Clinical trial NCT02633501
Conditions: CNS Lesion Blood Brain Barrier Defect
Sponsor: Guerbet
Start date: 2016-06-01; Completion date: 2018-01-01
Enrollment: 312 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to determine a safe and effective dose of a new gadolinium-based contrast agent (GBCA) P03277 based on the Contrast to Noise Ratio (CNR) when comparing with gadobenate dimeglumine (MultiHance®) at 0.1 mmol/kg body weight (BW).

Contrast to Noise Ratio (CNR), a well-known quantitative parameter directly related to contrast medium/GBCA efficacy, was chosen as the primary endpoint in order to have a precise determination of P03277 clinical dose.

This was a multi-center, international, prospective, double-blind, randomized, controlled, parallel dose groups, cross-over with comparator study in male and female subjects presenting with known or highly suspected focal areas of disruption of the Blood Brain Barrier including at least one expected enhancing lesion of minimum 5 mm, who were scheduled to undergo a routine contrast-enhanced Magnetic Resonance Imaging (MRI) of Central Nervous System.

Detailed description:
Two subsets of subjects were included in the study:

* The subset 1 included the first randomized subject of each study center. Subjects were randomly assigned in a 1:1 ratio to receive 0.05 or 0.1 mmol/kg BW of P03277 and 0.1 mmol/kg BW of gadobenate dimeglumine.
* Subset 2 was composed of all subjects (except the first one of each study center) selected by the study center. Subjects were randomly assigned in a 1:1:1:1 ratio to receive 0.025, 0.05, 0.1 or 0.2 mmol/kg BW of P03277 and 0.1 mmol/kg BW of gadobenate dimeglumine.

During the course of the study, two MRIs were obtained from each subject: one unenhanced and P03277-enhanced MRI; and one unenhanced and gadobenate dimeglumine-enhanced MRI. MRI images were evaluated off-site by 3 independent blinded readers for the primary endpoint (CNR).

Arms: arm 1: One of the two doses of P03277 (0.05 or 0.1 mmol/kg)-enhanced MRI then gadobenate dimeglumine (0.1 mmol/kg)-enhanced MRI arm 2: Gadobenate dimeglumine (0.1 mmol/kg)-enhanced MRI then one of the two doses of P03277 (0.05 or 0.1 mmol/kg)-enhanced MRI arm 3: One of the four doses of P03277 (0.025, 0.05, 0.1 or 0.2 mmol/kg)-enhanced MRI then gadobenate dimeglumine (0.1 mmol/kg)-enhanced MRI arm 4: Gadobenate dimeglumine (0.1 mmol/kg)-enhanced MRI then one of the four doses of P03277 (0.025, 0.05, 0.1 or 0.2 mmol/kg)-enhanced MRI
Interventions: intervention 1: P03277 intervention 2: Gadobenate dimeglumine intervention 3: MRI
Intervention descriptions: intervention 1: Single intravenous (IV) bolus injection at a rate of 2 mL/second intervention 2: Single IV bolus injection at a rate of 2 mL/second intervention 3: None

Protocol documents:
Prot_002.pdf: 
Document Type 
Study Protocol 
Document Date 
July 11, 2016 
Official Title 
P03277 Dose Finding Study in Central Nervous System (CNS) 
Magnetic Resonance Imaging (MRI) 
NCT Number 
NCT02633501 
 


 
 
 
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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. 
 
 
Protocol No. GDX-44-004 
P03277 Dose Finding Study in Central Nervous System (CNS) Magnetic Resonance Imaging 
(MRI)  
Phase IIb Clinical Study 
 
Design: 
Multi-center, double-blind, randomized, controlled, parallel dose groups, cross-over design with 
comparator 
 
EudraCT No.: 2014-003576-23 
IND No.: 123673 
 
INTERNATIONAL COORDINATOR 
 
 
 
 
SPONSOR 
GUERBET, B.P. 57400, 95943 Roissy CdG Cedex, FRANCE  
CLINICAL PROJECT MANAGER 
 
  
 
PHARMACOVIGILANCE 
 
Fax: + 33 1 45 91 67 70 
E-mail: pharmacovigilance.headquarters@guerbet-group.com 
 
 
 


 
 
 
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STUDY SYNOPSIS 
Study Title: P03277 Dose Finding Study in Central Nervous System (CNS) Magnetic Resonance 
Imaging (MRI) 
Phase IIb Clinical Study 
Study Product(s): P03277 
 
 
Active Ingredient(s): P03277 
EudraCT No.: 2014-003576-23 
IND No.: 123673 
Participating countries (Number of sites): 
Worldwide study involving approximately 40 
centers 
Study Objectives 
Primary objective: 
To determine a safe and effective dose of P03277 based on the Contrast to Noise Ratio (CNR) when 
comparing with Gadobenate Dimeglumine (MultiHance®) at 0.1 mmol/kg body weight (BW).  
Secondary objectives:  
1. To assess technical adequacy of images 
2. To evaluate capacity of lesion detection  
3. To evaluate diagnostic information using lesion visualization variables (lesion border delineation, 
internal morphology and degree of contrast enhancement) 
4. To evaluate diagnostic confidence 
5. To compare overall diagnostic preference between P03277 and MultiHance® 
6. To assess P03277 dose / response relationship for CNR and lesion visualization variables  
7. To evaluate the impact of P03277 and MultiHance®-enhanced MRI on subject treatment plan 
8. To assess the safety profile of P03277 as compared to MultiHance® after intravenous 
administration 
Study design and methodology 
Multi-center, double-blind, randomized, controlled, parallel dose groups, cross-over design with 
comparator. 
The Investigational Medicinal Products used during the study are P03277 and MultiHance®. 
Two subsets of subjects will be included in the study: 
 The first subset will include the first subject of each study center. Subjects will be 
administered at 0.05 or 0.1 mmol/kg BW of P03277 and MultiHance®, 0.1 mmol/kg BW.  
Images from this subset of subjects will be used to provide training images for the independent 
blinded off-site readers, to ensure that the imaging protocol/acquisition sequences has been 
appropriately programmed, and that the MR images produced can be transferred to the core 
laboratory. Consequently, these subjects will not be included in the efficacy analysis but only 
for the safety assessment. 
 The second subset will be composed of all subjects (except the first one of each site) selected 
by the sites. Subjects will be administered at 0.025, 0.05, 0.1, 0.2 mmol/kg BW of P03277 and 


 
 
 
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0.1 mmol/kg BW of MultiHance®.  
The subjects will be randomly assigned to one of the doses of P03277 and to one series of 2 MRIs 
performed each at two study visits separated by a wash out period of 2 days minimum up to 14 days. 
The series are related to the use of contrast agent: one series will have P03277 at visit 2 and 
MultiHance® at visit 4 or vice versa for the other series. 
The randomization scheme will allocate subjects to the two P03277 treatment arms in a 1:1 ratio for 
the first subset of subjects and to the four P03277 treatment arms in a 1:1:1:1 ratio for the second 
subset of subjects. The P03277 will be injected at a rate of 2 mL/second. 
The same dose of MultiHance®, 0.1 mmol/kg BW by single IV injection at a rate of 2 mL/second, will 
be injected to all subjects. 
The investigator and the subject will remain blinded to IMPs allocation (nature of the IMPs and order 
of the IMP injection) as well as the dose of P03277 used. A designated unblinded site staff member 
will be in charge of preparation and administration of the IMPs. 
For the second subset of subjects, randomization will be stratified via IWRS by the following 
stratification factor: presence of brain metastasis (yes/no). Subjects with brain metastasis will be 
included at a minimum of 20%. MRI images will be evaluated on-site, by investigators and off-site by 
3 independent blinded readers. Contrast to Noise Ratio will be evaluated by 3 independent blinded 
readers and will serve as primary efficacy results.  
To allow exact matching of lesions throughout the different imaging sequences and the two MR 
examination with P03277 and MultiHance®, an independent radiologist (lesion tracker) will perform 
lesion tracking based only on the available CNS diagrams, separate from the investigator image and 
independent blinded reader image evaluations. 
The IWRS will be used to record subjects visits and allocate IMPs i.e., screening (visit 1), 
inclusion/first MRI (visit 2), second MRI (visit 4), safety visits (visit 3 and visit 5) and at any time to 
record screening failure (prior randomization) and premature study discontinuation (after 
randomization). 
For both subsets of subjects, safety will be assessed using vital signs, 12-lead ECGs, injection site 
tolerance, clinical laboratory parameters (blood and urine) and by adverse events (AEs) monitoring.  
Number of subjects / sample size 
Based on the hypothesis below, a total of 280 subjects will be enrolled in the study: 
- 
First subset: maximum 40 subjects (depending on the number of participating sites) on the 
basis of 1 subject per site. 
- 
 Second subset: 240 subjects based on the following assumption: the study aims at detecting a 
minimum of 30% increase of CNR for at least one of the four tested dose of P03277 compared 
to control arm MultiHance® at dose of 0.1 mmol/kg BW. A sample size of 50 evaluable 
subjects per group is required to obtain a power of at least 90%, using a t-test of a normal 
mean difference with a 1-sided significance level of 0.025 (Holm's step-down method in a 
Multiple 
Comparisons 
Design) 
and 
a 
common 
standard 
deviation 
of 
3.01. 
Therefore, a minimum of 50 evaluable subjects per dose group and a minimum of 200 
evaluable subjects in total will have to be enrolled in this study. It is anticipated that some of 
the subjects will not complete both MRI evaluations. To offset this, an additional 10 subjects 
per group will be added to the 50 required, resulting in a total sample size of a minimum of 


 
 
 
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240. In addition, subjects with brain metastasis will be randomized at a minimum of 20% of 
the second subset of subjects (a minimum of 20% of subjects with brain metastasis per group 
of P03277 doses).  
Eligibility criteria 
Inclusion criteria: 
1. Female or male adult subject (subject having reached legal majority age). 
2. Subject presenting, at the time of inclusion, with known or highly suspected focal areas of 
disrupted Blood Brain Barrier (BBB) (e.g., primary and secondary tumors, focal inflammatory 
disorders) including at least one expected enhancing lesion of minimum 5 mm (long axis). This 
lesion must have been detected on a previous imaging procedure (computerized Tomography (CT) 
or MRI). 
3. Subject scheduled for a routine CNS contrast-enhanced MRI examination for clinical reasons and 
agreeing to have a second contrast-enhanced MRI examination for the purpose of the study.  
4. Subject able and willing to participate to the study. 
5. Subject having read the information and having provided his/her consent to participate in writing 
by dating and signing the informed consent prior to any study related procedure being conducted. 
6. Subject affiliated to national health insurance according to local regulatory requirements. 
To be included in the study, the subject must meet all these inclusion criteria. 
Non-inclusion criteria: 
1. Subject presenting with acute or chronic Grade III (at least) renal insufficiency, defined as an 
estimated Glomerular Filtration Rate (eGFR) <60 mL/min/1.73m² based on one eGFR assessment 
performed the day of the MRI prior to the first contrast agent injection. 
2. Subject presenting with known class III/IV congestive heart failure according to the New York 
Heart Association classification (NYHA). 
3. Pregnant or breast-feeding female subject (a female subject of childbearing potential or with 
amenorrhea for less than 12 months must have a negative urine or serum pregnancy test within 24 
hours prior to study MRI and must be using a medically approved contraception method* until the 
last study visit). 
4. Subject having received any investigational medicinal product within 30 days prior to study entry. 
5. Subject previously enrolled in this study. 
6. Subject presenting with any contraindication to MRI examinations. 
7. Subject with known contra-indication(s) to the use or with known sensitivity to one of the 
products under investigation or other GBCAs. 
8. Subject having received any contrast agent (MRI or CT) within 3 days prior to study products 
administration, or scheduled to receive any contrast agent during the course of the study and 
within 24 hours after the second study product administration. 
9. Subject having received any treatment or medical procedure (e.g. chemotherapy, radiotherapy, 
biopsy or surgery etc…) within 7 days prior to the first MRI or expected/scheduled to have a 
change in any treatment or medical procedure (e.g. chemotherapy, radiotherapy, biopsy or surgery  
etc…) in-between the 2 MRI examinations.  


 
 
 
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10. Subject with anticipated, current or past condition (medical, psychological, social or geographical) 
that would compromise the subject’s safety or her/his ability to participate in the study. 
11. Subject unlikely to comply with the protocol (e.g., uncooperative attitude, inability to return for 
follow-up visits and/or unlikelihood of completing the study). 
12. Subject related to the Investigator or any other study staff or relative directly involved in the study 
conduct. 
13. Subject presenting with acute relapse of multiple sclerosis. 
* medically approved contraception methods include: female sterilization, barrier methods of 
contraception (condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/ vaginal suppository), use of oral, injected or implanted hormonal methods of 
contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), 
for example hormone vaginal ring or transdermal hormone contraception, placement of an Intrauterine 
Device (IUD) or Intrauterine System (IUS). 
Subjects presenting with one or more of these non-inclusion criteria must not be included in the study. 
The diagnosis obtained from previous imaging examinations will be considered as medical history to 
assess inclusion criteria. All study analyses will be based only on the images obtained through the 
study MRIs. 
Investigational Medicinal Product(s) administration 
Study product 1:  
P03277: single intravenous (IV) bolus injection at one of the following four doses (0.025, 0.05, 0.1, or 
0.2 mmol/kg BW) at a rate of 2 mL/second. 
Study product 2: 
MultiHance®: contrast agent approved for CNS imaging, administered at the approved dose of 0.1 
mmol/kg BW by single IV bolus injection at a rate of 2 mL/second. 
Study duration 
Minimum study duration for subjects: 4 days   
Maximum study duration for subjects: 22 days 
The study includes a maximum of 5 visits: 
- 
One screening visit up to 7 days prior to inclusion (screening could be done the same day as 
the inclusion visit if all the inclusion/exclusion criteria are met) 
- 
Two sequential imaging visits (minimum interval 2 days and up to 14 days): each visit will 
consist of  a P03277 injection or MultiHance® injection  and MRI procedure (if during the first 
visit the MRI procedure is performed with P03277 injection then the second visit will be done 
with MultiHance® injection and vice versa for the other series) . 
- 
Two safety visits: 1 day after each injection and MRI examination. 
The study will be considered as completed once all the images collected for all the subjects will have 
been reviewed by all the independent blinded readers.  
Evaluation criteria 


 
 
 
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Primary criterion:  
Contrast to Noise ratio (CNR) (for each of the 3 independent blinded readers evaluations (off-site 
read)) 
Signal Intensity (SI) measurements will be made in Region Of Interest (ROI) on the pre and post- 
injection, axial 3D T1 weighted Gradient Echo (GRE) for brain and sagittal T1-weighted Spin-Echo 
(SE) or Turbo Spin-Echo (TSE) for spine, image set. ROIs will be placed on a maximum of three 
visualized lesions in the largest conspicuous enhancing areas. CNR will then be calculated for each 
lesion according to the following equation: 
noise
ht
lesion
SD
SI
SI
CNR


  
where, 
SIlesion  = the SI in the Region of Interest (ROI) in the lesion 
SIht      = the SI in the ROI in healthy tissue (brain or spinal cord)  
SDnoise = standard deviation of background noise.  
The primary criterion is calculated by subject, and by independent blinded reader, in averaging the 
Contrast to Noise Ratio (CNR) for maximum 3 enhanced lesions. Only lesions which matched on both 
MRIs after lesion tracking will be used.  
Secondary criteria: 
1. Technical adequacy of images (on-site and off-site reads) 
Images will be evaluated as adequate or not. Images are considered technically inadequate if artifacts 
completely compromise image interpretability. 
2. Lesion detection capacity (on-site and off-site reads): 
Number, size and location of lesions detected, and the presence or absence of enhancement will be 
recorded. 
3. Diagnostic information using lesion visualization variables (on-site and off-site reads): 
Three variables (lesion border delineation, internal morphology and degree of contrast enhancement) 
will be assessed on combined unenhanced and enhanced MRI on a 4-point scale. 
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 (for extra-axial lesions, this pertains to 
the definition of the space in which the lesion is present, and for intra-axial lesions, it pertains to the 
invasion of white matter, gray matter, or both; the neuroanatomical distribution of the lesion; and its 
mass effect).  
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. 
 
o Degree of contrast enhancement: 
This criterion will be a qualitative visual assessment (not based on signal intensity measurement).  


 
 
 
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4. Diagnostic confidence (on-site and off-site reads): 
Diagnosis and diagnostic confidence will be recorded for each subject. 
5. Overall diagnostic preference in a global matched-pairs fashion (off-site read). 
6. P03277 dose / response relationship for CNR and lesion visualization variables. 
7. Impact of contrast agent-enhanced MRI on subject treatment plan (on-site read). 
8. Safety assessments: vital signs, 12-lead ECGs, injection site tolerance, clinical laboratory 
parameters (blood and urine) and adverse events (AEs) monitoring. 
 
Statistical methods 
Student t-test using Holm's step-down method in a Multiple Comparisons Design with 0.025 type-one 
error will be used to evaluate the dose-response of P03277 for each Independent Blinded Reader (IBR) 
with regards to the CNR value as the primary endpoint. The post-CNR value will be normalized by the 
pre-CNR value calculated on the same basis. 
Descriptive statistics will summarize demographics, efficacy and safety data. Dose/response 
relationship of P03277 will be investigated for each IBR. 
 
 


 
 
 
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Table 1: Study Flow Chart  
Evaluation/ 
procedure 
 
 
 
Time Point 
Screening  
(V1)  
 
Inclusion  
V2 (1) (Baseline (10)) 
Contrast injection 
P03277 or MultiHance®  
Safety follow up  
(V3) 
Post injection 
P03277 
or MultiHance® 
 
V4 (1) 
Contrast injection 
P03277 or MultiHance® 
Safety follow up  
(V5) 
Post injection 
P03277 
 or MultiHance® 
≤7 days 
Prior  
to MRI 
MRI 
45± 
15min 
2-4 
hrs 
1 day after V2 
Prior  
to MRI 
MRI  
45± 
15min 
2-4  
hrs 
1 day after V4 
Informed consent signature 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Physical examination(11) 
X 
 
 
 
 
 
 
 
 
 
 
Body weight  
 
X 
 
 
 
 
X 
 
 
 
 
Concomitant treatments 
X 
X 
X 
X 
X 
Pregnancy test (2) 
X 
X 
 
 
 
 
X 
 
 
 
 
Local e-GFR evaluation(3) 
 
X 
 
 
 
 
X 
 
 
 
 
Clinical laboratory parameters (4) 
 
X 
 
 
 
X 
X 
 
 
 
X 
Urinalysis (Dipstick) 
 
X 
 
 
 
X 
X 
 
 
 
X 
Vital signs (BP, PR) (5) 
 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
12-lead ECG(6) 
 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
IMP injection 
 
 
X 
 
 
 
 
X 
 
 
 
Images acquisition 
 
 
X 
 
 
 
 
X 
 
 
 
IWRS (9) 
X 
X 
 
 
 
X 
X 
 
 
 
X 
Injection-site tolerance(7) 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
Subject treatment plan evaluation 
 
 
 
X 
 
 
 
 
X 
 
 
Adverse events (AEs)(8) 
X 


 
 
 
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(1) 
MRI procedures, at V2 and V4, should be performed on the same day of IWRS connection and contrast agent injection.  
(2) 
Urine or serum pregnancy test (if applicable) is to be done on site, and results must be available prior to IWRS connection and administration of P03277 and 
MultiHance® 
(3) 
eGFR is to be done locally, and results must be available prior to IWRS connection and administration of P03277 and MultiHance® 
 
(4) 
Clinical laboratory parameters will be analysed by the central laboratory: haematology and biochemistry, Cystatin C, see Section 9.5.1 for details 
(5) 
Vital signs: BP=supine systolic and diastolic Blood Pressure, PR=Pulse Rate 
(6) 
12-lead ECG to record heart rate, RR interval, PR interval, QRS duration, QT, QTc Bazett and QTc Fridericia. Starting at V2, Triplicate ECGs (3 measurements 
taken at approximately 1 min intervals) will be recorded prior each MRI and at each post-injection time point 
(7) 
Injection-site tolerance (burning, pain, eruption, extravasation, inflammation, or other) is to be assessed during the injection and at 45 ± 15 min and 2-4 hours 
post injection. 
(8) 
AEs will be assessed as soon as the subject’s informed consent is signed and will end after the last follow up evaluation (1 day after last  injection), unless the 
investigator becomes aware of a related, serious or not, adverse event after the last evaluation. 
(9) 
IWRS: connection should be done at each study visit and in case of screening failure or premature discontinuation 
(10) 
All the assessments performed prior to the first MRI at V2 will be considered as baseline value 
(11) 
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. 
 


 
 
 
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Figure 1 : Study Diagram 
 
 


 
 
 
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SIGNATURE PAGE 


 
 
 
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ABBREVIATIONS  
AE 
 
Adverse Event 
AR 
 
Adverse Reaction 
ALT 
 
Alanine Amino Transferase 
AST 
 
Aspartate Amino Transferase 
ATC 
 
Anatomical Therapeutic Chemical classification system 
BBB 
 
Blood Brain Barrier 
BMI 
 
Body Mass Index 
BP 
 
Blood Pressure 
BUN 
 
Blood Urea Nitrogen 
BW 
 
Body Weight 
CA 
 
Competent Authority 
CNS 
 
Central Nervous System 
eCRF  
electronic Case Report Form 
CRO 
 
Contract Research Organization 
CT 
 
Computerized Tomography 
CNR 
 
Contrast to Noise Ratio 
DSMB  
Data Safety Monitoring Board  
ECG 
 
Electrocardiogram 
EMA  
European Medicine Agency 
FAS 
 
Full Analysis Set 
FDA 
 
Food and Drug Administration 
FSE 
 
Fast Spin Echo 
GBCA  
Gadolinium Based Contrast Agent 
GCP 
 
Good Clinical Practice 
Gd 
 
Gadolinium 
eGFR  
estimated Glomerular Filtration Rate 
GMP  
Good Manufacturing Practice 
GRE 
 
Gradient Echo 
HSA 
 
Human Serum Albumin 
IB 
 
Investigator’s Brochure 
IBR 
 
Independent Blinded Reader 


 
 
 
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ICH 
 
International Conference on Harmonization 
IEC 
 
Independent Ethics Committee 
IMP 
 
Investigational Medicinal Product 
INV 
 
Investigator 
IRB 
 
Institutional Review Board 
ISF 
 
Investigator Site File 
ITT 
 
Intent ToTreat 
IUD 
 
Intrauterine Device 
IUS 
 
Intrauterine System 
IV 
 
Intravenous 
IWRS  
Interactive Web Response System 
LDH 
 
Lactate Dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCV  
Mean red blood Cells Volume 
MR 
 
Magnetic Resonance 
MRI 
 
Magnetic Resonance Imaging 
PR 
 
Pulse Rate 
PT 
 
Preferred Term  
RBCs  
Red Blood Cells 
ROI 
 
Region Of Interest 
RT 
 
Recovery Time 
SAE 
 
Serious Adverse Event 
SAR 
 
Serious Adverse Reaction 
SE 
 
Spin Echo 
SI 
 
Signal Intensity 
SNR 
 
Signal to Noise Ratio 
SOC 
 
System Organ Classes  
SPC/SmPC 
Summary of Product Characteristics 
Subject ID 
Subject IDentification 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TE 
 
Time of Echo 
TI 
 
Time of Inversion 
TOI 
 
Tissue Of Interest 


 
 
 
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TSE 
 
Turbo Spin Echo 
VAS 
 
Visual Analogic Scale 
WBCs  
White Blood Cells 
 


 
 
 
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TABLE OF CONTENTS 
STUDY SYNOPSIS ................................................................................................................................ 2 
SIGNATURE PAGE ............................................................................................................................. 11 
ABBREVIATIONS ............................................................................................................................... 12 
1 
INTRODUCTION AND STUDY RATIONALE ........................................................................ 20 
2 
STUDY OBJECTIVES ................................................................................................................ 22 
2.1 
Primary Objective .................................................................................................................. 22 
2.2 
Secondary Objectives ............................................................................................................ 22 
2.3 
Sub-Study / Ancillary Study Objectives ................................................................................ 22 
3 
STUDY DESIGN ......................................................................................................................... 23 
3.1 
Protocol Description .............................................................................................................. 23 
3.2 
Study Duration ...................................................................................................................... 24 
3.3 
Interim analysis ..................................................................................................................... 24 
3.4 
Study Committee ................................................................................................................... 24 
4 
SUBJECT SELECTION ............................................................................................................... 25 
4.1 
Inclusion Criteria ................................................................................................................... 25 
4.2 
Non-Inclusion Criteria ........................................................................................................... 25 
4.3 
Subject Identification ............................................................................................................ 26 
5 
INVESTIGATIONAL MEDICINAL PRODUCTS ..................................................................... 27 
5.1 
Investigational Medicinal Product(s) .................................................................................... 27 
5.1.1. 
Investigational Medicinal Product 1 ......................................................................... 27 
5.1.2. 
Investigational Medicinal Product 2 ......................................................................... 28 
5.2 
Packaging, Labeling, Storage ................................................................................................ 28 
5.3 
Condition of Investigational Medicinal Product allocation ................................................... 29 
5.3.1 
Investigational Product(s) Allocation / Randomization ................................................ 29 
5.3.2 
Double-Blind Conditions ............................................................................................... 30 
5.3.3 
Individual Study Treatment Unblinding ........................................................................ 30 
5.4 
Investigational Medicinal Product Management ................................................................... 31 
5.5 
Non Investigational Medicinal Product(s) and Other Study Products ................................... 31 
5.6 
Study Product(s) Compliance and Accountability ................................................................ 31 
6 
CONCOMITANT TREATMENTS ............................................................................................. 32 
6.1 
Concomitant Treatments of Special Attention ...................................................................... 32 
6.2 
Prohibited Concomitant Treatments ...................................................................................... 32 
7 
EVALUATION CRITERIA ......................................................................................................... 33 


 
 
 
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7.1 
Primary Criterion ................................................................................................................... 34 
7.2 
Secondary Criteria ................................................................................................................. 35 
7.2.1 
Technical adequacy of images (on-site and off-site reads) ........................................... 35 
7.2.2 
Lesion detection capacity (on-site and off-site reads) ................................................... 35 
7.2.3 
Lesion visualization variables (on-site and off-site reads) ............................................ 36 
7.2.4 
Diagnostic confidence (on-site and off-site reads) ........................................................ 37 
7.2.5 
Overall diagnostic preference (off-site read) ................................................................ 37 
7.2.6 
P03277 dose / response relationship for CNR and lesion visualization variables ........ 38 
7.2.7 
Impact of IMPs-enhanced MRI on subject treatment plan (on-site read) ..................... 38 
7.2.8 
Safety assessment........................................................................................................... 38 
8 
NUMBER OF SUBJECTS ........................................................................................................... 41 
9 
STUDY SCHEDULE AND PROCEDURES............................................................................... 42 
9.1 
Study Schedule ...................................................................................................................... 42 
9.1.1 
Screening Visit – Visit 1 (Day -7 to Day 0) ................................................................... 42 
9.1.2 
Inclusion and imaging Visit – Visit 2 (Day 0) – First MRI examination ....................... 42 
9.1.3 
Safety Visit – Visit 3 (1 day post visit 2) ........................................................................ 44 
9.1.4 
Imaging Visit - Visit 4 (from 2 days, up to 14 days post visit 2) – Second MRI 
examination .................................................................................................................................. 44 
9.1.5 
Safety Visit – Visit 5 (1 day post visit 4) ........................................................................ 45 
9.2 
Imaging Protocol ................................................................................................................... 46 
9.2.1 
MR equipment ................................................................................................................ 46 
9.2.2 
MRI sequences ............................................................................................................... 46 
9.3 
On Site Reading of Images .................................................................................................... 47 
9.4 
Off Site Reading of Images ................................................................................................... 47 
9.4.1 
Manuals and Supplies.................................................................................................... 47 
9.4.2 
Site Qualification ........................................................................................................... 47 
9.4.3 
Receipt and Tracking of Images .................................................................................... 48 
9.4.4 
Image Processing and Quality Check ........................................................................... 48 
9.4.5 
Independent Blinded Readers Training ......................................................................... 48 
9.4.6 
Image Randomization .................................................................................................... 48 
9.4.7 
Blinded Assessment of Images ....................................................................................... 49 
9.4.8 
Inter & Intra-Reader Variability Assessment ................................................................ 49 
9.4.9 
Lesion tracking (not applicable for global matched-pairs reads) ................................. 49 
9.4.10 
Image Warehouse and Final Deliverables .................................................................... 50 
9.5 
Other Centralized Study Procedures ..................................................................................... 50 


 
 
 
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9.5.1 
Clinical laboratory parameters ..................................................................................... 50 
9.5.2 
Centralized assessment of ECG ..................................................................................... 50 
10 
SAFETY REPORTING ................................................................................................................ 52 
10.1 
Adverse Event ....................................................................................................................... 52 
10.1.1 
Definition of Adverse Event ........................................................................................... 52 
10.1.2 
Recording/Collection of Adverse Events ....................................................................... 52 
10.1.3 
Description of Adverse Events ....................................................................................... 52 
10.2 
Serious Adverse Event .......................................................................................................... 54 
10.2.1 
Definition of Serious Adverse Event .............................................................................. 54 
10.2.2 
Procedure for Reporting Serious Adverse Events ......................................................... 55 
10.3 
Pregnancy and Adverse Events of Special Interest ............................................................... 56 
10.3.1 
Pregnancy ...................................................................................................................... 56 
10.3.2 
Adverse Events of Special Interest ................................................................................ 56 
10.4 
Unblinding Procedures .......................................................................................................... 57 
11 
PREMATURE DISCONTINUATION OF THE STUDY ........................................................... 58 
11.1 
Premature Discontinuation of the Study per Guerbet Decision............................................. 58 
11.2 
End of Study Participation for a Subject ............................................................................... 58 
12 
STATISTICAL ANALYSIS ........................................................................................................ 60 
12.1 
Subjects Included in the Analysis .......................................................................................... 60 
12.2 
Demographic and Baseline Data ........................................................................................... 60 
12.3 
Efficacy Data/ Dose selection ............................................................................................... 60 
12.4 
Safety Data ............................................................................................................................ 64 
12.5 
Handling of Missing Data ..................................................................................................... 66 
12.6 
Interim Analysis .................................................................................................................... 66 
13 
STUDY COMMITTEE ................................................................................................................ 67 
14 
ETHICAL AND REGULATORY CONSIDERATIONS ............................................................ 68 
14.1 
References ............................................................................................................................. 68 
14.2 
Institutional Review Board/Independent Ethics Committee and Regulatory/Competent 
Authorities ......................................................................................................................................... 69 
14.3 
Subject Informed Consent ..................................................................................................... 69 
14.4 
Study Records and Archiving ................................................................................................ 70 
15 
QUALITY CONTROL / QUALITY ASSURANCE ................................................................... 71 
15.1 
Direct Access to Source Data/Documents ............................................................................. 71 
15.2 
Clinical Monitoring ............................................................................................................... 71 
15.3 
Clinical Data Handling .......................................................................................................... 71 


 
 
 
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15.3.1 
Data Reported in the eCRF ........................................................................................... 71 
15.3.2 
Data Reported in the eCRF according to Subject Status .............................................. 72 
15.3.3 
Data Management System ............................................................................................. 72 
15.4 
Audits and Inspections .......................................................................................................... 72 
 
 
17 
REFERENCES ............................................................................................................................. 74 
18 
COMPANY LIABILITY INSURANCE ...................................................................................... 76 
19 
APPENDICES .............................................................................................................................. 77 
19.1 
Volume of P03277 injection by dose group and body weight .............................................. 77 
19.2 
Volume of MultiHance® injection by dose group and body weight ...................................... 78 
 
 
 
 
 


 
 
 
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LIST OF FIGURES 
 
Figure 1 : Study Diagram ...................................................................................................................... 10 
 
 
LIST OF TABLES 
Table 1: Study Flow Chart ...................................................................................................................... 8 
Table 2: Overview of Efficacy Variables .............................................................................................. 33 
Table 3: Images sets per subject ............................................................................................................ 34 
Table 4: Imaging diagnosis ................................................................................................................... 37 
Table 5: Time period for the assessment of AEs ................................................................................... 64 


 
 
 
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1 
INTRODUCTION AND STUDY RATIONALE 
The use of Gadolinium-Based Contrast Agents (GBCAs) has revolutionized the radiologic field since 
their introduction 25 years ago. These contrast agents have been used extensively in a large range of 
indications, particularly Central Nervous System (CNS) Magnetic Resonance Imaging (MRI) 
examinations. Contrast enhancement has enabled improving tissue contrast and lesion characterization 
and more sensitive detection of even very small lesions. Contrast-enhanced MRI of brain lesions also 
plays a vital role during the post-therapeutic or intervention phase in determining treatment response: 
early identification of the lack of treatment efficacy can facilitate selection of an alternative therapeutic 
approach, potentially improving subject outcomes.  
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. 
For morphologic MR imaging, r1-relaxivity is the primary determining factor for contrast efficacy. 
Most of the GBCAs available have similar T1 relaxivity, and thus their contrast-enhancing capabilities 
are comparable. Exception is gadobenate-dimeglumine (MultiHance®), due to its weak and transitive 
interaction with human serum proteins (albumin, HSA), the resulting r1 relaxivity for MultiHance® is 
approximately 1.5- to 2 fold higher than other conventional relaxivity agents measures in human plasma 
at 37ºC [1-4].  
One of the common strategies for increasing MRI sensitivity in the detection of brain lesions is 
increasing the dose of the contrast agent. While a standard dose of Gd contrast agent is considered to be 
0.1 mmol/kg body weight, many studies have been published demonstrating improved diagnostic 
performance with double (0.2 mmol/kg) or even triple (0.3 mmol/kg) doses [5-11]. However, higher 
doses of contrast agent increased the cost of MRI and were associated with potentially more false-
positive results [11-12]. Additionally, there has been increased concern for the development of 
Nephrogenic Systemic Fibrosis (NSF) in at–risk subjects when higher doses are used [13-15]. More 
recently, there have been a number of studies [16-24] suggesting that trace amounts of Gd may be 
released and retained in tissues (bone, brain) in subjects with normal renal function. The possible release 
and deposition of even small amounts of Gd into the body is of particular importance in subjects who 
undergo repeated contrast-enhanced MR imaging with GBCA. 
Another alternative approach to improving diagnostic performance is the use of limited dose of a 
contrast agent with higher relaxivity. The significant evidence of improved diagnostic performance with 
the higher relaxivity agent has been demonstrated from a series of intra-individual comparative studies, 
the greatest benefit observed included those of particular relevance to neurosurgeons, such as lesion 
border definition, lesion extent and visualization of internal morphology of the lesion [25-33]. 
P03277 is a new chemical entity discovered and developed by Guerbet. It is a non-ionic macrocyclic 
gadolinium (Gd) complex intended to be used in human, by intravenous administration, as a contrast 
agent for MRI. 
P03277 has a molecular weight of 970.11 g/mol. 
 
P03277 is used as an aqueous injectable solution for injection at a concentration of 0.5 M. 
 


 
 
 
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P03277 is a Gd chelate with a very high stability, limiting the risk of release of toxic free Gd in the 
body. The results of preclinical data indicate a good tolerance and a low toxicity profile at dose levels 
and exposure much higher than the anticipated clinical dose. This satisfactory tolerance has been 
confirmed in a phase I study in a total of 54 healthy volunteers. No serious adverse events occurred in 
any of these volunteers at any of tested dose at 0.025, 0.5, 0.75, 0.1, 0.2, and 0.3 mmol/kg BW. No 
clinically significant changes in vital signs or laboratory findings were noted.  
The ability of P03277 to be a MR contrast agent has been demonstrated by at least two-fold higher T1 
relaxivity compared to other available GBCAs. A proof of concept has been obtained for the efficacy of 
P03277 as a MR contrast agent for CNS imaging in a model of brain tumor (C6 glioma) implanted in 
rats. In this experimental brain tumor model, the dose of 0.1 mmol/kg of P03277 allowed for an increase 
in contrast enhancement of at least 30% as compared to other GBCAs administered at dose of 0.1 
mmol/kg, including MultiHance® (highest relaxivity).  
The purpose of the study is mainly to determine the effective and safe clinical dose of P03277 injection 
to be recommended as the further P03277 approved dose for phase III studies, by comparing with 
approved GBCA for CNS indication (here MultiHance®, current commercial product with the highest 
relaxivity) using a cross-over design (allowing intra-subject comparison to evaluate the study primary 
criterion). This dose selection will be based on the superiority of P03277 in term of efficacy (based on 
CNR criterion) towards MultiHance® in subjects with CNS indication. 
 


 
 
 
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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
To determine a safe and effective dose of P03277 based on a comparison of Contrast to Noise Ratio 
(CNR) between several doses, 0.025, 0.05, 0.1, 0.2 mmol/kg, of P03277 and MultiHance® at 0.1 
mmol/kg. 
 
2.2 
Secondary Objectives 
 
To assess technical adequacy of images 
 
To evaluate capacity of lesion detection: number, size and location of lesions detected  
 To evaluate diagnostic information using lesion visualization variables (lesion border 
delineation, internal morphology and degree of contrast enhancement)  
 
To evaluate diagnostic confidence 
 
To compare overall diagnostic preference between P03277 and MultiHance® 
 
To assess P03277 dose / response relationship for CNR and lesion visualization variables  
 
To evaluate the impact of P03277 and MultiHance®-enhanced MRI on subject treatment plan 
 
To assess the safety profile of P03277 as compared to MultiHance® after intravenous 
administration 
 
2.3 
Sub-Study / Ancillary Study Objectives 
NA 
 


 
 
 
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3 
STUDY DESIGN 
3.1 
Protocol Description 
The purpose of this phase IIb study is to determine an effective and safe clinical dose of P03277 
injection for CNS lesion detection and visualization by conventional steady-state CNS imaging. 
Therefore, CNR, a well-known quantitative parameter directly related to contrast medium/GBCA 
efficacy, has been chosen as the primary endpoint in order to have a precise determination of P03277 
clinical dose. Clinically meaningful parameter as lesion visualization which correlates with CNR will 
also be assessed, as a secondary primary endpoint.  
This is a multi-center, international, prospective, double-blind, randomized, controlled, parallel dose 
groups, cross-over with comparator study in male and female subjects presenting with either known or 
highly suspected focal areas of disruption of the BBB (e.g. primary and secondary tumors, focal 
inflammatory disorders), who are scheduled to undergo a routine contrast-enhanced MRI of the CNS.  
This study will be conducted in approximately 40 centers worldwide. 
Two subsets of subjects (subset 1 and subset 2) will be included in the study. Subjects of the two subsets 
will be randomly assigned to one of the doses of P03277 and to one series of 2 MRIs performed each at 
two separate study visits (see Figure 1). 
The first subset will consist of the first subject of each site. Indeed, in order to provide training images 
for the independent blinded off-site readers, to ensure that the imaging protocol/acquisition sequences 
has been appropriately programmed, and that the MR images produced can be transferred to the core 
laboratory, a dedicated subset of subjects (subset 1) will be enrolled for this purpose. Subjects of the 
subset 1 will be administered at 0.05 or 0.1 mmol/kg of P03277 with a 1:1: ratio and at 0.1 mmol/kg of 
MultiHance® and will perform all the study evaluations and safety assessments (see Figure 1). The two 
P03277 doses have been chosen as they are surrounding the potential targeted clinical dose. These 
subjects will not be considered for the efficacy analysis but only for the safety assessment. A maximum 
of forty (40) subjects (depending of the number of participating sites) will be included in the subset 1. 
In addition of these subjects, two hundred and forty (240) subjects will be enrolled in a second subset 
(subset 2, see Figure 1). These subjects will be used for dose-finding part of the study in which the 
safety and diagnostic efficacy of P03277 will be evaluated in CNS MRI at doses of 0.025, 0.05, 0.1 and 
0.2 mmol/kg (doses driven by efficacy in a safety acceptable range) with a 1:1:1:1: ratio versus 
MultiHance® (0.1 mmol/kg BW).  
Subjects from both subsets will receive one of the doses of P03277 and one dose of MultiHance® by 
single IV injection at a rate of 2 mL/second followed by 0.9% saline flush in randomized order in two 
successive treatment periods separated by a wash out period of 2 days minimum up to 14 days. 
During the course of the study, 2 MRIs will be obtained from each subject: one unenhanced and 
P03277-enhanced MRI; and one unenhanced and MultiHance®-enhanced MRI. MRI evaluations will be 
performed by on-site investigators and 3 independent off-site blinded readers. 
To determine the exact matching of lesions throughout the different imaging sequences and MRI 
examination (P03277 and MultiHance®), an independent radiologist (lesion tracker) will perform ‘lesion 
tracking’ (except for the global matched pairs evaluation) based on the available CNS (brain/spinal 
cord) diagrams 
 


 
 
 
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The safety of subjects  will be assessed using vital signs, 12-lead ECGs, injection site tolerance, clinical 
laboratory parameters (blood and urine) and by monitoring of adverse events (AEs). Safety assessments 
will be conducted over 1 day follow-up period after each MRI visit.  
3.2 
Study Duration 
The study includes 5 visits: 1 screening visit, 2 MRI visits and 2 safety visits.  
 Subject eligibility will be determined at a screening visit performed up to 7 days prior to the first study 
MRI (the screening visit may occur the same day as visit 2 if all the inclusion/non-inclusion criteria are 
met).  
Two MRI visits are to be performed, one session with P03277 administration and another session with 
MultiHance® administration. The interval between the 2 MR examinations is ≥ 2 days to avoid 
carryover effects but ≤ 14 days to minimize the risk of measurable disease progression or lesion 
evolution. Eligibility criteria will be checked prior to MRI procedures and confirmed via the IWRS to 
validate IMPs allocation. 
Two safety visits will be performed during the study, one day after each MRI examination. 
The minimum study duration per subject is 4 days and the maximum duration is 22 days.  
The subject’s participation is defined as the period from the screening visit (ICF signature) to the last 
study visit and defined in Section 11 in case of premature discontinuation. 
The study will be considered as completed once all the images collected for all the subjects will have 
been reviewed by all the independent blinded readers.  
 
3.3 
Interim analysis  
No interim analysis is planned. 
 
3.4 
Study Committee 
A Data Safety Monitoring Board (DSMB) will be set up for assessing the safety of the Investigational 
Medicinal Products (IMPs) during the study and for monitoring the overall conduct of the clinical trial 
(see section 13). 
The investigators and Guerbet will be responsible to ensure the subjects stopping rules for safety 
reasons are applied (See section 11.2).  
 


 
 
 
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4 
SUBJECT SELECTION 
The subject population is divided in 2 subsets of subjects (subset 1 and subset 2) who will have to meet 
all the study inclusion/non-inclusion criteria. In addition, subjects with brain metastasis will be 
randomized at a minimum of 20% of the subset 2 (stratification of 20% of subjects with brain metastasis 
per group of P03277 doses). 
4.1 
Inclusion Criteria 
1. Female or male adult subject (subject having reached legal majority age). 
2. Subject presenting, at the time of inclusion, with known or highly suspected focal areas of 
disrupted Blood Brain Barrier (BBB) (e.g., primary and secondary tumors, focal 
inflammatory disorders) including at least one expected enhancing lesion of minimum 5 
mm (long axis). This lesion must have been detected on a previous imaging procedure 
(computerized Tomography (CT) or MRI).   
3. Subject scheduled for a routine CNS contrast-enhanced MRI examination for clinical 
reasons and agreeing to have a second contrast-enhanced MRI examination for the purpose 
of the study.  
4. Subject able and willing to participate to the study. 
5. Subject having read the information and having provided his/her consent to participate in 
writing by dating and signing the informed consent prior to any study related procedure 
being conducted. 
6. Subject affiliated to national health insurance according to local regulatory requirements. 
To be included in the study, the subject must meet all these inclusion criteria. 
 
4.2 
Non-Inclusion Criteria 
1. Subject presenting with acute or chronic Grade III (at least) renal insufficiency, defined as 
an estimated Glomerular Filtration Rate (eGFR) <60 mL/min/1.73 m² based on one eGFR 
assessment performed the day of the MRI prior to the first contrast agent injection. 
2. Subject presenting with known class III/IV congestive heart failure according to the New 
York Heart Association classification (NYHA). 
3. Pregnant or breast-feeding female subject (a female subject of childbearing potential or with 
amenorrhea for less than 12 months must have a negative urine or serum pregnancy test 
within 24 hours prior to study MRI and must be using a medically approved contraception 
method* until the last study visit). 
4. Subject having received any investigational medicinal product within 30 days prior to study 
entry. 
5. Subject previously enrolled in this study. 
6. Subject presenting with any contraindication to MRI examinations. 
7. Subject with known contra-indication(s) to the use or with known sensitivity to one of the 
products under investigation or other GBCAs. 


 
 
 
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8. Subject having received any contrast agent (MRI or CT) within 3 days prior to study 
products administration, or scheduled to receive any contrast agent during the course of the 
study or within 24 hours after the second study product administration. 
9. Subject having received any treatment or medical procedure (e.g. chemotherapy, 
radiotherapy, biopsy or surgery  etc…) within 7  days prior to the first  MRI or is expected/ 
scheduled to have a change in any treatment or medical procedure (e.g. chemotherapy, 
radiotherapy, biopsy or surgery  etc…) in-between the 2 MRI examinations. 
10. Subject with anticipated, current or past condition (medical, psychological, social or 
geographical) that would compromise the subject’s safety or her/his ability to participate in 
the study. 
11. Subject unlikely to comply with the protocol, e.g. uncooperative attitude, inability to return 
for follow-up visits and/or unlikelihood of completing the study. 
12. Subject related to the Investigator or any other study staff or relative directly involved in the 
study conduct. 
13. Subject presenting with acute relapse of multiple sclerosis.. 
* medically approved contraception methods include: female sterilization, barrier methods of 
contraception (condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/ vaginal suppository), use of oral, injected or implanted hormonal methods of 
contraception or other forms of hormonal contraception that have comparable efficacy (failure rate 
<1%), for example hormone vaginal ring or transdermal hormone contraception, placement of an 
Intrauterine Device (IUD) or Intrauterine System (IUS). 
 
Subjects presenting with one or more of these non-inclusion criteria must not be included in the study. 
The diagnosis obtained from previous imaging examinations will be considered as medical history to 
assess inclusion criteria. All the study analysis will be based only on the images obtained through the 
study MRI. 
 
4.3 
Subject Identification 
After having signed their written informed consent, the subjects will be allocated an Identification 
Number (Subject ID). Once the subjects satisfied to all inclusion/non-inclusion criteria, they will be 
included in the study.  
This Subject ID will be unique and will contain 6 digits: the first two digits corresponding to the country 
number, the following two digits corresponding to the site number, which are attributed at the beginning 
of the study, and the last two digits being chronologically implemented depending on subject 
enrollment. The lowest enrollment number will correspond to the first subject enrolled at this site and 
the highest number to the last subject enrolled.  


 
 
 
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5 
INVESTIGATIONAL MEDICINAL PRODUCTS 
Investigational Medicinal Product(s) (IMPs) 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 an individually packaged vial in a carton box with a single use detachable label 
that will allow ensuring accuracy of IMP allocation per subject. 
Allocation of IMP to subject will be performed by an Interactive Web Response System (IWRS). The 
designated investigational staff will log into the system which will ensure that the appropriate IMP is 
allocated per subject. 
5.1 
Investigational Medicinal Product(s) 
5.1.1. Investigational Medicinal Product 1 
Name: P03277 
 
Pharmaceutical form: vial of 20 ml  
P03277 is an aqueous solution. Each vial contains 20 mL of solution presented as a sterile, clear, 
yellow, ready-to-use solution for injection. 
Concentration: 0.5 M 
P03277 dose per administration: P03277 will be injected according to randomization at 1 of 4 different 
doses (1 dose per subject according to allocated randomized arm):  
 
First subset of subjects: 0.05 or 0.1 mmol/kg BW (corresponding to 
0.1 or 0.2 mL/kg body weight) in a 1:1ratio. 
 
Second subset of subjects: 0.025, 0.05, 0.1 or 0.2 mmol/kg body 
weight (corresponding to 0.05, 0.1, 0.2 or 0.4 mL/kg body weight) in a 
1:1:1:1 ratio.   
Sufficient IMP must be allocated to one subject by IWRS. 
Route and method of administration: by intravenous (IV) bolus injection at 2 mL/s rate without dilution, 
followed by a saline flush to ensure complete injection of the contrast medium. 
The P03277 administration is preferably performed by power injector in order to better control injection 
rate, but manual injection is also permitted in case it is necessary. 
Please refer to the Investigator Brochure for more information on P03277. 


 
 
 
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5.1.2. Investigational Medicinal Product 2 
Name: Gadobenate dimeglumine (529 mg / mL) 
Brand name: MultiHance® 
Pharmaceutical form: vial of 20 ml.  
It 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 
Dose per administration (as per Summary of Product Characteristics (SmPC)): 0.1 mmol/kg body 
weight. This corresponds to 0.2 mL/kg body weight. 
The same dose of MultiHance®, 0.1 mmol/kg BW by single IV injection at a rate of 2 mL/second, will 
be injected to all subjects (subset 1 and 2) 
Sufficient IMPs must be allocated to one subject by IWRS. 
Route and method of administration: by intravenous (IV) bolus injection at 2 mL/s rate without dilution, 
followed by a saline flush to ensure complete injection of the contrast medium. 
MultiHance® administration is preferably performed by power injector in order to better control 
injection rate, but manual injection is also permitted in case it is necessary. 
Please refer to the local SmPC for more information on MultiHance®.  
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 P03277 and MultiHance® will be performed by Guerbet (or its designee).  
The outer packaging will be the same for P03277 and MultiHance®, 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 and other locally required information. 
This label will be stuck on the subject file or study documentation. 
IMP will consist in a box that contains one 20 ml vial of P03277 or one 20 ml vial of MultiHance®.  
In case of damaged IMP, a new IMP will be allocated to the subject 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 study completion, all used (including empty vials) and unused IMPs should have been 
returned to the Sponsor or to the predefined location for storage before destruction. 
 
 
 
 
 


 
 
 
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5.3 
Condition of Investigational Medicinal Product allocation 
5.3.1 
Investigational Product(s) Allocation / Randomization 
At visit 2, the subjects will be randomly assigned to one of the doses of P03277 and to one series of 2 
MRIs performed each at two study visits separated by a wash out period of 2 days minimum up to 14 
days. One series consists of the use of P03277 as contrast agent at visit 2 and MultiHance® at visit 4. 
The second series consists of the use of MultiHance® at visit 2 and P03277 at visit 4. 
The P03277 dose to be injected to the subjects will be attributed by randomization (according to 
randomization list) at the time of visit 2 simultaneously with the MRIs order allocation. 
The randomization scheme will allocate subjects to the two P03277 treatment arms (0.05 or 0.1 
mmol/kg BW) in a 1:1 ratio for the first subset of subjects and to the four P03277 treatment arms 
(0.025, 0.05, 0.1 or 0.2 mmol/kg BW ) in a 1:1:1:1 ratio for the second subset of subjects. The P03277 
will be injected at a rate of 2 mL/second. 
The same dose of MultiHance®, 0.1 mmol/kg BW by single IV injection at a rate of 2 mL/second, will 
be injected to all subjects. 
The randomization will be done via IWRS with a stratification factor for the subset 2: presence of brain 
metastasis (yes/no) and performed in blocks to prevent unequal treatment allocation. For the subset 2, 
subjects with brain metastasis will be included at a minimum of 20% in each dose group of P03277. 
The study design and the injection of the IMPs require identifying before the study start, two separate 
teams in each study 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 
separated subject’s file all the unblinded information related to the IMPs and will have to complete a 
dedicated eCRF pages with restricted access. 
During the course of the study, the two teams should not exchange any information regarding the 
subjects enrolled and the IMPs (nature, order of administration, dose). The subjects’ files with 
unblinded data should not be filled with the subjects medical and study 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 subject recruitment progress of a given investigational site. The site should ensure to have 
enough IMPs before including a new subject. 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.  
Subject numbers will be sequential within each center.  
At visit 2 and visit 4, once the 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 subject), 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 


 
 
 
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situation is under control again. Detailed instructions can be found in the IWRS manual provided to the 
sites. 
5.3.2 
Double-Blind Conditions  
In order to ensure the appropriate blinding of the study, several procedures will be put in place and are 
described below: 
To ensure blinding of the investigator to the nature of the IMPs injected (P03277 or MultiHance®), a 
third party (site nurse, technician or physician) will be responsible for preparing and administrating the 
IMPs. This person ensures non-disclosure of information.  He /she will stick the detachable label of the 
vial into the Subject’s records or appropriate form. He /she will also write his/her name, date and 
signature and the subject number on the box, and after use, he/she will close the box with a seal. 
The off-site blinded images evaluations will be performed by experienced radiologists who will not 
have been involved in the on-site clinical portion of the study. Image readings of all subjects will be 
evaluated in blinded conditions regarding the contrast agent injected, as described in Section 9.4. The 
images used for blinded evaluation sessions must not contain any information regarding the subject’s  
clinical data, study site, nature of IMP or the dose of P03277 (section 9.4.6). The steps for anonymizing 
images and transferring images to the Imaging Core Laboratory will be detailed in the “Site Imaging 
Manual”. 
Any disclosure relating to the nature of the contrast agent injected by the person responsible for IMP 
allocation will be considered a protocol violation. 
5.3.3 
Individual Study Treatment Unblinding  
Unblinding of study product will be managed through the IWRS. In case of emergency, investigators 
will be allowed to request to the IWRS to unblind the study product allocated to a given subject under 
their responsibility. Study product should only be unblinded if absolutely necessary for the safety of the 
subjects and if unblinding impacts the management of medical cares (see Section 10.4). 
Details concerning the decoding and the circumstances for breaking the code will be reviewed with the 
investigator and his/her team during the initiation visit. 
The persons authorized to unblind study product during the study usually are: the principal investigator 
and the Sponsor Pharmacovigilance physician/officer.  
If the Clinical Project Manager receives an external request for unblinding (Authorities, health care 
professionals taking care of the subject, etc.), he/she must inform the Sponsor Drug Safety Officer. 
If the investigator and the Sponsor Pharmacovigilance physician/officer unblind the study product, 
he/she must inform the Clinical Project Manager as soon as possible by letter, fax or e-mail but shall not 
reveal the nature of the study product in order to protect as much as possible the double-blind design of 
the study.  
Unblinding must be documented by indicating the subject number and demography characteristics (age, 
gender), the reason for unblinding, the date, time and identity of the person who performed the 
unblinding.  
In case of unblinding, the subject will be withdrawn from the study. 


 
 
 
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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 study 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 study protocol, or dispose of IMP in any other manner. 
If during the administration of IMP, the subject experiences a Serious Adverse Event (SAE), the IMP 
administration must be discontinued and the subject rendered emergency medical care and monitored 
until the event is resolved (see section 10.2) 
 
5.5 
Non Investigational Medicinal Product(s) and Other Study Products 
Not applicable. 
 
5.6 
Study Product(s) Compliance and Accountability 
An unblinded third party designated by the investigator will be in charge of product management and 
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 subject.  
The dosing information will be recorded in individual subject’s records managed by the unblinded staff 
(see section 5.3.2). When protocol required IMP administration conditions are not followed, reason(s) 
will be given and recorded by the third party. 
These rules apply for both study subsets of subjects. 
 
 


 
 
 
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6 
CONCOMITANT TREATMENTS 
Any treatment, including all medically approved contraception methods, homeopathic products, over-
the-counter treatments, as well as prescription drugs, on-going at the time of subject’s informed consent 
signed and/or any treatments administered during the study will be recorded in the medical file. 
The following information must be provided:  
- 
Drug (brand name or generic name) 
- 
Route of administration 
- 
Purpose (medical history/AE/ imaging pre-treatment/contraception/prophylaxis) 
- 
Indication  
- 
Duration of treatment  
 
6.1 
 Concomitant Treatments of Special Attention 
In order to limit any interference with the safety and efficacy evaluation of Investigational Product, the 
following precaution and restriction must be considered: 
Currently, no treatment has been identified that is capable of preventing an allergic reaction with any 
gadolinium-based contrast agents. Thus, no pre-treatment of any nature will be recommended before 
contrast-enhanced MRI. Nevertheless, if the investigator decides to premedicate a subject, the treatment 
must be documented in the medical file and then in the eCRF. 
In general, there are no specific recommendations regarding Gadolinium-Based Contrast Agents, and 
therefore, no specific hydration procedure is defined in this protocol. Nonetheless, whenever possible, 
the subject 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 
study. However warnings and precautions for use of the concomitant treatments taken by the subject 
should be considered. 
In addition, no change should occur in any treatment or medical procedure (e.g., chemotherapy, 
radiotherapy, biopsy or surgery etc…) in-between the two MRIs.  
 
6.2 
Prohibited Concomitant Treatments  
NA 




 
 
 
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Following are the image sets that will be evaluated per subject: 
Table 3: Images sets per subject  
mage Set Number 
Type 
1a 
Unenhanced MRI before P03277 
1b 
Unenhanced MRI before MultiHance® 
2 
P03277-enhanced MRI (GRE sequence for brain/SE sequence for spine) 
3 
MultiHance®-enhanced MRI (GRE sequence for brain/SE sequence for 
spine) 
4 
Global matched-pairs fashion (Combined unenhanced and P03277-
enhanced MRI, Combined unenhanced and MultiHance®-enhanced MRI) 
Combined set for P03277 is defined as unenhanced and P03277-enhanced MRI (set 1a and 2)  
Combined set for MultiHance® is defined as unenhanced and MultiHance®-enhanced MRI (set 1b and 3)  
 
7.1 
Primary Criterion  
The primary criterion (off-site read) is calculated by subject, and by independent blinded reader in a 
centralized procedure (off-site readers), in averaging the Contrast to Noise Ratio (CNR) for maximum 3 
enhanced lesions. Only lesions detected by both MRIs after lesion tracking will be used. The evaluation 
will be done on combined images sets (1a, 2) and (1b, 3). 
CNR is a variable derived for each lesion, from the Signal Intensity (SI) measurement. CNR will be 
calculated according to the following formula: 
noise
ht
lesion
SD
SI
SI
CNR


 
where, 
SIlesion  = the SI in the Region Of Interest (ROI) in the lesion 
SIht  
= the SI in the ROI in healthy tissue (brain or spinal cord)  
SDnoise  = standard deviation of background noise.  
The SI measurement will be performed by the independent blinded readers on the pre and post-
injection, axial 3D T1 weighted Gradient Echo (GRE) for brain and sagittal T1-weighted Spin-Echo 
(SE) or Turbo Spin-Echo (TSE) for spine, sequences. The post CNR value will be normalized by the 
pre-CNR (baseline) value.  
Measurements of the SI of the lesion are to be made on the best representative images of the pathology, 
along with the SI of normal brain (white or gray matter) or spinal cord tissue, and of the image 
background.   
 


 
 
 
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These images will be selected according to the following:  
 
Up to 3 most representative lesions (largest enhancing lesion) will be measured separately.  
 
The lesion must have a size of at least 5 mm (long axis) to avoid partial volume averaging. 
 
The ROI for a lesion will encompass a homogeneous area within the lesion as large as 
possible.  
 
Normal tissue SI should be measured on the slice where lesion is present. For brain lesions, 
normal tissue ROI must always be drawn inside the brain, if possible, on the contra lateral 
hemisphere with respect to the identified lesions and regardless whether the lesions are 
intra- or extra parenchymal. Normal tissue ROI should be drawn in white matter if possible. 
For spine lesions, normal tissue ROI must always be drawn in adjacent portion of lesions in 
the spine, it can be done, if possible, in sagittal. For vertebral disease or disc disease, normal 
tissue ROI should be drawn in similar anatomy of non-involved level.  
 
Background measurement should be outside the brain but within the scan frame, phase shift 
noise should be avoided as much as possible.  
 
7.2 
Secondary Criteria 
The following criteria will be evaluated either by the investigators (on-site read) or by the independent 
blinded readers (off-site read) or by both of them. 
The evaluation will be done on image sets describe in Table 3.  
7.2.1 
Technical adequacy of images (on-site and off-site reads) 
Combined images sets (1a, 2) and (1b, 3) will be evaluated as adequate or not. Images are considered 
technically inadequate if artifacts completely compromise image interpretability. The reasons will be 
recorded: 
o 1 = Artifacts due to  subject   
o 2 = Artifacts due to machine 
o 3 = Artifacts due to contrast agent 
o 4 = Injection technical failure 
o 5 = Other, specify  
7.2.2 
Lesion detection capacity (on-site and off-site reads) 
Number, size and location of lesions detected and the presence or absence of enhancement will be 
recorded. 
For each combined image set (1a, 2) and (1b, 3), the investigator/independent blinded reader is to record 
the following:  
o Number of lesions 
o For the 3 most representative lesions, the following will be recorded for each lesion 
separately:  
 
The largest diameter of the lesion 
 
The location of the lesion 


 
 
 
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 
Presence or absence of enhancement (based on the evaluation ‘Degree of contrast 
enhancement (see 7.2.3)) 
o In case that more than 3 lesions are present, the investigator/independent blinded reader has 
to enter in the eCRF how many lesions are present (total number) and to specify the 
diameter of the smallest lesion.  
7.2.3 
Lesion visualization variables (on-site and off-site reads) 
The investigator/ independent blinded reader will record each of lesion visualization variables (lesion 
border delineation, internal morphology and degree of contrast enhancement) for up to 3 most 
representative enhancing lesions, referring mainly to axial 3D T1-weighted GRE images for brain and 
sagittal T1-weighted SE/TSE images for spine, on a 4-point scale of the combined images sets (1a, 2) 
and (1b and 3).  
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 (for extra-axial 
lesions, this pertains to the definition of the space in which the lesion is present, and for 
intra-axial lesions, it pertains to the invasion of white matter, gray matter, or both; the 
neuroanatomical distribution of the lesion; and its mass effect). 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 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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7.2.4 
Diagnostic confidence (on-site and off-site reads) 
The investigator/independent blinded reader will record in the eCRF his/her diagnosis and his/her 
confidence in diagnosis for each subject for each combined image set (1a, 2) and (1b, 3) according to 
Table 4. 
Table 4: Imaging diagnosis  
Diagnosis 
Primary 
 
 
Tumors  
 
Secondary 
Glial tumor, low grade (I/II) 
Glial tumor, high grade (III/IV) 
Glial tumor, tumor grade cannot be determined  
Meningioma 
Others, to be specified 
 
Brain metastasis 
Inflammatory diseases 
to be specified 
Infectious diseases 
Abscess 
Others, to be specified 
Vascular diseases 
Stroke 
Others, to be specified 
Others 
To be specified 
 
Diagnostic confidence will be evaluated to determine the level of certainty that the 
investigator/independent blinded readers assign to a diagnosis. This is defined as the degree of 
confidence that the information on the images represents the true and complete clinical picture of a 
subject.  
The degree of confidence will be rated on a 5 point scale:  
o 1 = nil: Very uncertain 
o 2 = poor: Uncertain 
o 3 = moderate: Moderately certain 
o 4 = high: Good certainty  
o 5 = excellent: Very certain 
When the investigator/independent blinded reader chooses ‘not assessable’ for diagnosis, by definition 
the confidence level is 1 (= very uncertain).  
7.2.5 
Overall diagnostic preference (off-site read) 
The evaluation will be performed in a global matched-pairs fashion (image set 4). For each randomized 
subject, all images (combined pre-injection and post-injection images) from the first MR examination, 
labeled as examination 1, will be displayed simultaneously with the corresponding images (combined 
pre-injection and post-injection images) from the second MR examination, labeled as examination 2.  
 


 
 
 
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The assessment will be performed on all post-contrast T1-weighted images (i.e. axial 3D T1 weighted 
GRE for brain and sagittal T1-weighted SE/TSE for spine) with three-point scales: 
o 1: for which examination 1 is preferred to examination 2 
o 0: for which no preference is observed 
o 2: for which examination 2 is preferred to examination 1 
Readers 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 (i.e., high or low grade in 
the case of intraaxial gliomas), definition of extent of disease, or other reasons that had 
to be specified on the eCRF) 
7.2.6 
P03277 dose / response relationship for CNR and lesion visualization 
variables 
The relationship between dose and response will be evaluated graphically based on mean profile. 
Depending on the graphical results, a more complex model including study drug dose (as continuous 
variable) could be fitted to evaluate the relationship between dose and CNR increase. 
7.2.7 
Impact of IMPs-enhanced MRI on subject treatment plan (on-site read) 
The impact on subject treatment plan will be assessed by on-site radiologists and will be summarized 
for each product group. 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 sets 1a, 2 or sets 1b, 3), the investigator will have 
to document if the subject 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: 
- 
Surgery 
- 
Biopsy 
- 
Chemotherapy 
- 
Radiotherapy 
- 
Other treatment: specify 
7.2.8 
Safety assessment 
The safety assessments will be based on the following: Adverse Events (AEs), injection site tolerance, 
clinical laboratory parameters (blood and urine), vital signs and 12-lead ECGs. A central laboratory will 
be used to analyze and report blood chemistry/hematology/Cystatin C (eGFR would also have been 
evaluated locally prior to the MRIs). A central ECG vendor will be used to collect, assess and reports 
ECGs. 
o Adverse events 
Adverse Event monitoring will be recorded throughout subject participation (see section 3.2).  


 
 
 
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o Injection-site tolerance  
For all subjects, injection-site tolerance (burning, pain, eruption, extravasation, inflammation, or 
other) will be assessed over 1 day following each contrast injection (during the injection, 45 min 
± 15 min, 2-4 h 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 subject will be 
asked to specify the level of pain using a visual analogic scale (VAS
 from 0 (no 
pain) to 10 (maximal pain). 
o Clinical laboratory parameters and urinalysis  
For each subject, central blood samples and urinalysis will be performed from visit 2 to visit 5.  
 The following parameters will be obtained and assessed:  
 
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, glucose, Blood Urea Nitrogen (BUN) / 
urea, creatinine, eGFR, 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 
and Cystatin C.  
 
Urinalysis (dipstick): visual and chemical examinations (including color, appearance, 
specific gravity, pH, protein, glucose, ketones, occult blood, leukocyte esterase, nitrite, 
bilirubin and urobilinogen). 
 
In female subjects of childbearing potential, a urine or serum pregnancy test will be performed 
on-site prior to the administration of IMPs.  
For all other laboratory assessments, 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) and the investigator will report any values considered clinically significant as 
an AE.  
o Vital signs 
Vital signs (supine systolic and diastolic blood pressures, pulse rate) will be measured and 
recorded according to the following schedules: 
 
Immediately prior to each contrast agent injection (baseline value)    
 
At 45 ± 15 minutes and 2-4 hours following each contrast agent injection 
 
One day after each contrast injection 
If significant changes in vital signs occur, vital signs should be recorded more frequently, and for 
as long as necessary, to ensure that the changes have been resolved and/or that the subject is 
stable. All clinically significant abnormal value or change value will be recorded as AEs. 
A significant clinically change is defined as follows: Pulse Rate < 40 or >100 bpm; systolic Blood 
Pressure < 90 or >160 mmHg; diastolic Blood Pressure > 100 mmHg. 
Blood pressure and pulse rate will be measured after a rest of 10 minutes in supine position. 
Blood pressure will not be measured on the arm used for the injection.  


 
 
 
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o ECG monitoring 
The following parameters will be collected via an ECG device supplied by the ECG core 
laboratory: heart rate (RR interval), PR interval, QRS duration, QT, QTc Bazett, QTc Fridericia. 
The 12-lead ECGs will be measured prior to each contrast injection, and at 45 minutes ± 15 
minutes, at 2-4 hour, and 1 day after each contrast injection. 
The ECG measured prior to the 1st contrast injection (at visit 2) will be considered as the baseline 
evaluation. 
Triplicate ECGs (3 measurements taken at approximately 1 min intervals) will be recorded prior 
to each MRI and at each post-injection time point.  
The subject is to be at rest for at least 5 minutes prior to any ECG recording.  
All ECGs will be independently reviewed by a central reader (independent reviewer). Instructions 
for the collection and transmission of the ECGs to the independent reviewer will be provided in 
the ECG investigator manual. 
The investigator would have to give an overall interpretation of the ECG at each time point. All 
clinically significant abnormal changes will be recorded as AEs. Any clinically significant 
abnormal changes from baseline (Visit 2, prior to the MRI) must be followed until the 
abnormality is resolved or is adequately explained.  
For ECGs a notable QTc change is defined as a QTc (Fridericia’s or Bazett’s) interval of greater 
than 450 ms for males and females. All such ECGs will be flagged by the core laboratory’s 
cardiologist and require assessment for clinical relevance by the Investigator and if clinically 
significant to be reported as AEs.  
 


 
 
 
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8 
NUMBER OF SUBJECTS 
Based on the hypothesis below, a total of 280 subjects will be enrolled in the study: 
- 
First subset: maximum 40 subjects (depending of the number of participating sites) on the basis 
of 1 subject per site. 
- 
Second subset: 240 subjects based on the following assumption:  the study aims at detecting a 
minimum of 30% increase of CNR for at least one of the four tested dose of P03277 compared 
to control arm MultiHance® at dose of 0.1 mmol/kg BW. A sample size of 50 evaluable subjects 
per group is required to obtain a power of at least 90%, using a t-test of a normal mean 
difference with a 1-sided significance level of 0.025 (Holm's step-down method in a Multiple 
Comparisons Design) and a common standard deviation of 3.01. Therefore, a minimum of 50 
evaluable subjects per dose group and a minimum of 200 evaluable subjects in total will have to 
be enrolled in this study.  
An evaluable subject is defined as a randomized subject, 2 contrast agents administered, having 
undergone 2 complete, assessable and interpretable MRI examinations, presenting with at least 
one enhancing lesion of minimum 5 mm (long axis). 
It is anticipated that some of the subjects will not complete both MRI evaluations. To offset this, 
an additional 10 subjects per group will be added to the 50 required leading to a total of 240 
randomized subjects. 
The number of non-evaluable subjects will be monitored to assess the necessity for a sample 
size increase. The decision to increase the sample size will be made by the sponsor when 
approximately 80% of the planned 240 randomized subjects are enrolled. The actual rate of 
drop-out subjects will be considered to assess the new number of subjects to be enrolled.  
Subjects with brain metastasis will be randomized at a minimum of 20% of the second subset of 
subjects. Randomization will be stratified within brain metastasis (yes/no) in order to prevent 
unequal treatment allocation. 
 


 
 
 
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9 
STUDY SCHEDULE AND PROCEDURES 
9.1 
Study Schedule 
9.1.1 
Screening Visit – Visit 1 (Day -7 to Day 0)  
During this visit, the following tasks or assessments will be performed: 
 A written informed consent will be obtained from the subject as described in Section 
14.3; 
 The subject will be attributed a subject ID by eCRF; 
 Verification of  inclusion and non-inclusion criteria; 
 Recording of demographic data (such as sex, ethnic data, date of birth (complete or 
partial as per local regulation)) measurement of height. 
 Documentation of relevant medical history/current medical condition present before 
signing the informed consent. The Investigator will also question on any possible 
previous contrast agents injection intolerance (name of contrast agent injected and 
tolerance will be recorded); 
 Documentation of presence/absence of brain metastasis; 
 Documentation of CNS disease justifying the MRI (e.g., brain metastasis of primary lung 
cancer);  
 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; 
 A review and record of concomitant treatments; 
 A urine pregnancy test for all women of childbearing potential should be done and must 
be negative.  
 IWRS connection for recording the subject screening visit; 
 First study MRI visit and examination needs to be scheduled within 7 days (or the same 
day if all the inclusion/exclusion criteria are met). 
 
9.1.2 
Inclusion and imaging Visit – Visit 2 (Day 0) – First MRI examination 
Procedures to be performed prior to MRI examination: 
 Check of the eligibility criteria; 
 Measurement of body weight; 
 Any changes in concomitant treatments since the last visit will be documented;  
 A urine or serum pregnancy test for female subject of childbearing potential will be 
performed prior to the study MRI and must be negative (do not perform the test if a 
negative pregnancy test result performed within 24 h prior to the MRI is available); 


 
 
 
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 Blood sample collection for serum creatinine dosage and verification of local estimated 
GFR value ≥ 60 mL/min/1.73 m2 prior to the first MRI; 
 Blood samples will be collected according to central laboratory manual; 
 A urine dipstick will be done and results will be recorded on source documentation; 
 Vital signs (systolic and diastolic Blood Pressure in supine position, Pulse Rate) and 12-
lead ECGs (triplicate, 3 measurements taken at approximately 1 min intervals) will be 
recorded prior to contrast agent injection; 
 Assessment of AEs will be documented;  
 IWRS connection will be done to randomize the subject and to obtain the IMPs box 
number.  
Unenhanced and contrast-enhanced MRI examinations: 
 Unenhanced and contrast-enhanced MRI will be performed according to the required 
pulse sequences specified in Section 9.2.2. 
The appropriate dose/volume of P03277 or MultiHance® (see Appendices 19.1 and 19.2) will be 
administered by IV as a bolus at the rate of 2 mL/second using ideally a power injector via a peripheral 
vein (the antecubital vein is preferred). The IV injection line will consist of a large bore indwelling 
catheter (at least 18 gauge). P03277 or MultiHance® will be followed by a 0.9% saline flush using 
ideally a power injector. 
The following information will be documented in the source document and reported on the restricted 
eCRF pages (unblinded staff access): the location of the IV injection line, the injection method (power 
injector or manual), actual volume injected and actual rate of the injection.  
The start time of contrast injection and start time of post injection axial 3D T1 weighted GRE for brain 
and sagittal T1-weighted SE/TSE for spine, will be recorded. Any deviation from the specified MRI 
procedures and the reason for it (scanner-related problem or subject-related problem) will be also 
documented.  
Procedures to be followed after MRI examination: 
The subject will stay at the study site for at least 2-4 hours after the MRI examination is completed and 
the following procedures will be performed:  
 Use/change of concomitant treatments during the visit; 
 Vital signs (systolic and diastolic Blood Pressure and PR) and 12-lead ECG (triplicate 
ECGs, 3 measurements taken at approximately 1 min intervals) will be obtained 45 
minutes ± 15 minutes and between 2-4 hours after the injection of contrast agent. If 
significant changes in vital signs occur, vital signs should be recorded more frequently 
and for as long as necessary, to ensure that the changes are resolved, and/or that the 
subject is stable; 
 Injection-site tolerance (burning, pain, eruption, extravasation, inflammation, or other) is 
to be assessed during the injection , 45 minutes ± 15 minutes and between 2-4 hours after 
the injection of contrast agent; 
 Assessment of AEs will be documented;  
 Evaluation of the potential impact of IMP-enhanced MRI on subject treatment plan; 


 
 
 
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 Safety follow-up visit (Visit 3) needs to be scheduled 1 day post contrast agent injection; 
 Scheduling of the second MRI examination (visit 4) between 2 days and 14 days post 
visit 2. 
9.1.3 
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 will be documented;  
 Blood samples will be collected according to central laboratory manual;  
 A urine dipstick will be done and the results will be documented on the source 
documentation; 
 Vital Signs (systolic and diastolic Blood Pressure in supine position, PR) and 12-lead 
ECG (triplicate ECGs, 3 measurements taken at approximately 1 min intervals) should be 
recorded; 
 Injection-site tolerance is to be evaluated;  
 Assessment of AEs will be documented;  
 IWRS connection to record the study visit; 
 Remind the date of visit 4 to the subject. 
9.1.4 
Imaging Visit - Visit 4 (from 2 days, up to 14 days post visit 2) – Second MRI 
examination 
Procedures to be performed prior to MRI examination: 
 Measurement of body weight; 
 Any changes in concomitant treatments since the last visit will be documented;  
 A urine or serum pregnancy test for female subject of childbearing potential will be 
performed prior to the study MRI; and must be negative; 
 Blood sample collection for serum creatinine dosage and verification that the local eGFR 
value is ≥ 60 mL/min/1.73 m2;  
 Blood samples will be collected according to central laboratory manual; 
 A urine dipstick will be done and results will be recorded on source documentation; 
 Vital Signs (systolic and diastolic Blood Pressure in supine position, PR) and 12-lead 
ECGs (triplicate, 3 measurements taken at approximately 1 min intervals) will be 
recorded prior to contrast agent injection; 
 Assessment of AEs will be documented;  
 IWRS connection will be done to obtain the IMPs box number; 
Unenhanced and contrast-enhanced MRI examinations: 
 Unenhanced and contrast-enhanced MRI will be performed according to the required 
pulse sequences specified in Section 9.2.2. 
The appropriate dose/volume of P03277 or MultiHance® (see Appendices 19.1 and 19.2) will be 
administered by IV as a bolus at the rate of 2 mL/second using ideally a power injector via a peripheral 
vein (the antecubital vein is preferred). The IV injection line will consist of a large bore indwelling 


 
 
 
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catheter (at least 18 gauge). P03277 or MultiHance® injections will be followed by a 0.9% saline flush 
using ideally a power injector. 
The following information will be documented in the source document and reported on the restricted 
eCRF pages (unblinded staff access): the location of the IV injection line, the injection method (power 
injector or manual), actual volume injected and actual rate of the injection. 
The start time of contrast injection and start time of post injection axial 3D T1 weighted GRE for brain 
and sagittal T1-weighted SE/TSE for spine, will be recorded. Any deviation from the specified MRI 
procedures and the reason for it (scanner-related problem or subject-related problem) will be also 
documented.  
Procedures to be followed after MRI examination: 
The subject will stay at the study site for at least 2-4 hours after the MRI examination is completed and 
the following procedures will be performed:  
 Use/change of concomitant treatments during the visit; 
 Vital signs (systolic and diastolic Blood Pressure and PR) and 12-lead ECG (triplicate 
ECGs, 3 measurements taken at approximately 1 min intervals) will be obtained 45 
minutes ± 15 minutes and between 2-4 hours after the injection of contrast agent. If 
significant changes in vital signs occur, vital signs should be recorded more frequently 
and for as long as necessary, to ensure that the changes are resolved, and/or that the 
subject is stable; 
 Injection-site tolerance (burning, pain, eruption, extravasation, inflammation, or other) is 
to be assessed during the injection, 45 minutes ± 15 minutes, and between 2-4 hours after 
the injection of contrast agent; 
 Assessment of AEs will be documented; 
 Evaluation of the potential impact of IMP-enhanced MRI on subject treatment plan; 
 Safety follow-up visit (Visit 5) needs to be scheduled 1 day post contrast agent injection.  
9.1.5 
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 will be documented;  
 Blood samples will be collected according to central laboratory manual;  
 A urine dipstick will be done and the results will be documented on the source 
documentation; 
 Vital Signs (systolic and diastolic Blood Pressure in supine position, PR) and 12-lead 
ECG (triplicate ECGs, 3 measurements taken at approximately 1 min intervals)) should 
be recorded; 
 Injection-site tolerance is to be evaluated;  
 Assessment of AEs will be documented; 
 IWRS connection to record the subject end of study.  
 


 
 
 
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The schedule of time and events to be performed is given in Table 1 (study flow chart). 
During the course of the study, if a subject is screen failed or is prematurely discontinued, the new 
subject status should be recorded in the IWRS and in the eCRF. 
 
9.2 
Imaging Protocol 
9.2.1 
MR equipment 
The procedure will be performed using a MRI scanner that can perform the required pulse sequences 
with a dedicated head coil or a spine coil. MRI units with 1.5T or 3T magnetic field will be used, 
regardless of the manufacturer. The following information must be recorded: the manufacturer, model, 
software version, and field strength of the MRI device.  
For a single subject, it is mandatory to use the same MR equipment for the two MRI examinations 
required by the protocol. 
 
9.2.2 
MRI sequences 
The same parameter setting must be used for unenhanced images and for contrast-enhanced images in 
each subject (i.e., axial 3D T1 weighted GRE for brain and sagittal T1-weighted SE/TSE for spine).  
The required sequences and parameters for P03277 and MultiHance® per subject should be identical as 
follows:  
For brain (axial orientation and whole brain are required): 
 Unenhanced : 
 
3D T1-weighted GRE images  
 
2D T2-FLAIR  
 
T2-weighted TSE images  
 Contrast-enhanced: 
 
2D T1-weighted SE/TSE images 
 
3D T1-weighted GRE images (sequence parameters and slice positioning 
should be identical to pre-contrast 3D T1-weighted GRE) 
The 3D sequence has the advantage of enabling multiplanar reformatted images to different 
orientations. 3D-GRE provided significantly better images than the SE sequence in terms of the border 
and delineation of lesions and overall image quality. In addition, the 3D-GRE sequence is supposed to 
show fewer pulsation artifacts. 3D-GRE is more sensitive sequence for detecting small lesions.  
For spine: 
 Unenhanced : 
 
T2-weighted TSE images (sagittal) 
 
T1-weighted SE/TSE images (sagittal) 
 Contrast-enhanced : 
 
T1-weighted SE/TSE (axial) 
 
T1-weighted SE/TSE (sagittal) 


 
 
 
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It is not allowed to add any sequence, other than the one described above, between contrast agent 
injection and axial 3D T1-weighted GRE for brain and sagittal T1-weighted SE/TSE for spine. 
Deviations from the specified MRI procedure will be recorded in the CRF.  
Sequence parameters for brain and spine imaging will be provided in the site imaging manual. 
9.3 
On Site Reading of Images 
For each investigational site, one experienced neuroradiologist  or radiologist experienced in neuro-
imaging will be appointed at the start of the study to read all images of subjects included at the site. As 
far as possible, a second (neuro)radiologist should be identified in each site and trained to the protocol 
in case the first (neuro)radiologist is not available to read the images.  
 
9.4 
Off Site Reading of Images 
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 subject or center 
identification. For all images, any sequence information will be removed. Scalar information in the MR 
images will be preserved. A complete audit trail of any changes to the file headers will be maintained.  
The blinded image evaluations will be performed by 3 independent blinded radiologists. An 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 study purpose are documented by the independent blinded readers.  
9.4.1 
Manuals and Supplies 
Guerbet (or the imaging core laboratory) will document the imaging tasks and obligations of the 
investigational site in a site imaging manual. As defined in Section 9.2, the standardized image 
acquisition guidelines or imaging protocol will be provided to the sites as part of the site imaging 
manual. 
In addition, the site imaging manual will detail the steps required for masking confidential subject 
information and transferring images to the imaging core laboratory.  
Guerbet (or its imaging core laboratory) will document the central imaging process in a blinded image 
evaluation charter. 
9.4.2 
Site Qualification 
Guerbet’s designee (imaging core laboratory) will perform pre-study site selection and site training. 
These contacts will ensure that the protocol-stipulated imaging can be performed by the site, might be 
programmed and prepared prior to enrollment of the first subject and that the site imaging manual will 
be accurately followed by the investigator. 
The images collected from the first subject (subset 1) of each site will be used by the imaging core 
laboratory to confirm to the sites that they are in accordance with the study imaging protocol 
requirements (see section 9.4.4). Guerbet or its designee (imaging core laboratory) should confirm first 
to the investigator that the site is qualified before continuing subject’s enrolment. 


 
 
 
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9.4.3 
Receipt and Tracking of Images 
Guerbet (or 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 study start. Images will be tracked in 
the database of the imaging core laboratory. 
9.4.4 
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. Subject 
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 image parameters with the imaging protocol, poor quality images), the investigational 
site will be notified on 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 re-training for investigator sites with 
recurring image quality issues. 
9.4.5 
Independent Blinded Readers Training 
All independent off-site readers will be trained to the study reading specifications. Before the readers 
start the readings, they will have to successfully complete a serial of training sessions (refer to “blinded 
image evaluation charter” for details).  
Each reader will need to acquire an adequate understanding of definition of terms to be used in image 
evaluation and classification. To sufficiently understand different point scales used to evaluate lesions 
by reviewing training cases in order to reach an acceptable intra-reader and inter-reader variability. 
The images collected from the subjects of the subset 1 as well as images from other studies will be used 
to conduct the training of the independent blinded readers (off-site). 
The independent blinded readers (off-site) will not been trained on the study inclusion/non-inclusion 
criteria. Details on the protocol and anatomic orientation to the images will not be provided to the 
independent blinded readers. 
9.4.6 
Image Randomization 
Blinded image evaluations will be conducted per batch such that each blinded image evaluation session 
will contain an appropriate number of cases to enable completion by a reader. The subjects within each 
batch will be ordered at random without stratification into groups of subjects (when applicable). Various 
modalities of images from the same subject 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 from two 
modalities for the same subject, to minimize recall bias. Each images set will be assigned 1 
randomization number. The randomization lists for all 3 blinded image evaluation sessions will be 
created by the core laboratory. The randomization codes will be kept during the study by the imaging 
core laboratory. The access to the randomization codes will be strictly limited. Randomization codes 
will be transferred to Guerbet after database lock. 
The blinded image evaluations will be performed in parallel to the ongoing recruitment in the clinical 
trial. For the first 4 image sets (see Table 3), the image material will be ordered according to the sorted 
order of the randomization lists that are prepared prior to the blinded reading.  


 
 
 
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9.4.7 
Blinded Assessment of Images 
Imaging database including all evaluable MR images will be assessed by three independent, board-
certified and fully blinded readers, with expertise in the interpretation of MRI of the CNS diseases, who 
will not participate in the study, and do not have affiliation with any institution where the study will be 
conducted.  
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. 
The term “fully blinded” means that the readers will not have any knowledge of (i.e., will be blinded to) 
the following information: 
 
Subject-specific information (including name, identifiers, medical history, clinical examination, 
and laboratory results) 
 
Institution name 
 
Subject enrolment information (including inclusion and non-inclusion criteria) 
 
Results of any imaging examination other than the imaging examination to be read 
 
Findings of any other readers (e.g., investigators, on-site readers and other central readers) 
 
Data related to contrast medium nature and dosage 
 
Type of MRI and image sequence other than information apparent from the aspect of the images 
themselves  
 
Final diagnosis and subject outcome 
No communication on subject specific image findings will be allowed between the 3 independent 
blinded 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). 
9.4.8 
Inter & 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 study subjects, since each case will 
be read by 3 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 30 cases are reviewed and no 
sooner than two weeks from the original reviews of these subjects. 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. 
9.4.9 
Lesion tracking (not applicable for global matched-pairs reads) 
All 3 blinded readers will independently identify the location of all the lesion(s) detected in the image 
sets. The location for each lesion will be marked along with a number in ascending order on a CNS 
diagram 
  
To allow exact matching of lesions throughout the different imaging sequences examinations, an 
independent radiologist (lesion tracker) will perform the ‘lesion tracking’ based only on the available 
CNS diagrams for a given subject. All CNS diagrams for each subject will be displayed simultaneously.  


 
 
 
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Because a unique numbering of the lesions cannot be ensured during the blinded image evaluations by 3 
readers, the lesion tracker will assign a new number for each lesion to be tracked, which will then be 
matched and correlated to the numbers indicated on the CNS diagrams.  
The independent lesion tracker will not obtain any information about the contrast medium used for the 
enhanced MRI. 
9.4.10 Image Warehouse 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 study. Measurements will also be stored so that these data may be audited if 
necessary. The resulting database will be transferred to Guerbet after database lock for archiving. 
The CDs/DVDs produced to record the ROIs (for off-site read only) are to be used for SI measurements 
and will be given to Guerbet at the end of the study once the off-site readers would have completed all 
the images reads. 
9.5 
Other Centralized Study Procedures  
9.5.1 
Clinical laboratory parameters 
A central laboratory will be used for all scheduled laboratory tests in this study except for the pregnancy 
test which will be done locally and eGFR which will be assessed locally and centrally. The investigator 
will be provided with a list of normal ranges prior to the start of the study. The central laboratory will 
provide the necessary kits to collect the blood samples and will also provide appropriate information 
regarding shipping of the samples.  
Care should be taken during blood sampling in order to avoid potential generation of false positive 
blood value (e.g., by inappropriate use of the tourniquet or forceful withdrawal of blood). Each original 
laboratory report will be filled with the subject’s source document.  
All laboratory reports must be promptly reviewed by the Investigator, and upon review, initialed and 
dated by the Investigator. Change(s) in post-dose test values considered clinically significant, which 
would require either additional control or therapy, must be documented in the subject’s source 
document and, in case of disturbing or influencing factor(s) on values/samples, details of the appropriate 
value(s) and the source of disturbance or influence (e.g. quality of sample, co-treatment etc.) are to be 
recorded. All values considered clinically significant will be reported as AEs. 
Laboratory samples obtained for this study will be used only for this study. Samples obtained in this study 
will not be retained or used for any other purposes.  
9.5.2 
Centralized assessment of ECG 
The 12-lead ECGs will be sent to the ECG core laboratory continuously during the course of the study 
for evaluation by an independent cardiologist. The following parameters will be evaluated for individual 
subjects and time points:  
 
RR interval and heart rate  
 
Intervals: PR, QRS, QT [plus calculated QTc (Fridericia and Bazett methods)]  
 
ST segments, T-wave morphology, U-wave 
 
Global morphology 


 
 
 
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The QTc is the heart rate corrected QT interval (calculation according to Fridericia and Bazett method).  
The ECG core laboratory will record whether the cardiologist is unable to evaluate the ECG. A 
comment field will be provided for the cardiologist to indicate factors that effected the interpretation; 
e.g. lead reversal.  
All ECGs changes considered as abnormal and clinically significant will be reported as AEs. 
For ECGs a notable QTc change is defined as a QTc (Fridericia’s or Bazett’s) interval of greater than 
450 ms for males and females – all such ECGs will be flagged by the core laboratory’s cardiologist and 
require assessment for clinical relevance by the Investigator. 


 
 
 
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10 SAFETY REPORTING 
10.1 Adverse Event 
10.1.1  Definition of Adverse Event 
An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment.  
An adverse event (AE) can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.  
Any disease identified and diagnosed by study contrast-enhanced MRI will not be considered as AE.  
10.1.2 Recording/Collection of Adverse Events 
The Investigator or his/her designee will invite the subject to report any experienced abnormality as part 
of the usual clinical follow-up. 
All Adverse Events, whether considered as related or not to the Investigational Medicinal Product 
and/or the imaging procedure should be reported in the medical file and the eCRF and monitored from 
onset to resolution or stabilization of sequelae. If no follow-up is performed, the investigator must 
provide a justification in the medical file. 
In order to ensure complete safety data collection, all Adverse Events occurring during the time of the 
subject’s participation in the study, must be reported and monitored even if no IMP was administered. 
The investigator shall document all Adverse Events in the medical file and the appropriate section of the 
eCRF. 
As a reminder the subject’s participation is defined as the period from the screening visit (ICF 
signature) to the last study visit and defined in Section 11 in case of premature discontinuation. 
Safety information is to be collected by the investigator with the same procedure as Adverse Events: 
treatment errors and uses outside what is foreseen in the protocol, including misuse and abuse of the 
product, suspicion of transmission of an infectious agent via an IMP, overdose (symptomatic or not), all 
reports of pregnant or breastfeeding women exposure even if uneventful, all reports of suspected drug-
drug interaction with another product (symptomatic or not). 
As an exception, as the study aims to assess the effective dose of P03277, doses with lesser efficacy are 
expected and will be considered while analyzing the primary endpoint. 
In this protocol, the overdose is defined as more than 0.3 mmol/kg for P03277 and more than 0.2 
mmol/kg for MultiHance®. Any overdose, with or without adverse event, will be reported as AE and, in 
addition, on SAE form if the associated event is serious. 
10.1.3 Description of Adverse Events 
The following guidelines and definitions should be used by the investigator for the description of an AE 
when reporting information: 
 
Nature of AE: preferably an overall diagnosis or syndrome, rather than individual symptoms or 
signs. The investigator must report AE using standard medical terminology. The same terms 
should be used in the source documentation and in the eCRF. 


 
 
 
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 
Date and time of onset: date and clock time of the AE start. 
 
Intensity: 
o Mild: the subject 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 subject or it is 
of some clinical consequence. 
o Severe: the subject 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): The real date of event end will be entered if the 
event has come to its end on the date of end of subject’s follow-up. If the AE is still ongoing by 
the time of end of study follow-up for the subject (i.e. last study visit), the subject should be 
followed-up until AE resolution or a justification should be provided by the Investigator (i.e. 
chronic disease) in the medical file. 
 
Causal relationship to the Investigational Medicinal Product: 
o Related: the definition of adverse reaction 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 study 
drug and the event, but an obvious alternative cause exists (e.g. the subject’s 
underlying medical condition or concomitant therapy). 
 
Causal relationship to a study procedure – apart from imaging procedure: 
o Related. 
o Not related. 
 
Outcome: 
o Recovered/Resolved: the AE is no longer present at any intensity. 
o Recovered/Resolved with sequelae: the AE is resolved but residual effects are 
still present. 
o Not Recovered/Not Resolved: the AE is still present at the last contact with the 
subject. 
o Fatal: this AE caused or directly contributed to subject’s death. 
 
Action taken with regard to administration of the IMP: 
o No action: for AE occurring during the pre-treatment/procedure or post-
treatment/procedure period, or if the Investigational Medicinal Product 
dosing/administration remained the same in spite of AE being present. 
o Action taken :  
 Study treatment unblinding 
 IMP definitively stopped: IMP was permanently discontinued. 
 
Other action taken: 
o AE-targeted treatment: the subject took a treatment (either prescription or non-
prescription) specifically for this AE. The drug(s) should be reported in the 
appropriate section of the eCRF (“concomitant drug” section) 
o Other AE-targeted action: subject used other therapeutic measures (e.g. ice, 
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additional laboratory test…) for this AE. The therapeutic measure(s) should be 
reported in the appropriate section of the eCRF.  
 
Assessment of the seriousness of the AE: see Section 10.2 for SAE definition. 
 
10.2 Serious Adverse Event 
10.2.1 Definition of Serious Adverse Event 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose:  
- Results in death 
- Is life-threatening 
- Requires hospitalization or prolongation of hospitalization 
- Results in persistent or significant disability or incapacity 
- Is a congenital anomaly or birth defect 
- Is medically important: adverse events that are not immediately life-threatening or do 
not result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above, should 
also be considered serious. 
Life-threatening in the definition of a serious adverse event refers to an event in which the subject was 
at risk of death at the time of event; it does not refer to an event which hypothetically might have caused 
death if it were more severe. 
Medical judgment should be exercised in deciding whether an adverse event/reaction is serious in other 
situations. In case of a SAE, the investigator is responsible for the measures to be taken to ensure the 
safety of the study participants. 
The following safety issues qualify for immediate reporting to Guerbet since they may alter the current 
benefit-risk assessment of an investigational medicinal product, or would be sufficient to consider 
changes in the study drug administration or in the overall conduct of the study:  
- Any post-study related adverse event that occurs after the subject has completed the 
study and that is considered as related to the Investigational Medicinal Product by the 
investigator (causality not excluded). 
- Any new event likely to affect the safety of the subjects and that may be related to the 
conduct of the study or the development of the study drug such as:  
o 
A SAE which could be associated with the study procedures and which could 
modify the conduct of the study 
o 
A significant hazard such as an unusual failure in efficacy. 
o 
A new finding from a newly completed animal study. 


 
 
 
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Severe / Serious: the term “severe” is often used to describe the intensity (severity) of a specific event 
(within the scale mild, moderate, severe). The event itself, however, may be of relatively minor medical 
significance. This is not the same as “serious”, which is based on subject/event outcome or action 
criteria. 
In this protocol, the following situations will not be considered as SAE, providing that they are clearly 
documented as such in the subject’s source data:  
- Any hospitalization that had been planned before the study and that will take place 
during the study, 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 checkup). 
10.2.2 Procedure for Reporting Serious Adverse Events 
SAEs occurring from ICF signature until completion of the study for each subject are to be reported to 
Guerbet Pharmacovigilance department. 
The investigator must immediately and within 24 hours forward to Guerbet Pharmacovigilance 
department a duly completed SAE report form provided by Guerbet with study documents, even if it is 
obvious that more data will be needed in order to draw any conclusion: 
- By Fax #: + 33 (0)1 45 91 67 70 
or  
- by e-mail to: pharmacovigilance.headquarters@guerbet-group.com 
In case of emergency, Guerbet Pharmacovigilance department may be contacted at:  
+ 33 (0)1 45 91 50 00. 
Additional information (e.g., autopsy, lab reports…) may be required by Guerbet in a timely fashion to 
ensure accurate follow-up and assessment of each case and should be forwarded, anonymized, with a 
new form specifying basic information (follow-up number, subject details and number, adverse event, 
study product, causal relationship) and the new information. 
The initial and follow-up reports shall identify the study subject by his/her identification (subject ID) 
number assigned for the purpose of the study. 
In order to allow the assessment and eventual subsequent regulatory reporting of the case, the following 
minimum information should be filled in:  
- Subject’s details including age, sex and subject’s study enrolment number 
- Subject’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 first notification) 
- Name of the investigational drug or procedure, date and time of administration, dose 
and volume administered 
- Causal relationship to the investigational drug or procedure (mandatory) 
- Outcome at the time of reporting 
Any event leading to a SAE report should be reported in the medical file and in the adverse event 
section of the eCRF as requested in Section 10.1.2 


 
 
 
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SAEs should be followed up by the investigators until complete recovery of the subject or, if not 
possible, until stabilization of sequelae. The investigator may be requested by Guerbet to provide 
follow-up information in order to comply with current regulations as well as for comprehensive 
assessment purposes. 
SAEs associated with study procedures are to be notified using the same reporting procedure as 
described above. 
In addition, if occurring after the end of the subject’s follow-up period defined for this study (i.e. within 
1 day post second IMP administration), serious adverse and/or unexpected events that the Investigator 
thinks may be associated with the study treatment/procedure must be reported to Guerbet regardless of 
the time between the event and the end of the study.  
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, if applicable. 
 
10.3 Pregnancy and Adverse Events of Special Interest 
In addition to the above AEs, the special situations described below should be handled with the same 
procedure as the SAE reporting procedure.  
10.3.1 Pregnancy 
Any pregnancy (with or without an AE of women participating in the study and partners of men 
participating in the study) that occurs during the study and up to 7 days post visit 4 must be reported to 
Guerbet via the SAE report form.  
Any participating subject who becomes aware of a pregnancy (subject’s or subject’s partner) during 
study participation should inform immediately the investigational site. The female subject should be 
immediately withdrawn from IMP administration. 
Pregnancy will be monitored until completion or termination. If the pregnancy continues to term, the 
outcome (health of infant up to 8 weeks of age) will be reported to Guerbet using specific forms 
“history and start of pregnancy” and “course and outcome of pregnancy” that will be provided to the 
investigational sites. Any complication of pregnancy will be reported as an AE or SAE, as appropriate.  
 
10.3.2 Adverse Events of Special Interest 
An Adverse Event of Special Interest (AESI) is an AE designated by Guerbet for transmission to 
Pharmacovigilance in the same time frame as an SAE. 
The AESI for this protocol is the following: Nephrogenic Systemic Fibrosis (NSF). 
Also, any suspicion of transmission of an infectious agent via an IMP should be considered as a serious 
and processed as an SAE. 
In addition, any adverse reaction resulting from an occupational exposure (i.e. exposition to IMP of an 
investigating site staff member) may be directly reported to Guerbet. 
 


 
 
 
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10.4 Unblinding Procedures 
The investigator may, under exceptional circumstances unblind the individual study treatment group if 
he/she considers that this procedure is relevant to the safety of the study subject. Individual study 
treatment unblinding is described in Section 5.3.3. Unblinding must be documented in the subject 
medical file, completed in the SAE form 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 personnel responsible for study management, data analysis, 
and interpretation of results at the study’s conclusion. 


 
 
 
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11 PREMATURE DISCONTINUATION OF THE STUDY 
11.1 Premature Discontinuation of the Study per Guerbet Decision 
Guerbet reserves the right to discontinue the study at any time for medical, administrative or other 
reasons. 
Guerbet will inform the relevant authorities in each country, the ethics committees, the study site 
investigators, pharmacists, if applicable and hospital authorities according to the regulatory texts in 
force. 
 
11.2 End of Study Participation for a Subject 
Screening failures: Subjects who signed the informed consent form and discontinue before Visit 2 (first 
contrast agent injection and MRI procedures) will be considered screening failures. 
If a subject discontinues before Visit 2, the IWRS must be notified and only the reason for being 
screening failure will be documented on the source document and in the eCRF (see section 15.3.2) 
Criteria for premature discontinuation of subjects: 
- Adverse Event (according to the investigator’s judgment); 
- Withdrawal of subject’s consent; 
- Subject lost to follow-up (date of last contact will be documented in the medical file and 
the eCRF). Any effort will be undertaken to know the reason for this loss to follow-up 
and/or to exclude any adverse reaction as this reason. This will be documented in the 
medical file; 
- Any treatment or medical procedure (e.g. chemotherapy, radiotherapy, biopsy or 
surgery  etc…) between the two MRIs; 
- At the discretion of the investigator if, for example,  the subject safety or well-being is 
not compatible with study continuation; 
Specific subjects study stopping rules: 
If any of the events described below occur, injection of IMPs should not be done and the subject should 
be discontinued from the study:  
- Renal toxicity characterized by an increase in serum creatinine by more than 25% or 0.5 
mg/dl (44 µmol/l) and/or an increase in serum cystatin C by more than 25%  compared 
to the baseline value 
- QTc Bazett or QTc Fridericia >500 ms or an increase of > 60 ms over baseline 
- Any events which investigator or Guerbet considers raising a significant concern 
The data to be reported in the eCRF for subjects subsequently discontinuing from the study are detailed 
in the protocol section 15.3.2. 


 
 
 
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For subjects withdrawn from the study, all data available at the time of withdrawal will be reported in 
the medical file and the eCRF (e.g.: inclusion data, safety data, administration data, imaging data, 
reason for withdrawal…). The investigator must make every effort to collect and record all follow-up 
safety information (i.e., AEs and injection-site tolerance, as appropriate), unless the subject withdraws 
consent for further data collection/participation for/in the study. 
Enrollment of additional subjects:  
There is no replacement scheduled for subjects withdrawn prematurely. However, if the number of 
subject prematurely withdrawn is higher than expected the sample size will be increased to ensure a 
number of evaluable subjects equal to 50 for each study group. 
Management care of discontinued subject: 
In the event of premature discontinuation, subjects will receive adequate follow-up from on-site 
investigators; other diagnostic products available will be introduced if necessary.  


 
 
 
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12 STATISTICAL ANALYSIS 
The following section summarizes the statistical analysis method, which will be fully described in the 
Statistical Analysis Plan. 
12.1 Subjects Included in the Analysis 
There will be four subject sets defined for this study: the Extended Set (ES), the Safety Set (SS), the 
Full Analysis Set (FAS) and the Per-Protocol Set (PPS). 
The Extended Set will include all subjects with available data. This set will be used for subject 
disposition summaries and individual listings. 
The Safety Set will include all subjects, receiving at least one injection of contrast agent, regardless of 
the quantity. Subjects of subset 1 will be included in this set. This set will be used for evaluation of 
safety. 
The Full Analysis Set will include all subjects, except subjects from subset 1, who have valid 
assessments of the primary criterion. This set will be used for description of demographic data, baseline 
characteristics data, medical history, concomitant treatment and evaluation of efficacy.  
The Per Protocol Set will be a subset of the FAS and will include all subjects who have no major 
protocol deviations throughout their whole study period. This set will be used for the evaluation of the 
primary efficacy criterion. 
If the PP set differs from the FAS by more than 15%, description of demographic data, medical history, 
concomitant treatment and evaluation of efficacy will be repeated for this set. 
 
12.2 Demographic and Baseline Data 
Demographic parameters are age, gender, ethnic origin, childbearing potential, body weight, height, and 
body mass index (BMI). Baseline characteristics are the subject's history (including the medical history, 
the clinical indication for MRI and the presence or absence of brain metastasis) 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 
gender, subjects' history characteristics and concomitant treatments.  
Subject's medical history will be coded using the MedDRA dictionary and tabulated by body system, 
preferred term and status (concomitant or not). 
Subject's concomitant treatments will be coded using the Anatomical Therapeutic Chemical (ATC) 
Drug dictionary and tabulated by ATC code. 
 
12.3 Efficacy Data/ Dose selection 
In this section, treatment groups refer to doses of P03277 (0.025, 0.05, 0.1 and 0.2) and matching 
MultiHance® administration (i.e. P03277 0.025 mmol/kg versus matching dose of MultiHance® 0.1 
mmol/kg; P03277 0.05 mmol/kg versus matching dose of MultiHance® 0.1 mmol/kg; P03277 0.1 


 
 
 
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mmol/kg versus matching dose of MultiHance® 0.1 mmol/kg and P03277 0.2 mmol/kg versus matching 
dose of MultiHance® 0.1 mmol/kg) 
Primary analysis of the primary criterion 
The primary objective of the study is to determine a safe and effective dose of P03277 based on a 
comparison of Contrast to Noise Ratio (CNR) between several doses, 0.025, 0.05, 0.1, 0.2 mmol/kg, of 
P03277 and MultiHance® at 0.1 mmol/kg. 
The primary criterion is the Contrast to Noise Ratio (CNR) calculated from the Signal Intensity (SI) 
measurement of maximum 3 enhanced lesions by the 3 independent blinded readers (see section 7.1) 
The primary analysis will test differences of means of primary criterion for each dose of P03277 
compared to MultiHance® and will be done for each of the 3 independent blinded readers (off-site) 
using the PPS. Holm’s step-down method will be used to address multiplicity testing considering the 4 
treatment groups to be tested. 
Statistical hypothesis for the primary analysis: 
For each reader and each treatment group, a covariance analysis for correlated data will be done for 
assessing the primary criterion. Factors include in the model are treatment (P03277 and MultiHance®) 
and the pre CNR measurement for unenhanced lesions (baseline). 
Differences between means will be tested for each treatment group using Student’s t-test according to 
the following items: 
- 
µi is the expected average of CNR of enhanced lesions for each dose of P03277 (where i is 
corresponding to one dose of P03277) 
- 
µ0 is the expected average of CNR of enhanced lesions for corresponding MultiHance® dose 
 
Null hypothesis 
Hi: µi - µ0 ≤ 0, i = 1…4  
Alternative hypothesis 
Ki: µi - µ0 > 0, i = 1…4 
For each treatment group, the p-value for comparing the doses of P03277 with corresponding 
MultiHance® is calculated for testing above hypotheses.  
Holm’s step-down method:  
Let p1, p2, p3, p4 be the ordered p-values (from the lower to the upper value) and H1, H2, H3, H4 be 
the corresponding ordered null hypothesis. The testing procedure starts with the most significant 
comparison and continues as long as tests are significant (meaning that the alternative statistics is met). 
The procedure stops the first time a non-significant comparison occurs and all remaining hypotheses 
will be not tested. 
In the first step, H1 is rejected if p1 ≤ α/4, in the second step (if any) H2 is rejected if p2≤ α/3, in the 
third step (if any), H3 is rejected if p3≤ α/2 and in the fourth and last step, H4 is rejected if p4≤ α, with α 
being the 1-sided significance level of 0.025. 


 
 
 
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Selection basis for clinical dose: 
The effective clinical P03277 doses will be the doses for which at least 2 out of the 3 off-site blinded 
readers meet the alternative hypothesis for the primary endpoint.  
If more than one effective clinical dose is identified based on the primary statistical analysis described 
above, then the clinical target dose will be selected  according to the clinical benefice/risk ratio for each 
of them including the efficacy secondary criteria analyzed in this study. 
Secondary analyses of the primary criterion 
o 
FAS analysis 
- 
The primary analysis will be repeated using the FAS. 
 
o 
Overall analysis 
- 
The primary analysis will be repeated by pooling together all off-site readers 
using the FAS and the PPS. 
 
o 
Centre Effect 
- 
By-site summaries will be produced to look for potential disparities among the 
sites (center effect) using the FAS and the PPS. The p-values will not be 
reported for the by-site summaries. 
 
o 
Dose/response evaluation 
- 
The relationship between doses of P03277 and response will be evaluated 
graphically based on mean profile during the study using the FAS and the PPS. 
- 
Depending on the graphical results, a more complex model including doses of 
P03277 (as continuous variable) could be fitted to evaluate the relationship 
between doses and CNR increase. 
 
Analyses of the secondary criteria  
All analyses of the secondary criteria (based on combined unenhanced/enhanced contrast images) will 
be done using the FAS except otherwise specified. 
 
o 
Technical adequacy of images 
- The adequacy of images will be assessed by off-site readers and on-site radiologists as 
adequate, yes or no and reason for inadequacy will be recorded using a 5-items list. 
Adequacy of images will be tabulated for each dose of P03277 by treatment groups; off-
site and on-site reader’s outcomes will be separately analyzed. 


 
 
 
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o 
Lesion visualization variables 
- Off-site blinded readers and on-site radiologists will grade the lesion visualization of the 
three largest representative lesions, using 3 variables (lesion border delineation, internal 
morphology and degree of contrast enhancement) assessed on a 4-point scale ranging 
from 1 to 4. 
For each variable, one subject score will be computed in adding up all lesion scores 
within subject by treatment groups. 
Subject score will be tabulated for each dose of P03277 by treatment groups; each off-
site and on-site reader’s outcomes will be separately analyzed. 
- Dose/response evaluation as per primary endpoint will be performed also for the subject 
score of each lesion visualization variable by each off-site reader. 
o 
Lesion detection capacity 
- The number of lesions by subject will be assessed by off-site readers and on-site 
radiologists for each dose of P03277 by treatment groups. Number of lesions will be 
tabulated for each dose of P03277 by treatment groups; off-site and on-site reader’s 
outcomes will be separately analyzed.  
- The size of the three largest representative lesions by subject will be assessed by off-site 
readers and on-site radiologists for each dose of P03277 by treatment groups. Size of 
lesion will be summarized for each dose of P03277 by treatment groups; off-site and 
on-site reader’s outcomes will be separately analyzed. 
- The localization of the three largest representative lesions by subject will be assessed by 
off-site readers and on–site radiologists for each dose of P03277 by treatment groups. 
Localization of lesion will be displayed for each dose of P03277 by treatment groups; 
off-site and on-site reader’s outcomes will be separately analyzed. 
- 
The presence or absence of contrast enhancement for the three largest representative 
lesions will be assessed by off-site readers and on-site radiologists for each dose of 
P03277 by treatment groups. Contrast enhancement of lesion will be displayed for each 
dose of P03277 by treatment groups; each off-site and on-site reader’s outcomes will be 
separately analyzed. 
o 
Diagnostic confidence 
- 
The diagnosis of each lesion according to off-site readers and on-site radiologists when 
evaluating each dose of P03277 by treatment groups will be displayed; off-site and on-
site reader’s outcomes will be separately analyzed. 
- 
The level of diagnostic confidence of off-site readers and on-site radiologists when 
evaluating each dose of P03277 by treatment groups will be graded using a 5-point 
scale with the following points: nil, poor, moderate, high and excellent. Diagnostic 
confidence will be tabulated for each dose of P03277 by treatment groups; off-site and 
on-site reader’s outcomes will be separately analyzed. 
o 
Overall diagnostic preference 
- 
The level of overall diagnostic preference of images of off-site readers when evaluating 
in global matched-pairs fashion all post contrast T1-weighted images (i.e. axial 3D T1 




 
 
 
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Events will be classified as treatment-emergent if they started or increased in severity during period 2 or 
period 3. This will also include events with missing intensity if the end time is after induction or 
missing.  
Partial start dates/times will be queried. If information is not available to reliably allocate to a session 
and period, the allocation will be agreed at the data review meeting before database lock. If there is any 
doubt about treatment emergence, AEs will be classified as treatment emergent. 
In all summaries, recurring AEs (AEs classified with the same preferred term) for a given subject in a 
given period will be counted as a single AE. If severity is summarized, this will be the maximum 
severity. 
Overall overview  
The number (%) of subjects having at least one Treatment Emergent AE (TEAE) as follows will be 
summarized for the combined periods 2 and 3 and for each period separately for: 
 
At least one TEAE 
 
At least one adverse reaction (relationship to study treatment classified as ‘Related’) 
 
At least one TEAE with each of the following classifications of action taken with study 
treatment: 
o Dose not changed 
o IMP withdrawn 
 
At least one TEAE with each of the following classifications of outcome: 
o Recovered/resolved 
o Recovered/resolved with sequelae 
o Not recovered/Not resolved 
o Fatal 
 
The table will show the same information for serious AE, defined as AEs with serious classified as ‘yes’ 
or missing. 
The table will be repeated for all AEs (periods 1 to 3 combined). 
Distribution of AEs and SAEs 
A table will be presented showing the total numbers of AEs and SAEs and the distribution of AEs 
(number [%] of subjects with 0, 1, 2 etc… AEs) for the combined periods 2 and 3 and for each period 
separately. The table will also show the same information for SAEs defined as TEAEs with serious 
classified as ‘yes’ or missing, unless the number of SAEs make this uninformative. 
Summaries by System Organ Classes (SOC) and Preferred Term (PT)  
Summaries by SOC and PT will be presented for treatment-emergent events for the combined periods 2 
to 3 and for each period separately for: 
 
At least one TEAE  
 
At least one of the most common TEAEs (PT occurring in at least 10% of subjects on P03277 
0.2 mg) 
 
At least one TEAE by most severe intensity ( i.e. classified as ‘severe’) 
The table of summaries of at least one TEAE will be repeated by SOC only (without the breakdown by 
PT).  


 
 
 
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 Injection site tolerance  
Number of subjects experiencing burning, pain, eruption, extravasation and inflammation at site 
injection will be tabulated. Pain at injection site will be measured using the Visual Assessment Scale 
(VAS) and VAS measurements for these subjects will be tabulated. 
Laboratory data 
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. 
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. 
Vital signs 
Vital signs will be analyzed quantitatively and qualitatively. Qualitative analyses will be done via 
comparison of vital signs data to their normal ranges (see section 7.2.8) and according to their clinical 
significant changes. Quantitative analyses will be done by tabulating raw data and change from 
baseline. 
ECG 
ECG data will be analyzed quantitatively and qualitatively. Qualitative analyses will be done via 
comparison of ECG data to their normal ranges and according to their clinical significant changes. 
Notable QTc value will be presented for raw data and changes (see section 7.2.8). Quantitative analyses 
will be done by tabulating raw data and change from baseline. 
 
12.5 Handling of Missing Data 
No imputation will be performed in this study. 
 
12.6 Interim Analysis 
Not applicable. 
 


 
 
 
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13 STUDY COMMITTEE 
The purpose of this phase IIb study is primarily to determine an effective and safe dose of P03277 
injection, by comparing with GBCA approved for CNS indication.  
The IMPs used, in this study, as contrast agents belong to a well-known product class (GBCA) and there 
is, a priori, no particular expected safety concerns. In addition, the P03277 has a linear pharmacokinetic 
profile similar to the other Gd chelates and the preliminary results obtained during the phase I study 
with several doses of P03277 showed no clinical and biological alert signal.  
The study duration per subject is short (maximum 22 days), the IMPs are injected only once at 2 
different visits and the P03277 doses selected for the current study are within the range of those tested 
during the phase I study for which no safety alert was identified. 
Specific subjects study stopping rules have been set up in the study protocol (see section 11.2) and 
check points (see Study Flow Chart) are done before performing the second MRI. 
For all these reasons, an IDMC (Independent Data Monitoring Committee) has not been established for 
the study. 
However, a Data Safety Monitoring Board (DSMB) will be set up for assessing the safety of the 
Investigational Medicinal Product (IMP) during the study and for monitoring the overall conduct of the 
clinical trial as well as ensuring that the subjects stopping rules for safety reasons are applied when 
required.  
The DSMB members will be: the international coordinator and Guerbet team (drug safety physician, 
Medical Expert, clinical project manager and ad-hoc team members). All the members will remain 
blinded regarding all the study data. The role and responsibilities of this DSMB will be described in a 
separate document (Data Safety Monitoring Plan). 
 


 
 
 
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14 ETHICAL AND REGULATORY CONSIDERATIONS 
14.1 References 
The study 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: Guideline for Good Clinical Practice E6 (R1) Current Step 
4 version dated 10 June 1996 
- 
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 
- 
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 
- 
Regional / local regulations  
 


 
 
 
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14.2 Institutional Review Board/Independent Ethics Committee and Regulatory/Competent 
Authorities 
As per international regulation, the clinical study may be initiated only after having received the 
approval by an 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 study conduct at this 
particular site. Amongst all documents required locally, the approval and authorization must be obtained 
for the protocol, investigator’s brochure, the subject informed consent form and any other written 
information or document to be provided to the subjects. 
In case of modifications to the study protocol, subject informed consent form or any other written 
information provided to the subjects, or to any study 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 subjects’ 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 Study Master File at 
Guerbet and at the investigational sites in their respective Investigator Site File (ISF). 
Notifications 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 10 of the 
present protocol. 
 
14.3 Subject Informed Consent 
Prior to participation, all subjects must confirm their free and voluntary willingness to participate in the 
study. This confirmation is obtained in writing after having received a full oral and written explanation 
on the study: 
- 
Aims, methodology and duration of the study; 
- 
Potential benefits, foreseeable risks and inconveniencies related to the study; 
- 
Rights and responsibilities of subjects, with particular emphasis on the right to refuse study 
participation or to withdraw consent to participation at any time without consequences or 
penalties; 
- 
Information on IMP and its administration; 
- 
Contact details of persons dedicated to the study at the investigational site. 
The language used when informing the subjects and answering their questions must be as 
understandable as possible and shall not induce any misunderstanding or feeling to be influenced to 
participate. Subjects must be given ample time to decide whether they agree to participate or not. 
Subjects 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. 


 
 
 
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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 subject consented freely and voluntarily, 
according to local regulation. 
The information of subjects may only be conducted by qualified investigational site personnel, whose 
involvement and responsibility for subject 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 subject informed consent form or of any other document to be provided 
to the subjects and approved by the Sponsor, the IRB/IEC approval must be obtained prior to 
implementing the new document(s). Subjects 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. 
 
14.4 Study Records and Archiving 
During the course of the clinical study, investigational sites must ensure completeness and accuracy of 
the study records that are to be filed in the 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 or Monitor). The final check will occur at the close out visit when investigational 
site participation is over. 
At the end of the study, 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 study completion. Guerbet will notify the investigational sites in writing when study 
documents are no longer needed for retention. 


 
 
 
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15 QUALITY CONTROL / QUALITY ASSURANCE 
15.1 Direct Access to Source Data/Documents 
The investigator will allow Guerbet representatives, the persons responsible for audit conduct, 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 study 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 subject 
data before collection by Guerbet. Especially the name and address of the subjects will not be captured 
by any medium such as document for biological results, digital supports, ECG tracings etc... 
For this study, the following will be considered as source data (as a minimum): subjects medical files, 
images.  
If computerised medical files are used, the investigator must: 
- 
At the start of the study, print, sign and date all the medical files of all subjects,  
- 
During the study, print, sign and date in real time each data entry and each data change, 
- 
In case printing of files is not possible, the computerized system must be validated and 
access should be granted to Guerbet or its representative. 
 
15.2 Clinical Monitoring 
Before the study is conducted at a given investigational site and until the study is completed/ terminated 
at the same given investigational site, Guerbet will mandate a representative to perform a close 
monitoring of the study conduct that will ensure that the investigational site is properly equipped; the 
staff is adequately experienced and knowledgeable of regulatory and ethical requirements. 
The representative will perform regular investigational site visits and report all discussions, subject and 
IMP data verification performed with particular attention to subjects’ safety, well-being and study data 
accuracy and completeness. 
A representative in charge of monitoring of blinded data and another one in charge of unblinded data 
review will be involved in the clinical monitoring of the study. 
 
15.3 Clinical Data Handling 
15.3.1 Data Reported in the eCRF 
The eCRF will allow recording of the data required by the protocol. 
The investigator or the designated person from his/her team agrees to complete the eCRF, at each 
subject visit, and all other documents provided by Guerbet (e.g.; documents relating to the IMP 
management) and to reply to any raised data clarifications in a timely manner. 
The investigator must attest: 
- 
The authenticity of the data collected in the eCRF;  


 
 
 
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- 
The consistence between the data in the eCRF and those in the source documents 
15.3.2 Data Reported in the eCRF according to Subject Status  
For screening failure, only the date of visit, date of informed consent signature, demographic data, the 
adverse event and the reason for non-selection will be reported. 
For included subjects, withdrawn before the administration of the IMP, only the selection data, the 
safety data and the reason for withdrawal will be reported. 
For subjects withdrawn from the study after the administration of the IMP, all data available at the time 
of withdrawal will be reported in the medical file and the eCRF (e.g.: inclusion data, safety data, 
administration data, imaging data, reason for withdrawal…). 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 subject withdraws consent for further data collection/participation for/in the 
study. 
15.3.3 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. 
 
15.4 Audits and Inspections 
At any time during the study 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 
study 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 study conduct Regulatory/Competent/ 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 study material, 
- 
To meet all members of his/her team involved in the study, 
- 
To have direct access to study data and source documents, 
- 
To consult all of the documents relevant to the study. 


 
 
 
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17 REFERENCES 
 
1. 
Rohrer M, Bauer H, Mintorovitch J, et al. Comparison of magnetic properties of MRI contrast 
media solutions at different magnetic field strengths. Invest Radiol 2005;40:715–24. 
2. 
Cavagna FM, Maggioni F, Castelli PM, et al. Gadolinium chelates with weak binding to serum 
proteins: a new class of high-efficiency, general purpose contrast agents for magnetic resonance 
imaging. Invest Radiol 1997;32:780–96. 
3. 
Giesel FL, von Tengg-Kobligk H, Wilkinson ID, et al. Influence of human serum albumin on 
longitudinal and transverse relaxation rates (R1 and R2) of magnetic resonance contrast agents. 
Invest Radiol 2006;41:222–28. 
4. 
Pintaske J, Martirosian P, Graf H, et al. Relaxivity of gadopentetate dimeglumine (Magnevist), 
gadobutrol (Gadavist), and gadobenate dimeglumine (MultiHance®) in human blood plasma at 
0.2, 1.5, and 3 Tesla. Invest Radiol 2006;41:213–21, Erratum in Invest Radiol 2006; 41:859 
5. 
Goyen M Gadofosveset-enhanced magnetic resonance angiography. Vasc Health Risk Manag 
2008; 4:1–9. 
6. 
Yuh WT, Engelken JD, Muhonen MG, et al. Experience with high-dose gadolinium MR 
imaging in the evaluation of brain metastases. AJNR Am J Neuroradiol 1992;13:335–345. 
7. 
Yuh WT, Fisher DJ, Engelken JDet al. MR evaluation of CNS tumors: dose comparison study 
with gadopentetate dimeglumine and gadoteridol. Radiology 1991;180:485–491. 
8. 
Haustein J, Laniado M, Niendorf HP, et al. Triple-dose versus standard-dose gadopentetate 
dimeglumine: a randomized study in 199 patients. Radiology 1993; 186:855–860. 
9. 
Yuh WT, Fisher DJ, Runge VM, et al Phase III multicenter trial of high-dose gadoteridol in MR 
evaluation of brain metastases. AJNR Am J Neuroradiol 1994; 15:1037–1051. 
10. 
Runge VM, Kirsch JE, Burke VJ, et al. High-dose gadoteridol in MR imaging of intracranial 
neoplasms. J Magn Reson Imaging 1992; 2:9–18. 
11. 
Sze G, Johnson C, Kawamura Y, et al. Comparison of single and triple-dose contrast material in 
the MR screening of brain metastases. AJNR Am J Neuroradiol 1998 :19:821–828. 
12. 
Schneider G, Kirchin MA, Pirovano G, et al. Gadobenate dimeglumine-enhanced magnetic 
resonance imaging of intracranial metastases: effect of dose on lesion detection and delineation. 
J Magn Reson Imaging 2001;14:525–539. 
13. 
Broome DR, Girguis MS, Baron PW, et al. Gadodiamide-associated nephrogenic systemic 
fibrosis: why radiologists should be concerned. AJR Am J Roentgenol 2007; 188:586–592. 
14. 
Sadowski EA, Bennett LK, Chan MR, et al.) Nephrogenic systemic fibrosis: risk factors and 
incidence estimation. Radiology 2007: 243:148–157. 
15. 
Kanal E, Broome DR, Martin DR, et al. Response to the FDA’s May 23, 2007, nephrogenic 
systemic fibrosis update. Radiology 2008; 246:11–14. 
16. 
White GW; Gbibby WA ; Tweedle MF. Comparison of Gd(DTPA-BMA) (Omniscan) versus 
Gd(HP-DO3A) (ProHance) relative to gadolinium retention in human bone tissue by inductively 
coupled plasma mass spectroscopy. Invest Radiol. 2006;41:272-278. 
17. 
Xia D, Davis RL, Crawford JA et al. Gadolinium released from MR contrast agents is deposited 
in brain tumors: in situ demonstration using scanning electron microscopy with energy 
dispersive x-ray spectroscopy. Acta Radiol 2010; 51:1126-1136. 
18. 
Kanda T, Ishii K, Kawaguchi H, et. al., High Signal Intensity in the Dentate Nucleus and 
Globus Pallidus on Unenhanced T1-weighted MR Images: Relationship with Increasing 
Cumulative Dose of a Gadolinium-based Contrast Material. Radiology 2014; 270:.834-841. 


 
 
 
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19. 
Errante Y et al, Progressive Increase of T1 Signal Intensity of the Dentate Nucleus on 
Unenhanced Magnetic Resonance Images Is Associated With Cumulative Doses of 
Intravenously Administered Gadodiamide in Patients With Normal Renal Function, Suggesting 
Dechelation. Investigative Radiology, 2014; 49:685–690 
20. 
Kanda T, et al., High Signal Intensity in Dentate Nucleus on Unenhanced T1-weighted MR 
Images: Association with Linear versus Macrocyclic Gadolinium Chelate Administration.  
Radiology 2015; 275: 803–809 
21. 
McDonald, R.J., et al., Intracranial Gadolinium Deposition after Contrast-enhanced MR 
Imaging. Radiology 2015; 275: 772–782 
22. 
Radbruch, A. et al., Gadolinium Retention in the Dentate Nucleus and Globus Pallidus Is 
Dependent on the Class of Contrast Agent. Radiology 2015; 275: 783–791 
23. 
Ramalho J, Castillo M, AlObaidy M, et al. High signal intensity in globus pallidus and dentate 
nucleus on unenhanced T1-weighted MR images: evaluation of two linear gadolinium-based 
contrast agents. Radiology. 2015;276 (3):836-44 
24. 
Weberling LD, Kieslich PJ, Kickingereder P, et al. Increased Signal Intensity in the Dentate 
Nucleus on Unenhanced T1-Weighted Images After Gadobenate Dimeglumine Administration. 
Investigative Radiology, preprint September 2015 
25. 
Colosimo C, Ruscalleda J, Korves M, et al. Detection of intracranial metastases: a multicenter, 
intrapatient comparison of gadobenate dimeglumine-enhanced MRI with routinely used contrast 
agents at equal dosage. Invest Radiol 2001; 36:72–81. 
26. 
Knopp MV, Runge VM, Essig M, et al. Primary and secondary brain tumors at MR imaging: 
bicentric intraindividual crossover comparison of gadobenate dimeglumine and gadopentetate 
dimeglumine. Radiology 2004; 230:55–64. 
27. 
Colosimo C, Knopp MV, Barreau X, et al. A comparison of Gd-BOPTA and Gd-DOTA for 
contrast-enhanced MRI of intracranial tumours. Neuroradiology 2004;46:655–65. 
28. 
Essig M, Tartaro A, Tartaglione T, et al. Enhancing lesions of the brain: intra-individual 
crossover comparison of contrast enhancement after gadobenate dimeglumine versus 
established gadolinium comparators. Academic Radiology 2006;13:744–51. 
29. 
Maravilla KR, Maldjian JA, Schmalfuss IM, et al. Contrast enhancement of central nervous 
system lesions: multicenter intraindividual crossover comparative study of two MR contrast 
agents. Radiology 2006; 240:389–400. 
30. 
Kuhn MJ, Picozzi P, Maldjian JA, et al. Evaluation of intraaxial enhancing brain tumors on 
magnetic resonance imaging: intraindividual crossover comparison of gadobenate dimeglumine 
and gadopentetate dimeglumine for visualization and assessment, and implications for surgical 
intervention. J Neurosurg 2007; 106:557–66. 
31. 
Rowley HA, Scialfa G, Gao PY, et al. Contrast-enhanced MRimaging of brain lesions: a large-
scale intraindividual crossover comparison of gadobenate dimeglumine versus gadodiamide. 
AJNR Am J Neuroradiol 2008; 29:1684–91. 
32. 
Rumboldt Z, Rowley HA, Steinberg F, et al. Multicenter, doubleblind, randomized, intra-
individual crossover comparison of gadobenate dimeglumine and gadopentetate dimeglumine in 
MRI of brain tumors at 3 Tesla. J Magn Reson Imaging 2009;29:760–67. 
33. 
Seidl Z, Vymazal J, Mechl M, et al. Does higher gadolinium concentration play a role in the 
morphologic assessment of brain tumors? Results of a multicenter intraindividual crossover 
comparison of gadobutrol versus gadobenate dimeglumine (the MERIT Study). AJNR Am J 
Neuroradiol 2012; 33:1050–58. 
 


 
 
 
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18 COMPANY LIABILITY INSURANCE 
Guerbet’s liability, as well as the liability of the investigators participating to this study, 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 study protocol, 
 
An accident occurring for a subject whose consent to participation was not adequately collected. 
 








 
 
 
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SAP_003.pdf: 
Document Type 
Statistical Analysis Plan 
Document Date 
January 9, 2018 
Official Title 
P03277 Dose Finding Study in Central Nervous System (CNS) 
Magnetic Resonance Imaging (MRI) 
NCT Number 
NCT02633501 
 


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This document is the exclusive property of Guerbet. It may not be forwarded or reproduced  
 
STATISTICAL ANALYSIS PLAN No GDX-44-004 
 
P03277 DOSE FINDING STUDY IN CENTRAL NERVOUS SYSTEM (CNS) MAGNETIC 
RESONANCE IMAGING (MRI) 
 
 
Phase IIb clinical study 
 
 
 
 
SPONSOR 
GUERBET 
 
B.P. 57400 
95943 ROISSY CHARLES DE GAULLE CEDEX - 
FRANCE 
 
Tel.: 33-1-45-91-5000 
Fax: 33-1-45-91-5199 
STATISTICAL ANALYSIS PLAN 
APPROVAL 
BIOSTATISTICIAN
 
 
 
 
 
 
BIOSTATISTICIAN 
 
 
 
 
 
 
 


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HISTORY FORM 
Version 
Date 
Reason for change 
1.0 
09 JAN 2018 
Initial version. 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
 
AE 
Adverse Event 
ALT 
Alanine Amino Transferase 
ANOVA 
ANalysis Of VAriance 
AST 
Aspartate Amino Transferase 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
bpm 
beats per minute 
BUN 
Blood Urea Nitrogen 
BW 
Body Weight 
CI 
Confidence Interval 
CNR 
Contrast to Noise Ratio 
CNS 
Central Nervous System 
CSF 
CerebroSpinal Fluid 
CSR 
Clinical Study Report 
CT 
Computed Tomography 
CZ 
Czech Republic 
DBP 
Diastolic Blood Pressure 
ECG 
ElectroCardioGram 
eCRF 
electronic Case Report Form 
eGFR 
estimated Glomerular Filtration Rate 
FAS 
Full Analysis Set 
ICC 
Intra-Class Correlation 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IMP 
Investigational Medicinal Product 
ITT 
Intention To Treat 
IWRS 
Interactive Web Response System 
LBR 
Lesion-to-Brain Ratio 
LDH 
Lactate DeHydrogenase 
LLT 
Lowest Level Term 
LS 
Least Squares 
MAR 
Missing At Random 
MCV 
Mean Corpuscular Volume 
MED 
Minimum Effective Dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI  
Magnetic Resonance Imaging 
PPS 
Per Protocol Set 
PT 
Preferred Term 
Q-Q 
Quantile-Quantile 
RBC 
Red Blood Cells 
ROI 
Region Of Interest 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 


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SD 
Standard Deviation 
SI 
Signal Intensity or Standard International 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
VAS 
Visual Analogic Scale 
WBC 
White Blood Cells 
WHO 
World Health Organization 
 
 


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TABLE OF CONTENTS 
HISTORY FORM ........................................................................................................................................... 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................................ 3 
1. 
SUMMARY OF THE STUDY PROTOCOL ........................................................................................ 9 
1.1. 
STUDY OBJECTIVES ............................................................................................................................. 9 
1.2. 
STUDY DESIGN .................................................................................................................................... 9 
2. 
EVALUATION CRITERIA .................................................................................................................. 10 
2.1. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ............................................................... 10 
2.2. 
EFFICACY CRITERIA .......................................................................................................................... 10 
2.2.1. 
Primary criterion ....................................................................................................................... 10 
2.2.2. 
Secondary efficacy criteria ........................................................................................................ 10 
2.3. 
SAFETY CRITERIA .............................................................................................................................. 12 
2.4. 
OTHER CRITERIA ............................................................................................................................... 12 
3. 
STATISTICAL METHODS .................................................................................................................. 13 
3.1. 
GENERAL CONSIDERATIONS .............................................................................................................. 13 
3.2. 
NULL AND ALTERNATIVE HYPOTHESIS ............................................................................................. 13 
3.3. 
DETERMINATION OF SAMPLE SIZE ..................................................................................................... 14 
3.4. 
ADJUSTMENT FOR COVARIATES ........................................................................................................ 14 
3.5. 
HANDLING OF DROPOUTS OR MISSING DATA .................................................................................... 14 
3.5.1. 
Efficacy Analyses ....................................................................................................................... 14 
3.5.2. 
Missing and Partially Known Dates (Except AE Start Dates)................................................... 15 
3.5.3. 
Missing and Partially Known AE Start Dates ........................................................................... 15 
3.5.4. 
Missing Codes for End Date of Concomitant Medication ......................................................... 16 
3.6. 
INTERIM ANALYSES AND DATA MONITORING ................................................................................... 16 
3.7. 
MULTICENTER STUDIES ..................................................................................................................... 16 
3.8. 
MULTIPLE COMPARISONS/MULTIPLICITY ......................................................................................... 16 
3.9. 
USE OF AN “EFFICACY SUBSET” OF SUBJECTS ................................................................................... 16 
3.10. 
ACTIVE CONTROL STUDIES INTENDED TO SHOW EQUIVALENCE ................................................... 16 
3.11. 
EXAMINATIONS OF SUBGROUPS .................................................................................................... 16 
4. 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES .......................... 17 
5. 
STATISTICAL AND ANALYTICAL PLANS ................................................................................... 18 
5.1. 
DISPOSITION OF SUBJECTS................................................................................................................. 18 
5.2. 
DATA SETS ANALYSED AND PROTOCOL DEVIATIONS ....................................................................... 18 
5.2.1. 
Data Sets Analysed .................................................................................................................... 18 
5.2.2. 
Protocol Deviations ................................................................................................................... 19 
5.3. 
MEASUREMENTS OF STUDY DRUG COMPLIANCE .............................................................................. 25 
5.4. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .............................................................. 25 
5.4.1. 
Demographic data ..................................................................................................................... 25 
5.4.2. 
Study disease .............................................................................................................................. 26 
5.4.3. 
Risk factors ................................................................................................................................ 26 
5.4.4. 
Medical history and concomitant diseases ................................................................................ 26 


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5.4.5. 
Clinical laboratory evaluation at baseline ................................................................................ 27 
5.4.6. 
Vital signs, physical findings and other observations related to safety at baseline .................. 27 
5.4.7. 
Prior therapies ........................................................................................................................... 27 
5.4.8. 
Other baseline characteristics ................................................................................................... 28 
5.4.8.1 
Subject Intolerance to Contrast Agent History ................................................................... 28 
5.4.8.2 
Physical Examination ......................................................................................................... 28 
5.4.8.3 
Pregnancy Test ................................................................................................................... 28 
5.4.8.4 
MRI Examination ............................................................................................................... 28 
5.5. 
EFFICACY EVALUATION .................................................................................................................... 29 
5.5.1. 
Primary analysis of the primary criteria ................................................................................... 29 
5.5.1.1 
Statistical Hypothesis for the Primary Analysis ................................................................. 29 
5.5.1.2 
Holm’s Step-Down Method ............................................................................................... 29 
5.5.1.3 
SAS® Procedure .................................................................................................................. 30 
5.5.1.4 
Validation of Statistical Model ........................................................................................... 30 
5.5.1.5 
Selection Basis for Clinical Dose ....................................................................................... 30 
5.5.2. 
Supportive analyses of primary criterion .................................................................................. 31 
5.5.2.1 
FAS Analysis ...................................................................................................................... 31 
5.5.2.2 
Overall Analysis ................................................................................................................. 31 
5.5.2.3 
Descriptive Statistics .......................................................................................................... 31 
5.5.2.4 
Sensitivity Analysis on Subjects With Region of Interest Similarly Placed in MRI 1 and 
MRI 2 
32 
5.5.3. 
Additional analyses of primary criterion ................................................................................... 32 
5.5.3.1 
Dose/Response Relationship .............................................................................................. 32 
5.5.3.2 
Intra- Off-Site Reader Variability ....................................................................................... 33 
5.5.3.3 
Inter- Off-Site Reader Variability ....................................................................................... 34 
5.5.4. 
Analysis of secondary criteria ................................................................................................... 34 
5.5.4.1 
CNR Calculated Based on Cerebrospinal Fluid ................................................................. 34 
5.5.4.2 
Lesion-to-Brain Ratio ......................................................................................................... 35 
5.5.4.3 
Contrast Enhancement Percentage ..................................................................................... 35 
5.5.4.4 
Technical Adequacy of Images .......................................................................................... 35 
5.5.4.5 
Lesion Detection Capacity ................................................................................................. 35 
5.5.4.6 
Lesion Visualization Variables ........................................................................................... 36 
5.5.4.7 
Diagnostic Confidence ....................................................................................................... 37 
5.5.4.8 
Overall Diagnostic Preference ............................................................................................ 38 
5.5.4.9 
Impact on Subject Treatment Plan ...................................................................................... 38 
5.6. 
SAFETY EVALUATION ....................................................................................................................... 38 
5.6.1. 
Extent of Exposure ..................................................................................................................... 38 
5.6.1.1 
Summary of Durations in the Study ................................................................................... 39 
5.6.1.2 
Study Contrast Agent Administration Modalities .............................................................. 39 
5.6.2. 
Adverse Events ........................................................................................................................... 39 
5.6.2.1 
Overall Safety Summary .................................................................................................... 40 
5.6.2.2 
TEAEs ................................................................................................................................ 40 
5.6.2.3 
TEAEs with Causal Relationship to the IMP ..................................................................... 40 
5.6.2.4 
TEAEs with Causal Relationship to a Study Procedure ..................................................... 41 
5.6.3. 
Deaths, serious adverse events and other significant adverse events ........................................ 41 
5.6.4. 
Clinical laboratory evaluation ................................................................................................... 41 
5.6.5. 
Vital signs, physical findings and other observations related to safety ..................................... 44 
5.6.5.1 
ECG .................................................................................................................................... 44 


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5.6.5.2 
Vital Signs .......................................................................................................................... 44 
5.6.5.3 
Injection Site Tolerance ...................................................................................................... 44 
5.6.6. 
Concomitant medications and procedures................................................................................. 45 
6. 
LIST OF TABLES, FIGURES AND LISTINGS ................................................................................ 46 
6.1. 
CONTENTS OF CLINICAL STUDY REPORT SECTION 14 ........................................................................ 46 
6.1.1. 
Demographic Data Summary and Figures (Section 14.1 of ICH Report) ................................. 46 
6.1.1.1 
Disposition of Subjects ....................................................................................................... 46 
6.1.1.2 
Protocol Deviations ............................................................................................................ 46 
6.1.1.3 
Data Sets Analyzed ............................................................................................................. 46 
6.1.1.4 
Demographics and Baseline Characteristics ....................................................................... 46 
6.1.1.5 
MRI Examination ............................................................................................................... 47 
6.1.1.6 
Compliance ......................................................................................................................... 47 
6.1.2. 
Efficacy Data Summary Figures and Tables (Section 14.2.1 of ICH Report) ........................... 47 
6.1.2.1 
Primary Efficacy Criterion ................................................................................................. 47 
6.1.2.1.1 Primary Analysis of the Primary Criterion ..................................................................... 47 
6.1.2.1.2 Supportive Analyses of the Primary Criterion ................................................................ 47 
6.1.2.1.3 Additional Analyses of the Primary Criterion................................................................. 48 
6.1.2.2 
Secondary Efficacy Criteria................................................................................................ 49 
6.1.2.2.1 Contrast to Noise Ratio Based on CSF ........................................................................... 49 
6.1.2.2.2 Lesion-to-Brain Ratio ..................................................................................................... 49 
6.1.2.2.3 Contrast Enhancement Percentage .................................................................................. 50 
6.1.2.2.4 Technical Adequacy of Images ....................................................................................... 50 
6.1.2.2.5 Lesion Detection Capacity: Number, Size and Location of Lesions and Absence of 
Contrast Enhancement ...................................................................................................................... 51 
6.1.2.2.6 Lesion Visualization Variables: Lesion Border Delineation, Visualization of Lesion 
Internal Morphology and Degree of Lesion Contrast Enhancement ................................................. 52 
6.1.2.2.7 Level of Diagnostic Confidence...................................................................................... 52 
6.1.2.2.8 Overall Diagnostic Preference ........................................................................................ 52 
6.1.2.2.9 Impact on Subject Treatment Plan .................................................................................. 52 
6.1.3. 
Safety Data Summary Figures and Tables (Section 14.3 of ICH Report) ................................. 53 
6.1.3.1 
Extent of Exposure ............................................................................................................. 53 
6.1.3.2 
Displays of Adverse Events ................................................................................................ 53 
6.1.3.2.1 Overall Safety Summary ................................................................................................. 53 
6.1.3.2.2 Treatment Emergent Adverse Events .............................................................................. 53 
6.1.3.2.3 Treatment Emergent Adverse Events with Causal Relationship to the IMP .................. 53 
6.1.3.2.4 Treatment Emergent Adverse Events with Causal Relationship to a Study Procedure .. 53 
6.1.3.2.5 Listings of Deaths, Other Serious and Significant Adverse Events ................................ 53 
6.1.3.3 
Display of Clinical Laboratory Data .................................................................................. 53 
6.1.3.4 
Vital Signs, Physical Findings and Other Observations Related to Safety ........................ 54 
6.1.3.4.1 ECG ................................................................................................................................. 54 
6.1.3.4.2 Vital Signs ....................................................................................................................... 54 
6.1.3.4.3 Other Safety Observations .............................................................................................. 54 
6.2. 
CONTENTS OF CLINICAL STUDY REPORT SECTION 16.2 ..................................................................... 54 
6.2.1. 
Disposition of Subjects (Section 16.2.1 of ICH Report) ............................................................ 54 
6.2.2. 
Protocol Deviations (Section 16.2.2 of ICH Report) ................................................................. 55 
6.2.3. 
Subjects Excluded from Efficacy Analysis (Section 16.2.3 of ICH Report) ............................... 55 
6.2.4. 
Demographic Data and Baseline Characteristics (Section 16.2.4 of ICH Report) ................... 55 


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6.2.5. 
Compliance and/or Drug Concentration Data (Section 16.2.5 of ICH Report) ........................ 55 
6.2.6. 
Individual Efficacy Response Data (Section 16.2.6 of ICH Report) .......................................... 55 
6.2.6.1 
Primary Efficacy Criterion and Secondary Efficacy Criteria Derived From the Signal 
Intensity Measurement ......................................................................................................................... 55 
6.2.6.2 
Other Secondary Efficacy Criteria ..................................................................................... 56 
6.2.7. 
Adverse Event Listings (Section 16.2.7 of ICH Report) ............................................................. 57 
6.2.8. 
Listing of Individual Laboratory Measurements (Section 16.2.8 of ICH Report) ..................... 57 
6.2.9. 
Vital Signs, Physical Findings and Other Observations Related to Safety ............................... 57 
7. 
SHELLS FOR TABLES, FIGURES AND LISTINGS ....................................................................... 58 
7.1. 
CONTENTS OF CLINICAL STUDY REPORT SECTION 14 ........................................................................ 58 
7.2. 
CONTENTS OF CLINICAL STUDY REPORT SECTION 16.2 ..................................................................... 58 
8. 
REFERENCES ....................................................................................................................................... 59 
9. 
APPENDICES ........................................................................................................................................ 60 
 
 


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1. SUMMARY OF THE STUDY PROTOCOL 
This document presents the Statistical Analysis Plan (SAP) for Guerbet, Protocol No. GDX-44-004: “P03277 
Dose Finding Study in Central Nervous System (CNS) Magnetic Resonance Imaging (MRI)”. 
This analysis plan is based on the protocol Version 2.0 including amendment n°1 dated 11 July 2016. 
 
1.1. Study objectives 
The primary objective is to determine a safe and effective dose of P03277 based on a comparison of Contrast 
to Noise Ratio (CNR) between several doses, 0.025, 0.05, 0.1 and 0.2 mmol/kg of P03277 and MultiHance® 
at 0.1 mmol/kg. 
 
The secondary objectives of the trial are: 
 
To assess technical adequacy of images. 
 
To evaluate capacity of lesion detection: number, size and location of lesions detected. 
 
To evaluate diagnostic information using lesion visualization variables (lesion border delineation, internal 
morphology and degree of contrast enhancement). 
 
To evaluate diagnostic confidence. 
 
To compare overall diagnostic preference between P03277 and MultiHance®. 
 
To assess P03277 dose/response relationship for CNR and lesion visualization variables. 
 
To evaluate the impact of P03277 and MultiHance®-enhanced MRI on subject treatment plan. 
 
To assess the safety profile of P03277 as compared to MultiHance® after intravenous administration. 
 
1.2. Study design 
Design: GDX-44-004 is a Phase IIb, multicenter, double-blind, randomized, controlled, parallel dose groups, 
cross-over design with comparator. 
 
Centers: worldwide study involving 28 active centers. 
 
Study arms: 
Two subsets of subjects: 
 
Subset 1: first subject of each study center randomized 1:1 as follows. 
a. 0.05 or 0.1 mmol/kg Body Weight (BW) of P03277 then 0.1 mmol/kg of MultiHance® (1:1). 
b. 0.1 mmol/kg of MultiHance® then 0.05 or 0.1 mmol/kg BW of P03277 (1:1). 
 
Subset 2: all subsequent subjects randomized 1:1 as follows. 
a. 0.025, 0.05, 0.1 or 0.2 mmol/kg BW of P03277 then 0.1 mmol/kg of MultiHance® (1:1:1:1). 
b. 0.1 mmol/kg of MultiHance® then 0.025, 0.05, 0.1 or 0.2 mmol/kg BW of P03277 (1:1:1:1). 
 
 


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2. EVALUATION CRITERIA 
2.1. Demographic and other baseline characteristics 
Demographic and other baseline characteristics include: 
 
Demographic data. 
 
Medical history. 
 
Previous medications. 
 
Subject intolerance to contrast agent history. 
 
Study disease diagnosis. 
 
Physical examination. 
 
Pregnancy test. 
 
Local serum creatinine and estimated Glomerular Filtration Rate (eGFR). 
 
MRI examination. 
 
2.2. Efficacy criteria 
2.2.1. Primary criterion 
 
The primary criterion (off-site readings) is calculated by subject, and by independent blinded reader in a 
centralized procedure (off-site readers), in averaging the CNR for maximum 3 enhanced lesions. For the 
primary analysis, only lesions detected by both MRIs after lesion tracking will be used. 
 
CNR is a variable derived for each lesion, from the Signal Intensity (SI) measurement. CNR will be calculated 
according to the following formula: 
 
𝐶𝑁𝑅= 𝑆𝐼𝑙𝑒𝑠𝑖𝑜𝑛− 𝑆𝐼ℎ𝑡
𝑆𝐷𝑛𝑜𝑖𝑠𝑒
 
 
where SIlesion = the SI in the Region Of Interest (ROI) in the lesion. 
SIht = the SI in the ROI in healthy tissue (brain or spinal cord). 
SDnoise = Standard Deviation (SD) of background noise. 
 
2.2.2. Secondary efficacy criteria 
 
Secondary efficacy criteria include: 
 
 
Technical adequacy of images (off-site and on-site readings): yes or no and reason if no (1 = Artefacts 
due to subject, 2 = Artefacts due to machine, 3 = Artefacts due to contrast agent, 4 = Injection technical 
failure, 5 = Other, specify). 


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 
Lesion detection capacity: number of enhancing lesions (off-site and on-site readings) and number of 
lesions detected (off-site readings only); for the 3 most representative lesions: size of lesions (largest 
diameter), location of lesions and presence or absence of contrast enhancement (off-site and on-site 
readings). Contrast enhancement is absent if the degree of contrast enhancement is 1 = No: no 
enhancement and present if it is 2 = Moderate: weakly enhanced, 3 = Good: clearly enhanced or 4 = 
Excellent: clearly and brightly enhanced. 
 
 
Lesion visualization variables: lesion border delineation, visualization of lesion internal morphology 
and degree of lesion contrast enhancement assessed on 4-point scales (off-site and on-site readings). 
Lesion border delineation: 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. 
Visualization of lesion internal morphology: 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. 
Degree of lesion contrast enhancement: 1 = No: no enhancement, 2 = Moderate: weakly enhanced, 3 
= Good: clearly enhanced, 4 = Excellent: clearly and brightly enhanced. 
 
 
Radiological diagnosis and level of diagnostic confidence (off-site and on-site readings). 
Radiological diagnosis is assessed according to the 9 following categories: 1 = Glial tumor, low grade 
(I/II), 2 = Glial tumor, high grade (III/IV), 3 = Glial tumor, tumor grade cannot be determined, 4 = 
Meningioma, 5 = Brain metastasis, 7 = Stroke, 8 = Abscess, 9 = Other (to be specified), 0 = Not 
assessable. 
Level of diagnostic confidence is assessed on a 5-point scale: 1 = Nil: very uncertain, 2 = Poor: 
uncertain, 3 = Moderate: moderately certain, 4 = High: good certainty, 5 = Excellent: very certain. 
 
 
Overall diagnostic preference and reason (off-site readings). 
Overall diagnostic preference is assessed on a 3-point scale: 1 = Examination 1 is preferred to 
examination 2, 0 = No preference is observed, 2 = Examination 2 is preferred to examination 1. 
Reason may be one or more of the 6 following ones: 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 
(reason(s) to be specified). 
 
 
Impact on subject treatment plan (on-site reading): “could it be changed?” yes, no or no opinion and 
detail if yes (surgery, biopsy, chemotherapy, radiotherapy or other treatment to be specified). 
 


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2.3. Safety criteria 
Safety criteria include: 
 
Study contrast agent administration modalities. 
 
Adverse Events (AEs). 
 
Hematology, biochemistry and urinalysis. 
 
ElectroCardioGram (ECG) and vital signs. 
 
Injection site tolerance and subject pain evaluation. 
 
Concomitant medications. 
 
2.4. Other criteria 
Not applicable. 
 
 


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3. STATISTICAL METHODS 
3.1. General considerations 
After the database lock, the statistical analysis will be performed by Inferential under the supervision of Benoit 
Piednoir, Guerbet biostatistician, on the basis of the present document. A quality control of the statistical 
analysis will be performed to ensure the reliability of the results. 
Thorough description of all parameters reported will be presented separately by group. Summary tabulated 
results will be provided by group and assessment time, if relevant or they will be replaced by the corresponding 
individual data listings if too few subjects are concerned. 
Tabulations of quantitative parameters will include the following summary statistics: number of subjects, 
mean, SD, minimum, median and maximum. If for a given parameter, the raw value has been collected with 
x decimal places, the mean, median and SD will be rounded to x+1 decimal places, while the minimum and 
maximum values will be tabulated as reported with x decimal places. 
Tabulations of frequencies for categorical data will include all possible categories and will display the number 
of observations in a category as well as the percentage (%) relative to the respective group. Percentages will 
be rounded to one decimal place. The category missing will be displayed only if there are actually missing 
values. Percentages will be calculated on the total of non-missing recorded categories. 
For safety analyses, the baseline value will be defined as the last available value prior to administration of the 
Investigational Medicinal Product (IMP). For the primary analysis of the primary efficacy criterion, the 
baseline value will be the pre CNR measurement for unenhanced lesions for each contrast agent period. 
All statistical tests will be performed at the significant threshold of 2.5% one-sided. P-values will be displayed 
with 4 decimal places. 
SAS® version 9.2 will be used for all descriptive summaries and inferential analyses. 
 
3.2. Null and alternative hypothesis 
Stating the following notations: 
 
μi is the expected average of CNR of enhanced lesions for each dose of P03277 (where i is corresponding 
to one dose of P03277). 
 
μ0 is the expected average of CNR of enhanced lesions for corresponding MultiHance® group. 
 
Statistical hypotheses for the primary analysis of the primary criterion are: 
 
Null hypothesis 
Hi: μi - μ0 ≤ 0, i = 1…4 
 
Alternative hypothesis 
Ki: μi - μ0 > 0, i = 1…4 
 


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3.3. Determination of sample size 
Based on the hypothesis below, a total of 280 subjects were to be enrolled in the study: 
 
Subset 1: maximum 40 subjects (depending of the number of participating sites) on the basis of 1 subject 
per site. 
 
Subset 2: minimum 240 subjects based on the following assumption: the study aims at detecting a 
minimum of 30% increase of CNR for at least one of the four tested dose of P03277 compared to control 
arm MultiHance® at dose of 0.1 mmol/kg BW. A sample size of 50 evaluable subjects per group was 
required to obtain a power of at least 90%, using a t-test of a normal mean difference with a one-sided 
significance level of 0.025 (Holm’s step-down method in a multiple comparisons design [1]) and a 
common SD of 3.01. Therefore, a minimum of 50 evaluable subjects per dose group and a minimum of 
200 evaluable subjects in total would have to be enrolled in this study. 
An evaluable subject was defined as a randomized subject, 2 contrast agents administered, having undergone 
2 complete, assessable and interpretable MRI examinations, presenting with at least one enhancing lesion of 
minimum 5 mm (long axis). 
It was anticipated that some of the subjects would not complete both MRI evaluations. To offset this, an 
additional 10 subjects per group were added to the 50 required leading to a total of 240 randomized subjects. 
The number of non-evaluable subjects was monitored to assess the necessity for a sample size increase. The 
decision to increase the sample size would be made by the sponsor when approximately 80% of the planned 
240 randomized subjects were enrolled. The actual rate of drop-out subjects was considered to assess the new 
number of subjects to be enrolled. 
Subjects with brain metastasis were randomized at a minimum of 20% of the second subset of subjects. 
Randomization was stratified within brain metastasis (yes/no) in order to prevent unequal contrast agent 
allocation. 
 
3.4. Adjustment for covariates 
The pre CNR measurement for unenhanced lesions (baseline value) will be included as covariate in the 
statistical models for the primary and supportive analyses of the primary criterion. 
The stratification factor (brain metastasis at screening) will not be included as covariate in the statistical 
models. Indeed, it was judged as having no impact on the primary criterion. However, the analysis of number 
of lesions will be provided only on the subset of subjects with brain metastasis at screening. 
 
3.5. Handling of dropouts or missing data 
3.5.1. Efficacy Analyses 
 
No imputation will be performed in this study. Mixed models will be performed only on subjects with both 
MRIs: on Per Protocol Set (PPS) and on Full Analysis Set (FAS) from which only subjects whose the criterion 


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of interest is available at both MRIs will be selected. The mention “Subjects Having Undergone the Two MRI” 
will be subtitled to the relevant tables and figures for the FAS. 
 
3.5.2. Missing and Partially Known Dates (Except AE Start Dates) 
 
Unless otherwise specified, partially known dates will be defined as follows for duration computation: 
 
Partially known start date 
 If only the day is missing, it is estimated as the first day of the month or day of the first date in the study if 
it is the same month and year. 
 If month and day are missing, they are estimated as January 1 or day and month of the first date in the study 
if it is the same year. 
 
Partially known end date 
 If only the day is missing, it is estimated as the last day of the month or day of the last date in the study if 
it is the same month and year. 
 If month and day are missing, they are estimated as December 31 or day and month of the last date in the 
study if it is the same year. 
 
The original dates without estimation will be presented in the listings. 
 
General rules for calculating the durations 
 
Durations calculated in minutes: if any one of the times from the start and end "datetimes" used for the 
calculation of the duration is/are missing, the duration is missing. 
 
Durations calculated in days: if any one of the times from the start and end "datetimes" used for the 
calculation is/are missing, the date part of the datetime will be used to compute the duration. 
 
3.5.3. Missing and Partially Known AE Start Dates 
 
If an AE start date is missing or unknown, the AE will be considered as treatment emergent. 
 
When the start date of an AE is only partially known, it will be categorized as not emergent or emergent using 
the following rules: 
 
If the partial start date is before (<) the injection at the 1st MRI procedure visit date (i.e., year or year & 
month is/are before those of the date of the injection) then the AE is not emergent. 
 
If the partial start date is after (≥) the injection at the 1st MRI procedure visit date (i.e., year or year & 
month is/are the same as or after those of the date injection) then the AE is emergent. 
 


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3.5.4. Missing Codes for End Date of Concomitant Medication 
 
In case of missing code for end date of a concomitant medication, it will be replaced by the code 2 = “Between 
first and second IMP administration”, so that the medication will be considered as concomitant (see Sections 
5.4.7 and 5.6.6). 
 
3.6. Interim analyses and data monitoring 
No interim analysis is planned. 
 
3.7. Multicenter studies 
Twenty-eight (28) active centers are involved worldwide in the study, the center factor will not be included in 
the multivariate models for efficacy. The number of subjects included in each center will be displayed in a 
disposition table. Furthermore, the primary criterion will be tabulated by center without statistical inference. 
 
3.8. Multiple comparisons/Multiplicity 
A global one-sided α level of 0.025 will be guaranteed for the primary analysis of the primary criterion by use 
of the Holm’s step-down method [1]. 
 
3.9. Use of an “efficacy subset” of subjects 
Some efficacy analyses will be performed on the following subsets of the FAS: 
 The PPS. 
 The PPS restricted to subjects with ROI similarly placed in MRI 1 and MRI 2. 
 The FAS restricted to subjects with an available criterion of interest at both MRIs. 
 The FAS restricted to subjects with an available criterion of interest at both MRIs and with presence of 
brain metastasis. 
 
3.10. 
Active control studies intended to show equivalence 
Not applicable. 
 
3.11. 
Examinations of subgroups 
 Descriptive analyses of the primary criterion will be performed by center and by magnetic field. 
 Descriptive analyses of the number of enhancing lesions (secondary efficacy criterion) will be performed 
by presence or absence of brain metastasis (stratification factor). 
 
 


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4. CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES 
The protocol was amended on one occurrence. See amended protocol for a full list of changes. 
 
RATIONALE FOR ANY DEVIATION FROM PRE-SPECIFIED ANALYSIS PLAN PERFORMED 
 
It was planned in the protocol to repeat on the PPS the evaluation of secondary efficacy criteria in case of a 
difference from the FAS by more than 15%. It has been decided that only the analyses of data from off-site 
readings for some relevant secondary criteria will be repeated on the PPS. 
 
Further, three secondary criteria have been added since the last amendment: The Contrast-to-Noise Ratio 
calculated based on the noise issued from the CerebroSpinal Fluid (CSF): CNRCSF, the Lesion-to-Brain Ratio 
(LBR) and the Contrast enhancement percentage. The three criteria are calculated by subject, and by 
independent blinded reader in a centralized procedure (off-site readers) and the result is provided by exam for 
each reader by averaging the parameter for maximum 3 enhanced lesions. 
 
CNRCSF is derived for each lesion, from the SI measurement, according to the following formula: 
 
CNRcsf = 𝑆𝐼𝑙𝑒𝑠𝑖𝑜𝑛−𝑆𝐼ℎ𝑡
𝑆𝐷𝑛𝑜𝑖𝑠𝑒
 
 
where SIlesion = the SI in the ROI in the lesion. 
SIht = the SI in the ROI in healthy tissue (brain or spinal cord). 
SDnoise = SD of CSF noise. 
 
LBR is derived for each lesion, from the SI measurement, according to the following formula: 
 
LBR = 𝑆𝐼𝑙𝑒𝑠𝑖𝑜𝑛
𝑆𝐼ℎ𝑡
 
 
where SIlesion = the SI in the ROI in the lesion. 
SIht = the SI in the ROI in healthy tissue (brain or spinal cord). 
 
Contrast enhancement percentage is derived for each lesion, from the SI measurement, according to the 
following formula: 
 
𝐶𝑜𝑛𝑡𝑟𝑎𝑠𝑡 𝐸𝑛ℎ𝑎𝑛𝑐𝑒𝑚𝑒𝑛𝑡 𝑃𝑒𝑟𝑐𝑒𝑛𝑡𝑎𝑔𝑒= 𝑆𝐼𝑝𝑜𝑠𝑡− 𝑆𝐼𝑝𝑟𝑒
𝑆𝐼𝑝𝑟𝑒
 
 
where SIpost = the SI in the ROI in the lesion post contrast media administration. 
SIpre = the SI in the ROI in the lesion pre contrast media administration. 
 
These three criteria will be analyzed as the primary criterion. 
 
 


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5. STATISTICAL AND ANALYTICAL PLANS 
5.1. Disposition of subjects 
The following descriptions (number and percentage of subjects) will be performed with regards to the 
disposition of subjects: 
 
Subject overall disposition on the Extended Set for each subset separately: 
o Subjects present at each study visit by contrast agent, sequence and globally. 
o Subjects screened, subjects randomized, subjects administered at the first MRI procedure, 
subjects administered at the second MRI procedure and subjects who completed the study by 
contrast agent, sequence and globally. 
o Subjects screen failure, reasons of screen failure, premature discontinuation from the study 
before receiving the 1st and the 2nd contrast agent and reasons why subjects were prematurely 
discontinued by contrast agent, sequence and globally. 
 
Subjects globally recruited in each center sorted by country on the Extended Set. 
The tables that will be displayed are detailed in Section 6.1.1.1 and the listings in Section 6.2.1. 
5.2. Data Sets Analysed and protocol deviations 
5.2.1. Data Sets Analysed 
 
There will be four subject sets defined for this study: the Extended Set, the Safety Set, the FAS and the PPS. 
 
The Extended Set will include all subjects having signed the Informed Consent Form (ICF). This set will be 
used for subject disposition summaries, overall summary of AEs and individual listings. 
 
The Safety Set will include all subjects, receiving at least one injection of contrast agent, regardless of the 
quantity. Subjects of subset 1 will be included in this set. This set will be used for description of demographic 
data, medical history, previous treatments and evaluation of safety. Analyses using the Safety Set will be based 
on the contrast agent actually received. 
 
The FAS will include all subjects from subset 2 who have a CNR from both enhanced and unenhanced 
measurements derivable from one MRI by at least one off-site blinded reader. This set will be used for 
description of demographic data, baseline characteristics data, medical history, previous treatments and 
evaluation of efficacy. Analyses using the FAS will be based on the contrast agent allocated by the 
randomization whatever the contrast agent actually received, following the Intention To Treat (ITT) principle. 
 
The PPS will be a subset of the FAS and will include all subjects who have no major protocol deviations (see 
below) throughout their whole study period. This set will be used for the evaluation of the primary efficacy 
criterion and main secondary criteria. 
 


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Analysis data sets will be presented on the Extended Set: subjects included in the Safety Set by contrast agent 
actually received and globally and included in the FAS and in the PPS by contrast agent allocated by the 
randomization and globally. 
 
The tables and the listing that will be displayed are detailed in Sections 6.1.1.3 and 6.2.3. 
 
5.2.2. Protocol Deviations 
 
As per International Conference on Harmonization (ICH) E3 guideline [2], a protocol deviation is any change, 
divergence or departure from the study design or procedures defined in the protocol, with or without impact 
to the subject safety or the efficacy assessments. Protocol deviations are displayed in the Clinical Study Report 
(CSR) as a metric of the feasibility and reliability of the study. The list of protocol deviations is presented in 
the table below and can be updated if necessary before breaking the blind. Protocol deviations will be gathered 
from monitoring files, clinical database and external vendors of off-site data (imaging, laboratory data, 
ECG…). 
 
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 criteria. A first categorisation is done in this document, then final 
categorisation will be done before breaking the blind. The decision will be duly described in the meeting 
minutes. 
 
The deviations are listed in the table below: 
 
Category 
Description 
Source 
Status 
Inclusion criteria 
not 
met/Non 
inclusion criteria 
met 
Subject not having reached legal majority age 
Clinical data base 
Non major 
 
Subject not presenting, at the time of inclusion, with 
known or highly suspected focal areas of disrupted 
Blood Brain Barrier (BBB) (e.g., primary and 
secondary 
tumors, 
focal 
inflammatory 
or 
demyelinating disorders) including at least one 
expected enhancing lesion of minimum 5 mm (long 
axis). This lesion must have been detected on a 
previous 
imaging 
procedure 
(computerized 
Tomography (CT) or MRI) 
Clinical data base 
Major 
 
Subject not scheduled for a routine CNS contrast-
enhanced MRI examination for clinical reasons or 
not agreeing to have a second contrast-enhanced 
MRI examination for the purpose of the study 
Clinical data base 
Non major 
 
Subject not able or not willing to participate to the 
study 
Clinical data base 
Non major 
 
Subject not having provided his/her consent to 
participate in writing by dating and signing the 
informed consent prior to any study related 
procedure being conducted 
Clinical data base 
Non major 


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Subject not affiliated to national health insurance 
according to local regulatory requirements 
Clinical data base 
Non major 
 
Subject presenting with acute or chronic Grade III (at 
least) renal insufficiency, defined as an estimated 
Glomerular 
Filtration 
Rate 
(eGFR) 
<60 
mL/min/1.73 m² based on two eGFR assessments, 
one within 7 days before the first study MRI and one 
the day of the MRI (if any of the eGFR result is < 60 
mL/min/1.73m², the subject is not eligible) 
Clinical data base 
Non major 
 
Subject presenting with known class III/IV 
congestive heart failure according to the New York 
Heart Association classification (NYHA) 
Clinical data base 
Non major 
 
Pregnant or breast-feeding female subject (a female 
subject of childbearing potential or with amenorrhea 
for less than 12 months must have a negative urine 
or serum pregnancy test within 24 hours prior to 
study MRI and must be using a medically approved 
contraception method* until the last study visit) 
Clinical data base 
Non major 
 
Subject 
having 
received 
any 
investigational 
medicinal product within 30 days prior to study entry 
Clinical data base 
Non major 
 
Subject previously enrolled in this study 
Clinical data base 
Non major 
 
Subject presenting with any contraindication to MRI 
examinations 
Clinical data base 
Non major 
 
Subject with known contra-indication(s) to the use or 
with known sensitivity to one of the products under 
investigation or other GBCAs 
Clinical data base 
Non major 
 
Subject having received any contrast agent (MRI or 
CT) within 3 days prior to study products 
administration, or scheduled to receive any contrast 
agent during the course of the study or within 24 
hours after the second study product administration 
Clinical data base 
Non major 
 
Subject having received any treatment or medical 
procedure within 7 days prior to the first MRI or 
expected/ scheduled to have a change in any 
treatment or medical procedure in-between the 2 
MRI examinations 
Clinical data base 
Non major 
 
Subject with anticipated, current or past condition 
(medical, psychological, social or geographical) that 
would compromise the subject’s safety or her/his 
ability to participate in the study 
Clinical data base 
Non major 
 
Subject unlikely to comply with the protocol, e.g. 
uncooperative attiude, inability to return for follow-
up visits and/or unlikelihood of completing the study 
Clinical data base 
Non major 
 
Subject related to the Investigator or any other study 
staff or relative directly involved in the study 
conduct 
Clinical data base 
Non major 


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Subject presenting with acute relapse of multiple 
sclerosis 
Clinical data base 
Non major 
 
eGFR 
on 
local 
measurements 
below 
60 
mL/min/1.73m2 at visit 2 or visit 4 and contrast 
media administration performed 
Clinical data base 
Non major 
 
eGFR 
on 
central 
measurements 
below 
60 
mL/min/1.73m2 at visit 2 or visit 4 and contrast 
media administration performed 
Laboratory 
data 
base 
Non major 
 
eGFR on local measurements not performed one day 
before contrast media administration 
Clinical data base 
Non major 
 
eGFR on local measurements at visit 1 not 
performed within 7 days before first contrast media 
administration 
Clinical data base 
Non major 
 
eGFR method is not accurate 
Clinical data base 
Non major 
 
No pregnancy test done 1 day before contrast media 
administration for female of childbearing potential 
Clinical data base 
Non major 
Study 
disease 
diagnosis 
Procedure used for documenting at least one 
enhancing lesion is not provided 
Clinical data base 
Non major 
 
Time between procedure used for documenting at 
least one enhancing lesion and first study procedure 
is greater than 12 months for Czech Republic 
(CZ) 
Clinical data base 
Non major 
Imaging 
Not matching lesion: among subjects with both MRI 
examinations done, those without enhancing lesions 
matching at both examination for all off-site readers 
Imaging data base 
Major 
 
Scanner-related deviation from the MRI procedures 
Clinical data base 
Non major 
 
Subject-related deviation from the MRI procedures 
Clinical data base 
Non major 
 
Anatomy (Brain/Spine) is different between on-site 
and off-site evaluation 
Clinical data base 
and imaging data 
base 
Non major 
 
Anatomy is Brain for one period and Spine for the 
other one in the off-site evaluation for at least one 
off-site reader 
Imaging data base 
Non major 
 
Anatomy is Brain for one period and Spine for the 
other one in the on-site evaluation 
Clinical data base 
Non major 
 
Imaging protocol not respected with major impact on 
primary criterion 
Monitoring 
Major 
 
Imaging protocol not respected with impact on 
primary criterion 
Monitoring 
Non major 
 
 


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Subject 
not 
withdrawn as per 
protocol 
Stopping rules detected on local measurements and 
subject not withdrawn: Increase in serum creatinine 
by more than 25% or 0.5 mg/dL (44 umol/L) 
compared to the baseline value 
Clinical data base 
Non major 
 
Stopping rules detected on central measurements and 
subject not withdrawn: Increase in serum creatinine 
by more than 25% or 0.5 mg/dL (44 umol/L) 
compared to the baseline value 
Central laboratory 
data base 
Non major 
 
Stopping rules detected on central measurements and 
subject not withdrawn: Increase in cystatin C by 
more than 25% compared to the baseline value 
Central laboratory 
data base 
Non major 
 
Stopping rules detected on central measurements and 
subject not withdrawn: triplicate QTc Bazett or QTc 
Fridericia > 500 ms or in increase of > 60 ms over 
baseline 
Central ECG data 
base 
Non major 
 
Result of pregnancy test positive and subject not 
withdrawn 
Clinical data base 
Non major 
Unblinding 
Blind not maintained on site 
Monitoring 
Non major 
 
Blind not maintained at central reading level 
Monitoring 
Major 
Forbidden 
concomitant 
medication 
Concomitant medication taken in or medical 
procedure between the two MRI impacting lesion 
size based on investigator assessment 
Clinical data base 
Major 
IMP deviation 
Subject not allocated in the good stratification factor Clinical data base 
and IWRS data base  
Non major 
 
Subject not allocated in the good sequence 
Clinical data base 
and IWRS data base 
Major 
 
Subject having performed MRI examination but not 
administered with the IMP 
Clinical data base 
Major 
 
The IMP volume actually administered is different 
from the theoretical one from 10 to 20% 
Clinical data base 
and IWRS data base 
Non major 
 
The IMP volume actually administered is different 
from the theoretical one from more than 20% 
Clinical data base 
and IWRS 
Major 
 
Location of IMP injection site is not adequate 
Clinical data base 
Non major 
 
Actual IMP injection rate is not adequate 
Clinical data base 
Non major 
 
Temperature excursion for IMP 
Monitoring 
Non major 
 
IMP management not appropriate 
Monitoring 
Non major 
 
Extravasation 
Clinical data base 
Major 
Missing data 
Date of birth is missing 
Clinical data base 
Non major 
 
Sex is missing 
Clinical data base 
Non major 
 
Height is missing 
Clinical data base 
Non major 
 
Race is missing 
Clinical data base 
Non major 
 
Physical examination not performed 
Clinical data base 
Non major 
 
Blood sample for central laboratory assessment not 
performed 
Clinical data base 
Non major 


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Central 
Laboratory 
Biochemistry 
results 
not 
available 
Laboratory 
data 
base 
Non major 
 
Central Laboratory Hematology results not available Laboratory 
data 
base 
Non major 
 
Urinalysis not performed 
Clinical data base 
Non major 
 
Vital signs not measured 
Clinical data base 
Non major 
 
Vital sign result missing 
Clinical data base 
Non major 
 
ECG not performed/performed but not in triplicate 
Clinical data base  
Non major 
 
ECG result missing 
Central ECG data 
base 
Non major 
 
Tolerance at injection site is not filled in for patient 
receiving the study product 
Clinical data base 
Non major 
 
No VAS completed in case of injection site pain 
Clinical data base 
Non major 
Non respect of 
study’s schedule 
and procedures 
MRI examination not performed 
Clinical data base 
Major 
 
Time between the two MRI procedures is strictly 
greater than 14 days and less or equal to 21 days 
Clinical data base 
Non major 
 
Time between the two MRI procedures is strictly 
greater than 21 days 
Clinical data base 
Major 
 
Time between contrast media administration and 3-
D GRE acquisition for Brain and T1WSE/TSE 
acquisition for spine is greater than 10 minutes 
Clinical data base 
Non major 
 
Two different MRI system manufacturer used for 
both assessments 
Imaging data base  
Non major 
 
Two different MRI system model used for both 
assessments 
Imaging data base 
Non major 
 
Two different MRI system software version used for 
both assessments 
Imaging data base  
Non major 
 
Two different magnetic field strength used for both 
assessments 
Imaging data base  
Non major 
 
Two different MRI machines used for both 
assessments 
Monitoring 
Non major 
 
MRI machine used not qualified 
Monitoring  
Non major 
 
MRI exam for subject of subset 2 performed prior 
investigator’s qualification 
Monitoring 
Non major 
 
Time between contrast media administration and 3-
D GRE acquisition for Brain and T1WSE/TSE for 
spine acquisition is different of more than 10 minutes 
but less than 30 minutes between the two MRI for a 
single patient 
Clinical data base 
Non major 
 
Time between contrast media administration and 3-
D GRE acquisition for Brain and T1WSE/TSE for 
spine acquisition is different of more than 30 minutes 
between the two MRI for a single patient 
Clinical data base 
Major 
 
Time between screening visit and first contrast 
media administration is strictly greater than 7 days 
Clinical data base 
Non major 


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Prior to MRI blood sample for central laboratory 
assessment is not drawn before contrast media 
administration 
Clinical data base 
Non major 
 
Prior to MRI urinalysis is not performed before 
contrast media administration 
Clinical data base 
Non major 
 
1 day post MRI blood sample for central laboratory 
assessment is not drawn the day after contrast media 
administration 
Clinical data base 
Non major 
 
1 day post MRI urinalysis is not performed the day 
after contrast media administration 
Clinical data base 
Non major 
 
Before injection vital sign is not taken before 
contrast media administration 
Clinical data base 
Non major 
 
45-minute after injection vital sign is not taken 
between 30 and 60 minutes after contrast media 
administration 
Clinical data base 
Non major 
 
Between 2 and 4 hours after injection vital sign is not 
taken between 2 and 4 hours after contrast media 
administration 
Clinical data base 
Non major 
 
1 day post MRI vital sign is not taken the day after 
contrast media administration 
Clinical data base 
Non major 
 
Before injection ECG is not performed before 
contrast media administration 
Clinical data base 
Non major 
 
45-minute after injection ECG is not performed 
between 30 and 60 minutes after contrast media 
administration 
Clinical data base 
Non major 
 
Between 2 and 4 hours after injection ECG is not 
performed between 2 and 4 hours after contrast 
media administration 
Clinical data base 
Non major 
 
1 day post MRI ECG is not performed the day after 
contrast media administration 
Clinical data base 
Non major 
GCP deviation 
ICF deviation 
Monitoring 
Non major 
 
Source document management not appropriate 
Monitoring 
Non major 
 
Subjects presenting at least one protocol deviation with a status major will be excluded from the PPS. 
 
Frequency and percentages of subjects with protocol deviations will be presented breaking down by status 
(major/non major). 
 
Subjects with major protocol deviations throughout the study causing exclusion from the PPS will be presented 
by contrast agent and globally on the Extended Set for each subset separately: subjects with at least one major 
protocol deviation and subjects with each major protocol deviation. Non major protocol deviations will follow 
the same disposition. 
 
The tables and listings that will be displayed are detailed in Sections 6.1.1.2 and 6.2.2. 
 


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5.3. Measurements of study drug compliance 
The subject’s theoretical dose of contrast agent calculated for each subject was given by Interactive Web 
Response System (IWRS). The subject’s actual dose administered was recorded in the electronic Case Report 
Form (eCRF). When the actual dose was different from the theoretical dose, the reason had to be given and 
recorded in the eCRF. Subjects with a difference between theoretical and actual volumes of study product will 
be described using the FAS. The difference in mL and in % will be presented for these subjects by descriptive 
statistics. The reasons of the differences will be listed only. 
 
The table and the listing that will be displayed are detailed in Sections 6.1.1.6 and 6.2.5. 
 
5.4. Demographic and Other Baseline Characteristics 
Demographic data will be described using the FAS, the PPS and the Safety Set, medical history and previous 
medications will be described using the FAS and the Safety Set whereas other baseline characteristics will be 
described using the FAS only. 
For tables described on the FAS (and the PPS if any, see Section 5.2.1), 5 columns will be displayed: “P03277 
0.025 mmol/kg”, “P03277 0.05 mmol/kg”, “P03277 0.1 mmol/kg”, “P03277 0.2 mmol/kg” and “Total”, the 
dose being the one allocated by the randomization (either at the 1st or the 2nd period). 
For tables described on the Safety Set, 7 columns will be displayed: “P03277 0.025 mmol/kg”, “P03277 0.05 
mmol/kg”, “P03277 0.1 mmol/kg”, “P03277 0.2 mmol/kg”, “Total P03277”, “MultiHance®” and “Total”, the 
dose being the one actually received (either at the 1st or the 2nd period). It corresponds to the disposition of 
safety tables, except for tables of AEs in which period (MRI 1 and MRI 2) will appear also. 
 
5.4.1. Demographic data 
 
Demographic characteristics collected at screening, except for weight at Visit 2 and Visit 4, include the 
following parameters: 
 
Age (years) calculated using the following formula: (inclusion visit date - birth date) / 365.25. 
 
Gender: Male; Female. 
o If Female, contraceptive status: Woman of childbearing potential using effective contraception; Post-
menopausal (with minimum 12 months of amenorrhea); Surgically sterilized. 
 
Weight at Visit 2 and Visit 4 (kg). 
 
Height (cm). 
 
Body Mass Index (BMI) at Visit 2 and Visit 4: 
2)
(
)
(
m
Height
Kg
BodyWeight
BMI 
 
where height is in m and weight in kg. BMI will be displayed as a quantitative variable only. 
 
Ethnicity: Hispanic or Latino; Not Hispanic nor Latino. 


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 
Race (multiple choices): American Indian or Alaska Native; Asian; Black or African American; Native 
Hawaiian or other Pacific islander; White; Other. 
The tables and the listing that will be displayed are detailed in Sections 6.1.1.4 and 6.2.4 respectively. 
 
5.4.2. Study disease 
 
Study disease is assessed by the imaging procedure documenting the study disease, the presence of brain 
metastasis or not and the diagnosis. 
 
The most recent imaging procedure documenting at least one enhancing lesion with a size of minimum 5 mm 
will be described: Computed Tomography (CT), MRI, other. Time from this procedure to the first injection of 
contrast agent will be presented in months: (injection date - procedure date) / 30.4. 
 
Presence of brain metastasis will be described. 
 
Study disease diagnosis will be coded in Primary System Organ Class (SOC) and Preferred Terms (PT) using 
the Medical Dictionary for Regulatory Activities (MedDRA) dictionary version 20.1. The table will be sorted 
by descending global frequencies of SOC and by descending global frequencies of PT within each SOC and 
presented by presence of brain metastasis or not. 
 
The tables and the listing that will be displayed are detailed in Sections 6.1.1.4 and 6.2.4 respectively. 
 
5.4.3. Risk factors 
 
Not applicable. 
 
5.4.4. Medical history and concomitant diseases 
 
Medical history collected at screening visit will be classified as follows: 
 
Past diseases are defined as diseases which are not “ongoing” at the time of the assessment of the subject’s 
medical history. 
 
Concomitant diseases are defined as diseases which are “ongoing” at the time of the assessment of the 
subject’s medical history. 
 
Medical history will be coded in Primary SOC and PT using the MedDRA dictionary version 20.1. Data on 
medical history recorded at screening visit will be summarized according to SOC and PT. 
 
The table will be sorted by descending frequency of SOC and, within each SOC, by descending frequency of 
PT. 
 
The tables and the listing that will be displayed are detailed in Sections 6.1.1.4 and 6.2.4 respectively. 
 


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5.4.5. Clinical laboratory evaluation at baseline 
 
Serum creatinine and eGFR locally analyzed at Visit 2 and Visit 4 will be described as baseline characteristics 
using the Safety Set. These parameters will be described as quantitative variables in both Standard 
International (SI) and conventional (i.e. United States) units. Numbers and percentages of subjects with a value 
of eGFR < 60 mL/min/1.73m² will also be presented. 
 
Serum creatinine and eGFR locally analyzed at Visit 1 will be only listed. 
 
Hematology and biochemistry parameters centrally analyzed before the 1st injection of contrast agent will be 
presented as part of safety analysis (see Section 5.6.4) along with those collected after. Urinalysis data will be 
listed only. 
 
The tables and the listing that will be displayed are detailed in Sections 6.1.1.4 and 6.2.4 respectively. 
 
5.4.6. Vital signs, physical findings and other observations related to safety at baseline 
 
ECG and vital signs data measured before the 1st injection of contrast agent will be presented as part of safety 
analysis (see Section 5.6.5). 
 
5.4.7. Prior therapies 
 
Previous medications are medications ended before the first administration of contrast agent. They correspond 
to medications with the category of end period: 1 = “Before first IMP administration”. 
 
Subject’s previous medications will be coded using the World Heath Organization (WHO) Drug dictionary 
version B3 WHO DDE sept 2017. The number and percentage of subjects who took concomitant medications 
ended before the first administration of contrast agent will be summarized according to Anatomical 
Therapeutic Chemical (ATC) system main group (ATC1, ATC first level corresponds to the first letter of the 
ATC code). 
 
The table will be sorted according to the percentage of subjects reporting at least one previous medication 
from the most to the least frequent globally. 
 
The tables and the listing that will be displayed are detailed in Sections 6.1.1.4 and 6.2.4 respectively. 
 


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5.4.8. Other baseline characteristics 
 
Other baseline characteristics collected are subject intolerance to contrast agent history, physical examination, 
pregnancy test and MRI examination. 
 
5.4.8.1 
Subject Intolerance to Contrast Agent History 
 
Subject intolerance to contrast agent history at screening includes the following parameters: 
 
Previous intolerance due to contrast agent: Yes; No. 
 
If yes, Type of product (multiple choices): Gadolinium complex; Iodinated contrast agent; Barium; 
Diagnostic radiopharmaceutical; Other. 
 
These data will be displayed in a listing only (see Section 6.2.4). 
 
5.4.8.2 
Physical Examination 
 
These data will be displayed in a listing only (see Section 6.2.4). 
 
5.4.8.3 
Pregnancy Test 
 
These data will be displayed in a listing only (see Section 6.2.4). 
 
5.4.8.4 
MRI Examination 
 
MRI examination at Visit 2 and Visit 4 includes the following parameters: 
 
MRI performed: Yes; No. 
 
If yes: 
o Time between the injection of contrast agent and T1 post-injection sequence (minutes) 
calculated for each of the MRI procedure using the following formula: Date/time of the T1 
post-injection - Date/time of the injection of contrast agent. 
o MRI examination: Brain; Spine. 
o Magnetic field strength: 1.5 Tesla (T); 3.0T. Any other value will be considered as missing. 
 
Descriptive statistics for MRI examination will be presented by contrast agent using the FAS. The occurrence 
of any deviation from the MRI procedures (Yes; No; If yes, Specification (multiple choices): Scanner-related 
deviation; Subject-related deviation) and the anatomy, that is to say the MRI examination as per central 
readers, will be only listed. 
 
The table and the listing that will be displayed are detailed in Sections 6.1.1.5 and 6.2.5 respectively. 
 


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5.5. Efficacy evaluation 
Listing of all efficacy data will be presented in CSR appendix 16.2.6. 
 
5.5.1. Primary analysis of the primary criteria 
 
The primary objective of the study is to determine a safe and effective dose of P03277 based on a comparison 
of CNR between several doses, 0.025, 0.05, 0.1 and 0.2 mmol/kg of P03277 and MultiHance® at 0.1 mmol/kg. 
 
The primary criterion is the CNR calculated from the SI measurement of maximum 3 enhanced lesions by the 
3 independent blinded readers. CNR averaged for matching lesions per subject will be used in the primary 
analysis. 
 
The primary analysis will test differences of means of primary criterion for each dose of P03277 compared to 
MultiHance® and will be done for each of the 3 independent blinded readers (off-site) using the PPS. Holm’s 
step-down method [1] will be used to address multiplicity testing considering the 4 contrast agents to be tested. 
 
A subject will be analyzed as soon as he has a matching evaluation of the CNR at both MRIs by at least one 
off-site reader. Therefore the numbers of subjects analyzed by reader may be different. 
 
5.5.1.1 
Statistical Hypothesis for the Primary Analysis 
 
For each of the 3 readers and each dose of P03277 (4 doses), a mixed model for correlated data will be done 
for assessing the primary criterion. Factors included in the 12 different models are contrast agent (P03277 and 
MultiHance®) and the pre contrast CNR measurement (baseline). 
 
Differences between means for each contrast agent versus MultiHance® will be tested according to the 
following items: 
 
μi is the expected average of CNR of enhanced lesions for each dose of P03277 (where i is corresponding 
to one dose of P03277). 
 
μ0 is the expected average of CNR of enhanced lesions for corresponding MultiHance® group. 
 
Null hypothesis 
Hi: μi - μ0 ≤ 0, i = 1…4 
 
Alternative hypothesis 
Ki: μi - μ0 > 0, i = 1…4 
 
For each contrast agent, the p-value for comparing the doses of P03277 with corresponding MultiHance® is 
calculated for testing above hypotheses and the associated 95% two-sided Confidence Interval (CI) is 
provided. 
 
5.5.1.2 
Holm’s Step-Down Method 
 
Let p1, p2, p3 and p4 be the ordered p-values (from the lower to the upper value) and H1, H2, H3 and H4 be the 
corresponding ordered null hypothesis. The testing procedure starts with the most significant comparison and 


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continues as long as tests are significant (meaning that the alternative statistics is met). The procedure stops 
the first time a non-significant comparison occurs and all remaining hypotheses will not be tested. 
 
In the first step, H1 is rejected if p1 ≤ α/4, in the second step (if any) H2 is rejected if p2 ≤ α/3, in the third 
step (if any), H3 is rejected if p3 ≤ α/2 and in the fourth and last step, H4 is rejected if p4 ≤ α, with α being 
the one-sided significance level of 0.025. 
 
The models will include the contrast agent group, the period and the unenhanced value as baseline data. The 
parameters of the mixed models will be estimated using the SAS® procedure Mixed. The difference between 
contrast agent groups in mean score and associated 95% two-sided CI will be computed. 
 
5.5.1.3 
SAS® Procedure 
 
The SAS® procedure used for the primary analysis of the primary criterion will be the following: 
 
proc mixed data = XXX method = REML; 
  class subject trt period; 
  model eval = trt period baseline; 
  random subject / type = cs; 
  lsmeans trt / pdiff = controlu(‘MultiHance’) tdiff cl alpha = 0.025; 
  /* The following code is needed as previous statement lsmeans does not provide the upper limit of CI */ 
  lsmeans trt; 
  estimate "P03277 - MultiHance" trt 1 -1 /cl; 
run; 
 
A plot of Least Squares (LS) means from the mixed models for correlated data will be designed. The figure 
will display the doses on X axis and the difference versus MultiHance® on Y axis 
 
5.5.1.4 
Validation of Statistical Model 
 
The validation of the statistical model used for the primary analysis will be done through graphical method. A 
normal Quantile-Quantile (Q-Q) plot will be drawn for each off-site reader. If we observe visually a strong 
deviation from normality hypotheses, alternative methods can be proposed to fit more appropriately the data 
distribution (log transformation, non-parametric analyses, …). 
 
5.5.1.5 
Selection Basis for Clinical Dose 
 
The clinical dose will be selected according to the clinical benefit/risk ratio among the four doses evaluated 
based on the primary and secondary efficacy criteria analyzed in this study. A dose of P03277 which is not 
proved to be superior to the comparator on the primary criterion could however be recommended for use. 
 
The table and the figures that will be displayed are detailed in Section 6.1.2.1.1 and the listings in Section 
6.2.6.1. 
 
 
 


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5.5.2. Supportive analyses of primary criterion 
 
5.5.2.1 
FAS Analysis 
 
The primary analysis will be repeated using the FAS. However, this analysis will be restricted to subjects with 
CNR data at both MRIs. It will avoid the mixed model to impute any missing CNR data. All lesions will be 
considered, including not matched lesions, on the contrary to the primary analysis. Lesions not matching 
between both MRIs will therefore be included in this supportive analysis. 
 
The table and the figure that will be displayed are detailed in Section 6.1.2.1.2. 
 
5.5.2.2 
Overall Analysis 
 
The primary analysis will be repeated using the PPS for matching lesions only and considering in the same 
model data from the 3 off-site readers. The reader factor will be included in the model and repeated by subject. 
 
For each dose of P03277 SAS® procedure used for this analysis will be the following: 
 
proc mixed data = XXX method = REML; 
  class subject trt period reader; 
  model eval = trt period baseline reader trt*reader; 
  random subject / type = cs; 
  lsmeans trt / pdiff = controlu(‘MultiHance’) tdiff cl alpha = 0.025; 
  lsmeans trt; 
  estimate "P03277 - MultiHance" trt 1 -1 /cl; 
run; 
 
The table that will be displayed is detailed in Section 6.1.2.1.2. 
 
5.5.2.3 
Descriptive Statistics 
 
Results of CNR from both unenhanced and contrast enhanced SI measurements will be presented at subject 
level (mean by subject) for each off-site reader and each dose of P03277 by period and combined periods 1 
and 2 according to the contrast agent group. 
 
By-site summaries will be produced to look for potential disparities among the sites (center effect). The 
presentation will be limited to descriptive statistics of contrast enhanced SI measurements in total. The p-
values will not be reported for the by-site summaries. 
 
Descriptive statistics of CNR from contrast enhanced SI measurements in total will be presented at subject 
level (mean by subject) for each off-site reader according to the contrast agent group and magnetic field: 1.5T 
or 3.0T. 
 
Every descriptive analyses will be performed using the FAS restricted to patients with CNR data at both MRIs. 
Global descriptive statistics will be performed also using the PPS for matching lesions only. 
 
The tables that will be displayed are detailed in Section 6.1.2.1.2. 
 


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5.5.2.4 
Sensitivity Analysis on Subjects With Region of Interest Similarly Placed in MRI 1 and MRI 2 
 
The primary analysis will be repeated per reader using the PPS for matching lesions only on lesions with ROI 
similarly placed in MRI 1 and MRI 2 according to the lesion tracker. 
 
The table that will be displayed is detailed in Section 6.1.2.1.2. 
 
5.5.3. Additional analyses of primary criterion 
 
5.5.3.1 
Dose/Response Relationship 
 
The relationship between doses and CNR will be explored by two modeling approaches on all data observed 
under P03277. On the contrary to previous analyses, all subjects from the FAS with data under P03277 will 
be taken into account in the analysis, even if they had no MultiHance® in MRI 2. The following models will 
be performed considering the dose as a continuous variable: 
 
The linear model whose use is justified by the fact that it is the easiest approach needing no a priori 
knowledge of the pattern of relationship between dose and response. 
 
The Emax model, linear in log-dose, which may also be adequate based on existing data of CNR with 
P03277. 
These analyses will be performed for the 3 off-site readers independently. 
 
The linear model fits the dose/response function g(dose) according to the following formula: 
 
g(dose) = E0 + δ * dose, where E0 is the response at baseline (i.e., absence of dose) and δ is a slope factor. 
 
The SAS® procedure used for these analyses will be the following: 
 
proc reg data=XXX; 
  model eval =dose; 
  output out=XXX predicted=xx; 
run; 
 
The 4-parameter Emax model fitting the dose/response function g(dose) according to the following formula will 
be used: 
 
g(dose) = E0 + (Emax* doseλ) / (ED50λ + doseλ) 
 
where E0 is the response at baseline (i.e., absence of dose), Emax is the asymptotic maximum dose effect 
(maximum effect attributable to the contrast agent), ED50 is the dose which produces 50% of the maximal 
effect and λ is a slope factor. 
 
 
 


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The SAS® procedure used for these analyses will be the following: 
 
proc nlin data = XXX; 
  parms E0 = xxx Emax = xxx ED50 = xxx lambda = xxx; 
 /* Initial parameters may be estimated based on study data; in particular, lambda may be retrieved from 
the estimated slope parameter in proc reg above */ 
  model eval = E0 + (Emax * dose** lambda) / (ED50** lambda + dose** lambda); 
  output out=XXX predicted=xx; 
run; 
 
Results from these models will be displayed in tables containing estimates and in figures: 
 
Dose on X axis. 
 
CNR on Y axis. 
 
Adjusted line (linear model) or curve (Emax model). 
 
The tables and figures that will be displayed are detailed in Section 6.1.2.1.3. 
 
5.5.3.2 
Intra- Off-Site Reader Variability 
 
Intra-reading variability will be analyzed in a subgroup of 10% of subjects randomly selected for whom the 
off-site readers have re-read the images. 
 
Intra-central reader variability will be studied by a Bland-Altman graph [3]: 
 
Average of 1st and 2nd reading on X axis. 
 
Difference 2nd reading - 1st reading on Y axis. 
 
Horizontal lines at 0, Mean + 1.96SD and Mean - 1.96SD, where Mean and SD are the mean and the SD 
of the averages of 1st and 2nd readings. 
 
One scatter plot per reader will be presented with different colors for each dose of P03277. 
 
Descriptive statistics and the Intra-Class Correlation (ICC) [4] will also be provided. It will be based on a one-
way random effect model without observed effect: 
Yijk =  + i + ijk 
with i ~ N(0,) and ijk ~N(0,2) and ijk is independent of i. 
ICC = 2 / ( + 2) 
which is estimated by 
(MS – MS) / (MS + MS
where MS and MS are the mean sums of squares from the one-way ANalysis Of VAriance (ANOVA) 
model for between and within subjects, respectively. 
 
 
 


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SAS® procedure used for the analyses of this secondary efficacy criterion will be the following for each off-
site reader: 
 
ods output OverallANOVA =icc0; 
proc glm data=intra; 
  class patno reading; 
  model BV = patno reading; 
run; 
data ICC; 
  retain sb sw; 
  set icc0 end=last; 
  if source='Model' then sb=ms; 
  if source='Error' then sw=ms; 
  if last then do;  
    ICC=round((sb-sw)/(sb+sw), 0.01); 
    output; 
  end; 
run; 
 
The analyses will be performed using the FAS. 
 
The tables and figures that will be displayed are detailed in Section 6.1.2.1.3. 
 
5.5.3.3 
Inter- Off-Site Reader Variability 
 
Inter-reading variability will be evaluated on the whole set of study subjects, since each case was read by 3 
different readers. 
 
The same methodology as the one presented above for intra-off-site variability will be applied. One scatter 
plot for each of the 3 comparisons will be presented. The factor “reader” will be used instead of the factor 
“reading” in the model. 
 
The tables and figures that will be displayed are detailed in Section 6.1.2.1.3. 
 
5.5.4. Analysis of secondary criteria 
 
Depending on the way they were collected, the criteria will be displayed for the off-site readings and/or the 
on-site reading. Descriptions will be systematically done by reader. Analyses of secondary criteria will be 
described using the FAS only, except the first three criteria for which the PPS will be considered also (for 
matching lesions only). 
 
5.5.4.1 
CNR Calculated Based on Cerebrospinal Fluid 
 
As described in the Section 4, CNR calculated based on cerebrospinal fluid (CNRCSF) is added as secondary 
criterion. CNRCSF will be analyzed as the primary criterion but limited to the following analyses: PPS analysis, 
FAS analysis, descriptive analysis overall and dose response. 
 


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The tables and figures that will be displayed are detailed in Section 6.1.2.2.1 and the listings in Section 6.2.6.1. 
 
5.5.4.2 
Lesion-to-Brain Ratio 
 
As described in the Section 4, Lesion-to-Brain Ratio (LBR) is added as secondary criterion. LBR will be 
analyzed as the primary criterion but limited to the following analyses: PPS analysis, FAS analysis, descriptive 
analysis overall and dose response. 
 
The tables and figures that will be displayed are detailed in Section 6.1.2.2.2 and the listings in Section 6.2.6.1. 
 
5.5.4.3 
Contrast Enhancement Percentage 
 
As described in the Section 4, Contrast Enhancement Percentage is added as secondary criterion. It will be 
analyzed as the primary criterion without adding the pre contrast administration value in the models but limited 
to the following analyses: PPS analysis, FAS analysis, descriptive analysis overall and dose response. 
 
The tables and figures that will be displayed are detailed in Section 6.1.2.2.3 and the listings in Section 6.2.6.1. 
 
5.5.4.4 
Technical Adequacy of Images 
 
The adequacy of images was assessed by off-site readers and on-site radiologists as adequate or not and reason 
for inadequacy (with specification in case of other reason) recorded using a 5-items list. 
 
Descriptive statistics for these secondary efficacy criteria will be presented by contrast agent group. 
 
The tables and listings that will be displayed are detailed in Sections 6.1.2.2.4 and 6.2.6.2 respectively. 
 
5.5.4.5 
Lesion Detection Capacity 
 
The number of enhancing lesions, the size of the three largest representative lesions through their largest 
diameter and the location of the three largest representative lesions by subject were assessed by off-site 
readers and on-site radiologists for each dose of P03277 by contrast agent. 
 
Descriptive statistics will be presented for the largest diameter (mm) and the location of each of the three most 
representative lesions according to the contrast agent group and for each of the three independent off-site 
readers and the on-site reader. 
 
The number of enhancing lesions and the largest diameter of the smallest lesion detected will be analyzed in 
the same way with the following specifications: 
 
The exact number of enhancing lesions is not collected for off-site readings in case of > 10 lesions. A 
conventional value of 11 will be considered for both quantitative description and modeling (see below). 
 
The number of enhancing lesions will be described by presence of brain metastasis or not. This disposition 
is justified by an expected link of this stratification factor to the number of enhancing lesions. 
 
If ≤ 3 lesions are detected, the smallest lesion is the one with the smallest largest diameter. If > 3 lesions 
are detected, the largest diameter of the smallest lesion is specifically collected. 
 


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The number of enhancing lesions will be fitted by a multivariate model also. The negative binomial 
distribution is more appropriate than the more standard Poisson one for modeling lesion count data (see [5] in 
multiple sclerosis) and will therefore be used. 
 
The dependent variable will be the count of enhancing lesions. The model will include the factor contrast agent 
group and period. The model will be limited to the subjects with presence of brain metastasis which is 
supposed to be linked to the number of enhancing lesions. Each off-site reader will be analyzed by a specific 
model and on-site reading will be analyzed in the same way. The parameters of the model will be estimated 
using the SAS® procedure Glimmix. The difference between contrast agent groups in mean of lesions detected 
and associated 95% CI will be computed for each dose of P03277. 
 
For each dose of P03277 SAS® procedure used for the analyses of this secondary efficacy criterion will be the 
following for each off-site reader and on-site reading: 
 
proc glimmix data = XXX; 
  class subject trt period; 
  model eval = trt period / dist = negbin link = id; 
  random _residual_ / subject = subject type = cs; 
  lsmeans trt / pdiff = controlu(‘MultiHance’) tdiff cl alpha = 0.025; 
  lsmeans trt; 
  estimate "P03277 - MultiHance" trt 1 -1 /cl; 
run; 
 
The number of lesions detected on off-site readings will be listed only. 
 
The absence of contrast enhancement is defined at lesion level by a degree of contrast enhancement equal to 
1 = no: no enhancement. The absence of contrast enhancement will be analyzed at subject level only by 
considering its absence as soon as it is absent for all lesions. It will be presented by descriptive statistics. 
 
The tables and listings that will be displayed are detailed in Sections 0 and 6.2.6.2 respectively. 
 
5.5.4.6 
Lesion Visualization Variables 
 
Off-site blinded readers and on-site radiologists graded the lesion visualization of the three largest 
representative lesions, using 3 variables (lesion border delineation, internal morphology and degree of 
contrast enhancement) assessed on a 4-point scale ranging from 1 to 4. For each variable, one subject score 
will be computed in adding up all lesion scores within subject by contrast agent. 
 
The above lesion variables will lead to 3 scores at subject level consisting in adding up scores of lesions for 
each subject: border delineation sum of scores, visualization of internal morphology sum of scores and degree 
of contrast enhancement sum of scores. 
 
For each of the three lesion variables, a sum of scores will be computed. Endpoints are defined based on a 4-
point scale ranging from 1 to 4 for the 3 most representative lesions. 
 
The sum of scores for each of the three variables will be calculated as follows: Sum of scores = score of the 
lesion number 1 + score of the lesion number 2 + score of the lesion number 3. The sum of scores for each of 


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the lesion endpoints will range from 0 to 12. The following rules will apply independently for each of the three 
variables: 
 
In case of absence of lesions, the sum of scores will be equal to 0. 
 
In case of one or two lesions only, the collected score(s) will be considered and added in case of two. 
 
If one score is missing for one lesion then the sum of scores will be missing. 
 
For each dose of P03277, the two contrast agent groups will be compared using a mixed model for correlated 
data. Each mixed model will be performed for the three independent off-site readers and the on-site reader. 
 
For each mixed model, the dependent endpoints will be the sum of scores of lesion border delineation, the 
sum of scores of visualization of lesion internal morphology and the sum of scores of degree of lesion contrast 
enhancement, respectively. 
 
The models will include the contrast agent group and the period. The parameters of the mixed models will be 
estimated using the SAS® procedure Mixed. The difference between contrast agent groups in mean score and 
associated 95% CI will be computed for each dose of P03277. 
 
Analyses using the FAS will be restricted to subjects whose the criterion of interest (lesion border delineation, 
internal morphology or degree of contrast enhancement) is available at both MRIs. 
 
For each dose of P03277 SAS® procedure used for the analyses of these secondary efficacy criteria will be: 
 
proc mixed data = XXX method = REML; 
  class subject trt period; 
  model eval = trt period; 
  random subject / type = cs; 
  lsmeans trt / pdiff = controlu(‘MultiHance’) tdiff cl alpha = 0.025; 
  lsmeans trt; 
  estimate "P03277 - MultiHance" trt 1 -1 /cl; 
run; 
 
Descriptive quantitative statistics for the 3 sums of scores for border delineation, visualization of internal 
morphology and degree of contrast enhancement will be presented by contrast agent group for each dose of 
P03277. 
 
The tables and listings that will be displayed are detailed in Sections 0 and 6.2.6.2 respectively. 
 
5.5.4.7 
Diagnostic Confidence 
 
Descriptive statistics for the diagnosis of the MRI and the level of diagnostic confidence will be presented by 
contrast agent group for each dose of P03277; off-site and on-site reader’s outcomes will be separately 
analyzed. 
 
The tables and listings that will be displayed are detailed in Sections 6.1.2.2.7 and 6.2.6.2 respectively. 
 
 
 


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5.5.4.8 
Overall Diagnostic Preference 
 
The level of overall diagnostic preference of images will be displayed as follows: 
 
P03277 is preferred to MultiHance®. 
 
No difference between the 2 contrast agents. 
 
MultiHance® is preferred to P03277. 
 
For each off-site reader, the overall diagnostic preference will be tabulated for each dose of P03277. Each 
dose of P03277 will be compared to MultiHance® by a Wilcoxon signed-rank test. 
 
SAS® procedure used for this analysis will be: 
 
proc univariate data=XXX; 
  class reader dose; 
  var diff; 
  output out=XXX probs=PROBS; 
run; 
 
The reason of this preference (at least one among a pre-specified list of 6) will be displayed according to the 
contrast agent preferred. 
 
The tables and listings that will be displayed are detailed in Sections 6.1.2.2.8 and 6.2.6.2 respectively. 
 
5.5.4.9 
Impact on Subject Treatment Plan 
 
The impact on subject treatment plan will be assessed by on-site radiologists and will be summarized for each 
dose of P03277 by contrast agent group. 
 
The table and the listing that will be displayed are detailed in Sections 6.1.2.2.9 and 6.2.6.2 respectively. 
 
5.6. Safety Evaluation 
All safety parameters will be analyzed using the Safety Set on the following contrast agent groups: “P03277 
0.025 mmol/kg”, “P03277 0.05 mmol/kg”, “P03277 0.1 mmol/kg”, “P03277 0.2 mmol/kg”, “Total P03277” 
and “MultiHance®”. A subject will be included in a group as soon as he actually received the displayed contrast 
agent, either at the 1st or the 2nd period. 
 
5.6.1. Extent of Exposure 
 
Extent of exposure will be described by a summary of durations in the study and a display of study contrast 
agent administration modalities. 
 
 
 


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5.6.1.1 
Summary of Durations in the Study 
 
The following times will be presented by descriptive statistics: 
 
Between the inclusion date and the 1st injection of contrast agent (days): date of the 1st injection of 
contrast agent - date of signature of the ICF. 
 
Between the 1st and the 2nd injection of contrast agent (days): date of the 2nd injection of contrast agent 
- date of the 1st injection of contrast agent. 
 
Between the 2nd injection of contrast agent and the last study visit (days): date of the subject’s last 
study visit - date of the 2nd injection of contrast agent. 
 
Between the inclusion visit and the last study visit (days): date of the subject’s last study visit - date 
of signature of the ICF. 
 
The table and the listing that will be displayed are detailed in Sections 6.1.3.1 and 6.2.5 respectively. 
 
5.6.1.2 
Study Contrast Agent Administration Modalities 
 
The following parameters will be presented by descriptive statistics: 
 
Location of injection site: Antecubital vein; Other (to be specified). 
 
Theoretical volume as per IWRS (mL). 
 
Volume of study contrast agent actually administered (mL). 
 
Occurrence of an overdose: Yes; No. 
 
Actual injection rate (mL/s): as a quantitative variable and as a categorical variable in 3 categories (< 
2 mL/s, [2 ; 3] mL/s and > 3 mL/s). 
 
Mode of injection: Manual; Power injector. 
 
The following parameters will be listed only: 
 
Number of vials dispensed: 1; 2; 3. 
 
Reason why the volume actually administered is different from the theoretical calculated volume as 
per IWRS (free specification). 
 
The table and the listing that will be displayed are detailed in Sections 6.1.3.1 and 6.2.5 respectively. 
 
5.6.2. Adverse Events 
 
AEs will be coded using MedDRA dictionary version 20.1. The time period for the assessment of AEs is the 
time interval between the signature of the ICF and the subject’s study end. AEs will be described 
systematically in terms of number and percentage of subjects with AEs and in terms of number of AEs. AEs 
will be displayed by period (MRI 1 and MRI 2) and overall. 
 
TEAEs will be defined as follows: 
 
If the AE starts prior to the 1st injection then the AE is not emergent (pre-injection). 
 
If the AE starts after the 1st injection, then the AE is emergent (post-injection). 
o If it starts between the 1st injection and the 2nd injection (<), then it will be considered as an 
emergent AE associated with the 1st contrast agent of the subject’s sequence. 
o If it starts after the 2nd injection (≥), then it will be considered as an emergent AE associated 
with the 2nd contrast agent of the subject’s sequence. 


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5.6.2.1 
Overall Safety Summary 
 
An overall summary of AEs will be presented using the Extended Set to catch AEs of subjects who did not 
receive at least one injection of contrast agent. The table will be presented with the overall “Total” column 
only with the following variables: 
 
Total number of AEs. 
 
Total number of subjects with at least one AE. 
 
Distribution of the number of AEs reported by subject (0, 1, 2 or 3 or more AEs). 
 
Total number of Serious AEs (SAEs) (variable “serious” classified as yes or missing). 
 
Total number of subjects with at least one SAE. 
 
Total number of AEs according to intensity. 
 
Total number of subjects with at least one AE according to intensity (subjects with AEs having 
different intensities will be counted in each category of intensity). 
 
Total number of AEs according to the outcome. 
 
Total number of subjects with at least one AE according to the outcome (subjects with AEs having 
different outcomes will be counted in each category of outcome). 
 
Total number of AEs requiring a concomitant drug (other action taken). 
 
Total number of subjects with at least one AE requiring a concomitant drug (other action taken). 
 
The same table will be displayed by dose of P03277 and period for Treatment Emergent AEs (TEAEs) using 
the Safety Set. The terms “AE” will be replaced by “TEAE”. The following variables will be also presented: 
 
Total number of TEAEs with causal relationship to the IMP. 
 
Total number of subjects with at least one TEAE with causal relationship to the IMP. 
 
Total number of TEAEs requiring withdrawal of study contrast agent (action taken). 
 
Total number of subjects with at least one TEAE requiring withdrawal of study contrast agent (action 
taken). 
 
The tables that will be displayed are detailed in Section 6.1.3.2.1. 
 
5.6.2.2 
TEAEs 
 
The number and percentage of subjects with at least one TEAE will be presented using the Safety Set by dose 
of P03277 and period according to Primary SOC and PT. 
 
The table will be sorted by descending frequency of SOC and, within each SOC by descending frequency of 
PT. 
 
The table that will be displayed is detailed in Section 6.1.3.2.2. 
 
5.6.2.3 
TEAEs with Causal Relationship to the IMP 
 
The number and percentage of subjects with at least one TEAE with causal relationship to the IMP will be 
presented by dose of P03277 and period according to Primary SOC and PT. AEs with causal relationship to 
the IMP are those described by the investigator with causal relationship to the IMP “related” or as AEs with 
unassessable relationship. 
 


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The table that will be displayed is detailed in Section 6.1.3.2.3. 
 
5.6.2.4 
TEAEs with Causal Relationship to a Study Procedure 
 
The number and percentage of subjects with at least one TEAE with causal relationship to a study procedure 
will be presented by dose of P03277 and period according to Primary SOC and PT. AEs with causal 
relationship to a study procedure are those described by the investigator with causal relationship to a study 
procedure “related” or as AEs with unassessable relationship. 
 
The table that will be displayed is detailed in Section 6.1.3.2.4. 
 
The listings that will be displayed on AEs and TEAEs are detailed in Section 6.2.7. They will present a 
complete description of the AE by Primary SOC, Lowest Level Term (LLT), PT and description, including 
date/time of onset, end date, duration, intensity, seriousness, causal relationship to the IMP, causal relationship 
to a study procedure, withdrawal of study contrast agent (action taken), concomitant drug (other action taken) 
and the outcome. The displayed duration of an AE will be computed in days using the following formula: 
event end date - date/time of onset + 1. In case one of the dates is missing or incomplete then the duration will 
be missing. The listings will be sorted by contrast agent group, subject number, date/time of onset, end date, 
Primary SOC, PT and description. 
 
5.6.3. Deaths, serious adverse events and other significant adverse events 
 
Deaths, if any, will be listed in Table 14.3.2.6. SAEs will be listed in Table 14.3.2.7. These listings will be 
sorted by contrast agent group, subject number, date/time of onset, end date, Primary SOC, LLT, PT and 
description. 
 
5.6.4. Clinical laboratory evaluation 
 
Hematology data from central laboratory include the following parameters (in SI and conventional units): 
 
 
SI units 
Conventional units 
Red Blood Cells (RBC) = Erythrocytes 
1012 /L 
106 /µL 
White Blood Cells (WBC) = Leukocytes 
109 /L 
103 /µL 
Neutrophils 
109 /L 
103 /µL 
Neutrophils/Total Cells 
% 
% 
Eosinophils 
109 /L 
103 /µL 
Eosinophils/Total Cells 
% 
% 
Basophils 
109 /L 
103 /µL 
Basophils/Total Cells 
% 
% 
Lymphocytes 
109 /L 
103 /µL 
Lymphocytes/Total Cells 
% 
% 
Monocytes 
109 /L 
103 /µL 


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SI units 
Conventional units 
Monocytes/Total Cells 
% 
% 
Platelet count 
109 /L 
103 /µL 
Hemoglobin 
g/L 
g/dL 
Hematocrit 
v/v 
% 
Mean Corpuscular Volume (MCV) 
fL 
fL 
 
Biochemistry data from central laboratory include the following parameters: 
 
 
SI units 
Conventional units 
Sodium 
mmol/L 
mEq/L 
Potassium 
mmol/L 
mEq/L 
Chloride 
mmol/L 
mEq/L 
Glucose 
mmol/L 
mg/dL 
Blood Urea Nitrogen (BUN) 
mmol/L 
mg/dL 
Urea 
mmol/L 
mg/dL 
Serum creatinine 
umol/L 
mg/dL 
eGFR 
mL/min/1.73m² 
mL/min/1.73m² 
Total protein 
g/L 
g/dL 
Calcium 
mmol/L 
mg/dL 
Phosphorus 
mmol/L 
mg/dL 
Total bilirubin 
umol/L 
mg/dL 
Indirect bilirubin 
umol/L 
mg/dL 
Conjugated bilirubin 
umol/L 
mg/dL 
Aspartate Amino Transferase (AST) 
U/L 
U/L 
Alanine Amino Transferase (ALT) 
U/L 
U/L 
Alkaline Phosphatase 
U/L 
U/L 
Lactate DeHydrogenase (LDH) 
U/L 
U/L 
Triglycerides 
U/L 
U/L 
Cystatin C 
U/L 
U/L 
 
Hematology and biochemistry parameters at visits 2, 3, 4 and 5 will be described as quantitative variables in 
both SI and conventional units. Numbers and percentages of subjects with values out of range (lower than the 
lower limit or higher than the upper limit of quantification) will also be presented, except if values for normal 
ranges are unknown for a parameter. 
 
Erythrocytes, neutrophils, eosinophils, basophils, lymphocytes, monocytes, hemoglobin and hematocrit 
(hematology) and potassium, chloride, BUN, urea, total protein, phosphorus, total bilirubin, AST, ALT, 
alkaline phosphatase, triglycerides and cystatin C (biochemistry) will be separately described by gender. 


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Change from baseline in serum creatinine, eGFR, BUN and cystatin C will be computed and described at 
visits 3, 4 and 5 in both SI and conventional units. The baseline value for each laboratory parameter will be 
the last value measured before the contrast agent administration (i.e. the assessment prior to 1st MRI). 
 
Shift tables presenting relative change from baseline in classes versus baseline in classes will be displayed for 
serum creatinine, eGFR, BUN and cystatin C. 
 
Baseline data will be classified as follows (no baseline categories will be used for cystatin C): 
 
SI units 
Conventional units 
 
Serum creatinine (umol/L): 
o < 20 
o ≥ 20 and < 40 
o ≥ 40 and < 60 
o ≥ 60 
 
 
eGFR (mL/min/1.73m²): 
o < 100 
o ≥ 100 and < 150 
o ≥ 150 and < 200 
o ≥ 200 
 
 
BUN (mmol/L): 
o < 2 
o ≥ 2 and < 4 
o ≥ 4 and < 6 
o ≥ 6 
 
Serum creatinine (mg/dL): 
o < 0.22 
o ≥ 0.22 and < 0.44 
o ≥ 0.44 and < 0.66 
o ≥ 0.66 
 
 
eGFR (mL/min/1.73m²): 
o < 100 
o ≥ 100 and < 150 
o ≥ 150 and < 200 
o ≥ 200 
 
 
BUN (mg/dL): 
o < 12 
o ≥ 12 and < 24 
o ≥ 24 and < 36 
o ≥ 36 
 
Relative change from baseline will be calculated as follows: 100* (post injection measurement - baseline 
measurement) / baseline measurement. Relative change from baseline will be classified as follows: 
 
≤ -50%. 
 
> -50% and ≤ -25%. 
 
> -25% and ≤ -15%. 
 
> -15% and < 0%. 
 
≥ 0% and < 15%. 
 
≥ 15% and < 25%. 
 
≥ 25% and < 50%. 
 
≥ 50%. 
 
Numbers and percentages of subjects in each class will be presented in both SI and conventional units for 
centrally analyzed data only. 
 
Urinalysis data will be only listed. 


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The tables and listings that will be displayed are detailed in Sections 6.1.3.3 and 6.2.8 respectively. 
 
5.6.5. Vital signs, physical findings and other observations related to safety 
 
5.6.5.1 
ECG 
 
Three values are expected at each time point (triplicate ECG): before injection, 45 (±15 minutes) after 
injection, between 2 and 4 hours after injection and 1 day after injection (for both injections). The value 
analyzed will be the mean of the non-missing values obtained from this triplicate ECG. 
 
The QT corrected (QTc) interval will be described, separating QTc Fridericia’s and QTc Bazett’s. These 
parameters at each time point will be described as quantitative variables. 
 
Change from baseline in ECG parameters will be computed and described at each post-baseline measurement. 
The baseline value will be the triplicate ECG measured prior to the injection of the 1st contrast agent. 
 
Numbers and percentages of subjects with values out of range will also be presented, based on a notable QTc 
> 450 ms, a notable QTc > 500 ms and a notable QTc change from baseline > 60 ms. 
 
Other ECG parameters than QTc will be listed only. 
 
The tables and the listing that will be displayed are detailed in Sections 6.1.3.4.1 and 6.2.9 respectively. 
 
5.6.5.2 
Vital Signs 
 
Vital signs were measured at 4 time points for both injections: before injection, 45 (±15) minutes after 
injection, between 2 and 4 hours after injection and 1 day after injection. Collected parameters were Systolic 
Blood Pressure (SBP) (mmHg), Diastolic Blood Pressure (DBP) (mmHg) and pulse rate (beats per minute 
[bpm]). 
 
Descriptive statistics for each parameter will be computed at each time point. Changes in each vital signs 
parameter from baseline will be computed and described by parameter. The baseline value will be the vital 
signs measured prior to the injection of the 1st contrast agent. 
 
Numbers and percentages of subjects with values out of range will also be presented. Normal ranges are the 
following: [90; 160] mmHg for SBP, ≤ 100 mmHg for DBP and [40; 100] bpm for pulse rate. 
 
The tables and the listing that will be displayed are detailed in Sections 6.1.3.4.2 and 6.2.9 respectively. 
 
5.6.5.3 
Injection Site Tolerance 
 
Tolerance at the injection site was assessed at 4 time points for both injections: during injection, 45 (±15) 
minutes after injection, between 2 and 4 hours after injection and 1 day after injection. Occurrence or not of 
the following events was collected at each time point: burning, pain, eruption, extravasation, inflammation, 
other (to be specified). In case of pain, a subject pain evaluation was detailed through a Visual Analogic Scale 
(VAS) from 0 to 10 cm, with 0 being “no pain” and 10 being “maximal pain”. 


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The above parameters will be described at each time point. 
 
The tables and the listing that will be displayed are detailed in Sections 6.1.3.4.3 and 6.2.9 respectively. 
 
5.6.6. Concomitant medications and procedures 
 
Concomitant medications are medications ended after the first administration of contrast agent or ongoing at 
the end of the study. They correspond to medications with the categories of end period: 2 = “Between first and 
second IMP administration”, 3 = “After second IMP administration” and 4 = “Ongoing at the end of the study”. 
 
Subject’s concomitant medications will be coded using the WHO Drug dictionary version B3 WHO DDE sept 
2017. The number and percentage of subjects who took concomitant medications ended on or after the first 
administration of contrast agent will be summarized according to ATC1. 
 
The table will be sorted according to the percentage of subjects reporting at least one concomitant medication 
from the most to the least frequent globally. 
 
The table and the listing that will be displayed are detailed in Sections 6.1.3.4.3 and 6.2.4 respectively. 




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7. SHELLS FOR TABLES, FIGURES AND LISTINGS  
All outputs will be produced using SAS® version 9.2. 
All recorded data will be listed following the table order and structure of the eCRF. In addition, all derived 
data used in the analyses will be listed. The listings will include all subjects and will be ordered by site and 
subject. 
Unless otherwise indicated, in case of continuous or ordinal variables summary statistics are the n, mean, SD, 
median, minimum and maximum. The mean and median will be reported to 1 decimal more than the data; SD 
to 2 more decimals than the data; and minimum and maximum to the same number of decimals as the data. In 
case of nominal variables, summary statistics are the n and the frequency in terms of percentage. 
7.1. Contents of clinical study report section 14 
See appendices. 
7.2. Contents of clinical study report section 16.2 
See appendices. 
 
 


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8. REFERENCES 
1. Holm S et al. A Simple Sequentially Rejective Multiple Test Procedure. Scandinavian Journal of 
Statistics, 1979; 6: 65-70 
2. ICH-E3 Note for Guidance on Structure and Content of Clinical Study Reports 
3. Bland JM et al. Measuring agreement in method comparison studies. Statistical Methods in Medical 
Research, 1999; 8: 135-160 
4. Barnhart HX et al. An Overview On Assessing Agreement With Continuous Measurement. Journal 
of Biopharmaceutical Statistics, 2007; 17: 529-569 
5. Morgan CJ et al. Modeling lesion counts in multiple sclerosis when patients have been selected for 
baseline activity. Multiple Sclerosis 2010; 16: 926-934 
 
 


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9. APPENDICES 
Contents of clinical study report section 14: see attached document “Guerbet - GDX-44-004 - SAP - Final1.0 
- Attachment - Tables”. 
 
Contents of clinical study report section 16.2: see attached document “Guerbet - GDX-44-004 - SAP - Final1.0 
- Attachment - Listings”.