Efficacy and Safety of Gadopiclenol for Body Magnetic Resonance Imaging (MRI)
Phase: PHASE3
Conditions: Lesion in Body Region
Sponsor: Guerbet

Document Type 
Study Protocol 
Document Date 
June 30, 2020 
Official Title 
Efficacy and safety of gadopiclenol for body magnetic resonance 
imaging (MRI) 
Phase III Clinical Trial 
The PROMISE trial 
NCT Number 
NCT03986138 
 

 
 
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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. 
Efficacy and safety of gadoPiclenol foR bOdy MagnetIc reSonancE imaging (MRI)  
Phase III Clinical Trial 
The PROMISE trial 
 
 
EudraCT No.: 2018-003946-18 
IND No.: 123673 
 
COORDINATING INVESTIGATOR  
Christiane KUHL, MD 
Universitätsklinikum Aachen, GERMANY 
  
 
SPONSOR 
GUERBET, B.P. 57400, 95943 Roissy CdG Cedex, FRANCE  
 
 
 
GUERBET PHARMACOVIGILANCE  
Fax : + 33 1 45 91 67 70 
E-mail: pharmacovigilance.headquarters@guerbet.com 
 
 
 

 
 
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PROTOCOL SYNOPSIS 
Trial Title: Efficacy and Safety of Gadopiclenol for Body Magnetic Resonance Imaging (MRI)  
Phase III Clinical Trial – The PROMISE trial 
Trial Product(s): G03277 
Active Ingredient(s): gadopiclenol 
EudraCT No.: 2018-003946-18 
IND No.: 123673 
Potential participating countries (Potential number of sites):  
Worldwide trial involving approximately 50 sites  
Trial Objectives 
As the trial is a multi-regional one, trial objectives are presented in order to meet with the respective 
regulatory authorities’ submission purpose.  
Primary objective 1:  
o To demonstrate the superiority of gadopiclenol-enhanced MRI at 0.05 mmol/kg body weight 
(BW) compared to unenhanced MRI for patients referred for contrast-enhanced MRI of body 
regions, in terms of 3 lesion visualization co-primary criteria (border delineation, internal 
morphology and degree of contrast enhancement) using the patient as his/her own control. 
Primary objective 2: 
o To demonstrate the non-inferiority of gadopiclenol at 0.05 mmol/kg compared to gadobutrol 
at 0.1 mmol/kg in terms of 3 lesion visualization co-primary criteria (border delineation, 
internal morphology, degree of contrast enhancement) for patients referred for contrast-
enhanced MRI of body regions.  
For FDA, the primary objective 1 is to be achieved. The primary objective 2 will serve as one of the 
secondary objectives. 
For EMA, both primary objectives 1 and 2 are to be achieved. 
Secondary objectives: 
o To demonstrate the non-inferiority of gadopiclenol compared to gadobutrol in terms of 3 
lesion visualization co-primary criteria (border delineation, internal morphology, degree of 
contrast enhancement) for patients referred for contrast-enhanced MRI of body regions (for 
FDA only).   
o To assess the following parameters with gadopiclenol and gadobutrol  
 Lesion visualization assessment by investigator 
 Subgroup analysis by organ and/or region of the 3 lesion visualization co-primary 
criteria  
 Improvement in lesion visualization scores at patient level 
 Technical adequacy of images 
 Number, size and location of lesions  
 Diagnostic confidence 
 Impact of contrast-enhanced MRI on patient treatment plan 
 Percentage enhancement (E%) of lesion  

 
 
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 Lesion to Background Ratio (LBR)  
 Overall diagnostic preference  
o To assess the safety profile of gadopiclenol and gadobutrol  
Trial design and methodology 
The trial has a prospective, multi-center, randomized, double-blind, controlled and cross-over design. 
The Investigational Medicinal Products (IMPs) used during the trial are gadopiclenol and gadobutrol. 
The primary criteria 1 will compare gadopiclenol-enhanced MRI (pre + post images = paired images) 
to unenhanced MRI (pre images), using the patient as his/her own control. 
The primary criteria 2 will compare gadopiclenol-enhanced MRI (paired images) to gadobutrol-
enhanced MRI (paired images). 
Patients, once informed consent form (ICF) signed, will perform a screening visit (V1) to confirm 
trial eligibility, then will be randomized in the trial to determine the order of IMP injection. Each of 
the 2 MRI visits (V2 and V4) will be followed by a safety visit (V3 and V5) performed 1 day after 
the MRI visit. 
Two MRIs will be obtained for each patient: gadopiclenol-enhanced MRI and gadobutrol-enhanced 
MRI (see Figure 1), however the nature of the contrast agents injected at Visit 2 and at Visit 4 will 
be randomly assigned by Interactive Web Response System (IWRS). 
The investigator and the patient will remain blinded to IMPs allocation (nature of the IMPs and order 
of the IMP injection). A designated unblinded site staff member will be in charge of preparation and 
administration of the IMPs. 
The randomization scheme will allocate patients in a 1:1 ratio to the two arms, gadopiclenol-
gadobutrol or gadobutrol- gadopiclenol.  
For each investigational site, at least one radiologist experienced in planned imaged regions will be 
appointed at the start of the trial to read images of patients included at the site (on-site read). 
In addition, images will be evaluated by prospective evaluation of the blinded images in a centralized 
manner. All images will be sent to a core laboratory, which will prepare the images for evaluation. 
The blinded image evaluations (off-site read) will be performed by 3 independent blinded radiologists 
for the reading of random images and by 3 additional independent blinded radiologists for the global 
pairs assessment per body region. 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. 
To allow exact matching of lesions between imaging modalities (Pre and Paired), between the two 
MR examinations with gadopiclenol and gadobutrol, and among 3 readers, an independent radiologist 
(lesion tracker) will perform lesion tracking, separate from the image evaluation by the investigator 
and by the independent blinded readers. 
The IWRS will be used to randomize order of contrast agents to be injected, to allocate IMPs, to 
calculate the volume of IMP to be administered based on the body weight and to record patient’s 
visits. In addition it will guarantee an appropriate representation of the different body regions in 
ensuring the inclusion of at least 25 thorax patients, 50 abdomen patients, 25 pelvis patients and 25 
musculoskeletal patients. 

 
 
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During the trial, the safety will be monitored and assessed based on the reporting of adverse events 
(AEs), the results of vital signs measurements, the evaluation of injection site tolerance and the 
clinical laboratory parameters (blood samples). 
Number of patients: 300 
Eligibility criteria 
Inclusion criteria 
1. Female or male adult patient having reached legal majority age. 
2. Patient presenting with known or suspected enhancing abnormality(ies) and/or lesion(s) 
in at least one body region among head & neck, thorax (including breast), abdomen 
(including liver, pancreas and kidney), pelvis (including uterus, ovary and prostate) and 
musculoskeletal (including extremities) based on a previous imaging procedure 
performed within 12 months prior to ICF signature. US patients are restricted to the breast 
in compliance with local approved indications of gadobutrol. 
3. Patient scheduled for a contrast-enhanced MRI examination of a body region for clinical 
reasons and agreeing to have a second contrast-enhanced MRI examination for the 
purpose of the trial.  
4. If the patient was treated (either with radiation, surgery, biopsy or other relevant 
treatments) between previous imaging evaluation and trial MRI, there should still be a 
high suspicion of remaining enhancing abnormality(ies) and/or lesion(s) on the basis of 
available clinical information. 
5. Patient able and willing to participate in the trial. 
6. Patient having read the information and having provided his/her consent to participate in 
writing by dating and signing the informed consent prior to any trial related procedure 
being conducted. 
7. Patient affiliated to national health insurance according to local regulatory requirements. 
To be included in the trial, the patient must meet all the inclusion criteria. 
Non-inclusion criteria: 
1. Patients with known or suspected lesion(s) referred for contrast-enhanced MRI of CNS 
or of heart or for MR Angiography. 
2. Patient presenting with known class III/IV congestive heart failure according to the New 
York Heart Association classification (NYHA). 
3. 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. 
4. Patient previously randomized in this trial. 
5. Patient presenting with any contraindication to MRI examinations. 
6. Patient having received any contrast agent (for MRI or CT) within 3 days prior to trial 
products administration, or scheduled to receive any contrast agent during the course of 
the trial or within 24 hours after the second trial product administration. 
7. Patient expected/scheduled to have any treatment or medical procedure (e.g. 
chemotherapy, radiotherapy, biopsy or surgery etc…) that may impact the aspects of the 
imaged lesions between the 2 MRI examinations. (Patients under corticosteroids and/or 

 
 
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maintenance chemotherapy with a stable dose at the time of screening visit and 
throughout the trial can be included).  
8. 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. 
9. 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. 
10. Patient related to the Investigator or any other trial staff or relative directly involved in 
the trial conduct. 
Non-inclusion criteria to be checked at V1, V2 and V4: 
11. Patient presenting with acute or chronic renal insufficiency, defined as an estimated 
Glomerular Filtration Rate (eGFR) < 30 mL/min/1.73 m² assessed within 1 day prior to 
each contrast agent administration. 
12. Pregnant or breast-feeding female patient (a female patient of childbearing potential or 
with amenorrhea for less than 12 months must have a negative urine pregnancy test within 
1 day prior to trial MRI and must be using highly effective birth controlled method until 
the last trial visit). 
13. 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). 
Patients presenting with one or more of the non-inclusion criteria must not be included in the trial. 
The diagnosis obtained from previous (qualifying) imaging examinations will be considered as 
medical history to assess inclusion criteria. All the trial efficacy analyses will be only based on the 
images obtained through the trial MRI. 
Investigational Medicinal Product(s) administration 
Investigational Medicinal  Product (IMP) 1: 
 
gadopiclenol, single intravenous bolus injection at 0.05 mmol/kg BW 
Investigational Medicinal  Product (IMP) 2: 
 
gadobutrol, single intravenous bolus injection at 0.1 mmol/kg BW 
For both products the injection rate depends on scanned organ/region and a saline flush should follow, 
preferably via a power injector. 
Trial duration for patients: 
Minimum trial duration for patients: 4 days, if V1 and V2 are done on the same day and the second 
MRI is done 2 days after the first one. 
Maximum trial duration for patients: 23 days, if the screening period lasts 7 days and the second MRI 
is done 14 days after the first one.  
The trial includes a maximum of 5 visits: 
 
One screening visit (V1) up to 7 days prior to inclusion (V1 could be done on the same day 
as the randomization visit (V2) if all the inclusion/non-inclusion criteria are met). 

 
 
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 
Two sequential imaging visits (V2 and V4, minimum interval 2 days and up to 14 days): each 
visit will consist of gadopiclenol injection or gadobutrol injection and MRI procedure. 
 
Two safety visits (V3 and V5): 1 day after each injection and MRI examination. 
The trial is considered as completed once all the images collected for all the patients have been 
reviewed by all independent blinded readers. The patient’s participation is defined as the period from 
the screening visit (ICF signature) to the last trial visit. 
Evaluation criteria 
Primary criteria 1: 
o Lesion visualization (based on 3 co-primary criteria: border delineation, internal morphology 
and degree of contrast enhancement) will be assessed by 3 independent off-site blinded 
readers on Paired (pre+post) images versus Pre images for gadopiclenol using a 4-point scale 
(off-site read). 
Primary criteria 2 (for EMA, secondary criteria for FDA): 
o Lesion visualization (based on 3 co-primary criteria: border delineation, internal morphology 
and degree of contrast enhancement) will be assessed by 3 independent off-site blinded 
readers on Paired (pre+post) images for gadopiclenol as compared to gadobutrol using a 4-
point scale (off-site read). 
The evaluation for the primary criteria will be performed for up to the 3 most representative lesions. 
Representative lesion is defined according to lesion size and contrast enhancement.  For pre-contrast 
images read, as contrast enhancement cannot be completely foreseen, 3 largest potentially enhancing 
lesions should be selected. For paired images read, 3 largest enhancing lesions should be prioritized.  
The 3 co-primary criteria (border delineation, internal morphology and degree of contrast 
enhancement) will be assessed and the mean of scores for each of the co-primary criteria will be 
calculated as follows:  
Mean of scores = (score of the lesion 1 + score of the lesion 2 (if any) + score of the lesion 3 (if any)) 
divided by the number of lesions (up to 3 most representative lesions).  
For each reader, only matching lesion between Paired images and Pre images will be considered for 
the purpose of the primary criteria 1 evaluation and only matching lesion between Paired images of 
gadopiclenol and gadobutrol will be considered for the purpose of the primary criteria 2 evaluation.  
For each reader, if the MR images are not assessable or if no matching lesion between Paired images 
and Pre images is identified, then the patient will not be included in the primary criteria 1 evaluation. 
In the same way, if the MR images are not assessable or if no matching lesion between Paired images 
of gadopiclenol and gadobutrol is identified, then the patient will not be included in the primary 
criteria 2 evaluation. 
The mean of scores for each of the lesion visualization co- primary criteria and for each reader will 
range from 1 to 4.  

 
 
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Secondary criteria:  
The following parameters will be evaluated with gadopiclenol and gadobutrol:  
o Same as primary criteria 2, lesion visualization (based on 3 co-primary criteria: border 
delineation, internal morphology and degree of contrast enhancement) for gadopiclenol as 
compared to gadobutrol (off-site read) (For FDA only).  
o Lesion visualization (based on 3 co-primary criteria: border delineation, internal morphology 
and degree of contrast enhancement) by organ and/or region.  
o Improvement in lesion visualization scores at patient level: a comparison of paired images to 
pre images with respect to the proportion of patients who have paired image scores that are 
greater (“better”), or same/worse (“not better”) than the pre images scores.  
o Lesion visualization (based on 3 co-primary criteria: border delineation, internal morphology 
and degree of contrast enhancement) (on-site read).  
o Technical adequacy of images (on-site and off-site read) 
Images will be evaluated as technically adequate for diagnosis and assessable or not.  
o Number, size and location of lesions (on-site and off-site read) 
Number, size and location of lesions detected will be recorded for each patient. 
o Diagnostic confidence (on-site and off-site read) 
Degree of confidence will be assessed using a 5 point-scale. 
o Impact of contrast-enhanced MRI on patient treatment plan (on-site read) 
Assessment of potential impact of on-site images reading, at V2 and V4, on patient treatment 
plan.  
 
The two quantitative criteria (E%, LBR) will be calculated by patient in averaging the parameter for 
maximum 3 most representative lesions (off-site read). 
o Percentage enhancement (E%) of lesion 
𝐸% = 𝑆𝐼𝑝𝑜𝑠𝑡− 𝑆𝐼𝑝𝑟𝑒
𝑆𝐼𝑝𝑟𝑒
x100 
where  SIpost = Signal intensity of lesion on post injection images 
SIpre = Signal intensity of lesion on pre injection images 
o Lesion to Background Ratio (LBR) (pre and post) 
LBR = 𝑆𝐼𝑙𝑒𝑠𝑖𝑜𝑛
𝑆𝐼𝑏 
where  SIlesion = Signal intensity of  lesion  
SIb= Signal intensity of background (surrounding healthy tissue of the lesion). 
o Overall diagnostic preference (off-site read) 
The evaluation will be performed in a global matched-pairs fashion and preference will be 
determine on a 3-point scale. Reason for preference will also be recorded. 
o Safety profile of gadopiclenol and gadobutrol  
The safety assessments will be based on the reporting of adverse events (AEs), the results of 
vital signs measurement, the evaluation of injection site tolerance and the clinical laboratory 
parameters (blood samples). 

 
 
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Statistical methods 
Primary objective 1 (superiority of Paired images versus Pre images of gadopiclenol MR 
examination regarding lesion visualization co-primary criteria): 
For gadopiclenol, the difference “Paired” – “Pre” for each of the 3 co-primary criteria will be analyzed 
using paired t-tests on matching lesions. Results will be presented per reader. 
To be successful, 2 out of 3 readers will have to meet the alternative hypothesis for the 3 co-primary 
criteria in the gadopiclenol group: a statistically significant (one-sided p≥0.025) positive difference 
in mean scores in border delineation, internal morphology and degree of contrast enhancement of 
lesions simultaneously. 
Sample size assessment for the Primary objective 1: 
Expecting that for each co-primary criteria, the difference in mean scores will be 0.35 ([“Paired” – 
“Pre”] within patient mean of lesion scores) with 1.5 standard deviation based upon Gutierrez et al, 
2015, a sample of 200 patients in the gadopiclenol group will have 90% power when using a single 
group superiority t-test with a 0.025 one-sided significance level.  
As about a 33% non-evaluable patient rate (drop-out rate and non-valid primary criterion rate) is 
expected, sample size increases to 300 patients with enhancing abnormality(ies) and/or lesion(s) of 
various body organs. 
Primary objective 2 (non-inferiority of gadopiclenol versus gadobutrol regarding lesion 
visualization co-primary criteria): 
The Student’s t-based two-sided 95% confidence intervals of the difference between gadopiclenol 
and gadobutrol will be constructed for each of 3 co-primary criteria using matching lesions only. If 
the lower bound of this confidence interval is above the non-inferiority margin set to 0.35 for at least 
2 out of 3 readers and for the 3 co-primary criteria simultaneously, then non-inferiority between 
gadopiclenol and gadobutrol will be concluded.  
As soon as the non-inferiority is demonstrated, the superiority of the gadopiclenol over gadobutrol 
will be tested using the same method. No adjustment for multiplicity is needed as it is a simple closed 
testing procedure. 
Sample size for the primary objective 2: 
o Non-inferiority margin: 
For EMA, both primary objectives 1 and 2 are to be achieved, therefore, this trial will provide a direct 
demonstration of the superiority of Paired images with gadopiclenol over unenhanced images 
(objective 1). So, it can be considered as three-armed trial design with unenhanced images as placebo 
as described in EMA guideline on the choice of the non-inferiority margin. As such, it is not necessary 
to define a value for non-inferiority margin to establish that gadopiclenol has efficacy over 
unenhanced images.  
A 10% non-inferiority margin was considered clinically as an unimportant difference and therefore 
relevant to establish acceptable efficacy relative to gadobutrol (objective 2). Based on the Guerbet 
Phase IIb GDX-44-004 clinical trial results on lesion visualization co-criteria, the mean score for each 
of the 3 co-criteria is expected to be equal to 3.5. So the margin is set to 0.35 (10%).  

 
 
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o Sample size hypothesis: 
An enrollment of 200 patients is deemed necessary for the lower limit of the two-sided 95% CI to 
exceed the non-inferiority margin set to 0.35, assuming 80% power and for each co-primary criterion, 
the expected difference in mean scores is 0 with an expected standard deviation of 1.75. 
If one assumed a non-evaluable patient rate (drop-out rate and non-valid primary criterion rate) of 
about 33%, an enrollment of 300 patients with enhancing abnormality(ies) and/or lesion(s) various 
body organs is planned.  
Therefore, a total number of 300 patients will allow a sufficient power to meet both objectives. 

 
 
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TRIAL FLOW CHART 
Table 1: Trial flow chart 
 
Visit (1) 
V1 
V2 
V3 
V4 
V5 
Evaluation/ 
procedure 
 
Screening 
 
Randomization  
1st contrast injection 
(Baseline (10)) 
Safety follow up  
Post injection 
2nd contrast injection 
 (2 d up to 14 d post V2) 
Safety follow up  
Post injection 
Time Point 
≤7 days 
Prior  
to MRI 
MRI 
60± 
15min 
1 day after V2 
Prior  
to MRI MRI 
60± 
15min 
1 day after V4 
Informed consent signature 
X 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
X 
 
 
 
X (11) 
 
 
 
Demographic data & height 
X 
 
 
 
 
 
 
 
 
Medical history including disease requiring 
the trial MRIs 
X 
 
 
 
 
 
 
 
 
Contrast agents intolerance history 
X 
 
 
 
 
 
 
 
 
Physical examination(2) 
X 
 
 
 
 
 
 
 
 
Body weight  
 
X 
 
 
 
X 
 
 
 
Concomitant treatments 
X 
Pregnancy test (3) 
X 
X(3) 
 
 
 
X 
 
 
 
Local creatinine and e-GFR evaluation(4) 
 
X 
 
 
X 
X 
 
 
X 
Clinical laboratory parameters (5) 
 
X 
 
 
X 
X 
 
 
X 
Vital signs (BP, PR) (6) 
 
X 
 
X 
X 
X 
 
X 
X 
IMP injection 
 
 
X 
 
 
 
X 
 
 
Images acquisition 
 
 
X 
 
 
 
X 
 
 
IWRS (7) 
X 
X 
 
 
X 
X 
 
 
X 
Injection-site tolerance(8) 
 
 
X 
X 
X 
 
X 
X 
X 
Adverse events (AEs)(9) 
X 
Procedures/Therapeutic measures 
X 

 
 
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(1) 
V1 can be performed on the same day as V2. MRI procedures, at V2 and V4, should be performed on the same day as IWRS connection  
(2) 
Physical examination should be performed by a physician: examination of general appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, 
abdomen, back, lymph nodes, extremities, vascular and neurological. Information indicating the global assessment (normal or abnormal (specify)) of the physical 
examination should be recorded on source documentation. 
(3) 
Urine pregnancy test (if applicable) is to be done on site. At V2 and V4 results must be available 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. 
(4) 
At V2 and V4, creatinine and eGFR are to be evaluated locally, and results must be available prior to IWRS connection and administration of IMP. Starting at 
V3, change in local serum creatinine result should be checked as per ESUR guidelines (see section 7.2.11). The same local methods of serum creatinine dosage 
and eGFR calculation should be used throughout the trial for a same patient. 
(5) 
Clinical laboratory parameters will be analysed by the central laboratory: haematology and biochemistry (see section 8.5) 
(6) 
Vital signs: BP: Blood Pressure (supine systolic and diastolic), PR: Pulse Rate 
(7) 
IWRS: connection should be done at each trial visit and in case of screening failure or premature discontinuation 
(8) 
Injection-site tolerance (pain, eruption, extravasation, inflammation, or other) is to be assessed during the injection, 60 ± 15 min and 1 day post injection. 
(9) 
AEs occurring during the time of the patient’s participation in the trial, must be reported and followed, unless they meet the following definition: the events which 
that occur before the first IMP administration, and which are not serious and not related to the trial procedures may be recorded as medical history upon the 
investigator’s judgement. Procedures/therapeutic measures for AE are also to be reported  
(10) 
All the assessments performed prior to the first MRI at V2 will be considered as baseline value 
(11) 
Some non-inclusion criteria must be checked again at V4 (see section 4.2) 
 

 
 
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ABBREVIATIONS 
AE 
 
Adverse Event 
AESI  
Adverse Event of Special Interest 
ALT 
 
Alanine Amino Transferase 
AST 
 
Aspartate Amino Transferase 
ATC 
 
Anatomical Therapeutic Chemical 
BP 
 
Blood Pressure 
BUN 
 
Blood Urea Nitrogen 
BW 
 
Body weight 
BMI 
 
Body Mass Index 
CI 
 
Confidence Interval 
CNS 
 
Central Nervous System 
CRA 
 
Clinical Research Associate 
eCRF  
electronic Case Report Form 
CRO 
 
Contract Research Organization 
CT 
 
Computed Tomography 
DCE 
 
Dynamic Contrast Enhanced 
E% 
 
Percentage enhancement of lesion 
eGFR  
estimated Glomerular Filtration Rate 
EMA  
European Medicine Agency 
EU-QPPV 
European Qualified Person for Pharmacovigilance 
ESUR  
European Society of Urogenital Radiology 
FAS 
 
Full Analysis Set 
FDA 
 
Food and Drug Administration 
GBCA  
Gadolinium Based Contrast Agent 
GCP 
 
Good Clinical Practice 
Gd 
 
Gadolinium 
GRE 
 
Gradient Echo 
IBR  
 
Independent Blinded Readers 
ICH 
 
International Conference on Harmonization 
ID 
 
Identification 
ICF 
 
Informed Consent Form 
IEC 
 
Independent Ethics Committee 
IMP 
 
Investigational Medicinal Product 

 
 
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INV 
 
Investigator 
IRB 
 
Institutional Review Board 
ISF 
 
Investigator Site File 
IUD 
 
Intrauterine Device 
IUS 
 
Intrauterine System 
IV 
 
Intravenous 
IWRS  
Interactive Web Response System 
LBR 
 
Lesion to Background Ratio  
LDH 
 
Lactate Dehydrogenase 
MCV  
Mean red blood Cells Volume 
MRI 
 
Magnetic Resonance Imaging 
NPS 
 
Numeric Pain intensity Scale 
NSF 
 
Nephrogenic Systemic Fibrosis 
PC-AKI 
Post-Contrast-Acute Kidney Injury 
PK 
 
Pharmacokinetic 
PPS 
 
Per Protocol Set 
PR 
 
Pulse Rate 
PT 
 
Preferred Term  
RBCs  
Red Blood Cells 
SAE 
 
Serious Adverse Event 
SD 
 
Standard Deviation 
SI 
 
Signal Intensity 
SmPC  
Summary of Product Characteristics 
SOC 
 
System Organ Classes  
SS 
 
Safety Set 
SPS 
 
Screened Patient Set 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE  
Treatment Emergent Adverse Event 
WBCs  
White Blood Cells 
 
 

 
 
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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ........................................................................................................................ 2 
TRIAL FLOW CHART ........................................................................................................................ 10 
TRIAL DIAGRAM ............................................................................................................................... 12 
SIGNATURE PAGE ............................................................................................................................. 13 
ABBREVIATIONS ............................................................................................................................... 14 
TABLE OF CONTENTS ...................................................................................................................... 16 
GLOBAL AMENDMENT 2 ................................................................................................................. 22 
11.2 Sample Size ............................................................................................................................... 22 
11.2 Sample Size ............................................................................................................................... 22 
1 
INTRODUCTION ........................................................................................................................ 23 
1.1 
Trial Rationale ....................................................................................................................... 23 
1.2 
Background ........................................................................................................................... 23 
1.3 
Benefit/Risk Assessment ....................................................................................................... 24 
2 
TRIAL OBJECTIVES .................................................................................................................. 26 
2.1 
Primary Objectives ................................................................................................................ 26 
2.2 
Secondary Objectives ............................................................................................................ 26 
3 
TRIAL DESCRIPTION................................................................................................................ 27 
3.1 
Protocol Design ..................................................................................................................... 27 
3.2 
Justification for dose ............................................................................................................. 28 
3.3 
Trial Duration ........................................................................................................................ 28 
 Duration of patient’s participation ..................................................................................... 28 
 End of trial ......................................................................................................................... 28 
3.4 
Interim Analysis .................................................................................................................... 28 
3.5 
Trial Committee(s) ................................................................................................................ 28 
4 
PATIENT SELECTION ............................................................................................................... 29 
4.1 
Inclusion Criteria ................................................................................................................... 29 
4.2 
Non-Inclusion Criteria ........................................................................................................... 29 
4.3 
Patient Identification ............................................................................................................. 30 
5 
INVESTIGATIONAL MEDICINAL PRODUCTS ..................................................................... 32 
5.1 
Investigational Medicinal Product(s) Description ................................................................. 32 
 Investigational Medicinal Product 1 .................................................................................. 32 
 Investigational Medicinal Product 2 .................................................................................. 32 
5.2 
Packaging, Labeling, Storage ................................................................................................ 33 
5.3 
Condition of Investigational Medicinal Product Allocation .................................................. 33 
 Investigational Product(s) Allocation / Randomization .................................................... 33 

 
 
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 Double-Blind Conditions ................................................................................................... 34 
 Individual Trial Treatment Unblinding ............................................................................. 34 
5.4 
Investigational Medicinal Product Management ................................................................... 35 
5.5 
Auxiliary Medicinal Product(s) and Other Trial Products .................................................... 35 
5.6 
Trial Product(s) Compliance and Accountability .................................................................. 35 
6 
CONCOMITANT MEDICATIONS / PROCEDURES ............................................................... 36 
6.1 
Concomitant Medications ...................................................................................................... 36 
 Concomitant Medications of Special Attention ................................................................. 36 
 Prohibited Concomitant Medications ................................................................................ 36 
6.2 
Concomitant Procedures ........................................................................................................ 36 
7 
EVALUATION CRITERIA ......................................................................................................... 37 
7.1 
Primary Criteria (off-site read) .............................................................................................. 38 
 Primary criteria 1: Lesion visualization criteria for gadopiclenol-enhanced MRI compared 
to unenhanced MRI (off-site read) ............................................................................................... 38 
 Primary criteria 2: Lesion visualization criteria for gadopiclenol compared to gadobutrol 
(off-site read) ................................................................................................................................ 39 
7.2 
Secondary Criteria ................................................................................................................. 39 
 Lesion visualization criteria for gadopiclenol compared to gadobutrol (off-site read) for 
FDA only ...................................................................................................................................... 39 
 Lesion visualization (based on 3 co-primary criteria: border delineation, internal 
morphology and degree of contrast enhancement) by organ and/or region .................................. 39 
 Improvement in lesion visualization scores at patient-level, paired versus pre-contrast 
images ........................................................................................................................................... 40 
 Lesion visualization (on-site read) .................................................................................... 40 
 Technical adequacy of images (on-site and off-site read) ................................................. 40 
 Number, size and location of lesions (on-site and off-site read) ....................................... 40 
 Diagnostic confidence (on-site and off-site read) .............................................................. 41 
 Impact of contrast-enhanced MRI on patient treatment plan (on site) .............................. 41 
 Percentage enhancement (E%) of lesion and Lesion to Background Ratio (LBR) (off-site 
read) 41 
 Overall diagnostic preference (off-site read) ..................................................................... 42 
 Safety profile of gadopiclenol and gadobutrol (on-site) .................................................... 42 
8 
TRIAL SCHEDULE AND PROCEDURES ................................................................................ 44 
8.1 
Trial Schedule ........................................................................................................................ 44 
 Screening Visit – Visit 1 – Day (- 7) to Day 0 .................................................................. 44 
 Imaging/Randomization Visit – 1st MRI – Visit 2 – Day 0 ............................................... 44 
 Safety Visit – Visit 3 – 1 day post visit 2 .......................................................................... 46 
 Imaging Visit – Visit 4– 2nd MRI – 2 days up to 14 days post V2 .................................... 46 

 
 
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 Safety Visit – Visit 5 – 1 day post Visit 4 ......................................................................... 47 
8.2 
Imaging Characteristics ......................................................................................................... 48 
 Equipment ......................................................................................................................... 48 
 Imaging protocol ............................................................................................................... 48 
8.3 
On-Site Reading of Images ................................................................................................... 49 
8.4 
Off-Site Reading of Images ................................................................................................... 49 
 Manuals and Supplies ........................................................................................................ 49 
 Site Qualification ............................................................................................................... 49 
 Receipt and Tracking of Images ........................................................................................ 50 
 Image Processing and Quality Check ................................................................................ 50 
 Independent Blinded Readers Training ............................................................................. 50 
 Image Randomization ........................................................................................................ 50 
 Blinded Assessment of Images .......................................................................................... 51 
 Inter and Intra-reader Variability Assessment ................................................................... 51 
 Lesion tracking/Matching .................................................................................................. 51 
 Image Archive and Final Deliverables .............................................................................. 51 
8.5 
Non Imaging Central procedures: central laboratory ............................................................ 52 
9 
SAFETY REPORTING ................................................................................................................ 53 
9.1 
Adverse Event ....................................................................................................................... 53 
 Definition of Adverse Event .............................................................................................. 53 
 Collection and recording of Adverse Events ..................................................................... 53 
 Description of Adverse Events .......................................................................................... 54 
9.2 
Serious Adverse Event .......................................................................................................... 56 
 Definition of Serious Adverse Event ................................................................................. 56 
 Reporting Serious Adverse Events (SAE) ......................................................................... 57 
9.3 
Special situations ................................................................................................................... 58 
 Cases of overdose, lack of efficacy, interaction with drug or device, medication errors or 
misuses .......................................................................................................................................... 58 
 Pregnancy .......................................................................................................................... 58 
 Adverse Events of Special Interest .................................................................................... 59 
 Any suspicion of transmission of an infectious agent via an IMP .................................... 59 
9.4 
Other important safety issue / new fact ................................................................................. 59 
9.5 
Unblinding Procedures .......................................................................................................... 60 
10 
SCREEN FAILURE AND PREMATURE DISCONTINUATION............................................. 61 
10.1 
Screen failure ......................................................................................................................... 61 
10.2 
Premature Discontinuation of the trial per Guerbet Decision ............................................... 61 

 
 
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10.3 
Premature Discontinuation of the patient .............................................................................. 61 
10.4 
Reasons for patient’s screening failure and premature discontinuation ................................ 61 
10.5 
Enrolment of additional patients ........................................................................................... 61 
11 
STATISTICAL CONSIDERATIONS ......................................................................................... 62 
11.1 
Statistical Method .................................................................................................................. 62 
11.2 
Sample Size ........................................................................................................................... 62 
11.3 
Planned Analysis ................................................................................................................... 64 
 Disposition of patients ....................................................................................................... 64 
 Data Sets Analyzed............................................................................................................ 64 
 Protocol Deviations ........................................................................................................... 65 
 Demographics and Baseline Characteristics ...................................................................... 65 
 Compliance ........................................................................................................................ 65 
 Efficacy Analysis............................................................................................................... 65 
 Adverse Event ................................................................................................................... 68 
 Laboratory data .................................................................................................................. 69 
 Other safety observations .................................................................................................. 69 
11.4 
Specific Statistical Analytical considerations........................................................................ 70 
 Adjustments for Covariates ............................................................................................... 70 
 Handling of Dropouts or Missing Data ............................................................................. 70 
 Interim Analyses ................................................................................................................ 70 
 Multicenter Trial ................................................................................................................ 70 
 Multiple Comparisons/Multiplicity ................................................................................... 70 
 Use of an "Efficacy Subset" of patients ............................................................................. 70 
 Examination of Subgroups ................................................................................................ 70 
12 
TRIAL COMMITTEES................................................................................................................ 72 
13 
ETHICAL AND REGULATORY CONSIDERATIONS ............................................................ 73 
13.1 
References ............................................................................................................................. 73 
13.2 
Institutional Review Board/Independent Ethics Committee and Regulatory/Competent 
Authorities ......................................................................................................................................... 74 
13.3 
Patient Informed Consent ...................................................................................................... 74 
13.4 
Trial Records and Archiving ................................................................................................. 75 
14 
QUALITY CONTROL / QUALITY ASSURANCE ................................................................... 76 
14.1 
Direct Access to Source Data/Documents ............................................................................. 76 
14.2 
Clinical Monitoring ............................................................................................................... 76 
14.3 
Clinical Data Handling .......................................................................................................... 76 
 Data Reported in the eCRF ................................................................................................ 76 

 
 
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 Data Reported in the clinical eCRF according to Patient Status ....................................... 77 
 Data Management System ................................................................................................. 77 
14.4 
Audits and Inspections .......................................................................................................... 77 
 
 
16 
REFERENCES ............................................................................................................................. 79 
17 
COMPANY LIABILITY INSURANCE ...................................................................................... 80 
18 
APPENDICES .............................................................................................................................. 81 
18.1 
Numeric Pain intensity Scale (NPS) ...................................................................................... 81 
18.2 
Volume of IMP injection by body weight ............................................................................. 82 
 
 
 

 
 
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LIST OF TABLES 
Table 1: Trial flow chart ........................................................................................................................ 10 
Table 2:  Overview of imaging trial criteria .......................................................................................... 37 
Table 3: Images sets per patient ............................................................................................................ 37 
Table 4: Collection and reporting of AEs throughout and after the trial ............................................... 54 
 
LIST OF FIGURES 
Figure 1: Trial diagram .......................................................................................................................... 12 
 
 
 
 
 
 
 
 
 

 
 
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Protocol Amendment Summary of Changes Table 
DOCUMENT HISTORY 
Document 
Date 
Protocol V1.0 
[14 Jan 2019] 
Protocol V2.0 including global amendment 1  
[05 Jun 2020] Never submitted 
Protocol V3.0 including global amendment 2 
[30 Jun 2020] 
GLOBAL AMENDMENT 2 
Overall Rationale for the Amendment (non-substantial):  
In this trial, 200 evaluable patients (defined as patients who completed the trial and with a valid primary 
criterion) are to be secured to allow a sufficient statistical power to meet both study primary objectives. 
The initial sample size calculation was based on a non-evaluable patient rate (drop-out rate and non-
valid primary criterion rate) of 20% (50 patients), leading to a target of 250 enrolled patients. 
Based on 245 patients currently enrolled (98% of planned target), 25 patients are already dropped-out. 
This drop-out rate is partially due to the Covid-19 pandemic preventing 6 patients from completing the 
trial up to now. Furthermore, Covid-19 pandemic may continue to impact enrollment of patients and/or 
protocol compliance.   
In addition, the current estimated number of patients with no valid primary criterion is about 68 patients. 
Altogether, this current estimation of 93 (25+68) non-evaluable patients is expected to increase before 
the recruitment completion.  
As a consequence, the revised hypothesis for the non-evaluable patient rate is now about 33% and leads 
to an increase of the sample size from 250 to 300 enrolled patients.    
This amendment makes changes to the following sections of the protocol. Where applicable, the same 
changes have also been made to the corresponding sections of the protocol synopsis. 
New text is shown in bold font and deleted text in strikethrough. 
Section # and Name 
Description of Change 
Brief 
Rationale 
11.2 Sample Size 
Number of patients for 
the Primary objective 1: 
As about 20% a 33% non-evaluable patient rate 
(drop-out rate and non-valid primary criterion 
rate) is expected, sample size increases to 250 300 
patients with enhancing abnormality(ies) and/or 
lesion(s) of various body organs. 
New expected 
non-evaluable 
patient rate 
based on 
observed data 
after reaching 
98% 
enrollment 
target leading 
to an increase 
of the sample 
size 
11.2 Sample Size 
Number of patients for 
the primary objective 2: 
If one assumed a non-evaluable patient rate (drop-
out rate and non-valid primary criterion rate) of 
about 20% 33%, an minimum enrollment of 250 
300 patients with enhancing abnormality(ies) and/or 
lesion(s) of various body organs is planned.  
Therefore, a total number of 250 300 patients will 
allow a sufficient power to meet both primary 
objectives. 
 

 
 
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1 
INTRODUCTION  
1.1 
Trial Rationale 
Gadolinium-based contrast agents (GBCAs) consist of the active substance gadolinium (Gd) and a 
chelating agent. They can be categorized by their chemical structures into linear and macrocyclic agents 
and further subdivided by their charge (ionic or non-ionic). In vitro experiments have shown that the 
macrocyclic compounds are the most stable, with an undetectable release of Gd3+ ions under 
physiological conditions. 
Gadopiclenol (P03277) 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 
(IV) administration, as a contrast agent for magnetic resonance imaging (MRI). 
The ability of gadopiclenol to be a MRI contrast agent has been demonstrated by its at least two-fold 
higher T1 relaxivity compared to other available GBCAs. A proof of concept has been obtained for the 
efficacy of gadopiclenol as a MRI contrast agent for central nervous system (CNS) imaging in a model 
of brain tumor implanted in rats as well as during the phase IIa clinical trial. The safe and lowest effective 
clinical dose identified in phase IIb trial is 0.05 mmol/kg body weight (BW) based on comparison with 
gadobenate dimeglumine (MultiHance®) for the contrast-to-noise ratio (CNR) assessed as primary 
endpoint.  
One phase I/IIa trial and one phase IIb trial have been completed, with 304 patients exposed to 
gadopiclenol. On the basis of the extensive nonclinical trial program and the PK/ clinical safety data 
available from phase I/IIa and phase IIb trials, it is considered that there are sufficient guarantees to 
ensure the safety of gadopiclenol administration in adult and pediatric (from 2 to 17 years) patients at a 
single dose. 
At the launch of the phase III program and based on the initial clinical studies, the administrations of 
the gadopiclenol were well tolerated. More details on the safety are provided in the investigator’s 
brochure in force that is the reference safety information for the gadopiclenol. Likewise, the SmPC is 
the reference safety information for gadobutrol. 
 
1.2 
Background 
The use of GBCAs for MRI has revolutionized the radiologic field since their introduction 30 years ago. 
These contrast agents have been used extensively in a large range of indications such as CNS and body, 
the latter including head & neck, thorax (including breast), abdomen (including liver, pancreas, and 
kidney), pelvis (including uterus, ovary and prostate), and musculoskeletal (including extremities). 
While helical computed tomography (CT) has been the workhorse of most radiology departments, recent 
advances in MRI have moved it to the forefront of oncologic imaging for various body regions. 
Compared to CT, MRI of body regions, such as abdomen and pelvis, offers important advantages, 
including superior soft-tissue contrast. The multiplanar capabilities of MRI allow for direct coronal or 
sagittal imaging, providing a more accurate anatomic presentation of abdominal and pelvic masses. 
Among the recent advances in MRI are faster pulse sequences, breath-hold imaging, and use of 
intravenous contrast agents and surface coils, all of which have improved image quality and shortened 
examination times. The versatility of MRI is unmatched by any other imaging examination. For these 
reasons, MRI has evolved from a problem-solving study to become the primary imaging examination in 
many patients with malignancy. The imaging evaluation of oncology patients requires accurate depiction 
and characterization of tumors. 
Liver MRI: the depiction of a focal liver lesion requires a difference in signal intensity between the 
lesion and the adjacent liver parenchyma. The lesion may be either more or less intense than the 

 
 
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surrounding liver tissue. Most liver masses are easily depicted on unenhanced T1-weighted or T2-
weighted MRIs. However, some tumors produce minimal changes in T1- and T2-relaxation and, 
therefore, show limited contrast with the surrounding liver. Contrast agents are used to accentuate the 
inherent differences in liver-lesion signal intensity. These contrast agents facilitate differential 
enhancement of liver parenchyma and masses, as well as promote lesion depiction and, to some degree, 
lesion characterization [1, 2]. Gadolinium chelates rapidly equilibrate from the intravascular space into 
the extracellular space after injection. The use of gadolinium chelates has become an integral part of 
MRI of the liver and extrahepatic abdomen. Gadolinium chelates uniquely provide important 
information about tumor perfusion, which is key in the assessment of liver masses. They assist with the 
detection and characterization of liver lesions and in the establishment of the volume of viable perfused 
tumor. Gadolinium chelates are equally important for MRI of the extrahepatic abdomen. The interstitial 
accumulation of these agents within peritoneal, omental, and gastrointestinal tumor produces marked 
enhancement and is crucial to accurate tumor staging. Depiction of lesions within solid visceral organs, 
such as the pancreas, kidneys, and spleen, also improves following gadolinium injection [3, 4].  
Kidney MRI: the multiplanar capabilities, excellent soft-tissue contrast, and versatility of MRI make it 
the examination of choice for evaluating renal masses. Using axial helical CT, it can be difficult to depict 
small solid renal masses arising from the upper or lower pole of the kidney [5]. Coronal or sagittal MRIs 
provide a truer anatomic presentation of the kidneys, allowing for a better appreciation of the position 
of a renal mass and its relationship to surrounding structures. The detection and characterization of renal 
cell carcinoma are superior on MRI. Characterization of a renal mass as cystic or solid can be made with 
confidence on the gadolinium-enhanced images. Cysts show no evidence of enhancement on dynamic 
gadolinium-enhanced MRIs, whereas solid tumors that are vascular exhibit some degree of 
enhancement. Compared to helical CT, gadolinium-enhanced MRIs are much more sensitive to subtle 
enhancement of solid masses, allowing for more confident lesion characterization. The staging and 
presurgical evaluation of renal cell carcinomas requires accurate depiction of local tumor extent, venous 
tumor invasion, and nodal metastases. Previous studies have shown that MRI is superior to helical CT 
in depicting venous tumor extension [6]. 
Breast MRI: Breast cancer is the second leading cause of cancer deaths after lung cancer worldwide. 
Earlier detection through screening is a fundamental way to improve survival. Dynamic contrast 
enhanced (DCE-MRI) of the breast has a high sensitivity for breast cancer detection and is the most 
sensitive technique for screening high-risk women and detecting contralateral or multifocal disease in 
patients with recently diagnosed breast cancer. Early detection and diagnosis of breast cancer are 
essential for successful treatment. Currently mammography and ultrasound are the basic imaging 
techniques for the detection and localization of breast tumors. The low sensitivity and specificity of 
these imaging tools resulted in a demand for new imaging modalities and breast magnetic resonance 
imaging (MRI) has become increasingly important in the detection and delineation of breast cancer in 
daily practice. The clinical benefits of the use of pre-operative MRI in women with newly diagnosed 
breast cancer is also well recognized. The main additional diagnostic value of MRI relies on specific 
situations such as detecting multifocal, multicentric or contralateral disease unrecognized on 
conventional assessment (particularly in patients diagnosed with invasive lobular carcinoma), assessing 
the response to neoadjuvant chemotherapy, detection of cancer in dense breast tissue, recognition of an 
occult primary breast cancer in patients presenting with cancer metastasis in axillary lymph nodes, 
among others [7-10].   
 
1.3 
Benefit/Risk Assessment 
The results of the clinical trial phase IIa suggest that gadopiclenol have potential effectiveness as a 
contrast agent for MRI and is safe and well tolerated in patients with brain lesions up to a dose of 0.2 
mmol/kg. The phase IIb trial demonstrated the efficacy of gadopiclenol for CNS imaging in patients 

 
 
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with brain lesions as well as the good safety profile of the product. The use of gadopiclenol for MR 
imaging of body regions is expected to be as safe as for CNS MR imaging, as the dose of 0.05 mmol/kg 
to be evaluated in this trial and way of product administration were assessed in the phase IIb trial. 
 
 

 
 
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2 
TRIAL OBJECTIVES 
As the trial is a multi-regional one, trial objectives are presented in order to meet with the respective 
regulatory authorities’ submission purpose. 
2.1 
Primary Objectives 
Primary objective 1:  
o To demonstrate the superiority of gadopiclenol-enhanced MRI at 0.05 mmol/kg body weight 
(BW) compared to unenhanced MRI for patients referred for contrast-enhanced MRI of the body 
regions, in terms of 3 lesion visualization co-primary criteria (border delineation, internal 
morphology and degree of contrast enhancement) using the patient as his/her own control. 
Primary objective 2: 
o To demonstrate the non-inferiority of gadopiclenol at 0.05 mmol/kg compared to gadobutrol at 
0.1 mmol/kg in terms of 3 lesion visualization co-primary criteria (border delineation, internal 
morphology, degree of contrast enhancement) for patients referred for contrast-enhanced MRI 
of the body regions.  
For FDA, the primary objective 1 is to be achieved. The primary objective 2 will serve as one of the 
secondary objectives. 
For EMA, both primary objectives 1 and 2 are to be achieved. 
 
2.2 
Secondary Objectives 
o To demonstrate the non-inferiority of gadopiclenol compared to gadobutrol in terms of 3 lesion 
visualization co-primary criteria (border delineation, internal morphology, degree of contrast 
enhancement) for patients referred for contrast-enhanced MRI of body regions (idem primary 
objective 2, considered as secondary objective for FDA).   
o To assess the following parameters with gadopiclenol and gadobutrol  
 Lesion visualization assessment by investigator 
 Subgroup analysis by organ and/or region of the 3 lesion visualization co-primary 
criteria 
 Improvement in lesion visualization scores at patient level 
 Technical adequacy of images 
 Number, size and location of lesions  
 Diagnostic confidence 
 Impact of contrast-enhanced MRI on patient treatment plan 
 Percentage enhancement (E%) of lesion  
 Lesion to Background Ratio (LBR)  
 Overall diagnostic preference  
 
To assess the safety profile of gadopiclenol and gadobutrol  
 

 
 
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3 
TRIAL DESCRIPTION 
3.1 
Protocol Design  
The trial has a prospective, multi-center, randomized, double-blind, controlled and cross-over design. 
The Investigational Medicinal Products (IMPs) used during the trial are gadopiclenol and gadobutrol. 
The primary criteria 1 will compare gadopiclenol-enhanced MRI (pre + post images = paired images) 
to unenhanced MRI (pre images), using the patient as his/her own control. 
The primary criteria 2 will compare gadopiclenol-enhanced MRI (paired images) to gadobutrol-
enhanced MRI (paired images). 
Patients, once informed consent form (ICF) signed, will perform a screening visit (V1) to confirm trial 
eligibility, then will be randomized in the trial to determine the order of IMP injection. Each of the 2 
MRI visits (V2 and V4) will be followed by a safety visit (V3 and V5) performed 1 day after the MRI 
visit. 
Two MRIs will be obtained on each patient: gadopiclenol-enhanced MRI and gadobutrol-enhanced MRI 
(see Figure 1), however the nature of the contrast agents injected at Visit 2 and at Visit 4 will be 
randomly assigned by Interactive Web Response System (IWRS). 
The investigator and the patient will remain blinded to IMPs allocation (nature of the IMPs and order of 
the IMP injection). A designated unblinded site staff member will be in charge of preparation and 
administration of the IMPs. 
The randomization scheme will allocate patients in a 1:1 ratio to the two arms, gadopiclenol-gadobutrol 
or gadobutrol-gadopiclenol.  
For each investigational site, at least one radiologist experienced in planned imaged regions will be 
appointed at the start of the trial to read images of patients included at the site (on-site read). 
In addition, images will be evaluated by prospective evaluation of the blinded images in a centralized 
manner. All images will be sent to a core laboratory, which will prepare the images for evaluation. 
The blinded image evaluations (off-site read) will be performed by 3 independent blinded radiologists 
for the reading of random images and by 3 additional independent blinded radiologists for the global 
pairs assessment per body region. 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. 
To allow exact matching of lesions between imaging modalities (Pre and Paired), between the two MR 
examinations with gadopiclenol and gadobutrol, and among 3 readers, an independent radiologist (lesion 
tracker) will perform lesion tracking, separate from the image evaluation by the investigator and by the 
independent blinded readers. 
The IWRS will be used to randomize order of contrast agents to be injected, to allocate IMPs, to calculate 
the volume of IMP to be administered based on the body weight and to record patient’s visits. In addition 
it will guarantee an appropriate representation of the different body regions in ensuring the inclusion of 
at least 25 thorax patients, 50 abdomen patients, 25 pelvis patients and 25 musculoskeletal patients. 
During the trial, the safety will be monitored and assessed based on the reporting of adverse events 
(AEs), the results of vital signs measurements, the evaluation of injection site tolerance and the clinical 
laboratory parameters (blood samples). 
 

 
 
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3.2 
Justification for dose 
Based on Phase IIb results, gadopiclenol dose of 0.05 mmol/kg BW is deemed to be as efficient as all 
other available GBCAs at clinical dose of 0.1 mmol/kg BW. It will be investigated for lesion 
visualization in patients with known or suspected enhancing abnormality(ies) and/or lesion(s) in at least 
one body region among head & neck, thorax (including breast), abdomen (including liver, pancreas and 
kidney), pelvis (including uterus, ovary and prostate) and musculoskeletal (including extremities). 
Gadobutrol will be used, as an active comparator, at its standard approved dose of 0.1 mmol/kg BW.  
 
3.3 
Trial Duration 
 Duration of patient’s participation 
Minimum trial duration for patients: 4 days, if V1 and V2 are done on the same day and the second MRI 
is done 2 days after the first one. 
Maximum trial duration for patients: 23 days, if the screening period lasts 7 days and the second MRI 
is done 14 days after the first one. 
The trial includes a maximum of 5 visits: 
 
One screening visit (V1) up to 7 days prior to inclusion (V1) could be done the same day as the 
randomization visit (V2) if all the inclusion/non-inclusion criteria are met). 
 
Two sequential imaging visits (V2 and V4, minimum interval 2 days and up to 14 days): each 
visit will consist of gadopiclenol injection or gadobutrol injection and MRI procedure. 
 
Two safety visits (V3 and V5): 1 day after each injection and 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 the independent blinded readers.  
The patient’s participation is defined as the period from the screening visit (ICF signature) to the last 
trial visit.   
 
3.4 
Interim Analysis  
Not applicable 
 
3.5 
Trial Committee(s) 
Not applicable (see Section 12). 
 
 

 
 
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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 having reached legal majority age. 
2. Patient presenting with known or suspected enhancing abnormality(ies) and/or lesion(s) in 
at least one body region among head & neck, thorax (including breast), abdomen (including 
liver, pancreas and kidney), pelvis (including uterus, ovary and prostate) and 
musculoskeletal (including extremities) based on a previous imaging procedure performed 
within 12 months prior to ICF signature. US patients are restricted to the breast in 
compliance with local approved indications of gadobutrol. 
3. Patient scheduled for a contrast-enhanced MRI examination of a body region for clinical 
reasons and agreeing to have a second contrast-enhanced MRI examination for the purpose 
of the trial. 
4. If the patient was treated (either with radiation, surgery, biopsy or other relevant treatments) 
between previous imaging evaluation and trial MRI, there should still be a high suspicion 
of remaining enhancing abnormality(ies) and/or lesion(s) on the basis of available clinical 
information. 
5. Patient able and willing to participate in the trial. 
6. Patient having read the information and having provided his/her consent to participate in 
writing by dating and signing the informed consent prior to any trial related procedure being 
conducted. 
7. Patient affiliated to national health insurance according to local regulatory requirements. 
 
4.2 
Non-Inclusion Criteria 
Patients presenting with one or more of the following non-inclusion criteria must not be included in the 
trial: 
1. Patients with known or suspected lesion(s) referred for contrast-enhanced MRI of CNS or 
of heart or for MR Angiography. 
2. Patient presenting with known class III/IV congestive heart failure according to the New 
York Heart Association classification (NYHA). 
3. 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. 
4. Patient previously randomized in this trial. 
5. Patient presenting with any contraindication to MRI examinations. 
6. Patient having received any contrast agent (for MRI or CT) within 3 days prior to trial 
products administration, or scheduled to receive any contrast agent during the course of the 
trial or within 24 hours after the second trial product administration. 

 
 
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7. Patient expected/scheduled to have any treatment or medical procedure (e.g. chemotherapy, 
radiotherapy, biopsy or surgery etc…) that may impact the aspects of the imaged lesions 
between the 2 MRI examinations. (Patients under corticosteroids and/or maintenance 
chemotherapy with a stable dose at the time of screening visit and throughout the trial can 
be included).  
8. 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. 
9. 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. 
10. Patient related to the Investigator or any other trial staff or relative directly involved in the 
trial conduct. 
Non-inclusion criteria to be checked at V1, V2 and V4: 
11. Patient presenting with acute or chronic renal insufficiency, defined as an estimated 
Glomerular Filtration Rate (eGFR) < 30 mL/min/1.73 m² assessed within 1 day prior to each 
contrast agent administration. 
12. Pregnant or breast-feeding female patient (a female patient of childbearing potential or with 
amenorrhea for less than 12 months must have a negative urine pregnancy test within 1 day 
prior to trial MRI and must be using highly effective birth controlled method* until the last 
trial visit). 
13. 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). 
* 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 
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. 
 
The diagnosis obtained from previous (qualifying) imaging examinations will be considered as medical 
history to assess inclusion criteria. All the trial efficacy analyses will be only based on the images 
obtained through the trial MRI. 
 
 
4.3 
Patient Identification 
After having signed the written informed consent patients will be allocated a unique Identification 
Number (Patient ID). 

 
 
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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. 
 
 

 
 
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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: gadopiclenol 
 
Pharmaceutical form: vial of 20 mL 
Gadopiclenol is an aqueous solution. Each vial contains 20 mL of solution presented as a sterile, clear, 
ready-to-use solution for injection. 
Concentration: 0.5 M 
Route and method of administration: single intravenous (IV) bolus injection followed by a saline flush 
preferably via power injector. The injection rate is depending on scanned organ/region. 
Dose per administration: dose/volume of gadopiclenol to be administered will be calculated by IWRS 
based on patient’s weight at the dose of 0.05 mmol/kg BW. Volume to be injected will be rounded to 
the nearest whole number as described in section 5.6.  
Sufficient IMP must be allocated to one patient by IWRS. 
Please refer to the Investigator Brochure for more information on gadopiclenol. 
 
  Investigational Medicinal Product 2 
Name: gadobutrol 
Pharmaceutical form: vial of 15 ml 
Gadobutrol is an aqueous solution. Each vial contains 15 mL of solution presented as a sterile, clear, 
ready-to-use solution for injection. 
Concentration: 1 M 

 
 
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Route and method of administration: single intravenous (IV) bolus injection followed by a saline flush 
preferably via power injector. The injection rate depends on scanned organ/region and will be 
determined according to site’s practice. 
Dose per administration: dose/volume of gadobutrol to be administered will be calculated by IWRS 
based on patient’s weight at the dose of 0.1 mmol/kg BW. Volume to be injected will be rounded to the 
nearest whole number as described in section 5.6. 
Sufficient IMP must be allocated to one patient by IWRS. 
Please refer to the SmPC of gadobutrol for more information on the product. 
 
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 gadopiclenol and gadobutrol will be performed by Guerbet (or its 
designee).  
The outer packaging will be the same for both products in order to ensure the double-blind conditions. 
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 and patient number and 
other 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 of gadopiclenol or one 15 ml vial of gadobutrol. 
In case of issue related to IMP (damaged, broken vials…), a new IMP will be allocated to the patient 
via the IWRS. 
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 25°C or below in the original package, 
protected from light and not 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 series of 2 MRIs performed each at two trial 
visits separated by a wash out period of 2 days minimum and up to 14 days. One series consists of the 
use of gadopiclenol, single intravenous (IV) bolus injection, as contrast agent at visit 2 and gadobutrol, 
single intravenous (IV) bolus injection, at visit 4 and reverse order for the second series (see Figure 1). 
The randomization scheme will allocate patients in a 1:1 ratio to the two trial arms, gadopiclenol-
gadobutrol or gadobutrol-gadopiclenol. 
The randomization to determine the order of injection at visit 2 and visit 4 will be done via IWRS and 
performed in blocks to prevent unequal treatment allocation. 
The trial design and the injection of the IMPs require identifying before the trial start, two separate teams 
in each trial site. One will manage the blinded data and another one will be unblinded and will be in 
charge of the IMPs preparation and administration. The unblinded staff will have to document in a 

 
 
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separated patient’s file all the unblinded information related to the IMPs and will have to complete a 
dedicated restricted field in clinical eCRF pages. 
During the course of the trial, the two teams should not exchange any information regarding the IMPs 
(nature of IMP injected, order of administration). The patients’ files with unblinded data should not be 
filed with the patient’s medical and trial files in order to not break the blind. The unblinded 
documentation should be stored shielded from the view of the blinded staff. An initial shipment of IMPs 
will be sent to the investigational sites after having received regulatory authorization(s)/ethical 
approval(s) as per local requirements. Additional shipments will be sent according to patient recruitment 
progress of a given investigational site. The site should ensure to have enough IMPs before including a 
new patient. The site can log onto IWRS to know the IMPs stock status. 
IMP receipt will be acknowledged by the investigator (or any designated person in his/her team) via 
IWRS.  
At visit 2 and visit 4, once all the inclusion /non-inclusion criteria, including eGFR and pregnancy test, 
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 allocated treatment arm and to the contrast medium 
allocated for the enhanced MRI procedure. 
In case one IMP breaks or becomes non-sterile or is not available, or any problem of IMP allocation 
(e.g. wrong IMP administered to the 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. 
 
 Double-Blind Conditions 
To ensure that administration of the IMP is carried out under double-blind conditions, an unblinded team 
(nurse, technician or physician) will be responsible for preparing and administrating the IMP(s). This 
person will ensure non-disclosure of information.  He /she will stick the detachable label of the vial into 
the patient’s records or appropriate form. He /she will also write his/her name, date and signature and 
the patient number on the box, and after use, he/she will close the box with a seal. 
Any disclosure relating to the nature of the contrast agent injected by the person responsible for IMP 
allocation will be considered a protocol deviation. 
Image readings of all patients will be evaluated in blinded conditions regarding the contrast agent 
injected, as described in Section 8.4.  
 
 Individual Trial Treatment Unblinding 
In case of an adverse event occurring for a patient and which nature would require immediate knowledge 
of the allocated IMP, the individual trial treatment may be unblinded, if absolutely necessary for the 
safety of the patient and if unblinding impacts the management of medical cares (see section 9.5).  
Conditions and procedure for breaking the code will be reviewed with the investigator and his/her team 
during the initiation visit. 
The persons authorized to unblind trial product during the trial usually are: the investigators and Guerbet 
Pharmacovigilance physician/officer and European Qualified Person for Pharmacovigilance (EU-
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If the Clinical Project Manager receives an external request for unblinding (Authorities, health care 
professionals taking care of the patient, etc.), he/she must inform Guerbet Pharmacovigilance 
physician/officer. 
If the investigator and Guerbet Pharmacovigilance physician/officer unblind the trial product, he/she 
must inform the Clinical Project Manager as soon as possible but shall not reveal the nature of the trial 
product in order to protect as much as possible the double-blind design of the trial.  
Unblinding must be documented by indicating the patient’s identification number, age and sex, the date, 
time and the reason for unblinding, the identity of the person who performed the unblinding.  
Please refer to Section 9.5 for detailed information on patient safety monitoring. 
 
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 
An unblinded third party, 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 clinical eCRF. 
The volume (mL) of IMP to be injected to the patients will be determined by IWRS. The volume 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 contraception, homeopathic products, pre-medication, 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 medical file and in the patient’s clinical 
electronic Case Report Form (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 first administration, between first and second administration, after 
second (last) 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. 
In general, there are no specific recommendations regarding GBCAs, and therefore, no specific 
hydration procedure is defined in this protocol. Nonetheless, whenever possible, the patient should be 
encouraged to drink water and other non-alcoholic fluids liberally before and after the injection. 
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. 
In addition, no significant change should occur in any treatment or medical procedure (e.g. 
chemotherapy, radiotherapy, biopsy or surgery etc…) which may impact the appearance of lesion of the 
imaged body region between the 2 MRI examinations. However, patients under corticosteroids and/or 
maintenance chemotherapy with a stable dose at the time of screening visit and throughout the trial can 
be included. 
 
 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 second trial product administration are prohibited. 
  
6.2 
Concomitant Procedures 
Not applicable 
 
 

 
 
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7.1 
Primary Criteria (off-site read) 
 Primary criteria 1: Lesion visualization criteria for gadopiclenol-enhanced MRI 
compared to unenhanced MRI (off-site read) 
The lesion visualization criteria is based on 3 co-primary criteria: border delineation, internal 
morphology and degree of contrast enhancement assessed on the images acquired during the MRI 
performed with gadopiclenol. 
The IBR will record each of the 3 co-primary criteria for up to 3 most representative lesions. 
Representative lesion is defined according to lesion size and contrast enhancement.  For pre-contrast 
images read, as contrast enhancement cannot be completely foreseen, 3 largest potentially enhancing 
lesions should be selected. For paired images read, 3 largest enhancing lesions should be prioritized.  
The evaluation will be performed on Paired images (images set 1b) versus Pre images (images set 1a) 
on a 4-point scale as described below: 
o Border delineation: 
Delineation of the lesion border is defined as the distinction of lesion from surrounding tissues, 
structures, or edema; and the detection of extent of the lesion. This criterion will be assessed through 
the following scale: 
1 = None: no or unclear delineation 
2 = Moderate: some areas of clear delineation but also with some significant areas of 
non-distinct delineation 
3 = Good: almost clear but not complete delineation 
4 = Excellent: border outline is sharp with clear and complete delineation  
 
o Internal morphology: 
Internal morphology of the lesion includes an identification of lesion architecture and the intra-lesion 
features such as necrosis, hemorrhage and vascularity. This criterion will be assessed through the 
following scale: 
1 = Poor: poorly seen 
2 = Moderate: majority of lesion is poorly seen but with minor parts of lesion visible 
3 = Good: majority of lesion is clearly seen but with minor parts of lesion invisible 
4 = Excellent: lesion is well seen and can see “through” lesion to observe any complex 
areas of necrosis or hemorrhage or cyst formation 
 
o Degree of contrast enhancement:  
This criterion will be a qualitative assessment (not based on signal intensity measurement) according 
to the following scale: 
1 = No: no enhancement  
2 = Moderate: weakly enhanced 
3 = Good: clearly enhanced 
4 = Excellent: clearly and brightly enhanced 
 

 
 
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The mean of scores for each of the 3 lesion visualization co-criteria will be calculated as follows:  
Mean of scores = (score of lesion 1 + score of lesion 2 (if any) + score of lesion 3 (if any) divided by 
the number of lesions (up to 3 most representative lesions).  
For each reader, only matching lesion between paired images and pre images will be considered for the 
purpose of the primary criteria 1 evaluation.  
For each reader, if the MR images are not assessable or if no matching lesion is identified between 
Paired images and Pre images, then the patient will not be included in the primary criteria 1 evaluation. 
The mean of scores for each of the lesion visualization co- primary criteria 1 will range from 1 to 4.  
 
 Primary criteria 2: Lesion visualization criteria for gadopiclenol compared to 
gadobutrol (off-site read) 
As for primary criteria 1, the lesion visualization criteria is based on 3 co-primary criteria: border 
delineation, internal morphology and degree of contrast enhancement, assessed on the images acquired 
during the MRI performed with gadopiclenol and those performed with gadobutrol. 
The IBR will record each of the 3 co-primary criteria for up to 3 most representative lesions, on Paired 
images (images set 1b) performed with gadopiclenol and Paired images (images set 2b) performed with 
gadobutrol using a 4-point scale.  
Definitions of each co-primary criteria and score calculation are provided in section 7.1.1.  
For each reader, only matching lesion between paired images of gadobutrol and gadopiclenol will be 
considered for the purpose of the primary criteria 2 evaluation.  
For each reader, if the MR images are not assessable or if no matching lesion is identified on paired 
images between gadopiclenol and gadobutrol, then the patient will not be included in the primary criteria 
2 evaluation. 
The mean of scores for each of the lesion visualization co- primary criteria 1 will range from 1 to 4. 
 
7.2 
Secondary Criteria 
All secondary criteria will be evaluated for gadopiclenol and gadobutrol: 
 Lesion visualization criteria for gadopiclenol compared to gadobutrol (off-site read) 
for FDA only  
The criteria are the same as described in section 7.1.2. 
 
 Lesion visualization (based on 3 co-primary criteria: border delineation, internal 
morphology and degree of contrast enhancement) by organ and/or region 
The criteria are the same as described in section 7.1.2 
 

 
 
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 Improvement in lesion visualization scores at patient-level, paired versus pre-
contrast images 
Improvement in lesion visualization scores at patient-level is based on 3 co-primary criteria: border 
delineation, internal morphology and degree of contrast enhancement assessed on the images acquired 
during the MRI performed with gadopiclenol and gadobutrol. 
For each contrast agent on Pre and Paired images and for the 3 co-primary criteria, the lesion score is 
calculated and compared between Pre and Paired images. If the lesion score of Paired images is greater 
than those of Pre images then the Paired image will be classified as “Better”. If the mean score of Paired 
images is equal or less than those of Pre images then the Paired image will be classified as “Not Better”. 
 
 Lesion visualization (on-site read) 
The lesion visualization criteria are based on 3 co-criteria: border delineation, internal morphology and 
degree of contrast enhancement assessed on the images acquired during the MRI performed with 
gadopiclenol and gadobutrol. 
The investigator (radiologist) will record each of the 3 co-primary criteria for up to 3 most representative 
lesions, on Pre and Paired images (images set 1a, 2a, 1b and 2b) on a 4-point scale. 
The 3 co-criteria definition are listed in section 7.1.1. 
 
 Technical adequacy of images (on-site and off-site read) 
For each contrast agent, images will be evaluated as technically adequate for diagnosis on a 4-point scale 
and as assessable or not by investigators and IBR. 
  
The technical adequacy of images will be rated on a 4-point scale: 
1 = Non diagnostic 
2 = Poor 
3 = Fair  
4 = Good  
Images should be evaluated as assessable or not and if not, the reasons should be recorded: 
1 = Artifacts due to patient   
2 = Artifacts due to machine 
3 = Injection technical failure 
4 = Inadequate anatomic coverage  
5 = Other, specify 
 
 Number, size and location of lesions (on-site and off-site read) 
The investigator and IBR is to record the following:  
- 
Number of lesions on pre and paired images 
- 
For the most 3 representative lesions, the following will be recorded for each lesion separately:  
 
The largest diameter of the lesion 
 
The location of the lesion 
- 
In case that more than 3 lesions are present, the investigator/IBR has to enter in the eCRF how many 
lesions are present (total number). 
 

 
 
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 Diagnostic confidence (on-site and off-site read) 
The investigator/IBR will record in the eCRF his/her diagnosis and his/her confidence in diagnosis for 
each patient for each pre and paired images of each contrast agent according to the following diagnosis:  
1    = Negative 
2    = Benign   
3    = Probably Benign finding   
4A = Low Suspicion of Malignancy   
4B = Intermediate Suspicion of Malignancy  
4C = Moderately High Suspicion of Malignancy 
5    = Not assessable 
If malignancy is diagnosed, then whether the tumor is primary or secondary should be specified.  
Diagnostic confidence will be evaluated to determine the level of certainty that the investigator/IBR 
assign to a diagnosis. This is defined as the degree of confidence that the information on the images 
represents the true and complete clinical picture of a patient.  
The degree of confidence will be rated on a 5-point scale:  
1 = Nil: very uncertain 
2 = Poor: uncertain 
3 = Moderate: moderately certain 
4 = High: good certainty  
5 = Excellent: very certain 
When the investigator/IBR chooses ‘not assessable’ for diagnosis, by definition the confidence level is 
1 (= very uncertain). 
 
 Impact of contrast-enhanced MRI on patient treatment plan (on site) 
The impact on patient treatment plan will be assessed by on-site radiologists and will be summarized 
for each contrast agent. At the end of visit 2 and at the end of visit 4, after having completed all the 
sequences of images required by the protocol (images set 1b or set 2b), the investigator will have to 
document if the patient treatment plan could have been changed based on the images obtained (yes/no) 
and if yes, he/she would have to specify the therapeutic management proposed based on radiological 
assessment: 
o Surgery 
o Biopsy 
o Chemotherapy 
o Radiotherapy 
o Other treatment: specify 
 
 Percentage enhancement (E%) of lesion and Lesion to Background Ratio (LBR) 
(off-site read) 
The 2 quantitative criteria (E% and LBR) will be calculated by patient in averaging the parameter for 
maximum 3 most representative lesions. 
 

 
 
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o Percentage enhancement (E%) of lesion 
𝐸% = 𝑆𝐼𝑝𝑜𝑠𝑡− 𝑆𝐼𝑝𝑟𝑒
𝑆𝐼𝑝𝑟𝑒
x100 
where SIpost = Signal intensity of lesion on post injection images 
SIpre = Signal intensity of lesion on pre injection images 
 
o Lesion to Background Ratio (LBR) (pre and post) 
LBR = 𝑆𝐼𝑙𝑒𝑠𝑖𝑜𝑛
𝑆𝐼𝑏 
where SIlesion = Signal intensity of  lesion  
             SIb= Signal intensity of background (surrounding healthy tissue of the lesion) 
 
 
 Overall diagnostic preference (off-site read) 
The evaluation will be performed in a global matched-pairs fashion (images set 1b or 2b). For each 
patient who received the two different IMPs, all images (paired image set 1b or 2b) from the first MR 
examination, labeled as examination 1, will be displayed simultaneously with the corresponding paired 
images from the second MR examination, labeled as examination 2.  
The assessment will be performed based on 3-point scale: 
o 1: When examination 1 is preferred to examination 2  
o 0: When no preference is observed  
o 2: When examination 2 is preferred to examination 1  
 
IBRs need to select one or more of the following six reasons for this preference:  
 
Contrast enhancement was superior, 
 
Delineation of normal structure was better 
 
Delineation of at least one lesion was better 
 
Internal structure of lesions was better visualized  
 
More lesions were identified  
 
Diagnostic confidence was greater (specify one or more reason(s): detection of 
lesions, characterization of disease, assignment of a grade to disease, definition of 
extent of disease, or other reasons that had to be specified on the Imaging eCRF) 
 
 
 Safety profile of gadopiclenol and gadobutrol (on-site) 
The safety assessments will be followed up by evaluating results of vital signs, injection site tolerance, 
clinical laboratory parameters (blood samples) and adverse events (AEs) reporting. 

 
 
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o Vital signs 
Vital signs (supine systolic and diastolic blood pressures, pulse rate) will be measured and recorded 
according to the following schedules: 
 
Prior to each contrast agent injection (V2 is considered as baseline value)    
 
At 60 ± 15 minutes following each contrast agent injection 
 
One day after each contrast injection 
Prior to the first injection, all clinically significant abnormal value might be reported in medical history 
section or AE section as per investigator’s judgement. After the first contrast agent injection, all 
clinically significant abnormal value, as per investigator’s judgement, will be recorded as AEs. 
o Injection-site tolerance  
For all patients, injection-site tolerance (pain, eruption, extravasation, inflammation, or other) will be 
assessed over 1 day following each contrast injection (during the injection, 60 min ± 15 min post 
injection and the day after injection) and over a longer period if the investigator becomes aware of any 
related AE. In case of injection-site pain, the patient will be asked to specify the level of pain using a 
Numeric Pain intensity Scale (NPS
) from 0 (no pain) to 10 (maximal pain). 
o Local laboratory parameters 
Serum creatinine and eGFR will be obtained from local laboratory of each site prior to MRI and one 
day post IMP injection. 
The same local methods of serum creatinine dosage and eGFR calculation should be used throughout 
the trial for a same patient. 
According to ESUR guidelines: Post-contrast acute kidney injury (PC_AKI) is defined as an increase in 
serum creatinine of ≥ 0.3 mg/dL or of ≥ 1.5 times baseline, within 48-72 hours of intravascular 
administration of a contrast agent. 
For this trial, it is up to investigator to evaluate any change in serum creatinine within trial period as 
clinically significant or not; the investigator will report any clinically significant change as an AE. 
o Clinical laboratory parameters 
For each patient, blood samples will be performed from visit 2 to visit 5.  
The following parameters will be obtained and assessed centrally:  
 
Hematology: Red Blood Cells (RBCs), White Blood Cells (WBCs), neutrophils, eosinophils, 
basophils, lymphocytes and monocytes, platelet count, hemoglobin, hematocrit, Mean red 
blood Cells Volume (MCV). 
 
Biochemistry: Sodium, potassium, chloride, Blood Urea Nitrogen (BUN) / urea, total protein, 
calcium, phosphorus, total bilirubin (and indirect bilirubin), conjugated bilirubin, Aspartate 
Amino Transferase (AST), Alanine Amino Transferase (ALT), alkaline phosphatase, Lactate 
DeHydrogenase (LDH), Triglycerides, Cystatin C. 
The central laboratory will flag laboratory values falling outside of the normal ranges on the central 
laboratory report (which the investigator should review and sign off). 
Prior to the first injection, all clinically significant abnormal value might be reported in medical history 
section or AE section as per investigator’s judgement. After the first contrast agent injection, all 
clinically significant abnormal value, as per investigator’s judgement, will be recorded as AEs. 
o Adverse events 
Adverse Events will be recorded throughout patient participation (see section 9.1.2). 
 
 

 
 
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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 0 
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; 
 
The patient will be attributed an Identification Number (see section 4.3); 
 
Checking of all eligibility criteria; 
 
Recording of demographic data (sex, self-reported race/ethnic data, height, age); 
 
Documentation of relevant medical history/current medical condition present before 
signing the informed consent including the disease justifying the MRI; 
 
Recording of patient intolerance history related to contrast agent: if previous intolerance 
to contrast agent, the type of the product should be collected; 
 
Documentation of previous CT, MRI or other imaging procedures documenting the 
region planned to be imaged dated less than 12 months prior to trial MR; 
 
A routine physical examination (performed by a physician) including the examination 
of general appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, 
heart, abdomen, back, lymph nodes, extremities, vascular and neurological; Information 
indicating the global assessment (normal or abnormal (specify)) of the physical 
examination should be recorded on source documentation; 
 
Review and recording of concomitant treatments; 
 
A urine pregnancy test should be performed for all women of childbearing potential and 
must be negative.  
 
IWRS connection for recording the patient screening visit and to ensure an appropriate 
representation of the different body regions. This means that the patient’s inclusion may 
be refused due to the body region planned to be imaged. 
 
First trial MRI visit and examination needs to be scheduled within 7 days (or can be 
performed on the same day if all the inclusion/non-inclusion criteria are met). 
 
 Imaging/Randomization Visit – 1st MRI – Visit 2 – Day 0 
During this visit, the following assessments or tasks will be performed: 
Procedures to be performed prior to MRI examination: 
 
Checking of all the eligibility criteria; 
 
Any changes in concomitant treatments / procedures / therapeutic measures since the 
last visit will be documented;  
 
Measurement of vital signs (systolic and diastolic blood pressure (BP) and pulse Rate 
(PR)) and weight; 

 
 
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 
A urine pregnancy test will be performed for female patient of childbearing potential 
and must be negative (test done at V1 will not be repeated at V2 if V1 done one day 
prior to V2. If V1 and V2 are done on the same day, one pregnancy test should be 
performed prior to patient randomization);  
 
Blood sample collection for local dosage of serum creatinine and evaluation of eGFR 
(results should be available prior to patient randomization to check eligibility criteria. 
eGFR value should be ≥ 30 mL/min/1.73 m² prior to the first MRI); the same local 
methods of serum creatinine dosage and eGFR calculation should be used throughout 
the trial for a same patient; 
 
Blood samples will be collected according to central laboratory manual; 
 
Assessment of AEs will be documented;  
 
IWRS connection will be done to randomize the patient, to obtain the IMP box number, 
to calculate the volume of IMP to be administered based on the body weight and to 
record the date of the visit. 
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). 
The appropriate dose/volume of gadopiclenol and gadobutrol will be administered by IV as a bolus using 
preferably a power injector in a peripheral vein of the antecubital region (recommended). IMP injection 
will be followed by a saline flush injection. 
The following information will be documented in the source document and reported on clinical eCRF 
pages: date and time of contrast agent injection, location of injection site, actual volume administered 
(documentation of difference from theoretical volume), actual injection rate, overdose (if any), number 
of vials dispensed, number of IMP injected, injection method (power injector or manual), injection of 
saline flush (yes/no). 
The start time of contrast injection will be recorded.  
Procedures to be followed after MRI examination: 
The patient will stay at the trial site for 60 ± 15min after the MRI examination is completed and the 
following procedures will be performed:  
 
Use/change of concomitant treatments during the visit will be documented; 
 
Vital signs (systolic and diastolic BP and PR) will be obtained 60 minutes ± 15 minutes 
after the injection of contrast agent.  
 
Injection-site tolerance (pain, eruption, extravasation, inflammation, or other) will be 
assessed during the injection and 60 ± 15 minutes after the injection of contrast agent; 
In case of pain, the patient will have to complete a Numeric Pain intensity Scale to 
indicate the pain intensity. Any sign of local intolerance will be reported as AE in the 
corresponding clinical eCRF page. 
 
Assessment of AEs will be documented;  
 
Evaluation of the potential impact of contrast-enhanced MRI on patient treatment plan; 
 
Safety follow-up visit (Visit 3) needs to be scheduled 1 day post contrast agent injection; 

 
 
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 
Scheduling of the second MRI examination (visit 4) between 2 days and 14 days post 
visit 2. 
 
 
Safety Visit – Visit 3 – 1 day post visit 2 
During this visit, the following assessments or tasks will be performed: 
 
Use/change of concomitant treatments / procedures / therapeutic measures will be 
documented;  
 
Blood sample collection for local dosage of serum creatinine and evaluation of eGFR; 
The same local methods of serum creatinine dosage and eGFR calculation should be 
used throughout the trial for a same patient;  
 
Blood samples will be collected according to central laboratory manual;  
 
Vital Signs (systolic and diastolic BP, PR) should be recorded; 
 
Injection-site tolerance is to be evaluated; In case of pain, the patient will have to 
complete a Numeric Pain intensity scale to indicate the pain intensity. Any sign of local 
intolerance will be reported as AE in the corresponding clinical eCRF page. 
 
Assessment of local serum creatinine results as per ESUR guidelines (see section 
7.2.11) 
 
Assessment of AEs will be documented;  
 
IWRS connection to record the trial visit; 
 
Remind the date of visit 4 to the patient. 
 
 Imaging Visit – Visit 4– 2nd MRI – 2 days up to 14 days post V2 
Procedures to be performed prior to MRI examination: 
 
Checking  of certain non-inclusion criteria (see section 4.2);  
 
Measurement of vital signs (systolic and diastolic BP and PR) and weight; 
 
Any changes in concomitant treatments / procedures / therapeutic measures since the 
last visit will be documented;  
 
A urine pregnancy test will be performed for female patient of childbearing potential 
prior to the trial MRI and must be negative; 
 
Blood sample collection for serum creatinine dosage and verification that the local 
eGFR value is ≥ 30 mL/min/1.73 m²; The same local methods of serum creatinine 
dosage and eGFR calculation should be used throughout the trial for a same patient; 
 
Blood samples will be collected according to central laboratory manual; 
 
Assessment of local serum creatinine results as per ESUR guidelines (see section 
7.2.11) 
 
Assessment of AEs will be documented;  

 
 
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 
IWRS connection will be done to obtain the IMP box number, to calculate the volume 
of IMP to be administered based on the body weight and to record the date of the visit; 
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. 
The appropriate dose/volume of gadopiclenol and gadobutrol will be administered by IV as a bolus using 
preferably a power injector in a peripheral vein of the antecubital region (recommended). IMP injection 
will be followed by a 0.9% saline flush injection. 
The following information will be documented in the source document and reported on clinical eCRF 
pages: contrast agent injection date and time, location of injection site, actual volume administered 
(documentation of difference with theoretical volume), actual injection rate, overdose (if any), number 
of vials dispensed, number of IMP injected, injection method (power injector or manual), injection of 
saline flush (yes/no). 
The start time of contrast injection will be recorded.  
Procedures to be followed after MRI examination: 
The patient will stay at the trial site for 60 ± 15min after the MRI examination is completed and the 
following procedures will be performed:  
 
Use/change of concomitant treatments during the visit will be documented; 
 
Vital signs (systolic and diastolic BP and PR) will be obtained 60 minutes ± 15 minutes 
after the injection of contrast agent.  
 
Injection-site tolerance (pain, eruption, extravasation, inflammation, or other) will be 
assessed during the injection and 60 minutes ± 15 minutes after the injection of contrast 
agent; In case of pain, the patient will have to complete a Numeric Pain intensity scale 
to indicate the pain intensity. Any sign of local intolerance will be reported as AE in the 
corresponding clinical eCRF page. 
 
Assessment of AEs will be documented;  
 
Evaluation of the potential impact of IMP-enhanced MRI on patient treatment plan; 
 
Safety follow-up visit (Visit 5) needs to be scheduled 1 day post contrast agent injection;  
 
 Safety Visit – Visit 5 – 1 day post Visit 4 
During this visit, the following assessments or tasks will be performed: 
 
Use/change of concomitant treatments / procedures / therapeutic measures will be 
documented;  
 
Blood sample collection for local dosage of serum creatinine and evaluation of eGFR. 
The same local methods of serum creatinine dosage and eGFR calculation should be 
used throughout the trial for a same patient;  
 
Assessment of local serum creatinine results as per ESUR guidelines (see section 
7.2.11) 
 
Blood samples will be collected according to central laboratory manual;  

 
 
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 
Vital Signs (systolic and diastolic BP, PR) should be recorded; 
 
Injection-site tolerance is to be evaluated; In case of pain, the patient will have to 
complete a Numeric Pain intensity scale to indicate the pain intensity. Any sign of local 
intolerance will be reported as AE in the corresponding clinical eCRF page. 
 
Assessment of AEs will be documented (any AE not recovered should be followed up 
(see section 9.1.2);  
 
IWRS connection to record the trial visit; 
During the course of the trial, if a patient is screen failed or is prematurely discontinued (see section 
14.3.2), the new patient status should be recorded in the IWRS and in the clinical eCRF. 
 
8.2 
Imaging Characteristics  
 Equipment 
The procedure will be performed using a MRI scanner that can perform the required pulse sequences. 
MRI units with 1.5T or 3T magnetic field will be used, regardless of the manufacturer. The following 
information must be recorded in the clinical eCRF: the manufacturer and field strength of the MRI 
device.  
For a single patient, the same MR equipment for the two MRI examinations should be used. 
 
 Imaging protocol 
The same parameter setting for the same sequence should be used for unenhanced images and for 
contrast-enhanced images in each patient.  
The required sequences and parameters for gadopiclenol and gadobutrol per patient should be as similar 
as possible. Depending on scanned organs/regions, different scanning protocol should be used. Core 
sequences for the majority organs are required per protocol are listed. Details on required sequence and 
parameters will be provide in the Imaging Manual. 
 Breast MRI 
Morphological Pre contrast images (unenhanced MRI): 2D axial T1-weighted sequence and 2D axial 
T2-weighted sequence.  
Dynamic post contrast images (contrast-enhanced MRI): 3D axial T1 fat saturation weighted sequence 
without injection (mask) and after injection minimum 3 repetitions <2min.  
 Liver MRI 
Dynamic contrast-enhanced T1-weighted imaging with 3D fat-saturated acquisitions (precontrast, late 
arterial phase, portal venous phase, and delayed phase).  Fat and iron sensitive in-phase and opposed-
phase and T2-weighted imaging with fat saturation are required. 
 Prostate MRI 
Contrast-enhanced T1-weighted imaging will be obtained dynamically through the prostate. In addition, 
T2 weighted imaging will be obtained. 
 Female Pelvis MRI 
Contrast-enhanced T1-weighted imaging will be obtained. In addition, T2 weighted and T2 weighted 
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 Musculoskeletal MRI 
Contrast-enhanced T1-weighted imaging will be obtained. When post-contrast, non-fat-suppressed T1-
weighted imaging are required. 
 
8.3 
On-Site Reading of Images  
For each investigational site, at least one radiologist experienced in planned imaged regions will be 
appointed at the start of the trial to read images of patients included at the site. Whenever possible, a 
second radiologist should be identified in each site and trained to the protocol in case the first radiologist 
is not available to read the images. The same radiologist should read, as far as possible, images from the 
same patient. 
On-site image evaluations are image evaluations performed by blinded investigators involved in the 
conduct of the protocol or in the care of the patients. 
 
8.4 
Off-Site Reading of Images  
Off-site images 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 a core laboratory, 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 center identification. 
For all images, any sequence information will be removed. A complete audit trail of any changes to the 
file headers will be maintained.  
The blinded image evaluations will be performed by independent blinded radiologists per body region 
(3 independent blinded radiologists will evaluate primary criteria and 3 independent blinded radiologists 
will be involved to assess images on the global pairs fashion and 1 radiologist will perform lesion 
tracking). 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 imaging core laboratory) will document the imaging tasks and obligations of the 
investigational site in an Imaging Manual. As defined in Section 8.2.2, 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 Imaging Core Laboratory. 
Guerbet (or the Imaging Core Laboratory) will document the central imaging process in Blinded Images 
Evaluation Charter. 
 
 Site Qualification  
Guerbet’s agent (CRO, Imaging Core Laboratory or monitors) will perform pre-trial site selection. This 
contact will allow ensuring that the imaging protocol can be performed by the site, is programmed and 

 
 
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prepared prior to enrolment of the first patient and that the Imaging Manual will be accurately followed 
by the investigator. 
 
 Receipt and Tracking of Images  
Guerbet (or its Imaging Core Laboratory) will request that investigational sites submit anonymous 
images to the Imaging Core Laboratory in a format that will be agreed prior to trial start. Images will be 
tracked in the database of the Imaging Core Laboratory. 
 
 Image Processing and Quality Check  
Images received by the Imaging Core Laboratory as digital data will be translated from proprietary 
formats 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 Imaging Core Laboratory 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 Imaging Core Laboratory will follow-up on all cases requiring remedial action by the investigational 
sites. Guerbet (or the Imaging Core Laboratory) may conduct site training for investigator sites with 
recurring image quality issues. 
 
 Independent Blinded Readers Training  
A pool of independent readers (with specialty for the targeted organs/regions) with expertise in the 
interpretation of images from the trial diseases or imaging modality, 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. 
All 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 Image 
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 a sufficient number of 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.  
Various modalities of images from the same patient will not be presented in the same batch and the 
Imaging Core Laboratory will ensure an appropriate wash-out period between the evaluations of images 

 
 
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from two modalities (Pre and Paired images) and between two MR examinations for the same patient, 
to minimize recall bias. 
 
 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). 
 
 Inter and Intra-reader Variability Assessment  
The assessments of inter- and intra-reader variability will be done in the final analysis. 
Inter-reader variability will be evaluated on the whole set of trial patients, since each patient will be read 
by 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 approximately after the first 50 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  
A concordance reading process (lesion tracking) will be performed as an independent off-site procedure. 
The purpose is to guarantee an unambiguous assignment (matching) of the lesions between modalities 
(Pre and Paired images) of the same MR examination, between two MR examinations for the same 
patient, and among 3 readers. Lesion tracking will be carried out by another independent radiologist (so-
called concordance reader) in blinding condition (except the ID number of lesions) on the basis of the 
off-site readers’ assessments. Once the concordance process is done, a correspondence/tracking lesion 
table should be obtained, so that lesions could be compared for analysis within readers or for the inter- 
and intra-reader (refer to trial “Blinded Image Evaluation Charter” for details). 
 
 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. 
 

 
 
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8.5 
 Non Imaging Central procedures: central laboratory  
A central laboratory will be used for all scheduled laboratory tests in this trial except for the pregnancy 
test, creatinine and eGFR which will be assessed locally. The investigator will be provided with a list of 
normal ranges prior to the start of the trial. The central laboratory will provide the necessary kits to 
collect the blood samples and will also provide appropriate information regarding shipping of the 
samples to the central facilities.  
The following parameters will be obtained from the central laboratory:  
 
Hematology: Red Blood Cells (RBCs), White Blood Cells (WBCs), neutrophils, 
eosinophils, basophils, lymphocytes and monocytes, platelet count, hemoglobin, 
hematocrit, Mean red blood Cells Volume (MCV). 
 
Biochemistry: Sodium, potassium, chloride, Blood Urea Nitrogen (BUN) / urea, total 
protein, calcium, phosphorus, total bilirubin (and indirect bilirubin), conjugated 
bilirubin, Aspartate Amino Transferase (AST), Alanine Amino Transferase (ALT), 
alkaline phosphatase, Lactate DeHydrogenase (LDH), Triglycerides, Cystatin C. 
All laboratory reports must be promptly reviewed by the Investigator who will initial and date upon 
review. Change(s) in post-dose test values considered clinically significant, which would require either 
additional control or therapy, must be documented in the patient’s source document. All values 
considered clinically significant by the Investigator will be reported as AEs and followed until recovery 
or stabilization of the values if irreversible (sequelae). Each lab reports are to be filled with the patient’s 
source file. 
Samples obtained in this trial will not be retained or used for any other purposes.  
Name and address of the central laboratory will be detailed in the central laboratory manual. 
 
 
 
 

 
 
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9 
SAFETY REPORTING 
The Investigator will report to Guerbet any adverse event whether related or not to the investigational 
medicinal product, serious or not, that occurred in a trial patient during his/her 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.  
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. 
(Note: for US participating sites only: for Guerbet sponsored clinical studies, the term adverse events 
will be used (as opposed to adverse drug experience)). 
Any disease identified and diagnosed by trial imaging examination with contrast agent will not be 
considered as AE. It may be collected in clinical eCRF as trial disease 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 clinically 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 clinical 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 Table 4.  

 
 
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Table 4: Collection and reporting of AEs throughout and after the trial 
Periods and types of AEs to be 
reported 
Screening  
From randomization 
to last follow-up visit 
After end of 
participation 
Not related non-serious  AEs  
X* 
X 
 
Not related SAEs 
X 
X 
 
Adverse Event of Special Interest 
X 
X 
 
Related$ AEs (serious or not)  
X 
X 
X 
Pregnancy cases 
NA 
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. 
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 clinical eCRF. 
 
 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 clinical 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 clinical 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. 

 
 
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 
Causal relationship to the Investigational Medicinal Product: 
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). 
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 (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. 
o IMP definitively discontinued: the event leads to a definite contra-indication to the drug 
(e.g. confirmed hypersensitivity…).  
o IMP unblinding 
 
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 clinical 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 clinical eCRF 
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o Trial discontinuation: the AE leads to a patient discontinuation from the trial.  
 
Adverse event of special interest (AESI): 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.  
 
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). 
No anticipated SAE is defined in this protocol as patient population under trial is suffering from 
abnormalities of various body regions but not from a specific pathology therefore no anticipated SAE 
has been identified. 

 
 
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 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 
 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 clinical 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 
. 
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 
 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), 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 IEC/IRB, if applicable. 
 

 
 
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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 examination 
 
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 gadopiclenol and above 1.5 mmol/kg, or less according to local reference document 
(SmPC), for gadobutrol.  
 
 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 be immediately withdrawn from the trial and must not receive any IMP. 
Any pregnancy (with or without an Adverse Event) of a woman participating in the trial or of a partner 
of a man participating in the trial that is discovered after the ICF signature must be reported to Guerbet 
Pharmacovigilance via the SAE, AESI or pregnancy Report Form 
 (see section 9.2.2) unless 
the conception date is over one 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. 
A specific signed ICF should be obtained before collection of information if the pregnant woman is the 
partner of a trial patient. 
Pregnancy will be monitored until delivery (health of infant up to 8 weeks of age) or early termination.  
 
. 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. 
 

 
 
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 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 
. 
The AESI for this protocol is the following: Nephrogenic Systemic Fibrosis (NSF).  
 
 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 patients 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, SUSAR), 
 
A new major finding from an animal trial, 
 
A temporary halt of a trial for safety reasons if the trial is conducted with the same IMP  
in another country by the same sponsor, 
 
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 
The Reference Safety Information (RSI) used for the assessment of expectedness of serious adverse 
reactions is the investigator brochure in force for gadopiclenol and the SmPC for gadobutrol. 
 

 
 
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9.5 
Unblinding Procedures 
The investigator may, under exceptional circumstances unblind the individual trial treatment group if 
he/she considers that this procedure is relevant to the safety of the trial patient. Individual trial treatment 
unblinding is described in Section 5.3.3. Information that unblinding has been performed by the 
investigator must be documented in the patient medical file, in the clinical eCRF and in the report form 
for SAE, AESI or pregnancy sent to Guerbet Pharmacovigilance Department, if applicable. 
Suspected Unexpected Serious Adverse Reaction (SUSARs) will be unblinded by Guerbet 
Pharmacovigilance Department for regulatory reporting purposes; however, these SUSARs will remain 
blinded to the investigator and to Guerbet blinded personnel responsible for trial management, data 
analysis, and interpretation of results at the trial’s conclusion. 
 
 

 
 
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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 cannot be re-screened. 
For 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: Please 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: 
- 
Inclusion criteria not met /Non-inclusion criteria met; 
- 
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 clinical 
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 a patient enrolled in the trial; 
- 
At the discretion of the investigator if the patient safety or well-being is not compatible with trial 
continuation; 
- 
Other reason (to be specified). 
 
10.5 Enrolment of additional patients 
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.  
 

 
 
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11 STATISTICAL CONSIDERATIONS 
The following sections summarize the statistical considerations, which are fully described in the 
Statistical Analysis Plan. 
11.1 Statistical Method  
Primary objective 1: superiority of Paired images versus Pre images of gadopiclenol MR 
examination regarding lesion visualization co-primary criteria 
The null hypothesis is that the difference in mean scores between Paired images and Pre images for each 
of the 3 primary criteria is equal to 0. 
The alternative hypothesis is that the difference in mean scores between Paired images and Pre images 
for each of the 3 primary criteria is greater than 0. 
A paired t-test is performed at a one-sided 2.5% significance level for each co-primary criteria.  
All co-primary criteria are considered as following a standard normal distribution. Normality will be 
checked by means of plots. 
To conclude that gadopiclenol-enhanced MRI is superior to unenhanced MRI, the null hypothesis has 
to be rejected for all co-criteria simultaneously hence the overall Type I error rate does not need to be 
adjusted. 
 
Primary objective 2: non-inferiority of gadopiclenol versus gadobutrol regarding lesion 
visualization co-primary criteria  
The null hypothesis is that the difference in mean scores between gadopiclenol and gadobutrol for each 
of the 3 primary criteria is equal to the non-inferiority margin.  
The alternative hypothesis is that the difference in mean scores between gadopiclenol and gadobutrol 
for each of the 3 primary criteria is greater than the non-inferiority margin. 
Student’s t-based two-sided 95% confidence interval (95%CI) of the gadopiclenol-gadobutrol difference 
will be calculated for each co-primary criteria and compared to the non-inferiority margin. 
All co-primary criteria are considered as following a standard normal distribution. Normality will be 
checked by means of plots. 
To conclude that gadopiclenol is non inferior than gadobutrol, the null hypothesis has to be rejected for 
all co-criteria simultaneously hence the overall Type I error rate does not need to be adjusted. 
Further, after the non-inferiority is demonstrated, the superiority of gadopiclenol over gadobutrol will 
be tested using the same method. No adjustment for multiplicity is needed as it is a simple closed testing 
procedure. 
For FDA, primary objective 1 is to be achieved. 
For EMA, both primary objectives 1 and 2 are to be achieved. 
 
11.2 Sample Size 
Number of patients for the Primary objective 1: 
Expecting that for each of co-primary criteria, the difference in mean scores will be 0.35 ([“Paired” – 
“Pre”] within patient mean of lesion scores) with 1.5 standard deviation, a sample of 200 patients in the 

 
 
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gadopiclenol group will have 90% power when using a single group superiority t-test with a 0.025 one-
sided significance level.  
As about a 33% non-evaluable patient rate (drop-out rate and non-valid primary criterion rate) is 
expected, sample size increases to 300 patients with enhancing abnormality(ies) and/or lesion(s) of 
various body organs. 
The success hypothesis used in the sample calculation (“Paired” lesion score mean is at least 0.35 higher 
than “Pre” lesion score mean) is based upon the Gutierrez et All, 2015 [11] where the minimal observed 
difference mean was 0.41 with a SD ranging from 0.5 to 0.8. 
Mean (SD) of the difference between combined unenhanced and gadobutrol-enhanced imaging vs 
unenhanced imaging (N = 336).  
Reader 
Border delineation 
Internal 
Morphology 
Degree of Contrast 
Enhancement 
1 
0.67 (0.66) 
0.62 (0.47) 
1.26 (0.61) 
2 
0.72 (0.78) 
0.82 (0.61) 
1.59 (0.77) 
3 
0.43 (0.50) 
0.41 (0.52) 
1.06 (0.51) 
 
Considering that in the current trial the scale used is not exactly the same (4-point scale instead of 3-
point scale for one parameter) and to account for a possible greater heterogeneity, the difference is set 
to 0.35 with 1.5 standard deviation. 
Number of patients for the primary objective 2: 
 Non-inferiority margin: 
For EMA, both primary objectives 1 and 2 are to be achieved therefore this trial will provide a direct 
demonstration of the superiority of gadopiclenol images over unenhanced images (objective 1). So, it 
can be considered as three-armed trial design with unenhanced images as placebo as described in EMA 
guideline on the choice of the non-inferiority margin [12]). As such, it is not necessary to define a value 
for non-inferiority margin to establish that gadopiclenol has efficacy over unenhanced images. 
A 10% non-inferiority margin was considered clinically as an unimportant difference and therefore 
relevant to establish acceptable efficacy relative to gadobutrol (objective 2). Based on the Guerbet Phase 
IIb GDX-44-004 clinical trial results of lesion visualization criteria, the mean score for each of the 3 co-
criteria is expected to be equal to 3.5, so the margin is set to 0.35 (10%).  
 Sample size hypothesis: 
The standard deviation on lesion visualization criteria for gadopiclenol is estimated on the basis of the 
Guerbet Phase IIb GDX-44-004 clinical trial results on lesion visualization criteria presented in the table 
below. 
Mean (SD) of the combined unenhanced and gadopiclenol-enhanced imaging (N = 61).  
Reader 
Border delineation 
Internal 
Morphology 
Degree of Contrast 
Enhancement 
1 
3.37 (0.55) 
3.34 (0.64) 
3.23 (0.80) 
2 
1.97 (0.74) 
1.71 (0.75) 
3.76 (0.58) 
3 
3.72 (0.49) 
3.72 (0.49) 
3.68 (0.50) 
 
Considering that the results for gadobutrol would be similar (meaning that the standard deviation of the 
difference is expected ranging from √2*0.50=0.7 to √2*0.80=1.15) and taking into account a possible 

 
 
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greater heterogeneity of patient population to be included in the study, the expected standard deviation 
of difference between gadopiclenol and gadobutrol is estimated to 1.75.  
  
For this 2x2 cross-over design, the statistical analysis is based on the observed Student’s t-based two-
sided 95% confidence interval (95%CI) of the gadopiclenol-gadobutrol difference for each co-primary 
criteria. An enrollment of 200 patients is deemed necessary for the lower limit of the 95% CI to exceed 
the non-inferiority margin set to 0.35. Assuming 80% power and for each co-primary criteria, the 
expected difference in mean scores is 0 with an expected standard deviation of 1.75. 
If one assumed a non-evaluable patient rate (drop-out rate and non-valid primary criterion rate) of about 
33%, an enrollment of 300 patients with enhancing abnormality(ies) and/or lesion(s) of various body 
organs is planned.  
Therefore, a total number of 300 patients will allow a sufficient power to meet both primary objectives. 
 
11.3 Planned Analysis  
 Disposition of patients 
Number of patients undergoing each visit will be presented by series (gadopiclenol-gadobutrol / 
gadobutrol- gadopiclenol) and overall.  
The overall disposition will be presented by series and overall. The reason of screen failure will be 
presented overall and the reason of premature discontinuation will be presented by series and overall. 
(see section 10 for screen failure and premature discontinuation definition). 
Number of patients by site will be presented overall as well. 
 
 Data Sets Analyzed 
The patient sets for this trial are defined below: 
o The screened patients Set (SPS) will include all patients having signed the inform consent form 
o The Safety Set (SS) will include all patients having received at least one injection of IMP 
regardless of the quantity 
o The Full Analysis Set (FAS) will include all patients who have a valid primary criterion 
assessment 
- 
FAS1 will include all patients who have both gadopiclenol pre and paired images 
assessable (for primary objective 1) 
- 
FAS2 will include all patients who have both gadopiclenol and gadobutrol paired 
images assessable (for primary objective 2) 
o The Per-Protocol Set (PPS): will include all patients who have no major protocol deviations and 
a valid primary criterion assessment. 
- 
PPS1 will include all patients from the FAS1 who have no major protocol deviations 
for primary criteria 1  
- 
PPS2 will include all patients from the FAS2 who have no major protocol deviations 
for primary criteria 2  
 

 
 
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 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 patient safety or the efficacy assessments. 
Protocol deviations will be gathered from monitoring files, clinical database and external vendors of 
off-site data (imaging, laboratory data…). 
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 with known or suspected enhancing abnormality(ies) and/or lesion(s) in 
at least one body region among head & neck, thorax (including breast), abdomen (including 
liver, pancreas and kidney), pelvis (including uterus, ovary and prostate), musculoskeletal 
(including extremities) 
 
Imaging protocol not respected with major impact on primary criterion 
 
Informed consent not signed 
 
IMP not injected 
 
Other major 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 statistical analysis plan.  
Major and non-major deviations will be presented apart by series and overall. 
 
 Demographics and Baseline Characteristics 
Demographic parameters are age, sex, race, ethnic origin, childbearing potential, body weight, height, 
and body mass index (BMI). Baseline characteristics are the patient's history (including the medical 
history and the disease requiring the trial MRIs) and the concomitant treatments. 
Summary statistics (number [n], mean, standard deviation [SD], median, minimum, and maximum) will 
be calculated for age, body weight, height and BMI. Frequency and percentages will be calculated for 
sex, patient’s history characteristics and concomitant treatments. 
Patient's medical history will be coded using the MedDRA dictionary and tabulated by body system, 
preferred term and status (concomitant or not). 
Patient's concomitant treatments will be coded using the Anatomical Therapeutic Chemical (ATC) Drug 
dictionary and tabulated by ATC code. 
Demographics and baseline characteristics will be displayed by series and overall. 
 
 Compliance  
The number of patients with actual volume of trial product different from the theoretical one will be 
presented by contrast agent group (gadopiclenol and gadobutrol).  
The absolute (mL) and relative (%) differences between theoretical and actual volumes of trial product 
will be presented by contrast agent group. 
 
 Efficacy Analysis  
Primary analyses  

 
 
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Superiority of Paired images versus Pre images of gadopiclenol MR examination regarding lesion 
visualization co-primary criteria (objective 1) 
For gadopiclenol, the difference “Paired” – “Pre” for each of 3 co-primary criteria 1 will be analyzed 
using paired t-tests on the FAS1. Results will be presented per reader. 
To be successful, 2 out of 3 readers will have to meet the alternative hypothesis for the 3 co-primary 
criteria in the gadopiclenol group: a statistically significant (one-sided p≥0.025) positive difference in 
mean scores in border delineation, internal morphology and degree of contrast enhancement of lesions. 
 
Non-inferiority of gadopiclenol versus gadobutrol regarding lesion visualization co-primary 
criteria (objective 2) 
The Student’s t-based two-sided 95% confidence intervals of the difference between gadopiclenol and 
gadobutrol will be constructed for each of 3 co-primary criteria 2 using the PPS2. If the lower bound of 
this confidence interval is above the non-inferiority margin set to 0.35 for at least 2 out of 3 readers and 
for the 3 co-primary criteria simultaneously, then non-inferiority between gadopiclenol and gadobutrol 
will be concluded.  
As soon as the non-inferiority is demonstrated, the superiority of the gadopiclenol over gadobutrol will 
be tested using the same method and using the FAS2 and PPS2. No adjustment for multiplicity is needed 
as it is a simple closed testing procedure. 
 
Secondary analyses 
Additional analysis of the co-primary criteria 
Supportive analyses of the non-inferiority analysis 
The non-inferiority analysis will be repeated using the FAS2.  
Assay sensitivity: 
For gadobutrol, the difference “Paired” -”Pre” for each of 3 co-primary criteria will be analyzed using 
the same analysis as described for superiority on the FAS2. Results will be presented per off-site reader. 
Subgroup analysis 
Co-primary criteria descriptive statistics will be provided by organ and/or body region. In addition to 
the primary analyses not adjusted on subgroup, sensitivity analyses of the superiority analysis (objective 
1) and of the non-inferiority analysis (objective 2) will be conducted using the same linear model with 
organ and/or body region as additional factors. 
Intra-reader variability 
Intra-reader variability will be analyzed in a subgroup of 10% of patients randomly selected for whom 
the off-site readers have re-read the images. 
Intra-reader variability will be studied by a Bland-Altman graph. Descriptive statistics and the Intra-
Class Correlation (ICC) will also be provided.  
The analyses will be performed using the FAS1 and FAS2. 
Inter- reader variability 
Inter-reader variability will be evaluated on the whole set of trial patients, since each case was read by 
3 different readers. 
The same methodology as the one presented above for intra-reader variability will be applied. 
The analyses will be performed using the FAS1 and FAS2. 

 
 
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Secondary criteria analyses 
All analyses of the secondary criteria will be done using the FAS1 for analyses by MRI modalities and 
FAS2 for analyses by contrast agent groups, except otherwise specified. 
 
Lesion visualization (on site) 
Same analysis as off-site lesion visualization criteria will be carried out for on-site evaluation  
 
Improvement in lesion visualization scores at patient-level, paired versus pre images. 
Improvement in patient-level lesion visualization will be tabulated by contrast agent groups; off-site and 
on-site reader’s outcomes will be separately analyzed. 
 
Technical adequacy of images 
Technical adequacy and assessable status of images will be tabulated by MRI modalities and contrast 
agent groups; off-site and on-site reader’s outcomes will be separately analyzed. 
 
Number of lesions  
The number of lesions per patient will be tabulated by MRI modalities and contrast agent groups; MRI 
modalities (“Paired” vs. “pre”) and contrast agent groups (gadopiclenol vs. gadobutrol) will be 
compared with a multivariate model using the negative binomial distribution. Off-site and on-site 
reader’s outcomes will be separately analyzed. 
 
Size of lesions  
The size of the 3 largest representative lesions per patient will be assessed by off-site readers and on-
site radiologists and will be summarized by MRI modalities and by contrast agent groups; off-site and 
on-site reader’s outcomes will be separately analyzed. 
 
Location of lesions 
The localization of the 3 largest representative lesions by patient will be assessed by off-site readers and 
on–site radiologists and will be displayed by MRI modalities and contrast agent groups; off-site and on-
site reader’s outcomes will be separately analyzed. 
 
Diagnostic confidence 
The diagnosis of each lesion according to off-site readers and on-site radiologists will be displayed by 
MRI modalities and by contrast agent groups; off-site and onsite reader’s outcomes will be separately 
analyzed. 
Diagnostic confidence will be tabulated by contrast agent groups; off-site and on-site reader’s outcomes 
will be separately analyzed. 
 
Impact of contrast-enhanced MRI on patient treatment plan: 
The impact on patient treatment plan will be assessed by on-site radiologists and will be tabulated by 
contrast agent groups. 
 
Percentage enhancement (E%) of lesion  
E% is calculated from the Signal Intensity (SI) measurement of maximum 3 representative lesions by 
the 3 independent off-site readers (see section 7.2.9). 
For each reader, E% will be tabulated by contrast agent groups and differences between contrast agents 
will be tested using a Student’s t-test.  
 

 
 
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Lesion to Background Ratio (LBR)  
LBR is calculated from the Signal Intensity (SI) measurement of maximum 3 representative lesions by 
the 3 independent off-site readers (see section 7.2.9). 
For each reader, LBR will be tabulated by contrast agent groups and differences between contrast agents 
will be tested using a Student’s t-test.  
Overall diagnostic preference 
For each off-site reader, the overall diagnostic preference will be tabulated and gadopiclenol will be 
compared to gadobutrol by a Wilcoxon signed-rank test. 
 
The reason of this preference will be displayed according to the contrast media preferred. 
 
 Adverse Event 
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. The table will be presented overall only 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. 
- 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 contrast agent group for Treatment Emergent AEs 
(TEAEs) using the Safety Set. The following variables will be also presented: 
- Total number of TEAEs with causal relationship to the trial IMP. 

 
 
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- Total number of patients with at least one TEAE with causal relationship to the IMP. 
- Total number of TEAEs requiring interruption of trial IMP. 
- Total number of patients with at least one TEAE requiring withdrawal of trial IMP. 
The number and percentage of patients with at least one TEAE will be presented using the Safety Set 
by contrast agent group according to Primary SOC and PT. 
The number and percentage of patients with at least one TEAE with causal relationship to the IMP will 
be presented using the Safety Set by contrast agent group according to Primary SOC and PT. 
The number and percentage of patients with at least one AESI will be presented using the Safety Set by 
contrast agent group according to Primary SOC and PT. 
The number and percentage of patients with at least one AESI with causal relationship to the IMP will 
be presented using the Safety Set by contrast agent group according to Primary SOC and PT. 
 
 Laboratory data 
Laboratory data analysis will be done using the Safety Set. 
The statistical analysis will present results in standard international units and United States units. 
Original units will be only listed. Laboratory data will be analyzed quantitatively and qualitatively by 
contrast agent group. Qualitative analyses will be done via comparison of laboratory data to their 
reference ranges and according to their clinical significance. Quantitative analyses will be done by 
tabulating raw data and change from baseline. They will be displayed qualitatively as well by means of 
shift tables. 
 
 Other safety observations 
Other safety observations analysis will be done using the Safety Set. 
Extent of exposure 
Duration between ICF signature, IMP administrations and end of trial will be tabulated by contrast agent 
group.  
Volume actually administered and, actual rate of administration, will be tabulated by contrast agent 
group. 
 
Injection site tolerance  
Number of patients experiencing pain, eruption, extravasation and inflammation at site injection will be 
tabulated by contrast agent group. Pain at injection site will be measured using the Numeric Pain 
intensity Scale (NPS) and NPS measurements for these patients will be tabulated by contrast agent 
group. 
 
Vital signs 
Vital signs will be analyzed quantitatively and qualitatively by contrast agent. Qualitative analyses will 
be done via comparison of vital signs data to their normal ranges (see section 7.2.11) and according to 
their clinically significant changes. Quantitative analyses will be done by tabulating raw data and change 
from baseline. 
 

 
 
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11.4 Specific Statistical Analytical considerations   
 Adjustments for Covariates  
As no factor has been identified as having a large impact on the primary and secondary criteria of 
analysis, no covariates are added in the efficacy models for primary objectives 1 and 2. 
 
 Handling of Dropouts or Missing Data  
No imputation will be performed in this trial.  
 
 Interim Analyses  
No interim analysis is planned 
 
 Multicenter Trial 
As a high number of sites is expected for this trial, the site factor will not be included in the models for 
efficacy. The number of patients included in each site will be displayed in a disposition table. 
 
 Multiple Comparisons/Multiplicity  
For FDA, the primary objective 1 is to be achieved. The primary objective 2 will serve as one of the 
secondary objectives. 
For EMA, both primary objectives 1 and 2 are to be achieved  
Therefore, no multiplicity adjustment is needed for this trial as only one objective should be reached for 
FDA and the two primary objectives should be reached simultaneously for EMA. 
Furthermore, each objective (superiority of Paired vs Pre, and non-inferiority of the two contrast agents), 
will be considered achieved only if the null hypothesis is rejected for the 3 co-primary criteria 
simultaneously for at least two readers out of three. Each reader will be analyzed separately.  
 
 Use of an "Efficacy Subset" of patients 
As the primary objective 1 is superiority, the corresponding analysis will be done using the Full Analysis 
Set and then the analysis repeated using the Per Protocol Set. 
As the primary objective 2 is non-inferiority, the corresponding analysis will be done using the Per 
Protocol Set and then the analysis will be repeated using the Full Analysis Set.  
 
 Examination of Subgroups 
Co-primary criteria descriptive statistics will be provided by organ / body regions.  
Sensitivity analyses of the superiority analysis (objective 1) and of the non-inferiority analysis (objective 
2) will be conducted using the same linear model with body region as additional factors. 
The robustness of MRI modality or GBCA effect across different body regions and/or organs will be 
discussed with following information: 

 
 
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 
Descriptive summary statistics for each body region and/or organs 
 
Body region and/or organ effect and body region and/or organ *MRI modality/GBCA 
interactions tests. These tests are used as exploratory indexes meaning that conclusions of these 
tests are just used as a support for discussion. Absence of statistical significance should not be 
taken to imply consistency. Absence of statistical significance in an interaction test, or only 
directional consistency, would not be sufficiently sensitive filters to detect differences of 
potential interest.  
 
Effect estimations for each body region and/or organ with the associated 95% two-sided CI. 
Overlapping of all body regions and/or organs CI estimates with the confidence interval for the 
overall effect will be checked.  
Graphical visualization of the Body regions and/or organs with a Forest plot for each body region and/or 
organ of the LS Means difference and also the LS Means Ratio. 
 

 
 
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12 TRIAL COMMITTEES 
Based on safety related to non-specific macrocyclic GBCAs and results of gadopiclenol phase I to IIb 
trial, no committee will be set up for this trial. 
The overall gadopiclenol safety (based on consolidated available data from all gadopiclenol clinical 
studies) will be evaluated and followed up by an internal Guerbet safety committee, therefore no specific 
trial committee will be set up. 
The Guerbet Safety Committee whom core members are the European Qualified Person responsible for 
Pharmacovigilance (EU-QPPV), the Development, Medical and Regulatory Affairs Director, the Global 
Head of Regulatory Affairs who is also the Head of Preclinical Development including additional 
members such as medical expert and pharmacovigilance expert reviews gadopiclenol Integrated and 
compiled data (e.g. Initial Signal Report) every 3 months. 
The Safety Committee decisions may have an impact on other documents (e.g. clinical studies 
documents, etc.). The appropriate actions are taken accordingly. 
 
 

 
 
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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 
- 
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 
- 
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 

 
 
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- 
Regional / local regulations and other specific populations regulations 
 
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). 
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 their administration modalities; 
- 
Contact details of persons dedicated to the trial at the investigational site. 

 
 
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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 
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 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 15 years 
after trial completion. Sites should obtained Guerbet written approval before destroying trial documents.  
 
 
 

 
 
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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 documents: patient’s medical files, 
images. 
- 
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 
IMP 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. 
 
14.3 Clinical Data Handling 
 Data Reported in the eCRF 
The clinical eCRF will allow recording of data required by the protocol, except detailed central 
laboratory results and blinded imaging assessment performed by IBR entered in the Imaging eCFR. 
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 consistency between the data in the eCRF and those in the source documents. 
 

 
 
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 Data Reported in the clinical 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 clinical eCRF 
page), eligibility criteria, and any serious adverse event (SAE). 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 clinical 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. 
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. 
 
 

 
 
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16 REFERENCES  
1. Martin DR, Semelka RC. Magnetic resonance imaging of the liver: review of techniques and 
approach to common diseases. Semin Ultrasound CT MR. 2005;26:116–131. 
2. Low RN. Abdominal MRI advances in the detection of liver tumours and 
characterisation. Lancet Oncol. 2007;8:525–535.  
3. Yoshioka H, Takahashi N, Yamaguchi M, et al. Double arterial phase dynamic MRI with 
sensitivity encoding (SENSE) for hypervascular hepatocellular carcinomas. J Magn Reson 
Imaging. 2002;16:259–266.  
4. Silva AC, Evans JM, McCullough AE, et al. MR imaging of hypervascular liver masses: a 
review of current techniques. Radiographics. 2009;29:385–402.  
5. Takahashia T, Wang F, Quarles CC. Current MRI Techniques for the Assessment of Renal 
Disease. Curr Opin Nephrol Hypertens. 2015; 24: 217–223. 
6. Semelka RC, Shoenut JP, Magro CM, et al: Renal cancer staging: Comparison of contrast-
enhanced CT and gadolinium-enhanced fat-suppressed spin-echo and gradient-echo MR 
imaging. J Magn Reson Imaging 1993; 8: 597-602. 
7. Peters NH, Borel Rinkes IH, Zuithoff NP, et al. Meta-analysis of MR imaging in the diagnosis 
of breast lesions. Radiolog. 2008; 246: 116-124. 
8. Bazzocchi M, Zuiani C, Panizza P, et al. Contrast-enhanced breast MRI in patients with 
suspicious microcalcifications on mammography: results of a multicenter trial. AJR Am J 
Roentgenol 2006;186: 1723-32. 
9. Kuhl CK, Schrading S, Bieling HB, et al. MRI for diagnosis of pure ductal carcinoma in situ: 
a prospective observational trial. Lancet 2007; 370: 485-492. 
10. Plana MN, Carreira C, Muriel A, et al. Magnetic resonance imaging in the preoperative 
assessment of patients with primary breast cancer: systematic review of diagnostic accuracy 
and meta-analysis. Eur Radiol 2012; 22: 26-38. 
11. Gutierrez JE, Rosenberg J, et al. Safety and Efficacy of Gadobutrol for Contrast-enhanced 
Magnetic Resonance Imaging of the Central Nervous System: Results from a Multicenter, 
Double-blind, Randomized, Comparator Study. Magnetic Resonance Insights 2015;8:1–10. 
12. EMA. Guideline on the choice of the non-inferiority margin. 
https://www.ema.europa.eu/documents/scientific-guideline/guideline-choice-non-inferiority-
margin_en.pdf 
 
 
 

 
 
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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. 
 
 

 
 
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18 APPENDICES 
18.1 Numeric Pain intensity Scale (NPS) 
 
 
  
 
Circle the number corresponding to the pain intensity. 
 
 
 

 
 
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18.2 Volume of IMP injection by body weight 
 
 
gadopiclenol (0.5M) 
gadobutrol (1M) 
Adults 
Dose (mmol/kg) 
Dose (mmol/kg) 
0.05 
0.1 
Dose (ml/kg) 
Dose (ml/kg) 
0.1 
0.1 
Body Weight 
Volume (mL) 
Volume (mL) 
Kilograms (kg) Pounds (lb) 
40 
88 
4 
4 
50 
110 
5 
5 
60 
132 
6 
6 
70 
154 
7 
7 
80 
176 
8 
8 
90 
198 
9 
9 
100 
220 
10 
10 
110 
242 
11 
11 
120 
264 
12 
12 
130 
268 
13 
13 
140 
308 
14 
14 
150 
330 
15 
15