be coded using the Anatomical Therapeutic Chemical (ATC) Drug 
dictionary and tabulated by ATC code. 
Moreover, serum creatinine and eGFR data collected at V1 will be presented by group using the PPS, 
FAS and SS. Serum creatinine and eGFR data will be analyzed quantitatively. eGFR will be also 
analyzed qualitatively. 
Quantitative analyses will be done by tabulating the raw data. 
Qualitative analysis of eGFR will present number of patients with value <30 mL/min/1.73m2, ≥30 and 
<60 mL/min/1.73m2, ≥60 and <90 mL/min/1.73m2, ≥90 mL/min/1.73m2. 
 
 Compliance  
The number of patients with actual volume of IMPs different from the theoretical one will be presented 
by arm. 
Moreover, the absolute (mL) and relative (%) differences between theoretical and actual volumes of 
IMPs will be presented by arm. 
These analyses will be performed on the PPS and SS and presented by arm. 
 
 Efficacy Analysis 
All efficacy analyses will be done using the efficacy sets (PPS and FAS) and presented by arm. 
11.3.6.1 Primary analysis  
The primary endpoint of the trial is the proportion of patients presenting with images of excellent and 
good quality, according to off-site readers, in the Elucirem® and the Dotarem® arm. 
At the final analysis, non-inferiority will be assessed by calculating the difference in proportion between 
Elucirem® and Dotarem® arms, and by constructing a two-sided 95.2% CI around this difference. If the 
lower bound of the two-sided 95.2% CI is above the pre-stated margin of non-inferiority (-12%), 
Elucirem® will be declared non-inferior to Dotarem®. 
The Wald test statistic with a continuity correction will be used. 
In case of conclusion of non-inferiority of Elucirem® compared to Dotarem®, at the final analysis, the 
superiority of Elucirem® compared to Dotarem® will then be tested in the same way as described above 
for the non-inferiority. No adjustment for multiplicity is needed as it is a simple closed testing procedure. 
The primary analysis will be performed on the PPS and then on the FAS. 
 
 
 

 
 
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11.3.6.2 Secondary analysis  
Additional analyses of the primary criterion 
Intra-reader variability at patient level 
Intra-reader variability will be analyzed in a subgroup of 10% of patients randomly selected for whom 
the independent readers have re-read the images. 
For the primary evaluation criterion, intra-reader variability will be studied using the Cohen kappa (κ) 
statistics. Agreement will be classified according to the value of the Cohen kappa statistics as described 
in the table below: 
Table 4: Agreement according to Cohen kappa (κ) statistics 
Cohen kappa statistics 
Agreement 
< 0.2 
Poor agreement 
≥ 0.2 – ≤ 0.4 
Fair agreement 
> 0.4 – ≤ 0.6 
Moderate agreement 
> 0.6 – ≤ 0.8 
Good agreement 
> 0.8 – 1.0 
Very good agreement 
Inter- reader variability at patient level 
Inter-reader variability will be evaluated on the whole set of trial patients, since each case will be read 
by the two independent readers. 
The same methodology as the one presented above for intra-reader variability will be applied. 
Secondary criteria 
Diagnostic quality of the CBV map according to on-site readers 
The same methodology as the one presented for the primary criterion will be applied to diagnostic 
quality of the CBV map according to the on-site readers. 
As diagnostic quality of the CBV map according to on-site readers will not be analyzed at the interim 
analysis, a two-sided 95% CI will be computed at the final analysis. 
Technical adequacy of images (on-site and off-site assessment) 
Technical adequacy of images will be tabulated according to the following scale: 
 
non-diagnostic, 
 
poor, 
 
fair, 
 
good. 
For the images that will be evaluated by the on-site and off-site readers, as technically non-diagnostic 
(artifacts that completely compromise the image interpretability), the major artifacts will be tabulated: 
 
Movement artifacts, 
 
T2* artifacts, 
 
EPI distortion, 
 
Other, please specify. 

 
 
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Quantification of the relative CBV for differentiating tumor grade (off-site assessment) 
The Mann-Whitney U-test will be used to test the difference in rCBV between the two trial arms by 
tumor grade categorization (high grade on one hand and low grade on the other hand) and between 
patients with high-grade and low-grade gliomas, within each of the two study arms at the significant 
level of 5%. The analysis will be performed for off-site readers. 
Two analyses will be performed. The first one will consider the gliomas’ grade categorization (high-
grade versus low-grade) according to the stratification factor used at randomization, the second one will 
use the tumor grade categorization as per histological results (Standard of Truth) collected during the 
study. 
Categorization as per histological results will be the following: 
- 
Grade 1 and Grade 2 = Low grade, 
- 
Grade 3 and Grade 4 = High grade. 
The Benjamini-Hochberg method will be used to account for multiple testing. 
Assessment and evaluation of the T2* signal intensity time curve (on-site and off-site assessment) 
T2* signal intensity time curve will be visually assessed by on-site and off-site readers for the reliability 
of the curve in providing sufficient information for diagnosis purpose. 
Number and percentage of patients for whom the reliability of the curve provides suffice information 
will be tabulated by trial arms. 
For patients for whom the reliability of the curve provides suffice information, confidence in diagnosis 
will be presented for each arm using a 5-point scale: 
 
1 = nil: very uncertain, 
 
2 = poor: uncertain, 
 
3 = moderate: moderately certain, 
 
4 = high: good certainty, 
 
5 = excellent: very certain. 
Confidence in diagnosis will be summarized qualitatively and quantitatively by trial arm. The on-site 
and off-site read outcomes will be separately analyzed. 
Assessment and evaluation of the T2* signal intensity time curve (off-site assessment) 
Only for off-site readers, FWHM and the maximum signal drop will be compared between the trial arms 
using a Mann-Whitney U-test. 
 
 Adverse Event 
All AEs will be coded using the MedDRA in force at the time of the data base lock. 
An overall summary of AEs will be presented using the Screened Patient Set (SPS) to catch AEs of 
patients who did not receive trial drug that is to say Non-Treatment Emergent AEs (NTEAE). The table 
will be presented overall with the following variables: 
 
Total number of AEs. 
 
Total number of patients with at least one AE. 
 
Distribution of the number of AEs reported by patients (0, 1, 2 or 3 or more AEs). 
 
Total number of Serious AEs (SAEs) according to the seriousness criteria. 

 
 
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 
Total number of patients with at least one SAE according to the seriousness criteria. 
 
Total number of AESIs. 
 
Total number of patients with at least one AESI. 
 
Total number of AEs according to intensity (severity). 
 
Total number of patients with at least one AE according to intensity (severity). 
 
Total number of AEs according to the outcome. 
 
Total number of patients with at least one AE according to the outcome. 
 
Total number of AEs requiring a concomitant drug (other action taken)/procedure. 
 
Total number of patients with at least one AE requiring a concomitant drug / therapeutic 
measures (other action taken)/procedure. 
 
Total number of AEs leading to premature discontinuation. 
 
Total number of patients with at least one AE leading to premature discontinuation. 
 
Total number of AEs with causal relationship to the procedure. 
 
Total number of patients with causal relationship to the procedure. 
The same overall summary will be displayed by arm and overall for Treatment Emergent AEs (TEAEs) 
using the SS. The following variables will be also presented: 
 
Total number of TEAEs with causal relationship to the IMPs. 
 
Total number of patients with at least one TEAE with causal relationship to the IMPs. 
 
Total number of TEAEs leading to interruption of IMPs. 
 
Total number of patients with at least one TEAE leading to discontinuation of IMPs. 
The number and percentage of patients with at least one TEAE will be presented using the SS by arm 
and overall according to Primary SOC and PT. 
The number and percentage of patients with at least one TEAE with causal relationship to the IMPs will 
be presented using the SS by arm and overall according to Primary SOC and PT. 
The number and percentage of patients with at least one TEAE with causal relationship to the procedure 
will be presented using the SS by arm and overall according to Primary SOC and PT. 
The number and percentage of patients with at least one AESI will be presented using the SS by arm 
and overall according to Primary SOC and PT. 
The number and percentage of patients with at least one AESI with causal relationship to the IMPs will 
be presented using the SS by arm and overall according to Primary SOC and PT. 
 
 Laboratory data 
Not Applicable. 
 Other safety observations 
Other safety observations analysis will be done using the SS. 
Extent of exposure 
Duration between ICF signature and the IMPs administration, time from IMP administration to patient’s 
last contact date, and time from signature of ICF to patient’s last contact date will be tabulated by arm. 
Volume actually administered, occurrence of overdose (if any), actual injection rate of administration, , 
power injector used, and injection of saline flush (including volume) will be tabulated by arm. 
 

 
 
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11.4 Specific Statistical Analytical considerations (not applicable for trial including only 
descriptive analysis)  
 Adjustments for Covariates  
Not applicable. 
 
 Handling of Dropouts or Missing Data  
Not applicable. 
 
 Interim Analyses  
An interim analysis will be performed when 50% of the patients will be assessed by the off-site readers, 
in terms of diagnostic quality of images. 
At the interim analysis, only the primary criterion will be analyzed, that is to say the proportion of 
patients presenting with images of excellent and good quality, according to off-site readers, in the 
Elucirem® and the Dotarem® arm. 
An adjustment of the Type I error will be performed. The interim analysis will be performed at a 
significant level of 0.001 (unilateral, 0,002 bilateral) leading to the construction of a two-sided 99.8% 
CI for the non-inferiority testing. The final analysis will be performed at a significant level of 0.024 
(unilateral, 0.048 bilateral) leading to the construction of a two-sided 95.2% CI for the non-inferiority 
testing. 
The study will terminate early (at the interim analysis) if the lower bound of the two-sided 99.8% CI is 
above the pre-stated margin of noninferiority (-12%) as Elucirem® will be declared non-inferior to 
Dotarem®. Otherwise, the trial will continue until completion of the recruitment. 
The results of the interim analysis may be published before the completion of the recruitment. 
 
 Multicentre Trial 
The number of patients included in each site will be displayed in a disposition table overall and by arm. 
 
 Multiple Comparisons/Multiplicity  
For this trial, there will be one interim efficacy analysis, which will be conducted after 50% of the 
patients will be assessed, by off-site readers, in terms of diagnostic quality of images. As an interim 
analysis of the primary endpoint is planned, an adjustment of the Type I error will be performed. The 
interim analysis will be performed at a significant level of 0.001 (unilateral, 0,002 bilateral). The final 
analysis will be performed at a significant level of 0.024 (unilateral, 0.048 bilateral). 
When considering the testing of the superiority of Elucirem® compared to Dotarem® (after non-
inferiority was demonstrated), no adjustment for multiplicity is needed as it is a simple closed testing 
procedure. 
Regarding the quantification of rCBV for differentiating tumor grade, the Benjamini-Hochberg method 
will be used to account for multiple testing. 
 

 
 
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 Use of an "Efficacy Subset" of patients/ healthy volunteers/subjects 
As the primary objective is to demonstrate non-inferiority of Elucirem® compared to Dotarem®, the 
corresponding analysis will be done using the PPS and then will be repeated using the FAS. 
 
 Examination of Subgroups 
Not Applicable. 
 
12 TRIAL COMMITTEES 
Based on safety related to non-specific macrocyclic GBCAs and results of gadopiclenol phase I to III 
trials, no safety committee will be set up for this trial. 
An internal committee will assess efficacy results when the results of the interim analysis will be 
available. The internal committee is composed as following: clinical project manager, biostatistician, 
head of global medical affairs and clinical development, head of clinical projects – pharmaceuticals and 
coordinating investigator if any. Based on the evaluation of the internal committee, the Vice President 
Development, Medical & Regulatory Affairs may decide to stop prematurely the trial or to continue.  
 
13 ETHICAL AND REGULATORY CONSIDERATIONS 
13.1 References 
The trial will be conducted in accordance with the following regulatory / guidance texts: 
- 
World Medical Association Declaration of Helsinki, Ethical Principles for Medical Research 
Involving Human Subjects, June 1964, and amended in: October 1975 (Tokyo), October 1983 
(Venice), September 1989 (Hong Kong), October 1996 (Somerset West), Scotland, October 2000 
(Edinburgh), 2002 (Washington), 2004 (Tokyo), October 2008 (Seoul), October 2013 (Fortaleza) 
- 
International Conference on Harmonisation (ICH) of Technical Requirements for Registration of 
Pharmaceuticals for Human Use: Integrated Addendum to ICH E6(R1): Guideline for Good 
Clinical Practice E6 (R2) Current Step 4 version dated 19 November 2016 
- 
International Conference on Harmonisation (ICH) of Technical Requirements for Registration of 
Pharmaceuticals for Human Use: Clinical Safety Data Management: Definitions and Standards 
for Expedited Reporting E2A Current Step 4 version dated 27 October 1994 
- 
International Conference on Harmonisation (ICH) of Technical Requirements for Registration of 
Pharmaceuticals for Human Use: General Considerations for Clinical Trials E8 Current Step 4 
version dated 17 July 1997 
- 
Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the 
approximation of the laws, regulations and administrative provisions of the Member States 
relating to the implementation of good clinical practice in the conduct of clinical trials on 
medicinal products for human use 
- 
Commission Directive 2003/94/EC of 8 October 2003 laying down the principles and guidelines 
of good manufacturing practice in respect of medicinal products for human use and investigational 
medicinal products for human use 

 
 
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- 
Commission Directive 2005/28/EC of 8 April 2005 laying down principles and detailed 
guidelines for good clinical practice as regards investigational medicinal products for human use, 
as well as the requirements for authorisation of the manufacturing or importation of such products 
- 
International Conference on Harmonisation (ICH) of Technical Requirements for Registration of 
Pharmaceuticals for Human Use: Ethnic Factors in the Acceptability of Foreign Clinical Data 
E5(R1) Current Step 4 version dated 5 February 1998 
- 
International Conference on Harmonisation (ICH) of Technical Requirements for Registration of 
Pharmaceuticals for Human Use: Clinical Investigation of Medicinal Products in the Pediatric 
Population E11 Current Step 4 version dated 20 July 2000 and E11 (R1) Addendum dated 20 July 
2017 
- 
Regulation (EU) 2016/679 Of The European Parliament And Of The Council of 27 April 2016 
on the protection of natural persons with regard to the processing of personal data and on the free 
movement of such data, and repealing Directive 95/46/EC (General Data Protection Regulation) 
- 
EudraLex, The Rules Governing Medicinal Products in the European Union, Volume 4, EU 
Guidelines to Good Manufacturing Practice - Medicinal Products for Human and Veterinary Use, 
Annex 13 Investigational Medicinal Products 
- 
US Food and Drug Administration, Title 21 Code of Federal Regulations Part 11 on Electronic 
Records; Electronic Signatures 
- 
US Food and Drug Administration, Title 21 Code of Federal Regulations Part 211 on Current 
Good Manufacturing Practice for Finished Pharmaceuticals 
- 
Any applicable local regulation 
 
13.2 Institutional 
Review 
Board/Independent 
Ethics 
Committee 
and 
Regulatory/Competent Authorities 
As per international regulation, the clinical trial may be initiated only after having received the approval 
by and Institutional Review Board/Independent Ethics Committee (IRB/IEC) and the authorization by 
the national Regulatory/Competent Authority. The final written approval and authorization must be 
available for a given investigational site when initiating the trial conduct at this particular site. Amongst 
all documents required locally, the approval and authorization must be obtained for the protocol, 
investigator’s brochure, the patient informed consent form and any other written information or 
document to be provided to the patients. 
In case of modifications to the trial protocol, patient informed consent form or any other written 
information provided to the patients, or to any trial procedure; the modified documents will be submitted 
to IRB/IEC and Regulatory/Competent Authority opinions. Modifications may be implemented when 
the final approval and authorization are available. 
In case of an emergency situation when the patients’ safety may be at risk, Guerbet may implement 
emergency safety measures prior to obtaining IRB/IEC approval and Regulatory/Competent Authority 
opinion. In parallel to implementing these measures, Guerbet will immediately notify the concerned 
IRB/IEC and Regulatory/Competent Authorities of such implementation. 
The documentation related to the approvals and authorizations must be filed in the trial Master File at 
Guerbet and at the investigational sites in their respective Investigational Site File (ISF). 

 
 
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Notification of Serious Adverse Events/Reactions to IRB/IEC and Regulatory/Competent Authority will 
be made according to the national requirements. Safety reporting is described in section 9 of the present 
protocol. 
Notifications of non-compliance / deviations to IRB/IEC and Regulatory/Competent Authority will be 
made according to national requirements of participating countries and according to individual IRB/IEC 
requirements when applicable. 
 
13.3 Patient Informed Consent 
Prior to participation, all patients must confirm their free and voluntary willingness to participate in the 
trial. This confirmation is obtained in writing after having received a full oral and written explanation 
on the trial: 
- Aims, methodology and duration of the trial; 
- Potential benefits, foreseeable risks and inconveniencies related to the trial; 
- Rights and responsibilities of patients, with particular emphasis on the right to refuse trial 
participation or to withdraw consent to participation at any time without consequences or 
penalties; 
- Information on IMPs and administration modalities; 
- Contact details of persons dedicated to the trial at the investigational site. 
The language used when informing the patients and answering their questions must be as understandable 
as possible and shall not induce any misunderstanding or feeling to be influenced to participate. Patients 
must be given ample time to decide whether they agree to participate or not. 
Patients may consent to participate after having received all necessary information and all satisfactory 
answers to their questions. Their consent must be confirmed in writing by dating and signing the 
informed consent form(s) approved by the corresponding IRB/IEC. 
When the consent may not be directly obtained in writing, a legal representative/impartial witness may 
be involved in the process and confirm in writing that the patient consented freely and voluntarily.  Such 
involvement(s) must be fully documented in the patient’s medical records and the informed consent. 
The information of patients may only be conducted by qualified investigational site personnel, whose 
involvement and responsibility for patient information has been fully documented and approved by the 
Principal Investigator. 
The Principal Investigator must ensure that local applicable regulations/requirements are fully observed 
by the staff under her/his responsibility. 
In case of modifications of the patient informed consent or of any other document to be provided to the 
patients, the IRB/IEC approval must be obtained prior to implementing the new document(s). Patients 
who already consented may be asked to confirm their willingness to continue participating in writing. 
In any case, the same information and consent process as described above must be followed. 
 
13.4 Trial Records and Archiving 
The investigator/institution should maintain adequate and accurate source documents and trial records 
that include all pertinent observations on each of the site’s trial patients. Source data should be 
attributable, legible, contemporaneous, original, accurate, and complete. Changes to source data should 

 
 
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be traceable, should not obscure the original entry, and should be explained if necessary (e.g., via an 
audit trail). 
The investigator is responsible for supervising any individual or party to whom the investigator delegates 
trial -related duties and functions conducted at the trial site. 
During the course of the clinical trial, investigational sites must ensure completeness and accuracy of 
the trial records that are to be filed in the Investigator Site File (ISF) provided by Guerbet (or designee) 
at the initiation visit. The completeness and accuracy of such files will be checked regularly by Guerbet 
representative (Clinical Research Associate (CRA) or Monitor). The final check will occur at the close 
out visit when investigational site participation is over. 
At the end of the trial, investigational sites must ensure the ISF will be archived in an appropriate way 
that allows timely access and proper retention of documents. Retention period will be of at least 25 years 
after trial completion. Sites should obtain Guerbet written approval before destroying trial documents.  
 
14 QUALITY CONTROL / QUALITY ASSURANCE 
14.1 Direct Access to Source Data/Documents 
The investigator will allow Guerbet representatives, the persons responsible for the audit, the 
representatives of the Ethics Committees and of the Regulatory Authorities to have direct access to 
source data/documents. 
The investigator must guarantee the safety of the trial data in the medical files by implementing security 
measures to prevent unauthorised access to the data. 
The investigator undertakes, in accordance with the regulation in force, to make anonymous any patient 
data before collection by Guerbet. Especially the name and address of the patients will be deleted from 
any medium such as eCRF, document for biological results, X-Ray films or digital supports. 
- For this trial, the following will be considered as source data patients medical files, MR 
images, local lab results, power injector records. 
- If computerized medical files are used, the system must be evaluated by Guerbet (or 
representative): In case printing of files is not possible, the computerized system must be 
validated, and access should be granted to Guerbet or its representative. 
If the computerized system is not validated, the investigator must, at the start of the trial, print, sign and 
date all the medical files of all patients and during the trial, print, sign and date in real time each data 
entry and each data change. 
14.2 Clinical Monitoring 
Before the trial is conducted at a given investigational site and until the trial is completed/terminated at 
the same given investigational site, Guerbet will mandate a representative to perform a close monitoring 
of the trial conduct that will ensure that the investigational site is properly equipped; the staff is 
adequately experienced and knowledgeable of regulatory and ethical requirements. Monitors contact 
details will be listed on the trial team list. 
The representative will perform regular investigational site visits and report all discussions, patient and 
IMPs data verification performed with particular attention to patients’ safety and well-being and trial 
data accuracy and completeness. All monitoring procedures and requirements will be described in a 
monitoring plan. 
 

 
 
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14.3 Clinical Data Handling 
 Data Reported in the eCRF 
The eCRF will allow recording of all the data required by the protocol except blinded imaging 
assessment performed by independent readers entered in an imaging eCRF.  
The investigator or the designated person from his/her team agrees to complete the eCRF, at each patient 
visit, and all other documents provided by Guerbet (e.g., documents relating to the IMP management…) 
and to reply to any data clarifications raised in a timely manner. 
The investigator must attest: 
- The authenticity of the data collected in the eCRF; 
- The consistence between the data in the eCRF and those in the source documents, with the 
exception of those data recorded directly in the eCRF and considered as source data. For this 
trial, all on-site reading data can be directly entered into eCRF (i.e., no prior written or 
electronic record of data). 
 
 Data Reported in the eCRF according to patient Status  
A minimal set of screen failure information is required to ensure transparent reporting of screen failure 
patient to respond to potential queries from regulatory authorities.  
Minimal information includes demography, screen failure details (listed on end of trial eCRF page), 
eligibility criteria, and any adverse event (AE). Additional information such as medical history, 
concomitant medication etc…might be requested in case of SAE. 
For patients discontinued from the trial after randomization, all data available at the time of 
discontinuation will be reported in the medical file and the eCRF (e.g.: inclusion data, safety data, 
administration data, imaging data, reason for premature discontinuation…). The investigator must make 
every effort to collect and record all follow-up safety information (i.e., adverse events, injection-site 
tolerance, as appropriate), unless the patient withdraws consent for further data collection/participation 
for/in the trial. 
 
 Data Management System 
A validated clinical data management system will be used for data process and data storage. 
Data processing and control will be closely managed by Guerbet’s representative. 
 
14.4 Audits and Inspections 
At any time during the trial conduct, Guerbet may mandate a representative to perform an audit of 
investigational sites in order to assess compliance with the regulatory and ethical requirements, the trial 
protocol and related instructions and to assess the accuracy and completeness of data generated by the 
investigational sites. 
In parallel, at any time during the trial conduct, Competent/Regulatory Authorities may also carry out 
an inspection in the facilities of Guerbet and/or the investigational sites. Guerbet will inform all the 
investigators immediately upon notification of a pending inspection. Likewise, the investigator will 
inform Guerbet of any pending inspection. 

 
 
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Whether for an audit or for a regulatory inspection, Guerbet and the investigational sites both agree to 
cooperate in full transparency, confidentiality and professional secrecy. 
The investigator must allow the representatives of Guerbet (audit) and/or of the Competent/Regulatory 
Authorities (inspection):  
- 
To inspect the site, facilities and trial material, 
- 
To meet all members of his/her team involved in the trial, 
- 
To have direct access to trial data and source documents, 
- 
To consult all of the documents relevant to the trial. 
 
15 PUBLICATIONS RULES 
No unpublished data given to the Investigator may be transmitted to a third party without prior approval 
of Guerbet in writing. The trial data are the exclusive property of Guerbet. 
The investigator undertakes to submit to Guerbet any draft articles or papers related to this trial before 
their submission to the scientific journal review board (within 30 days) or the congress scientific 
committee (within 10 days).  
Guerbet or its designee, shall have the right to require amendments to any such proposed presentation 
or publication on reasonable grounds including without limitation: 
(a) 
to ensure the accuracy of the presentation or publication; 
(b) 
to ensure that proprietary information is not inadvertently divulged; 
(c) 
to enable intellectual property rights to be secured; 
(d) 
to enable relevant supplementary information to be provided. 
The Investigator shall be required to comply with any request to amend or delete any statement in a 
proposed publication, provided such request is based on any one of (a) to (d) above. 
All written or oral papers and publications must have the joint agreement of the investigator and Guerbet.  
Guerbet shall not use the Investigator’s name in any publication within public domain without prior 
written information of the investigator. 
The Investigator shall not use Guerbet’s name in any publication without the prior written permission 
of Guerbet. 
In addition, and according to local regulations, the trial may be registered on local regulatory or public 
databases by Guerbet. 
No direct registration of trial information will be made by the investigator on any database without prior 
agreement of Guerbet. 
 
16 REFERENCES 
1. 
Ostrom QT, Bauchet L, Davis FG, Deltour I, Fisher JL, Langer CE, Pekmezci M, 
Schwartzbaum JA, Turner MC, Walsh KM, Wrensch MR, Barnholtz-Sloan JS. Neuro Oncol. 
2014 Jul;16(7):896-913 
2. 
Essig M., Anzalone N., Combs S.E., Dörfler A., Lee S.K., Picozzi P., Rovira À., Weller M., 
Law M. MR imaging of neoplastic central nervous system lesions: Review and 
recommendations for current practice. Am. J. Neuroradiol. 2012;33: 803–817 

 
 
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3. 
Law M, Yang S, Wang H, et al. Glioma grading: sensitivity, specificity, and predictive 
values of perfusion MR imaging and proton MR spectroscopic imaging compared with 
conventional MR imaging. Am J Neuroradiol. 2003;24: 1989–1998. 
4. 
K Welker, J Boxerman, A Kalnin, T Kaufmann, M Shiroishi, M Wintermark. ASFNR 
recommendations for clinical performance of MR dynamic susceptibility contrast perfusion 
imaging of the brain. AJNR Am J Neuroradiol. 2015 Jun;36(6): E41-51. 
5. 
Thust SC, Heiland S, Falini A, Jäger HR, Waldman AD, Sundgren PC et al. Glioma imaging 
in Europe: A survey of 220 centres and recommendations for best clinical practice. Eur 
Radiol, 2018; 28(8):3306-3317. 
6. 
Ostergaard L. Principles of cerebral perfusion imaging by bolus tracking. J Magn Reson 
Imaging 2005;22: 710–717. 
7. 
Thompson G., Mills S.J., Coope D.J., O’Connor J.P., Jackson A. Imaging biomarkers of 
angiogenesis and the microvascular environment in cerebral tumours. Br. J. Radiol. 2011;84: 
S127–S144. 
8. 
Grobner T. Gadolinium--a specific trigger for the development of nephrogenic fibrosing 
dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant.2006;21:1104–
1108 
9. 
Kanal E, Broome DR, Martin DR, et al. Response to the FDA's May 23, 2007, nephrogenic 
systemic fibrosis update. Radiology. 2008; 246:11–14. 
10. 
Xia D, Davis RL, Crawford JA, et al. Gadolinium released from MR contrast agents is 
deposited in brain tumors: in situ demonstration using scanning electron microscopy with 
energy dispersive X-ray spectroscopy. Acta Radiol. 2010;51: 1126–1136. 
11. 
Kanda T, Ishii K, Kawaguchi H, et al. High signal intensity in the dentate nucleus and globus 
pallidus on unenhanced T1-weightedMR images: relationship with increasing cumulative 
dose of a gadolinium-based contrast material. Radiology. 2014;270: 834–841. 
12. 
Errante Y, Cirimele V, Mallio CA, et al. Progressive increase of T1 signal intensity of the 
dentate nucleus on unenhanced magnetic resonance images is associated with cumulative 
doses of intravenously administered gadodiamide in patients with normal renal function, 
suggesting dechelation. Invest Radiol. 2014;49: 685–690. 
13. 
Kanda T, Osawa M, Oba H, et al. High signal intensity in dentate nucleus on unenhanced 
T1-weighted MR images: association with linear versus macrocyclic gadolinium chelate 
administration. Radiology. 2015;275 :803–809. 
14. 
McDonald RJ, McDonald JS, Kallmes DF, et al. Intracranial gadolinium deposition after 
contrast-enhanced MR imaging. Radiology. 2015;275: 772–782. 
15. 
Radbruch A, Weberling LD, Kieslich PJ, et al. Gadolinium retention in the dentate nucleus 
and globus pallidus is dependent on the class of contrast agent. Radiology. 2015;275: 783–
791. 
16. 
Nael K, Mossadeghi B, Boutelier T, Kubal W, Krupinski EA, Dagher J, Villablanca JP. 
Bayesian estimation of cerebral perfusion using reduced-contrast-dose dynamic 
susceptibility contrast perfusion at 3T. AJNR Am J Neuroradiol 2015 Apr;36(4):710-8. 
17. 
Crisi G, Filice S, Erb G, Bozzetti F. Effectiveness of a High Relaxivity Contrast Agent 
Administered at Half Dose in Dynamic Susceptibility Contrast MRI of Brain Gliomas. J. 
Magn Reson Imaging 2017;45: 500–506 
18. 
Bendszus M, Roberts D, Kolumban B, Meza JA, Bereczki D, San-Juan D, Liu BP, Anzalone 
N and Maravilla K. Dose finding study of gadopiclenol, a new macrocyclic contrast agent, 
in MRI of central nervous system. Invest Radiol, 2020;55: 129–137. 
 

 
 
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17 COMPANY LIABILITY INSURANCE 
Guerbet’s liability, as well as the liability of the investigators participating to this trial, is covered by an 
insurance policy, a copy of the certificate being submitted to the investigator. 
Furthermore, Guerbet and the investigator undertake to comply with the locally applicable legal 
requirements with respect to insurance. 
However, Guerbet and its insurer reject all liability in the following cases, which are merely indicative 
and not exhaustive: 
An accident due to a cause other than the investigational medicinal product administered, 
An accident occurring during use of the investigational medicinal product differently from the 
instructions given in the trial protocol, 
An accident occurring for a patient whose consent to participation was not adequately collected. 
 
18 APPENDICES 
Not applicable