Clinical trial NCT02973516
Conditions: Chronic Liver Disease HepatoCellular Carcinoma
Sponsor: Guerbet
Start date: 2016-12-01; Completion date: 2019-04-04
Enrollment: 41 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is an exploratory study aiming to collect data about diagnosis efficacy (sensitivity and specificity) of P03277 triphasic liver imaging for HCC in subjects with suspected small nodules and chronic liver disease. 30 subjects will be included, having HCC confirmed or not by previous enhanced CT and/or MRI and before any biopsy for histology analysis. The standard of reference for diagnosis will be given by the site according to their standard of care and adapted from EASL/EORTC diagnostic criteria (considering previous contrast enhanced imaging (CT and/or MRI) and/or biopsy specimen analysis given on-site and/or the more recent AFP results available). 10 additional subjects will be included to explore the diagnostic efficacy for HCC at half dose of P03277.

Detailed description:

Arms: arm 1: P03277 will be administered in order to acquire triphasic liver imaging
Interventions: intervention 1: P03277 at 0.1 mmol/kg intervention 2: P03277 at 0.05 mmol/kg
Intervention descriptions: intervention 1: P03277 will be administered at 0.1 mmol/kg BW (corresponding to 0.2 mL/kg BW) by intravenous (IV) bolus injection at 2 mL/s rate without dilution, followed by a 0.9% saline flush. intervention 2: P03277 will be administered at 0.05 mmol/kg BW (corresponding to 0.1 mL/kg BW) by intravenous (IV) bolus injection at 2 mL/s rate without dilution, followed by a 0.9% saline flush.

Protocol documents:
Prot_000.pdf: 
Document Type 
Study Protocol 
Document Date 
December 12, 2017 
Official Title 
Proof of Concept study concerning efficacy of P03277 MR Imaging 
in HCC diagnosis 
NCT Number 
NCT02973516 
 


 
 
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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-44-008 
Proof of Concept study concerning efficacy of P03277 MR Imaging in HCC diagnosis 
Phase IIa Clinical Study 
 
Design 
Multicenter, exploratory, non randomized, open label, two cohorts, two doses, phase IIa study 
EudraCT No.: 2016-002930-62 
IND No.: 123673 
COORDINATING INVESTIGATORS 
 
 
 
 
 
 
 
 
 
 
SPONSOR 
GUERBET, B.P. 57400, 95943 Roissy CdG Cedex, FRANCE 
GUERBET MEDICAL EXPERT 
 
  
PHARMACOVIGILANCE 
 
Fax: + 33 1 45 91 67 70 
E-mail: pharmacovigilance.headquarters@guerbet-group.com 
 


 
 
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STUDY SYNOPSIS 
Study Title: 
Proof of Concept study concerning efficacy of P03277 MR Imaging in HCC diagnosis 
Protocol No: GDX-44-008 
Study product: P03277 
 
Active ingredient: P03277 
EudraCT number: 2016-002930-62 
IND Number: 123673 
Participating countries (Number of sites): 
Minimum 2 sites in France 
Study objectives 
Primary objective:  
To evaluate the diagnostic value for hepatocellular carcinoma (HCC) of P03277 in patients with 
suspected small nodules and chronic liver disease. 
Secondary objectives: 
To evaluate multiple quantitative and qualitative efficacy parameters and the safety (clinical and 
biological) profile of P03277 following single administration in suspected HCC patients 
Study Design and methodology  
Multi center, exploratory, non randomized, open label, two cohorts, two doses, phase IIa study. 
Number of Subjects / Sample size 
In total 40 subjects will be included in this exploratory study: 
- 
Firstly, 30 subjects in a first cohort with a P03277 dose of 0.1 mmol/kg 
- 
Then 10 subjects in a second cohort with a P03277 dose of 0.05 mmol/kg  
Site selection:  
The site should have appropriate expertise in liver MR imaging as well as clinical facilities. 
Investigators should have experience in conducting clinical studies and medical staff should have 
appropriate level of training. 
Eligibility criteria 
Selection/inclusion criteria : 
1. Female or male adult subject aged at least 18 years old or older (subject having reached legal 
majority age). 
2. Subject able and willing to participate to the study. 
3. 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. 
4. Subject presenting with liver cirrhosis or chronic liver diseases as shown by previous liver 
biopsy or by combination of clinical, endoscopic, biological, ultrasound parameters, and 
elastography 
5. Subject presenting with one to a maximum of 3 untreated hepatic nodule(s) of less than or equal 


 
 
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to 3 cm (long axis) previously identified and/or characterized through enhanced CT and/or MRI 
within a maximum of 21 days before P03277 imaging, confirmed for HCC or not  
6. Female subject must be using a medically approved contraception method* detailed below or be 
surgically sterilized or post-menopausal (>12 months amenorrhea)  
* 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). 
7. Subject affiliated to national health insurance according to local regulatory requirement 
To be selected and included in the study, the subject must meet all these inclusion criteria. 
 
Non-selection/non-inclusion criteria  
1. 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)  
2. Subject presenting with hepatic nodule more than 3 cm in addition to nodule(s) less than or 
equal to 3 cm 
3. Subject already treated for HCC by surgery or thermal ablation for which the resection or 
coagulation area is less than 2cm from the new nodule(s)  
4. Subject previously treated by transarterial chemoembolization 
5. Subject with moderate or severe renal impairment (eGFR < 60 mL/min/1.73m2) based on 
measurement done or available within the 7 days before P03277 administration and assessed 
after any iodinated contrast agent administration, or with dialysis end stage renal disease 
(ESRD)  
6. Subject with known class III/IV congestive heart failure according to the New York Heart 
Association classification 
7. Subject having received or is scheduled to receive any contrast agent within 7 days before 
P03277 planned administration date and within 3 days after P03277 planned administration 
date. 
8. Subject with known contra-indication(s) to the use or with known sensitivity to drugs from a 
similar pharmaceutical class as P03277 
9. Subject having received any investigational medicinal product within 7 days prior to  P03277 
planned administration date 
10. Subject presenting with any contraindication to MRI examination (see recommendations of the 
French Society of Radiology) 
11. Subject having planned palliative/treatment interventions for the suspected nodules 
(radiotherapy, chemotherapy or others) during the study period except for biopsy/surgery 
12. Subject related to the investigator or any other study staff or relative directly involved in the 
study conduct 


 
 
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13. Subject previously enrolled in this study 
14. 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. 
15. 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). 
16. Vulnerable subject according to article L1121-6 of the French Public Health Code, 
17. Subject under guardianship or unable to give his/her consent according to the article L1121-8 of 
the French Public Health Code  
Subjects presenting with one or more of these non-inclusion criteria must not be selected and included 
in the study. 
Investigational Medicinal Product administration:  
One single injection of P03277 to be administered with a power injector as an IV bolus at 2 mL/sec 
followed by a 0.9% saline flush at the same injection rate: 
- 
at a dose of 0.1 mmol/kg for the first cohort (30 subjects), 
- 
at a dose of 0.05 mmlo/kg for the second cohort (10 subjects). 
Study duration 
Subject participation duration could be from 2 days up to 3  months approximately 
- 
The maximal period between subject screening and P03277 administration in the trial is 7 days 
but can be the same day if eGFR measurement within the last 7 days is available.  
- 
Subject inclusion will be confirmed the day of administration with P03277 according to the 
eGFR results and urinary pregnancy test if applicable 
- 
Subject will be followed up at +1 day safety visit 
- 
Optionally and according to standard of care for histology analysis locally, the subject will have 
a specific biopsy or a surgically resected specimen collected at the time of loco-regional 
treatment. This procedure, whatever the type (biopsy, surgery), should be done between 3 days 
after P03277 administration and 13 weeks maximum. Alternatively it is acceptable to record 
results from histology done within 2 months prior to P03277 administration. 
The study will be considered as completed once all the images collected for all the subjects will 
have been reviewed by expert readers. 
Imaging Protocol 
1.5 T and 3T MR equipments will be accepted. The same machine for each site should be used all along 
the study. Automatic real time bolus tracking will be used.  
Standard Axial MR sequences will be used for pre-injection and post injection imaging. 
• 
Unenhanced imaging sequences: 
- 
GRE T1 in- and opposed-phase sequence 
- 
3D GRE T1 sequence with fat saturation 
- 
FSE T2 sequence with fat saturation (can be done after injection) 
 
• 
Contrast-enhanced imaging sequences - Post P03277 injection 
- 
3D GRE T1 sequences with fat saturation acquired during 3 time-points i.e. during arterial 


 
 
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(bolus track synchronization), portal (approx. 70-80 sec post injection) and delayed (3 minutes 
post injection) phases 
- 
3D GRE T1 sequences with fat saturation acquired at 15 ±5 minutes 
- 
3D GRE T1 sequences with fat saturation will be performed at 20mn, 1hour and 2 hours post-
injection for the first 5 subjects and then possibly extended to next subjects if significant liver 
parenchyma enhancement is depicted. 
Evaluation criteria:  
Primary criteria: 
 Nodule diagnosis at P03277 imaging (HCC, not HCC specify) will be assessed: 
• 
on a maximum of 3 hepatic nodules per subject 
• 
based on visual qualitative analysis of P03277 triphasic imaging (arterial, portal and 
delayed imaging) showing HCC typical hallmarks according to EASL/EORTC criteria 
(arterial hypervascularization and portal wash-out or delayed wash-out)  
• 
by two expert readers. In case of discordance, a consensus diagnostic will be obtained 
 The standard of reference for diagnosing liver nodules (HCC, other malignant, regenerative or 
dysplastic nodule, benign, uncertain) will be assessed by the site according to their standard of 
care and according to adapted EASL/EORTC diagnostic criteria, considering previous contrast 
enhanced imaging (CT and/or MRI) and/or histology analysis and/or the more recent AFP 
measurement available: 
HCC will be considered when:  
 
Histology is positive for HCC 
 
Or nodule identified and characterized by typical features using two different 
triphasic contrast enhanced modalities. Typical features are arterial 
hypervascularization and portal wash-out or delayed wash-out 
 
Or AFP>200ng/mL in a presence of a single nodule 
Other diagnosis than HCC could be based on imaging only and/or histology. 
Secondary criteria: 
Secondary criteria will consist of both efficacy and safety evaluations in participating subjects: 
Secondary efficacy criteria (by on-going on-site and/or expert reading):  
 Technical adequacy of images (on going on-site and expert reading): adequate, yes/no and 
reason for inadequate recorded (artifact due to subject, artifacts due to the machine, artifacts due 
to contrast agent, injection technical failure, other specify) 
 Visualization of biliary and liver vascular abnormalities (expert reading): presence of portal 
thrombosis, hepatic venous thrombosis, biliary tract invasion, and visualization of arterio-portal 
fistula.  
 Number of liver nodules detected (on going on-site and expert reading) 
 Qualitative evaluation (expert reading) 
• 
At each phase (unenhanced, arterial, portal, delayed, 15 ±5 minutes): nodule 
(maximum of 3) intensity relative to parenchyma according to the scale: 
hypointense, hyperintense or isointense (and relative to spleen on T2 if 
hyperintense); In addition nodules will be described as homogeneous or 
heterogeneous 
• 
Presence of fat and Iron within liver nodules at unenhanced in and opposed phase GRE 
sequence  
• 
Visualization (yes/no) of a perilesional capsule at portal or delayed phase or at 15 ±5 


 
 
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minutes 
 Quantitative evaluation (on going on-site): 
• 
At each phase, (unenhanced, arterial, portal, delayed, 15 ±5 minutes) SI measurement 
using ROIs placement in nodule (maximum of 3), liver, and background for SNR, CNR, 
percentage of nodule enhancement (PE)  
• 
On arterial  and on portal phase, SI measurement of the aorta and the portal vein 
maximum vessel enhancement for SNR calculation purpose  
 Qualitative evaluation (expert reading) for each available very delayed images (20mn, 1h, 2h) 
of any liver enhancement (hyperintense, isointense, hypointense) relative to the unenhanced fat-
suppresssed GRE T1 sequence and of nodule enhancement relative to parenchyma. 
 
Clinical and biological safety criteria: 
 For screening purpose, the subject will have physical examination (performed by a physician), 
vital signs (systolic and diastolic blood pressure in supine position, pulse rate), eGFR 
measurement locally if not available within 7 days before P03277 administration. Urine or 
blood sample for pregnancy test for women with childbearing potential should be done within 
24 hours prior to study MRI.  
 
The following evaluation will be done during the subject participation:  
 Vital signs (blood pressure, pulse rate): Before P03277 administration, 30 +/- 5 min after drug 
administration, and at Day +1 for all subjects 
 Biochemistry tests by central lab at screening visit or inclusion visit and after P03277 
administration at Day+1 for all subjects: sodium, potassium, chloride, random glucose, Blood 
Urea Nitrogen (BUN) / urea, creatinine, eGFR, Cystatin C, total protein, calcium, phosphorus, 
total bilirubin, conjugated bilirubin, unconjugated bilirubin, Aspartate Amino Transferase 
(AST), Alanine Amino Transferase (ALT), alkaline phosphatase, Lactate DeHydrogenase 
(LDH), Triglycerides (TG). 
 Hematology tests by central lab at screening visit or inclusion visit and after administration at 
Day+1 for all subjects : Red Blood Cells (RBCs), White Blood Cells (WBCs), neutrophils, 
eosinophils, basophils, lymphocytes and monocytes, platelet count, hemoglobin, hematocrit, 
Mean red blood Cells Volume (MCV). 
 Tolerance at the injection site will be recorded from time of administration of P03277 up to 30 
minutes post administration and 1 day after injection. 
 Adverse event (AE) will be recorded throughout the subject participation until the +1day safety 
FU. Only AE that the investigator considers as related to P03277 and/or the study procedures 
will be recorded at the optional Visit 4 between 3 days after P03277 administration up to 3 
month. 
Statistical methods:  
For primary endpoint: descriptive analysis of P03277 MRI sensitivity and specificity results using 
standard of reference will be presented by dose.  
Descriptive statistics will be provided for secondary efficacy endpoints will be presented by dose and 
clinical and biological safety and will presented by dose and overall. 


 
 
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STUDY FLOW CHART  
Visit 
Screening 
(V1) 
Inclusion and P03277 liver imaging visit 
(V2) 
Safety 
follow-
up 
(V3) 
Biopsy 
/procedure 
for specimen 
histology  
(V4 optional 
as per 
standard of 
care) 
Timing 
-7 to -0 days 
Inclusion 
Day 0 
Pre-injection 
Dosing 
Acquisition of 
triphasic MRI 
sequences 
30mn 
Optional very 
delayed 
acquisition 
Day +1 
Between 3 
days after 
V2 and up to 
13 weeks 
Informed consent signature 
x 
 
 
 
 
 
 
 
 
Eligibility criteria (1) 
x 
x 
 
 
 
 
 
 
 
Physical examination (2) 
x 
 
 
 
 
 
 
 
 
Demographic data 
x 
 
 
 
 
 
 
 
 
Medical history  
x 
 
 
 
 
 
 
 
 
Chronic liver disease 
status 
x 
 
 
 
 
 
 
 
 
Previous imaging results 
and AFP measurement 
collected for reference 
diagnosis 
x 
x 
 
 
 
 
 
 
 
Proposed diagnosis 
according to available 
examinations for standard 
reference (excluding 
histology and P03277 
images) 
 
 
 
 
 
 
 
x 
 
Biopsy histologic analysis 
for reference diagnosis (3) 
 
 
 
 
 
 
 
 
x 
Body weight  
 
x 
 
 
 
 
 
 
 
Concomitant treatments 
 
 
 
 
 
 
 
 
 
Pregnancy test (4) 
x  
x 
 
 
 
 
 
 
 
Vital signs (BP, HR) (5)  
x 
x 
 
 
 
x 
 
x 
 
Blood samples for 
laboratory parameters (6) 
(x) 
x 
 
 
 
 
 
x 
 
e-GFR for screening (7) 
x 
 
 
 
 
 
 
 
 
IP administration 
 
 
 
x 
 
 
 
 
 
MRI examination (8) 
 
 
x 
 
x 
 
(x) 
 
 
Injection-site tolerance (9) 
 
 
 
 
 
 
 
x 
 
Adverse events (AEs) (10) 
 
 
 
 
 
 
 
 
(x) 
 
(1) Inclusion criteria checked at the screening visit must be confirmed at the inclusion visit. 
(2) Physical examination should be performed by a physician: examination of general appearance, skin, neck 
(including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, vascular 
and neurological. Information indicating the global assessment (normal or abnormal (specify) of the physical 
examination should be recorded on source documentation. 
(3) It is acceptable to record results from histology done within 2 months prior to P03277 administration 
(4) Urinary or serum pregnancy test for woman of childbearing potential to be performed at inclusion. Results 
must be negative to continue in the trial.  
(5) Vital signs (blood pressure, pulse rate).  


 
 
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(6) Biochemistry and hematology tests to be done by central lab. Baseline can be done at screening or inclusion 
visit. 
(7) e-GFR to be done by local Lab, and results must be available prior to administration of P03277  
(8) MRI examination includes unenhanced sequences and triphasic post-injection sequences (arterial, portal, 
delayed, 15 ±5 minutes). Very delayed sequence will be performed at 20mn, 1hour and 2 hours post-injection 
for the first 5 subjects and then possibly extended to next subjects if parenchyma enhancement is visualized 
(9) Injection-site tolerance monitoring is to be assessed from injection up to 30 minutes post injection and then at 
day +1 after administration. 
(10) AEs will be assessed beginning with subject’s informed consent signed and will end after the last follow up 
evaluation at day+1 after injection, and /or over a longer period if the investigator becomes aware of an 
adverse reaction/serious adverse reaction. At the time of optional visit 4, adverse event considered as related 
to the product/to the study should be reported in the study database. 
 






 
 
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ABBREVIATIONS  
AE 
 
Adverse Event 
AFP 
 
Alpha fetoprotein 
AR 
 
Adverse Reaction 
ALT 
 
Alanine Amino Transferase 
AST 
 
Aspartate Amino Transferase 
ATC 
 
Anatomical Therapeutic Chemical classification system 
BMI 
 
Body Mass Index 
BP 
 
Blood Pressure 
BUN 
 
Blood Urea Nitrogen 
BW 
 
Body Weight 
CA 
 
Competent Authority 
CRF 
 
Case Report Form 
CRO 
 
Contract Research Organization 
CT 
 
Computerized Tomography 
CNR 
 
Contrast to Noise Ratio 
DSMB  
Data Safety Monitoring Board  
EMA  
European Medicine Agency 
FAS 
 
Full Analysis Set 
FDA 
 
Food and Drug Administration 
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 
ICH 
 
International Conference on Harmonization 
IEC 
 
Independent Ethics Committee 
IMP 
 
Investigational Medicinal Product 
INV 
 
Investigator 
IRB 
 
Institutional Review Board 
ISF 
 
Investigator Site File 


 
 
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ITT 
 
Intent ToTreat 
IV 
 
Intravenous 
LDH 
 
Lactate Dehydrogenase 
LSO 
 
Last Subject Out 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCV  
Mean red blood Cells Volume 
MR 
 
Magnetic Resonance 
MRI 
 
Magnetic Resonance Imaging 
PE 
 
Percentage enhancement 
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  
Subject ID 
Subject IDentification 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
VAS 
 
Visual Analogic Scale 
WBCs  
White Blood Cells 
 


 
 
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TABLE OF CONTENTS 
STUDY SYNOPSIS ................................................................................................................................ 2 
STUDY FLOW CHART ......................................................................................................................... 7 
STUDY DIAGRAM................................................................................................................................ 9 
SIGNATURE PAGE ............................................................................................................................. 10 
ABBREVIATIONS ............................................................................................................................... 11 
TABLE OF CONTENTS ...................................................................................................................... 13 
AMENDMENT N°2.............................................................................................................................. 16 
1. 
INTRODUCTION AND STUDY RATIONALE ................................................................. 22 
2. 
STUDY OBJECTIVES ......................................................................................................... 24 
2.1 
Primary Objective .............................................................................................................. 24 
2.2 
Secondary Objectives ........................................................................................................ 24 
2.3 
Sub-Study / Ancillary Study Objectives ............................................................................ 24 
3. 
STUDY DESIGN .................................................................................................................. 25 
3.1 
Protocol Description .......................................................................................................... 25 
3.2 
Study Duration .................................................................................................................. 25 
3.3 
Interim Analysis ................................................................................................................ 25 
3.4 
Study Committee(s) ........................................................................................................... 25 
4. 
SUBJECT SELECTION ....................................................................................................... 26 
4.1 
Inclusion Criteria ............................................................................................................... 26 
4.2 
Non Inclusion Criteria ....................................................................................................... 26 
4.3 
Subject Identification......................................................................................................... 27 
5. 
INVESTIGATIONAL MEDICINAL PRODUCTS .............................................................. 28 
5.1 
Investigational Medicinal Product: P03277 ...................................................................... 28 
5.2 
Packaging, Labeling, Storage ............................................................................................ 28 
5.3 
Condition of Investigational Medicinal Product Allocation .............................................. 29 
5.4 
Investigational Medicinal Product Management ............................................................... 29 
5.5 
Non Investigational Medicinal Product(s) and Other Study Products ............................... 29 
5.6 
Study Product(s) Compliance and Accountability ............................................................ 30 
6. 
CONCOMITANT TREATMENTS ...................................................................................... 31 
6.1 
General considerations ...................................................................................................... 31 
6.2 
Concomitant Treatments of Special Attention .................................................................. 31 
6.3 
Prohibited Concomitant Treatments .................................................................................. 31 
7. 
EVALUATION CRITERIA .................................................................................................. 32 
7.1 
Primary Criterion ............................................................................................................... 32 
7.2 
Secondary Criteria ............................................................................................................. 33 


 
 
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8. 
NUMBER OF SUBJECTS .................................................................................................... 36 
9. 
STUDY SCHEDULE AND PROCEDURES ....................................................................... 37 
9.1 
Study Schedule .................................................................................................................. 37 
9.2 
Imaging Protocol ............................................................................................................... 39 
9.3 
On Site on going Reading of Images ................................................................................. 40 
9.4 
Expert Reading of Images ................................................................................................. 40 
9.5 
Other Centralized Study Procedures.................................................................................. 41 
10. 
SAFETY REPORTING ........................................................................................................ 42 
10.1 
Adverse Event ................................................................................................................... 42 
10.2 
Serious Adverse Event ...................................................................................................... 43 
10.3 
Pregnancy and Adverse Events of Special Interest ........................................................... 46 
10.4 
Other important safety issue /New fact ............................................................................. 46 
10.5 
Unblinding Procedures ...................................................................................................... 47 
11. 
PREMATURE DISCONTINUATION OF THE STUDY .................................................... 48 
11.1 
Premature Discontinuation of the Study per Guerbet Decision ......................................... 48 
11.2 
End of Study Participation for a Subject ........................................................................... 48 
12. 
STATISTICAL ANALYSIS ................................................................................................. 49 
12.1 
Subjects Included in the Analysis ...................................................................................... 49 
12.2 
Demographic and Baseline Data ....................................................................................... 49 
12.3 
Efficacy Data ..................................................................................................................... 49 
12.4 
Safety Data ........................................................................................................................ 51 
12.5 
Handling of Missing Data ................................................................................................. 53 
12.6 
Interim Analysis ................................................................................................................ 53 
13. 
STUDY COMMITTEES(S) .................................................................................................. 54 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS ..................................................... 54 
14.1 
References ......................................................................................................................... 54 
14.2 
Institutional Review Board/Independent Ethics Committee and Regulatory/Competent 
Authorities .................................................................................................................................... 55 
14.3 
Subject Informed Consent ................................................................................................. 56 
14.4 
Study Records and Archiving ............................................................................................ 56 
15. 
QUALITY CONTROL / QUALITY ASSURANCE ............................................................ 58 
15.1 
Direct Access to Source Data/Documents ......................................................................... 58 
15.2 
Clinical Monitoring ........................................................................................................... 58 
15.3 
Clinical Data Handling ...................................................................................................... 58 
15.4 
Audits and Inspections ...................................................................................................... 59 
 
 


 
 
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17. 
REFERENCES ...................................................................................................................... 61 
18. 
COMPANY LIABILITY INSURANCE .............................................................................. 62 
19. 
APPENDICES ....................................................................................................................... 63 
19.1 
Child-Pugh Classification of Severity of Liver Disease .................................................... 63 
 
 
 
 
LIST OF TABLES 
Table 1: Overview of efficacy variables ............................................................................................... 32 
Table 2 : Diagnostic value evaluation for HCC .................................................................................... 50 
 
LIST OF FIGURES 
 
 
 
 
 














 
 
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1. INTRODUCTION AND STUDY RATIONALE 
Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide in men (554,000 
new cases in 2012) and the ninth in women (228,000 new cases in 2012) and the second cause of 
cancer death responsible for more than 746,000 deaths in 2012 (1).  
The dual arterial-portal blood supply is one specific complexity for the hepatic vascularization. The 
liver has a unique dual blood supply, with a compensatory relationship existing between the two 
sources so that the arterial flow increases when the portal venous flow decreases. HCC are highly 
vascular tumors and derive neovasculature through the process of angiogenesis. Multiphasic contrast 
enhanced computed tomography scan (CT), magnetic resonance imaging (MRI) or ultrasound (US) 
allow evaluation of the liver during both the arterial and the portal venous phases of contrast 
enhancement and therefore have become important modalities for the detection and characterization of 
HCC.  
Surveillance program have changed the spectrum of HCC by depicting more small HCCs than before. 
For example, in Japan, HCC less than 2cm represented 4.6% of the cases between 1976 and 1985 and 
33.1% between 1996 and 2000 (2). Diagnosis of mall HCCs is more difficult because they are less 
typical and may mimic benign lesions (3). On the contrary to lesions more than 3 cm, the specificity of 
diagnosing small HCC raises imaging specificity issues because of false positive cases corresponding 
to arterio-venous shunts, benign lesions or to other nodules (4). Dynamic characteristics with high 
intensity at arterial phase accompanied by a wash-out at portal or delayed phase are considered highly 
specific for HCC (5).  
Gadolinium-Based Contrast Agents (GBCAs) have been used extensively in a large range of 
indications in MRI examinations. 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 multiphasic MRI, GBCA were found to participate to the characterization of malignancy of 
nodules in the liver. Extracellular GBCA are used for their ability to show typical characteristics for 
HCC with 0.820 (95% CI50.776, 0.857) of sensitivity in patients with any-sized lesions; and estimated 
specificities were 0.934 (95% CI50.881, 0.964) according to a recent meta-analysis (6). 
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.  




 
 
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2. 
STUDY OBJECTIVES 
2.1 Primary Objective 
To evaluate the diagnostic value (specificity and sensitivity) for hepatocellular carcinoma of P03277 in 
patients with suspected small nodules and chronic liver disease. 
 
2.2 Secondary Objectives 
To evaluate multiple quantitative and qualitative efficacy parameters and the safety (clinical and 
biological) profile of P03277 following single administration in suspected HCC patients 
 
2.3 Sub-Study / Ancillary Study Objectives  
Not applicable 
 
 


 
 
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3. 
STUDY DESIGN 
3.1 Protocol Description 
Dual center, exploratory, non randomized, open label, two cohorts, two doses, phase IIa study. 
The standard of reference for diagnostic will be given by the site according to their standard of care 
and adapted from EASL/EORTC diagnostic criteria (7) and considering previous contrast enhanced 
imaging (CT and/or MRI) and/or biopsy specimen analysis given on-site and/or the more recent AFP 
results available. 
 
3.2 Study Duration 
Subject participation duration could be from 2 days up to 3 months approximately 
- 
The maximal period between subject screening and P03277 administration in the trial is 7 days 
but can be the same day if eGFR measurement within the last 7 days is available.  
- 
Subject inclusion will be confirmed the day of administration with P03277 according to the 
eGFR results and urinary pregnancy test if applicable 
- 
Subject will be followed up at +1 day safety visit 
- 
Optionally and according to standard of care for histology analysis locally, the subject will 
have a specific biopsy or a surgically resected specimen collected at the time of loco-regional 
treatment. This procedure, whatever the type (biopsy or surgery), should be done between 3 
days after P03277 administration and 13 weeks maximum. Alternatively it is acceptable to 
record results from histology done within 2 months prior to P03277 administration.  
 
The study will be considered as completed once all the images collected for all the subjects will have 
been reviewed by expert readers. 
3.3 Interim Analysis  
Not applicable 
3.4 Study Committee(s)  
Not applicable 
 
 
 
 


 
 
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4. 
SUBJECT SELECTION 
4.1 Inclusion Criteria 
1. Female or male adult subject aged at least 18 years old or older (subject having reached legal 
majority age). 
2. Subject able and willing to participate to the study. 
3. 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. 
4. Subject presenting with liver cirrhosis or chronic liver disease as shown by previous liver 
biopsy or by combination of clinical, endoscopic, biological, ultrasound parameters, and 
elastography 
5. Subject presenting with one to a maximum of 3 untreated hepatic nodule(s) of less than or 
equal to 3 cm (long axis) previously identified and/or characterized through enhanced CT 
and/or MRI within a maximum of 21 days before P03277 imaging, confirmed for HCC or not  
6. Female subject must be using a medically approved contraception method* detailed below or 
be surgically sterilized or post-menopausal (>12 months amenorrhea)  
*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). 
7. Subject affiliated to national health insurance according to local regulatory requirement 
To be selected and included in the study, the subject must meet all these inclusion criteria. 
4.2 Non Inclusion Criteria 
1. 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 and 
within 24 hours prior to study MRI). 
2. Subject presenting with hepatic nodule more than 3 cm in addition to nodule(s) less than or 
equal to 3 cm 
3. Subject already treated for HCC by surgery or thermal ablation for which the resection or 
coagulation area is less than 2cm from the new nodule(s)  
4. Subject previously treated by transarterial chemoembolization 
5. Subject with moderate or severe renal impairment (eGFR < 60 mL/min/1.73m2) based on 
measurement done or available within the 7 days before P03277 administration and assessed 
after any iodinated contrast agent administration, or with dialysis end stage renal disease 
(ESRD)  
6. Subject with known class III/IV congestive heart failure according to the New York Heart 
Association classification 


 
 
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7. Subject having received or is scheduled to receive any contrast agent within 7 days before 
P03277 planned administration date and within 3 days after P03277 planned administration 
date. 
8. Subject with known contra-indication(s) to the use or with known sensitivity to drugs from a 
similar pharmaceutical class as P03277 
9. Subject having received any investigational medicinal product within 7 days prior to  P03277 
planned administration date 
10. Subject presenting with any contraindication to MRI examination (see recommendations of 
the French Society of Radiology) 
11. Subject having planned palliative/treatment interventions for the suspected nodules 
(radiotherapy, chemotherapy or others) during the study period except for biopsy/surgery 
12. Subject related to the investigator or any other study staff or relative directly involved in the 
study conduct 
13. Subject previously enrolled in this study 
14. 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. 
15. 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). 
16. Vulnerable subject according to article L1121-6 of the French Public Health Code, 
17. Subject under guardianship or unable to give his/her consent according to the article L1121-8 
of the French Public Health Code  
 
Subjects presenting with one or more of these non-inclusion criteria must not be selected and included 
in the study. 
 
4.3 Subject Identification 
After having signed their written informed consent, the subjects will be allocated an Identification 
Number (Subject ID).  
Once the subject satisfies 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 
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. 
 
5.1 Investigational Medicinal Product: P03277 
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:  
- 
0.1 mmol/kg BW (corresponding to 0.2 mL/kg body weight) for the first cohort (30 subjects), 
- 
0.05 mmol/kg BW (corresponding to 0.1 mL/kg body weight) for the second cohort (10 
subjects). 
P03277 will be injected 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).  
Sufficient IMP must be allocated to one subject according to his/her body weight. 
Route and method of administration: by intravenous (IV) bolus injection at 2 mL/s rate without 
dilution, followed by a 0.9% saline flush at same rate to ensure complete injection of the contrast 
medium. 
The P03277 administration is to be performed by power injector in order to better control injection 
rate. 
Please refer to the Investigator Brochure for more information on P03277. 
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 will be performed by Guerbet (or its designee).  


 
 
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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 
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. 
 
5.3 Condition of Investigational Medicinal Product Allocation 
5.3.1 
Investigational Product(s) Allocation / Randomization 
Since the study design is open label, IMP will not be allocated by randomization. Sufficient IMP(s) 
will be assigned to each investigational site. The Investigator will use the IMP with the lowest IMP 
number available at the site (chronological assignment). This number will be independent from the 
subject’s identification number. 
5.3.2 
Double-Blind Conditions  
Not applicable 
5.3.3 
Individual Study Treatment Unblinding  
Not applicable 
 
5.4 Investigational Medicinal Product Management 
The investigator, the hospital pharmacist, or other personnel allowed to store and dispense 
Investigational Medicinal Product(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, allow 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 
 


 
 
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5.6 Study Product(s) Compliance and Accountability 
The investigator, the hospital pharmacist, or other allowed personnel will keep accurate records of 
Investigational Medicinal Products 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. When protocol required IMP 
administration conditions are not followed, reason(s) will be given and recorded by the investigator. 
 
 
 


 
 
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6. 
CONCOMITANT TREATMENTS 
6.1 General considerations 
Any medication, including contraception, homeopathic products, over-the-counter medications, as 
well as prescription drugs, on-going at the time of subject’s informed consent signed or administered 
during the study will be recorded in the subject CRF until safety follow-up visit (Day+1). The 
following information must be provided:  
 Drug (brand name or generic name) 
 Route of administration 
 Purpose (Medical history/study disease/ AE/Premedication/contraception/Prophylaxis) 
 Indication  
 Duration of treatment 
6.2 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 CRF. 
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. 
6.3 Prohibited Concomitant Treatments 
Any other contrast agent should not be administered with 7 days before and 3 days after P03277 
administration.   
 
 
 


 
 
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7. 
EVALUATION CRITERIA 
An overview of the efficacy variables is provided in the Table 1: Overview of efficacy variables below. 
Table 1: Overview of efficacy variables 
  
7.1 Primary Criterion 
For evaluation of diagnostic value (defined as Sensitivity and Specificity) of P03277 for HCC the 
following will be assessed:  
Primary criteria: 
 Nodule diagnosis at P03277 imaging (HCC, not HCC specify) will be assessed: 
• 
on a maximum of 3 hepatic nodules per subject 
• 
Based on visual qualitative analysis of P03277 triphasic imaging (arterial, portal and 
delayed phases) showing HCC typical hallmarks according to EASL/EORTC criteria 
(arterial hypervascularization and portal wash-out or delayed wash-out)  
• 
by two expert readers. In case of discordance, a consensus diagnostic will be obtained 
 
 The standard of reference for diagnosing liver nodules (HCC, other malignant, regenerative 
or dysplastic nodule, benign, uncertain) will be given by the site according to their standard of 
care and according to adapted EASL/EORTC diagnostic criteria, considering previous contrast 
enhanced imaging (CT and/or MRI) and/or histology analysis and/or the more recent AFP 
results available: 
HCC will be considered when:  
 
Histology is positive for HCC 
 
Or Nodule identified and characterized by typical features using two different 
triphasic contrast enhanced modalities. Typical features are arterial 
hypervascularization and portal wash-out or delayed wash-out 
Variables 
On-going on-site 
Reading 
Expert Reading 
Primary efficacy variables 
 
 
Nodule diagnosis 
 
 
Secondary efficacy variables 
 
 
Technical adequacy of images 
 
 
Number of nodules detected 
 
 
Qualitative evaluation (nodule intensity, presence of intranodule iron 
and fat and visualization of perilesional capsule) 
 
 
Visualization of biliary and liver vascular abnormalities 
 
 
Qualitative evaluation at available very delayed image, liver 
enhancement relative to the unenhanced fat-suppressed GRE T1 
sequence and nodule signal enhancement relative to parenchyma 
 
 
Quantitative evaluation  
SI measurements in nodules, liver, background, aorta and the portal 
vein for SNR CNR PE  
 
 


 
 
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 
Or AFP>200ng/mL in a presence of a single nodule 
Other diagnosis than HCC could be based on imaging only and/or histology. 
7.2 Secondary Criteria 
7.2.1 
Efficacy assessments of P03277 imaging 
 
 Technical adequacy of images (ongoing on-site and expert reading) will be assessed as 
adequate, yes or no and reason for inadequacy will be recorded using a 5 items ( 1= Artifacts 
due to  subject , 2 = Artifacts due to machine, 3 = Artifacts due to contrast agent, 4 = Injection 
technical failure, 5 = Other, specify)  
 Visualization of biliary and liver vascular abnormalities (expert reading) will be 
described: presence of portal thrombosis, hepatic venous thrombosis, biliary tract invasion, 
and visualization of arterio-portal fistula.  
 Number of nodules detected (ongoing on-site and expert reading) 
 Qualitative evaluation (expert reading) 
• 
At each phase (T2, T1 unenhanced, arterial, portal, delayed, 15 ±5 minutes): nodule 
(maximum of 3) intensity relative to parenchyma according to the scale: hypointense, 
hyperintense or isointense (and relative to spleen on T2 if hyperintense); In addition 
nodules will be described as homogeneous or heterogeneous 
• 
Presence of fat and Iron within the liver nodules at unenhanced phase in and opposed 
phase (intra nodule)  
• 
Visualization of a perilesional capsule (yes/no) at portal phase or delayed phase or at 
15 ±5 minutes 
 
 Quantitative evaluation (ongoing on-site reading) 
• 
At each phase, (T1 unenhanced, arterial, portal, delayed, 15 ±5 minutes) SI 
measurement on nodule (maximum of 3), liver, and background for SNR, CNR, and 
nodule percentage enhancement (PE)  
 
Nodule SNR (Signal to noise ratio) will be calculated at each phase using the 
following formula: SInodule/SDnoise where SI nodule is “nodule ROI intensity” 
and SDnoise is “Background ROI: SD intensity”. 
CNR (contrast to noise ratio) will be calculated at each phase using the following 
formula: (SInodule-SIliver)/ SDnoise where SInodule is “nodule ROI intensity”; 
SIliver is “liver parenchyma ROI intensity” and SDnoise is “Background ROI: SD 
intensity”. 
PE (Nodule Percentage Enhancement) will be calculated using the following 
formula: [(SIpost-SIpre)/SIpre)]*100 where SIpost is the nodule signal intensity at 
each phase (arterial, portal, delayed, 15 ±5 minutes) and SIpre is the nodule signal 
intensity at unenhanced sequence. 
• 
On arterial and on portal phase, SI measurement of the aorta and the portal vein 
maximum vessel enhancement for SNR calculation purpose.  
 
Vascular SNR (Signal to noise ratio) will be calculated using the following 
formula: SIaorta/SDnoise where SI aorta is “aorta ROI intensity” and SDnoise is 
“Background ROI: SD intensity” at arterial phase, SI portal vein/SDnoise where SI 


 
 
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portal vein is “portal vein ROI intensity” and SDnoise is “Background ROI: SD 
intensity” at portal and delayed phases and at 15 ±5 minutes 
 Qualitative evaluation (expert reading) for each available very delayed images (20mn, 1h, 
2h) for visualization of the parenchyma enhancement relative to unenhanced fat-suppressed 
GRE T1 sequence (hyperintense, isointense, hypointense) and nodule enhancement relative to 
parenchyma 
 
7.2.2 
Safety assessment 
The safety assessments will be based on the following: Adverse Events (AEs), injection site tolerance, 
clinical laboratory parameters (blood), vital signs. A central laboratory will be used to analyze and 
report blood chemistry/hematology. eGFR would also have been evaluated locally only for screening. 
eGFR evaluated centrally will be used for safety evaluation.  
o Adverse events 
Adverse Event monitoring will be recorded until Day+1. After, AEs that the investigator 
considers related to P03277 and/or study procedures will be recorded at optional V4. 
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 agent injection (during the injection 
up to 30 ± 5 mn, 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  
For each subject, blood samples will be performed at baseline and Day+1 for being analyzed by 
a central laboratory. 
  
 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, random glucose, Blood Urea Nitrogen 
(BUN) / urea, creatinine, eGFR, Cystatin C, total protein, calcium, phosphorus, total 
bilirubin, unconjugated and conjugated bilirubin, Aspartate Amino Transferase (AST), 
Alanine Amino Transferase (ALT), alkaline phosphatase, Lactate DeHydrogenase 
(LDH). Triglycerides (TG). 
 
In female subjects of childbearing potential, a urine or serum pregnancy test will be performed 
on-site prior to the administration of IMP.  
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 or alternatively according to investigator’s judgement as medical history if measured 
at baseline and related to an underlying disease.  


 
 
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o Vital signs 
Vital signs (systolic and diastolic blood pressure in supine position, pulse rate) will be measured 
and recorded according to the following schedules: 
 
Immediately prior to each contrast agent injection (baseline value)    
 
At 30+/-5 minutes following P03277 injection 
 
One day after P03277 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 or 
alternatively according to investigator’s judgement as medical history if measured at baseline 
and related to an underlying disease. 
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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8. 
NUMBER OF SUBJECTS 
As a proof of concept study, no statistical test is planned. Subjects’ data will be analyzed with 
descriptive statistics investigating the potential efficacy of P03277 in the liver for the diagnosis of 
HCC, by dose. 
In total 40 subjects will be included: 
- 
Firstly, 30 subjects in a first cohort with a P03277 dose of 0.1 mmol/kg 
- 
Then 10 subjects in a second cohort with a P03277 dose of 0.05 mmol/kg  
Number of subjects for the first cohort of the study is based on the hypothesis supported by a meta-
analysis of several publications (8) that among the 30 subjects with suspected nodules, around 66% 
would have a HCC and the remaining subjects would be negative (liver nodule proven as a non HCC) 
and or uncertain after biopsy. Those hypothetic figures would help to estimate sensitivity and 
specificity values with the limitations expected for such small sample size. 
It is considered that 10 subjects included in the second cohort will be sufficient to have an exploratory 
evaluation of the diagnostic value based on sensitivity and specificity. 
 
 
 


 
 
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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 Section14.3; 
• 
The subject will be attributed an Identification Number as described in Section 4.3; 
• 
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; 
• 
Recording of demographic data such as sex, age, measurement of height, ethnic origin (self-
reported race/ethnicity). 
• 
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 
(type 
of 
agent 
: 
iodinated, 
gadolinium 
complex, 
barium, 
radiopharmaceutical, other specify) and report them in medical history; 
• 
Documentation of chronic liver disease history and status: documentation supporting the 
diagnostic of chronic liver disease (biopsy, endoscopic, biological, ultrasound parameters, and 
elastography), aetiology of chronic liver disease (alcohol, HBV, HCV, non-alcoholic-NASH, 
other specify) and last evaluation of Child Pugh score (see appendix 1) available (including the 
date); 
• 
Documentation of suspected nodules detection modality and date; 
• 
Examination results available for standard of reference diagnosis evaluation per nodule 
before P03277 administration: 
o Liver map (according to Couinaud segmentation) identifying the localization of the nodule(s) 
(maximum of 3) for standard of reference 
o Size of the nodule (s) to be considered according to investigator’s choice among the several 
imaging modalities 
o Contrast enhanced imaging modalities used for characterization (CT and/or MRI), type of 
contrast agent used for MRI (extracellular, hepato-specific), date of acquisition and, for each 
of nodules if HCC typical hallmark is visualized according to EASL/EORTC criteria and in 
case of MRI using hepatospecific contrast agent, also if hyperintensity of parenchyma 
relative to the nodule is seen.  
o The more recent AFP measurements available and date 
• 
Biopsy or intervention for specimen surgery scheduled for histology analysis. The planned date 
should be recorded.  
• 
A urine or serum pregnancy test for all women of childbearing potential should be done and 
must be negative; 
• 
Verification of eligibility criteria. Criteria relative to eGFR measurement may not be available 
at screening ; 


 
 
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• 
Schedule of blood sample collection for serum creatinine dosage if applicable, in order to 
obtain the results and calculate eGFR at the time of inclusion at the latest;  
• 
If done at screening, blood samples for baseline hematology/biochemistry tests will be 
collected according to central laboratory manual. If not done at screening, they have to be 
scheduled at inclusion visit (V2). 
• 
Recording the subject screening visit in the CRF. 
 
9.1.2 
Inclusion Visit – Visit 2 – Day 0 
Inclusion visit can be the same day as screening if all eligibility criteria can be verified the same 
day.  
During this visit, the following tasks or assessments will be performed: 
• 
Verification of inclusion and non-inclusion criteria by the Investigator; creatinine results for 
eGFR calculation should be available before P03277 administration. 
• 
A urine or serum pregnancy test for female subject of childbearing potential will be performed 
prior to P03277 administration 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); 
• 
Any changes in concomitant treatments since the last visit will be documented;  
• 
Any AE occurred since the last visit will be documented 
• 
If not already done at screening, blood samples for baseline haematology/biochemistry tests 
will be collected according to central laboratory manual; 
• 
Measurement of body weight; 
• 
Vital signs (systolic and diastolic Blood Pressure in supine position, Pulse Rate) will be recorded 
prior to contrast agent injection; 
• 
One or two IMP will be allocated according to subject body weight; 
• 
The appropriate volume of P03277 will be administered by IV as a bolus at the rate of 2 
mL/second following a 0.9% saline flush at the same rate. The following information will be 
documented in the source document and reported on CRF pages: the location of the IV injection 
line, confirmation of power injector use and reason for not, actual volume injected and actual rate 
of the injection, and start time of injection, volume of saline flush, any reason for different rate 
than 2mL/s or different volumes of more than 10% than the calculated one;   
• 
Unenhanced and contrast-enhanced MRI will be performed according to the required 
sequences specified in imaging protocol section 9.2. Enhanced imaging sequences will be 
acquired according to imaging protocol and start time of each post injection sequences 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; 
• 
Vital signs (systolic and diastolic Blood Pressure and PR) will be obtained 30 ± 5minutes after 
the injection of P03277. 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 and up to 30 minutes after the injection of P03277; 


 
 
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• 
Assessment of AEs will be documented;  
• 
Safety follow-up visit (Visit 3) needs to be scheduled 1 day post P03277 injection. 
 
9.1.3 
Visit 3 – Day +1 
During this visit, the following assessments or tasks will be performed: 
• Use/change of concomitant treatments will be documented;  
• Blood samples for baseline haematology/biochemistry tests will be collected according to 
central laboratory manual;  
• Vital Signs (systolic and diastolic Blood Pressure in supine position, PR) should be recorded; 
• Injection-site tolerance is to be evaluated;  
• Assessment of AEs will be documented;  
• Proposed diagnosis as standard of reference for each nodule (HCC, other malignant, 
regenerative or dysplastic nodule, benign, uncertain) should be assessed according to available 
evaluations (excluding histology and P03277 images) . 
 
9.1.4 
Visit 4 – Optional (from 3 days up to 13 weeks) 
Optionally, a biopsy will be done or surgically resected specimen will be collected at the time of loco-
regional treatment and be analyzed for histology by local pathologist.  
This procedure, whatever the type (biopsy or surgery), should be done between 3 days after P03277 
administration to up to 13 weeks maximum. Aternativelly it is acceptable to record results from 
histology done within 2 months prior to P03277 administration. 
• Examination results available for standard of reference diagnosis evaluation  
o Date of nodule material collection (2 dates maximum) 
o Histological diagnosis per nodule : HCC, other malignant, regenerative or dysplastic 
nodule, benign, uncertain 
• Assessment of AEs that the investigator considers related to P03277 and/or study 
procedures. 
 
9.2 Imaging Protocol 
1.5 T and 3T MR equipments will be accepted. The same machine for each site should be used all 
along the study. Automatic real time bolus tracking will be used.  
Standard Axial MR sequences will be used for pre-injection and post injection imaging. 
• 
Unenhanced imaging sequences: 
- 
GRE T1 in- and opposed-phase sequence 
- 
3D GRE T1 sequence with fat saturation 
- 
FSE T2 sequence with fat saturation (can be done after injection) 
 
• 
Contrast-enhanced imaging sequences  - Post P03277 injection: 
- 
3D GRE T1 sequences with fat saturation acquired during 3 time-points at arterial (bolus track 
synchronization), portal (approx. 70-80 sec post injection) and delayed (3 minutes  post 


 
 
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injection) phases 
- 
3D GRE T1 sequences with fat saturation acquired at 15 ±5 minutes 
- 
Additional 3D GRE T1 sequences with fat saturation will be performed at 20mn, 1hour and 2 
hours post-injection for the first 5 subjects and then possibly proposed to next subjects if 
significant liver parenchyma enhancement is depicted. 
 
9.3 On Site on going Reading of Images  
For each investigational site, a radiologist expert in liver diseases will be appointed for on-site 
readings and provide on-site on-going reading results.  
 
9.4 Expert Reading of Images 
9.4.1 Manuals and Supplies 
Guerbet will document the imaging tasks and obligations of the investigational site in a Site Imaging 
Manual. The standardized image acquisition guidelines 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 Guerbet.  
Guerbet will document the expert imaging process in a Read Charter. 
9.4.2 
Site Qualification 
Guerbet’s monitors will perform pre-study site selection and site training. These contacts will ensure 
that the imaging protocol-stipulated can be performed by the site, are programmed and prepared prior 
to enrollment of the first subject and that the Site Imaging Manual will be accurately followed by the 
investigator.  
9.4.3 
Receipt, Tracking, Quality Check of Images 
During the study, Guerbet will request that investigational sites send anonymous images of the 
subjects to Guerbet. Their format will be agreed prior to study start and defined in the Site Imaging 
Manual. Images will be tracked within Guerbet. 
Guerbet will ensure that all imaging protocol requirements have been followed and will document this 
quality control. 
9.4.4 
Expert Readers training 
Two expert radiologists will be appointed from the participating sites, having expertise in the 
interpretation of MR images from of liver diseases and HCC.  
Before the expert readers start the readings, proper training will be delivered and documented 
according to the Read Charter.  
Reading software at each site will be recorded. 
9.4.5 
Image assessments 
After having received all the subject images acquired with P03277 for the study, Guerbet will be 
presenting them to expert readers. 
A specific CRF will be set-up for experts reading entry.  


 
 
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Both experts will provide evaluation for qualitative evaluations of P03277 imaging according to the 
Read Charter.  
9.4.6 
Nodule mapping 
Nodule tracking will be performed using a liver map according to Couinaud segmentation drawings 
completed on-site and by expert readers. The purpose is to guarantee an unambiguous assignment 
(matching) of the liver nodules between standard of reference and expert readings. Read charter will 
detail how nodule mapping will be organized. 
9.4.7 
Consensus meeting 
In case of diagnostic discordance (primary criterion), a consensus meeting will be organized after 
nodule concordance. In this case the qualitative evaluations will be reviewed globally and may be 
modified. 
 
9.4.8 
Image Warehouse and Final Deliverables 
All imaging data will be maintained in a secure environment. Guerbet 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 at reader site responsible for quantitative evaluation so 
that these data may be audited if necessary. 
 
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 (for screening) and 
centrally (for safety evaluation). 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 or 
alternatively according to investigator’s judgement as medical history if measured at baseline and 
related to an underlying disease. 
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. 
  
 


 
 
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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 investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. 
An adverse event can therefore be any unfavorable 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 abnormality experienced 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 CRF and followed up 
from onset to resolution or stabilization of sequelae. If no follow-up is performed, the investigator 
must provide a justification. 
In order to ensure complete safety data collection, all adverse events occurring from ICF signature 
until Day+1, must be reported and followed even if no IMP was administered. The investigator shall 
document all adverse events in the medical file and the appropriate section of the CRF. 
In addition, if occurring after the safety visit at Day+1, events that the investigator thinks may be 
associated with the study medication/procedure must be reported to the sponsor at the optional Visit 4 
and further regardless of the time between the event and the end of the study.  
Safety information to be collected by the investigator with the same procedure as adverse events: 
medication 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, unusual failure in efficacy, 
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). 
In this protocol, the overdose is defined as more than 0.3 mmol/kg for P03277. 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 CRF. 
• 
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 


 
 
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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 – appart from IMP: 
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 :   
 
No action 
 
IMP withdrawn 
• 
Other action taken:  
o AE-targeted medication: the subject took a medication (either prescription or non-
prescription) specifically for this AE. The drug(s) should be reported in the 
appropriate section of the CRF (“concomitant drug” section until V3). 
o Other AE-targeted action: subject used other therapeutic measures (e.g. ice, heating 
pad, brace, cast…) or subject underwent a procedure (physiotherapy, additional 
laboratory test…) for this AE. The therapeutic measure(s) should be reported in the 
appropriate section of the CRF (“Action other than drug administered for the AE” 
section) 
• 
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:  


 
 
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- 
Results in death 
- 
Is life-threatening 
- 
Requires hospitalization or prolongation of existing in subject’s 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 serious and/or unexpected 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. 
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. 
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. 
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 
check up). 
- 
Any hospitalization planned for the biopsy specimen collection for histology analysis (biopsy, 
resection, liver transplantation and any treatment) as part of the standard of care of the HCC  
 


 
 
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10.2.2  Procedure for Reporting Serious Adverse Events 
SAEs occurring from ICF signature until Safey visit at Day+1 are to be reported to Guerbet 
Pharmacovigilance department. 
The investigator must immediately 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 the Sponsor 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 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 Case Report Form as requested in Section 10.1.2. 
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. 
In addition, if occurring after the end of the subject’s follow-up period defined for this study, events, 
serious or not, that the Investigator thinks may be associated with the study medication/procedure 
must be reported to the sponsor regardless of the time between the event and the end of the study.  
 
SAEs associated with study procedures are to be notified using the same reporting procedure as 
described above. 
According to local requirements, Guerbet or its representatives will communicate relevant safety 
information to the appropriate agency(ies), IEC and/or all active investigators, as it becomes available. 


 
 
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The transmission of the information to the sponsor 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 adverse events, 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 adverse event 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 P03277 
administration 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 by the 
pharmacovigilance. 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). 
 
10.4 Other important safety issue /New fact 
Any safety issues that 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  would involve 
any update of study documents or in the overall conduct of the study should be evaluated by the 
sponsor. It includes 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:  
 
A SAE which could lead to the modification of the conduct of the study 
 
A significant hazard to the subject population such as lack of efficacy of an IMP used for 
the treatment of a life-threatening disease (if applicable). 
 
A new major finding from an animal study, 
 
A temporary halt of a trial for safety reasons if the trial is conducted with the same 
investigational medicinal products in another country by the same sponsor, 
 
Recommendations of the DMC, if any, where relevant for the safety of subjects, 
 
Any serious adverse reaction, expected or not, involving healthy volunteers. 
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. 
It might require other action, such as:  
 
urgent safety measures and their notification 


 
 
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 
substantial amendments 
 
early termination of the trial  
 
10.5 Unblinding Procedures  
Not applicable 
 
 
 


 
 
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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 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 P03277 
administration will be considered screening failures. 
Criteria for premature discontinuation of subjects: 
- eGFR < 60 mL/min/1.73m2 at local blood sample screening; 
- 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 CRF). 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) during the 
study period; 
- At the discretion of the investigator if the subject safety or well-being is not 
compatible with study continuation; 
- Examination for standard of reference not available. 
The data to be reported in the CRF for subjects subsequently discontinuing from the study are detailed 
in the protocol section 15.3.2. 
Subjects prematurely discontinuing the study will be replaced. It is expected to have around 3 subjects  
 
 
 


 
 
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12. 
STATISTICAL ANALYSIS 
The following section summarizes the statistical analysis method, which is fully described in the 
Statistical Analysis Plan. 
 
12.1 Subjects Included in the Analysis 
There will be four subject sets defined for this study: All subjects set, the Safety Set (SS), the Full 
Analysis Set (FAS) and the Per-Protocol Set (PPS). 
All subject 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 P03277, regardless of the 
quantity. This set will be used for evaluation of safety and description of demographic data and 
baseline characteristics. 
The Full Analysis Set will include all subjects who undergone P03277 imaging and a standard of 
reference completed. This set will be used for 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. Major deviations will be defined as having an 
impact on the primary efficacy criteria (e.g. P03277 wrong volume administered to the subject 
differing of more than 10% from the calculated one). Primary analysis will be repeated on this set. 
 
12.2 Demographic and Baseline Data 
Demographic parameters are age, sex, childbearing potential, body weight, height, and body mass 
index (BMI), ethnic origin (self-reported race/ethnicity). Baseline characteristics are the subject's 
history (including the medical history, intolerance history), the physical examination, chronic liver 
disease status at inclusion, documentation of suspected nodules, and the concomitant treatments on 
going at the time of screening/inclusion and before administration of P03277.  
Summary statistics (number [n], mean, standard deviation [SD], median, minimum, and maximum) 
will be calculated for age, body weight, height and BMI and displayed by dose and overall. Frequency 
and percentages will be calculated for sex, subject chronic liver disease status at inclusion, and 
concomitant treatments on going at the time of screening/inclusion and ended before administration of 
P03277. These parameters will be displayed by dose and overall. 
Subject's medical history will be coded using the MedDRA dictionary and tabulated by dose body 
system, preferred term and status (concomitant or not) and presented overall as well. 
Subject's concomitant treatments will be coded using the Anatomical Therapeutic Chemical (ATC) 
Drug dictionary and tabulated by dose ATC code and presented overall as well . 
 
12.3 Efficacy Data 
Efficacy data will be summarized and presented by dose using the FAS and PP set for primary 
efficacy analysis and only using FAS for any other efficacy analysis.  
Primary efficacy analysis 


 
 
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First of all, results of examinations results used for standard of reference will be presented: at 
subject level showing number and frequency of AFP results by category (>200ng/mL or ≤200ng/mL) 
and by number of nodules for a subject (multiple or single nodule), previous contrast enhanced 
imaging modalities (CT and/or MRI), timelines and type of contrast agent category for MRI. At 
nodule level, typical imaging hallmark obtained by nodule (CT and/or MRI) and intensity of 
parenchyma relative to the nodule at each available phase will be presented. Timelines for biopsy (or 
surgical specimen collection) will be presented at subject level and nodules histology results (HCC, 
other malignant, regenerative or dysplastic nodule, benign, uncertain) will be presented at nodule 
level. 
P03277 imaging diagnosis (HCC and not HCC) will be presented at nodule level displaying number 
and frequency for each standard of reference group HCC or not HCC according to the Table 2. 
Table 2 : Diagnostic value evaluation for HCC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The following parameters will be calculated: 
Sensitivity: the number of nodules showing true positive HCC divided by all nodules considered HCC 
according to standard of reference (n1 / n1+n3) 
Specificity: the number of nodules showing true negative HCC divided by all nodules considered as 
not HCC or uncertain as standard of reference (n4 / n2+n4) 
Accuracy: the number of nodules showing true positive HCC and true negative HCC over all nodules 
(n1+n4 /N+) 
Positive predictive value: the number of nodules showing true positive HCC /all nodules showing 
HCC according to P03277 imaging (n1 / n1+n2) 
Negative predictive value: the number of nodules showing true negative HCC /all nodules not 
showing HCC according to P03277 imaging (n4 / n3+n4) 
 
 
 
 
P03277 imaging expert reading results 
 
 
HCC: 
(Typical features on 
this MR 
examination) 
Not HCC 
(No nodule/atypical 
features) 
 
Standard of reference 
HCC: 
 
True positive 
n1 
False negative 
n3 
Total 
n1+n3 
Not HCC  
including 
uncertain 
cases 
 
False positive 
n2 
True negative 
n4 
Total 
n2+n4 
 
 
Total  
n1 + n2 
Total  
n3+n4 
All total 
N+ 


 
 
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Secondary efficacy analysis 
 
Technical adequacy of images  
Technical adequacy will be presented by reading type (on-site or expert reading), by displaying 
number and frequency of adequate and inadequate images and the categories for inadequacy.   
 
Visualization of biliary and liver vascular abnormalities 
Biliary and liver vascular abnormalities will be presented globally, by displaying number and 
frequency of portal thrombosis, hepatic venous thrombosis, biliary tract invasion, and visualization of 
arterio-portal fistula. 
Number of nodules detected  
Number of nodules detected will be presented at subject level, showing number [n], mean, standard 
deviation [SD], median, minimum, and maximum. 
 
Qualitative evaluation of nodule intensity and nodule description 
Qualitative evaluation of nodule intensity (hypointensity, hyperintensity, isointensity and 
hetero/homogeneous) relative to parenchyma at each phase as well as, presence of capsule, 
visualization of fat, and iron presence will be presented by displaying number and frequency for each 
standard of reference group (HCC or not HCC/uncertainty). 
 
Quantitative evaluation of nodule intensity  
Quantitative evaluations of nodule intensity (SI, SNR, CNR, and PE) will be presented for each 
standard of reference group (HCC or not HCC/uncertainty) by displaying number [n], mean, standard 
deviation [SD], median, minimum, and maximum.  
 
Quantitative evaluation of vascular intensity  
Quantitative evaluations of aorta intensity and portal vein intensity (SI and SNR) will be presented 
globally and for each standard of reference group of subjects (subject with at least HCC or subject 
without any HCC) by displaying number [n], mean, standard deviation [SD], median, minimum, and 
maximum. 
 
Qualitative evaluation at very delayed sequences for visualization of the parenchyma 
enhancement and nodule description  
Qualitative evaluations for visualization of the parenchyma enhancement will be presented globally 
showing number and frequency at three available very delayed images and sequences (20mn, 1h, 2h). 
Qualitative evaluations for nodule enhancement relative to parenchyma will be presented by 
displaying number and frequency for each reference group (HCC or not HCC/uncertainty) 
 
12.4 Safety Data 
Safety analysis will be done using the safety set presented by dose and overall. 
Extent of exposure 
Duration between IMP administration and end of study, volume theoretically administered, volume 
actually administered, actual rate of administration, theoretical rate of administration will be tabulated. 


 
 
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Frequency tabulation of theoretical volume actually administered and theoretical rate of administration 
actually performed will be also displayed. 
Adverse events  
All analyses of AEs will be based on the number of subjects with AEs. Adverse events occurring after 
D+1 that the investigators considers as related to P03277 /study procedures will be included in this 
analysis. 
Adverse events will be coded with the most recent version of MedDRA at the time of the database 
lock. 
The time period for the assessment of AEs will be divided into 3 mutually exclusive and exhaustive 
periods: before administration of P03277, after administration of P03277 until day +1 FU and after 
safety follow-up until biopsy if it is done.  
Events will be classified as treatment-emergent (TEAE) if they started or increased after P02377 
administration. This will also include events with missing intensity.  
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: 
At least one TEAE 
At least one adverse reaction (relationship to study treatment classified as ‘Related’) 
At least one TEAE with action taken with study treatment 
At least one TEAE with classifications of outcome 
 
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  
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) . 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)  
The table of summaries of at least one TEAE will be repeated by SOC only (without the breakdown by 
PT). 
Concomitant medication after P03277 administration 
Concomitant medications will be coded using the WHO Drug dictionary and be presented displaying 
number and frequency by ATC System Main Group and Therapeutic Subgroup. 
 


 
 
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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 as 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 7.2.2)  and according to their clinical 
significant changes. Quantitative analyses will be done by tabulating raw data and change from 
baseline. 
12.5 Handling of Missing Data  
No imputation or replacement of missing data will be carried out. 
12.6   Interim Analysis  
Not applicable 
 
 


 
 
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13. 
STUDY COMMITTEES(S) 
The IMP used, in this study, as contrast agent belongs 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.  
For all these reasons, an IDMC (Independent Data Monitoring Committee) has not been established 
for the study. 
However, the safety data will be monitored during the study conduct. 
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: ICH E5 Ethnic Factors in the Acceptability of Foreign 
Clinical Data 
- 
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 
- 
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 


 
 
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- 
US Food and Drug Administration, Title 21 Code of Federal Regulations Part 11 on 
Electronic Records; Electronic Signatures  
- 
French regulation : 
o Current version of the French Public Health Code 
o Decree 2016-1537 dated 16 November 2016 related to research involving human 
subjects 
o Loi n° 2004-806 du 9 août 2004 relative à la politique de santé publique 
o Loi n° 2002-303 du 4 mars 2002 relative aux « Droits des malades et la qualité du 
système de santé » 
o Loi n° 2004-801 du 6 août 2004 relative à la protection des personnes physiques à 
l'égard des traitements de données à caractère personnel et modifiant la loi n° 78-17 
du 6 janvier 1978 relative à l'informatique, aux fichiers et aux libertés et la Loi n° 94-
548 (1 juillet 1994) relative au traitement de données nominatives ayant pour fin la 
recherche dans le domaine de la santé. - Décret d’application n° 2005-1309 du 20 
octobre 2005. 
o Méthodologie de référence pour les traitements de données personnelles opérées dans 
le cadre des recherches biomédicales (MR001), octobre 2010 modifiée 21 juillet 2016. 
o Bonnes Pratiques de Fabrication, Journal officiel de la République française du 7 
janvier 2014, texte n°2 sur 82) 
 
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 and Institutional Review Board/Independent Ethics Committee (IRB/IEC) and the 
authorization by the national Regulatory/Competent Authority. The final written approval and 
authorization must be available for a given investigational site when initiating the 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 Investigational Site File. 
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. 


 
 
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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. 
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. 
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 or of any other document to be provided to 
the subjects, 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 Investigator Site File (ISF) provided by Guerbet at the 
initiation visit. The completeness and accuracy of such files will be checked regularly by Guerbet 
representative (Clinical Research Associate 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 the audit, the 
representatives of the Ethics Committees and of the Regulatory Authorities to have direct access to 
source data/documents. 
The investigator must guarantee the safety of the 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 be 
deleted from any medium such as CRF, document for biological results, X-Ray films or digital 
supports. 
For this study, the following will be considered as source data: expert reading data will be completed 
directly onto the CRF.  
If computerised medical files are used, the investigator must: 
- 
At the start of the study, to print, sign and date all the medical files of all subjects,  
- 
During the study, to 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 and well-being and 
study data accuracy and completeness. 
 
15.3 Clinical Data Handling 
15.3.1 Data Reported in the CRF 
The CRF will allow recording of all the data required by the protocol. 
The investigator or the designated person from his/her team agrees to complete the CRF, at each 
subject visit, and all other documents provided by Guerbet (e.g. documents relating to the IMP 
management…) and to reply to any data clarifications raised in a timely manner. 
The investigator must attest: 
- 
The authenticity of the data collected in the CRF;  
- 
The consistence between the data in the CRF and those in the source documents, with the 
exception of those data recorded directly in the CRF and considered as source data. 
 


 
 
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15.3.2 Data Reported in the CRF according to Subject Status  
For screening failure, only the date of visit, date of informed consent signature, demographic data, 
physical examination, the adverse events and the reason for withdrawal will be reported. If the visit 2 
was done without any P03277 administration, all data available at the time of 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 CRF (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’s representative. 
 
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, Competent/Regulatory Authorities may also carry out 
an inspection in the facilities of Guerbet and/or the investigational sites. Guerbet will inform all the 
investigators immediately upon notification of a pending inspection. Likewise, the investigator will 
inform Guerbet of any pending inspection. 
Whether for an audit or for a regulatory inspection, Guerbet and the investigational sites both agree to 
cooperate in full transparency, confidentiality and professional secrecy. 
The investigator must allow the representatives of Guerbet (audit) and/or of the Competent/Regulatory 
Authorities (inspection):  
- 
To inspect the site, facilities and 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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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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19. APPENDICES  
19.1 Child-Pugh Classification of Severity of Liver Disease 
Child-Pugh classification of severity of liver disease according to the degree of ascites, the plasma 
concentrations of bilirubin and albumin, the prothrombin time, and the degree of encephalopathy.  
Parameter 
Points assigned 
1 
2 
3 
Ascites 
Absent 
Slight 
Moderate 
Total Bilirubin, mg/dL 
</= 2 
2-3 
>3 
Albumin, g/dL 
>3.5 
2.8-3.5 
<2.8 
Prothrombin time 
Prolongation (s) 
 
<4.0 
  
4-6 
  
>6.0 
Encephalopathy 
None 
Grade 1-2 
Grade 3-4 
  
Class 
Points 
A: well-compensated disease 
5-6 
B: significant functional 
compromise 
7-9 
C: decompensated disease 
10-15 
  
 
 


 
 
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SAP_001.pdf: 
Document Type 
Statistical Analysis Plan 
Document Date 
June 11, 2019 
Official Title 
Proof of Concept study concerning efficacy of P03277 MR Imaging 
in HCC diagnosis 
NCT Number 
NCT02973516 
 






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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
 
AE 
Adverse Event 
AFP 
Alpha fetoprotein
ALT 
Alanine Amino Transferase 
AST 
Aspartate Amino Transferase 
ATC 
Anatomical Therapeutic Chemical Drug dictionary
BMI 
Body Mass Index
BUN 
Blood Urea Nitrogen 
BW 
Body Weight 
CNR 
Contrast to Noise Ratio 
CRF 
Case Report Form 
CRO 
Clinical Research Organization 
CSR 
Clinical Study Report 
CT 
Computed Tomography 
DRM 
Data Review Meeting 
EASL 
European Association for the Study of the Liver
eGFR 
estimated Glomerular Filtration Rate
EORTC 
European Organisation for Research and Treatment of Cancer
FAS 
Full Analysis Set
GRE 
Gradient echo sequences 
HBV 
Hepatitis B 
HCC 
Hepatocellular carcinoma 
HCV 
Hepatitis C 
IMP 
Investigational Medicinal Product
IV 
Intravenous 
LDH 
Lactate DeHydrogenase 
MCV 
Mean red blood Cells Volume 
MedDRA 
Medical Dictionary for Regulatory Activities
MRI  
Magnetic Resonance Imaging 
NASH 
Non-alcoholic steato hepatitis 
PE 
Percentage Enhancement 
PPS 
Per Protocol Set
PT 
Preferred Term 
RBC 
Red Blood Cells
ROI 
Region Of Interest 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SI 
Signal Intensity
SNR 
Signal to Noise Ratio 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event
TG 
Triglycerides 
WBC 
White Blood Cells 
 
 
 
 
 
 


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TABLE OF CONTENTS 
HISTORY FORM ............................................................................................................................................................ 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................................................. 3 
 
SUMMARY OF THE STUDY PROTOCOL ........................................................................................................ 6 
1.1. 
STUDY OBJECTIVES ............................................................................................................................................. 6 
1.2. 
STUDY DESIGN .................................................................................................................................................... 6 
 
EVALUATION CRITERIA ................................................................................................................................... 8 
2.1. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .................................................................................. 8 
2.2. 
EFFICACY CRITERIA ............................................................................................................................................ 8 
2.2.1. 
Primary criterion ....................................................................................................................................... 9 
2.2.2. 
Secondary efficacy criteria ........................................................................................................................ 9 
2.3. 
SAFETY CRITERIA ............................................................................................................................................. 11 
2.3.1. 
Adverse events.......................................................................................................................................... 11 
2.3.2. 
Tolerance at injection site ........................................................................................................................ 11 
2.3.3. 
Clinical laboratory parameters ............................................................................................................... 11 
2.3.4. 
Vital signs ................................................................................................................................................ 11 
2.3.5. 
Concomitant medications ......................................................................................................................... 11 
2.4. 
OTHER CRITERIA ............................................................................................................................................... 12 
 
STATISTICAL METHODS ................................................................................................................................. 13 
3.1. 
GENERAL CONSIDERATIONS ............................................................................................................................. 13 
3.2. 
NULL AND ALTERNATIVE HYPOTHESIS ............................................................................................................. 13 
3.3. 
DETERMINATION OF SAMPLE SIZE ..................................................................................................................... 13 
3.4. 
ADJUSTMENT FOR COVARIATES ........................................................................................................................ 14 
3.5. 
HANDLING OF DROPOUTS OR MISSING DATA ..................................................................................................... 14 
3.6. 
INTERIM ANALYSES AND DATA MONITORING .................................................................................................... 14 
3.7. 
MULTICENTER STUDIES .................................................................................................................................... 14 
3.8. 
MULTIPLE COMPARISONS/MULTIPLICITY ......................................................................................................... 14 
3.9. 
USE OF AN “EFFICACY SUBSET” OF PATIENTS ................................................................................................... 14 
3.10. 
ACTIVE CONTROL STUDIES INTENDED TO SHOW EQUIVALENCE .................................................................... 14 
3.11. 
EXAMINATIONS OF SUBGROUPS .................................................................................................................... 14 
 
STATISTICAL AND ANALYTICAL PLANS ................................................................................................... 15 
5.1. 
DISPOSITION OF PATIENTS ................................................................................................................................ 15 
5.2. 
DATA SETS ANALYSED AND PROTOCOL DEVIATIONS ....................................................................................... 15 
5.3. 
MEASUREMENTS OF STUDY DRUG COMPLIANCE ............................................................................................... 23 
5.4. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ............................................................................... 23 
5.4.1. 
Demographic data ................................................................................................................................... 23 
5.4.2. 
Study disease ............................................................................................................................................ 23 
5.4.3. 
Risk factors .............................................................................................................................................. 23 
5.4.4. 
Medical history and concomitant diseases .............................................................................................. 23 
5.4.5. 
Clinical laboratory evaluation at baseline .............................................................................................. 24 
5.4.6. 
Vital signs, physical findings and other observations related to safety at baseline ................................. 24 
5.4.7. 
Prior therapies ......................................................................................................................................... 24 
5.4.8. 
Other baseline characteristics ................................................................................................................. 24 
5.5. 
EFFICACY EVALUATION .................................................................................................................................... 26 
5.5.1. 
Primary analysis of the primary criteria ................................................................................................. 26 
5.5.2. 
Supportive analyses of primary criterion ................................................................................................. 27 
5.5.3. 
Additional analyses of primary criterion ................................................................................................. 27 
5.5.4. 
Analysis of secondary criteria ................................................................................................................. 27 
5.6. 
SAFETY EVALUATION ....................................................................................................................................... 28 
5.6.1. 
Extent of Exposure ................................................................................................................................... 28 


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5.6.2. 
Adverse Events ......................................................................................................................................... 29 
5.6.3. 
Deaths and other serious adverse events ................................................................................................. 30 
5.6.4. 
Clinical laboratory evaluation ................................................................................................................. 30 
5.6.5. 
Vital signs, physical findings and other observations related to safety ................................................... 31 
5.6.6. 
Concomitant medications ......................................................................................................................... 32 
 
SHELLS FOR TABLES, FIGURES AND LISTINGS ....................................................................................... 39 
7.1. 
CLINICAL STUDY REPORT IN-TEXT TABLES, FIGURES AND LISTINGS ................................................................. 39 
7.2. 
CONTENTS OF CLINICAL STUDY REPORT SECTION 14 ........................................................................................ 39 
7.3. 
CONTENTS OF CLINICAL STUDY REPORT SECTION 16.2 ..................................................................................... 39 
 
REFERENCES ...................................................................................................................................................... 40 
 
APPENDICES ........................................................................................................................................................ 41 
 
 
 


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 SUMMARY OF THE STUDY PROTOCOL  
This document presents the statistical analysis plan (SAP) for Guerbet, Protocol No. GDX-44-008: 
“Proof of Concept study concerning efficacy of P03277 MR Imaging in HCC diagnosis”. 
This analysis plan is based on the final protocol Version 4.0 including amendment n°2 dated 
December 12th, 2017.  
 
1.1. Study objectives 
The primary objective is to evaluate the diagnostic value (specificity and sensitivity) for 
hepatocellular carcinoma (HCC) of P03277 MR Imaging in patients with suspected small nodules 
and chronic liver disease. 
 
The secondary objectives of the study are to evaluate multiple quantitative and qualitative efficacy 
parameters and the safety (clinical and biological) profile of P03277 following single administration 
in patients with suspected HCC. 
 
1.2. Study design 
GDX-44-008 is a Phase IIa, dual center, exploratory, non-randomized, open label, two cohorts, two 
doses study. 
 
After a patient has satisfied all eligibility requirements, he will undergo 4 visits: 
 Visit 1: screening (D-7 to D0). The maximum period between patient’s screening and 
administration of P03277 is 7 days but can be the same day if eGFR measurement within 
the last 7 days is available. 
 Visit 2: inclusion/dosing/MRI and post-injection follow-up (D0). Patient inclusion will be 
confirmed on the day of administration of P03277 according to the eGFR results and 
urinary pregnancy test if applicable 
 Visit 3: safety visit (D+1 post injection).  
 Visit 4: Optionally and according to local standard of care for histology analysis, the 
patient will have a specific biopsy or a surgically resected specimen collected at the time 
of loco-regional treatment. This procedure, whatever the type (biopsy or surgery), should 
be done between 3 days after P03277 administration and 13 weeks maximum. 
Alternatively it is acceptable to record results from histology done within 2 months prior 
to P03277 administration. 
 
The standard of reference for diagnosis will be given by the site according to their standard of care 
and adapted from EASL/EORTC diagnostic criteria and considering previous contrast enhanced 
imaging (CT and/or MRI) and/or biopsy specimen analysis given on-site and/or the more recent AFP 
results available. 
 
The duration of patient’s participation could be from 2 days up to 3 months approximately. The study 
will be considered as completed once all the images collected for all the patients will have been 
reviewed by expert readers. 
 


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The images will be assessed for the primary criterion by 2 expert readers. For secondary criteria, they 
will also be assessed on-site by a radiologist expert in liver diseases and/or by the 2 expert readers. 
In case of diagnostic discordance for the primary criterion, a consensus meeting will be organized 
after nodule comparison. In this case the qualitative evaluations will be reviewed globally and may 
be modified. 
 
Safety assessments will be based on adverse events, injection site tolerance, clinical laboratory 
parameters and vital signs.  
 
The primary endpoint in this study is the nodule diagnosis with P03277 imaging compared to the 
nodule diagnosis obtained with the standard of reference. 
 
P03277 will be injected at a dose of 0.1 mmol/kg BW for cohort 1 (corresponding to 0.2 mL/kg BW) 
and 0.05 mmol/kg BW for cohort 2 (corresponding to 0.1 mL/kg BW) via a peripheral vein (the 
antecubital vein is preferred).  
P03277 will be administered by intravenous (IV) bolus injection at 2 mL/s rate without dilution, 
followed by a 0.9% saline flush at same rate to ensure complete injection of the contrast medium. 
The P03277 administration is to be performed by power injector in order to better control injection 
rate. 
 
 
 




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Number of nodules evaluated 
 
 
Imaging qualitative evaluation (nodule intensity, presence 
of intranodule iron and fat and visualization of perilesional 
capsule) 
 
 
Visualization of biliary and liver vascular abnormalities
 
Very 
delayed 
imaging 
qualitative 
evaluation 
for 
parenchyma enhancement and nodule signal enhancement 
relative to parenchyma 
 
 
Quantitative evaluation of nodule intensity and vascular 
intensity: SI measurements in nodules, liver, background, 
aorta and the portal vein for SNR CNR PE
 
 
 
2.2.1. Primary criterion 
The primary criterion of the study is the nodule diagnosis with P03277 imaging (HCC, not HCC). It 
will be assessed: 
 On a maximum of 3 hepatic nodules per patient 
 Based on visual qualitative analysis of P03277 triphasic imaging (arterial, portal and 
delayed phases) showing HCC typical hallmarks according to EASL/EORTC criteria 
(arterial hypervascularization and portal wash-out or delayed wash-out) 
 By two experts readers. In case of discordance, a consensus diagnosis will be obtained. 
 
The standard of reference for diagnosing liver nodules (HCC, other malignant, regenerative or 
dysplastic nodule, benign, uncertain) will be given by the site according to their standard of care and 
according to adapted EASL/EORTC diagnostic criteria, considering previous contrast enhanced 
imaging (CT and/or MRI) and/or histology analysis and/or the more recent AFP results available.  
 
HCC will be considered: 
 With P03277 when experts reading/consensus consider the nodule as being HCC 
 With standard of reference when: 
o Diagnosis of any biopsy is HCC 
o Diagnosis of the history imaging is HCC  
 
Suspected nodule characterization, mapping and measurement of previous contrast enhanced 
imaging will be described. Previous alpha-fetoprotein value will be presented. 
Nodule characterization from histopathology will be presented. 
Results (HCC, not HCC) of nodule examinations used for standard of reference from histopathology 
or previous imaging will be presented.  
2.2.2. Secondary efficacy criteria 
Secondary criteria to support the primary endpoint are the following: 
 Technical adequacy of images (on-site and expert reading) assessed as adequate, yes or 
no and reason for inadequacy will be recorded using a 5 items: 
o 1 = Artifacts due to subject 
o 2 = Artifacts due to machine 
o 3 = Artifacts due to contrast agent 


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o 4 = Injection technical failure 
o 5 = Other, specify 
 Visualization of biliary and liver vascular abnormalities (expert reading):  
o presence of portal thrombosis 
o hepatic venous thrombosis 
o biliary tract invasion 
o visualization of arterio-portal fistula within vascular territory of suspected nodule(s) 
 Number of nodules evaluated (on-site and expert reading) 
o Number of nodules suspected on-site by P03277 imaging corresponds to sum of 
nodules at the previous imaging (if same suspected nodules with no difference in 
segment and site) or sum of nodules reported in the mapping of P03277 imaging. 
o Total number of nodules suspected by experts reading 
 Localization and size of suspected nodules (on-site and expert reading) 
o Localization and size of suspected nodules on-site correspond to report at the 
previous imaging in case of same nodule(s) suspected or from mapping of P03277 
imaging  
 Imaging qualitative evaluation of nodule intensity and nodule description (expert reading) 
o At each phase (T2, T1 unenhanced, arterial, portal, delayed): nodule (maximum of 3) 
intensity relative to parenchyma according to the scale:  
 Hypointense 
 Hyperintense (and relative to spleen on T2 if hyperintense) 
 Isointense 
In addition nodules will be described as homogeneous or heterogeneous. 
o Presence of fat and iron within the liver nodules at unenhanced phase in and opposed 
phase (intra nodule) 
o Visualization of a perilesional capsule (yes/no) at portal phase or delayed phases 
o Wash-out? (Portal and delayed phases) 
 Imaging quantitative evaluation of nodule intensity and vascular intensity (on-site 
reading) 
o At each phase (T1 unenhanced, arterial, portal, delayed, 15 ±5 minutes) SI 
measurement on nodule (maximum of 3), liver, and background for SNR, CNR, and 
nodule percentage enhancement (PE): 
 Nodule SNR (Signal to noise ratio) will be calculated at each phase using the 
following formula: 𝑆𝐼௡௢ௗ௨௟௘𝑆𝐷௡௢௜௦௘
⁄
 where SI nodule is “nodule ROI 
intensity” and 𝑆𝐷௡௢௜௦௘ is “Background ROI: SD intensity”. 
 Nodule CNR (contrast to noise ratio) will be calculated at each phase using 
the following formula: ሺ𝑆𝐼௡௢ௗ௨௟௘െ𝑆𝐼௟௜௩௘௥ሻ𝑆𝐷௡௢௜௦௘
⁄
 where 𝑆𝐼௡௢ௗ௨௟௘ is 
“nodule ROI intensity”; 𝑆𝐼௟௜௩௘௥ is “liver parenchyma ROI intensity” and 
𝑆𝐷௡௢௜௦௘ is “Background ROI: SD intensity”. 
 PE (Nodule Percentage enhancement) will be calculated using the following 
formula: ሺ𝑆𝐼௣௢௦௧െ𝑆𝐼௣௥௘ሻ𝑆𝐼௣௥௘
⁄
∗100 where 𝑆𝐼௣௢௦௧ is the nodule signal 
intensity at each phase (arterial, portal, delayed, 15 ±5 minutes) and 𝑆𝐼௣௥௘ is 
the nodule signal intensity at unenhanced sequence. 
o On arterial and on portal phase, SI measurement of the aorta and the portal vein 
maximum vessel enhancement for SNR calculation purpose 
 Vascular SNR (Signal to noise ratio) will be calculated using the following 
formula: 𝑆𝐼௔௢௥௧௔𝑆𝐷௡௢௜௦௘
⁄
 where 𝑆𝐼௔௢௥௧௔ is “aorta ROI intensity” and 𝑆𝐷௡௢௜௦௘ 


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is “Background ROI: SD intensity” at arterial phase, 𝑆𝐼௣௢௥௧௔௟ ௩௘௜௡𝑆𝐷௡௢௜௦௘
⁄
 
where 𝑆𝐼௣௢௥௧௔௟ ௩௘௜௡ is “portal vein ROI intensity” and 𝑆𝐷௡௢௜௦௘ is “Background 
ROI: SD intensity” at portal and delayed (3 minutes, 15 ±5 minutes) phases. 
In case of several nodules, mean of SD of background will be used. 
 Very delayed imaging qualitative evaluation (expert reading) (15 ±5 minutes, 1h, 2h) for 
visualization of the parenchyma enhancement relative to unenhanced fat-suppressed GRE 
T1 sequence (hyperintense, isointense, hypointense) and nodule enhancement relative to 
parenchyma. 
 
2.3. Safety criteria 
2.3.1. Adverse events 
Adverse Events (AEs) will be recorded throughout the patient participation until 1 day after injection 
of P03277. Only AEs that the investigator considers as related to P03277 and/or the study procedures 
will be recorded at the optional visit 4 between 3 days and 3 months after P03277 administration. 
2.3.2. Tolerance at injection site 
For all patients, injection site tolerance (burning, pain, eruption, extravasation, inflammation or other) 
will be assessed over 1 day following the contrast agent injection (during the injection up to 30 ± 5 
minutes and the day after injection) and over a longer period if the investigator becomes aware of 
any related AE. In case of injection site pain, the patient will be asked to specify the level of pain 
using a visual analogic scale (VAS) from 0 (no pain) to 10 (maximal pain). 
2.3.3. Clinical laboratory parameters 
For each patient, blood samples will be performed at Day+1. A central laboratory will be used to 
analyse and report blood chemistry/haematology.  
The following parameters will be assessed: 
- 
Hematology: red blood cells (RBCs), hemoglobin, hematocrit, Mean red blood Cells Volume 
(MCV), white blood cells (WBCs), neutrophils, lymphocytes, monocytes, eosinophils, 
basophils and platelet count. 
- 
Biochemistry: sodium, potassium, chloride, calcium, phosphate, glucose, total protein, 
creatinine, eGFR, blood urea nitrogen (BUN) / urea, cystatin C, aspartate amino transferase 
(AST), alanine amino transferase (ALT), alkaline phosphatase, total bilirubin, conjugated and 
unconjugated bilirubin, triglycerides (TG), lactate dehydrogenase (LDH). 
2.3.4. Vital signs 
Vital signs (systolic and diastolic blood pressure in supine position, pulse rate) will be measured and 
recorded prior the contrast agent injection, at 30 ± 5 minutes and the day after injection. 
2.3.5. Concomitant medications 
Concomitant medications will be recorded at the time of informed consent form signature until end 
of the study.  
 


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2.4. Other criteria 
None. 
 


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 STATISTICAL METHODS 
3.1. General considerations 
After the database lock, the statistical analysis will be performed by a CRO under the supervision of 
Guerbet Biostatistician on the basis of the present document. 
A quality control of the statistical analysis will be performed both by the CRO and the sponsor to 
ensure the reliability of the results.  
The GUERBET validation strategy will be described in the Statistical Analysis Validation Plan which 
will be based on this present document. 
Thorough description of all parameters reported will be presented separately by group (HCC/Not 
HCC) defined by the standard of reference. Summary tabulated results will be provided overall and 
by assessment time, if relevant or they will be replaced by the corresponding individual data listings 
if too few patients are concerned. 
Tabulations of quantitative parameters will include the following summary statistics: Number of 
Patients / Mean / Standard Deviation / Minimum / Median / Maximum. If for a given parameter, the 
raw value has been collected with 𝑥 decimal places, the mean, median and standard deviation 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 
values. 
Both experts will provide evaluation for qualitative evaluations of P03277 imaging. In case of 
consensus meeting, the qualitative evaluations may be modified and will be replaced for analyses by 
expert reader (except data at delayed phases 1h and 2h). 
SAS® Version 9.4 will be used for all descriptive summaries and inferential analyses. 
 
3.2. Null and alternative hypothesis 
Not applicable in this study. 
 
3.3. Determination of sample size 
As a proof of concept study, no statistical test is planned. Patients’ data will be analyzed with 
descriptive statistics investigating the potential efficacy of P03277 in the liver for the diagnosis of 
HCC, by dose. 
 In total, 40 patients will be included in this 
study: 
- 
First, 30 patients in a first cohort with a P03277 dose of 0.1 mmol/kg 
- 
Then 10 patients in a second cohort with a P03277 dose of 0.05 mmol/kg.  


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3.4. Adjustment for covariates 
Not applicable. 
 
3.5. Handling of dropouts or missing data 
No imputation or replacement of missing data will be carried out. However, in case of missing data 
leading to a doubt in the classification of treatment-emergence, the event will be considered as 
treatment emergent. 
 
3.6. Interim analyses and data monitoring 
Safety analysis will be performed for signal detection during the trial. 
 
3.7. Multicenter studies 
Only the number of included patients will be presented for each center. 
 
3.8. Multiple comparisons/Multiplicity 
Not applicable. 
 
3.9. Use of an “efficacy subset” of patients 
If the Per Protocol Set defined in Section 5.2 differs from the Full Analysis Set by more than 10%, 
secondary efficacy analyses will be repeated for this set. 
 
3.10. Active control studies intended to show equivalence 
Not applicable. 
 
3.11. Examinations of subgroups 
None. 
 


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 STATISTICAL AND ANALYTICAL PLANS 
5.1. Disposition of patients 
Patient disposition will be based on all patients who have signed their inform consent form and 
tabulated by dose and overall for the following categories: 
 
 Total number of patients screened; 
 Number (percentage) of patients exposed to P03277; 
 Number (percentage) of patients completing the histopathology (V4) visit; 
 Number (percentage) of patients completing the study; 
 Number (percentage) and reasons of patients screen-failed; 
 Number (percentage) and reasons of patients prematurely discontinuing the study; 
 
5.2. Data Sets Analysed and protocol deviations 
Data sets analysed 
 
There will be four patient sets and two nodules sets defined for this study:  
 
 The All Patients Set will include all patients who have signed their inform consent form. This 
set will be used for patient disposition summaries and individual listings. 
 
 The Safety Set (SS) will include all patients who received at least one injection of P03277, 
regardless of the quantity. This set will be used for evaluation of safety and description of 
demographic data and baseline characteristics. 
 
 The Full Analysis Set (FAS) will include all patients who undergone P03277 imaging and 
with at least one standard of reference. This set will be used for description of demographic 
data and baseline characteristics. 
 
 The Full Analysis Set Nodules (FASN) will include all nodules with available P03277 
imaging and with a standard of reference. This set will be used for evaluation of efficacy.  
 
 The Per Protocol Set (PPS) will include all patients with at least one nodule in PPSN. 


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 The Per Protocol Set Nodules (PPSN) will include all nodules from the FASN who do not 
present any major protocol deviations or for whom the patient does not present any major 
deviation. Major deviations will be defined as having an impact on the primary efficacy 
criteria. Primary analysis will be repeated on this set. 
 
The number of patients by analysis set will be tabulated by dose and overall. 
 
The following table summarizes how the above defined patients sets will be used in the different 
analyses conducted.  
 
 
Analyses Sets 
All Patients 
Set
Safety Set 
Full Analysis 
Set (FAS) 
Per Protocol 
Set (PPS)
Disposition 
 
 
 
 
Demographics and Baseline 
characteristics 
 
 
 
 
Exposure 
 
 
 
 
Efficacy assessment : Primary 
criterion 
 
 
 
 
Efficacy assessment : Secondary 
criteria  
 
 
 
* 
Safety assessment  
 
 
 
 
Listings 
 
 
 
 
* If there is a difference higher than 10% between the number of patients in FAS and in PPS 
 
 
Protocol deviations 
 
As per ICH E3 guideline, 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 patient safety or the 
efficacy assessments. Protocol deviations are to be displayed in the Clinical Study Report (CSR) as 
a metric of the feasibility and reliability of the study. Protocol deviations are deviations that might 
significantly affect the completeness, accuracy, and/or reliability of the study data or that might 
significantly affect a subject's rights, safety, or well-being.  
The list of protocol deviations presented in the CSR is defined in this document but protocol 
deviations can be added during the Data Review Meeting (DRM). Protocol deviations will be 
extensively sought from monitoring files, clinical database and external vendors of off-site data 
(Imaging, Laboratory data…)  
Protocol deviations will be split in major and non-major deviations. A major deviation is defined as 
a deviation having an impact on the primary criterion (e.g. P03277 wrong volume administered to 
the patient differing of more than 10% from the calculated one). A first categorisation is done in this 














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5.3. Measurements of study drug compliance 
Study drug compliance in this study refers to the injection of P03277. The compliance will be 
computed in terms of percentage by  
𝐶𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒ൌ𝑎𝑐𝑡𝑢𝑎𝑙 𝑣𝑜𝑙𝑢𝑚𝑒െ𝑡ℎ𝑒𝑜𝑟𝑒𝑡𝑖𝑐𝑎𝑙 𝑣𝑜𝑙𝑢𝑚𝑒
𝑡ℎ𝑒𝑜𝑟𝑒𝑡𝑖𝑐𝑎𝑙 𝑣𝑜𝑙𝑢𝑚𝑒
ൈ100 
Number of patients with theoretical volume to be administered not equal to the one actually 
administered will be presented. Summary statistics (number [n], mean, standard deviation [SD], 
median, minimum, and maximum) will be calculated for difference between actual and theoretical 
and volumes of study product and displayed by dose. Frequency and percentage will be calculated 
for differences between volumes (< -10%, ≥ -10% and < 0 %, > 0% and ≤ 10%, >10%). 
 
5.4. Demographic and Other Baseline Characteristics 
The analysis will be done using the Safety Set and the Full Analysis Set. 
5.4.1. Demographic data 
Demographic parameters are age, sex, childbearing potential, body weight in kilograms (kg), height 
in centimetres (cm), body mass index (BMI in kg/m²) and ethnic origin (self-reported race/ethnicity). 
Summary statistics (number [n], mean, standard deviation [SD], median, minimum, and maximum) 
will be calculated for age, body weight, height and BMI and displayed by dose and overall. Frequency 
and percentages will be calculated for age (≥18 and <65, ≥65), sex and BMI (<18.5, ≥18.5 and <25, 
≥25 and <30, ≥30). 
5.4.2. Study disease 
Chronic liver disease status at inclusion visit will be displayed by dose and overall: 
Frequency and percentages of parameters supporting the diagnosis of chronic liver disease (biopsy, 
endoscopic, biological, ultrasound, elastography, other) will be presented. 
Frequency and percentages of parameters supporting the aetiology of chronic liver disease (alcohol, 
HBV, HCV, non-alcoholic-NASH, other) will be presented. 
Frequency and percentages will be presented for each class of the Child Pugh score calculated on the 
last evaluation available. The classes are defined as follows: 
 A: well-compensated disease (score between 5 and 6) 
 B: significant functional compromise (score between 7 and 9) 
 C: decompensated disease (score between 10 and 15). 
5.4.3. Risk factors 
Not applicable. 
5.4.4. Medical history and concomitant diseases 
Medical history and concomitant diseases will be coded in System Organ Classes (SOC) and 
preferred terms (PT) using the Medical Dictionary for Regulatory Activities (MedDRA) version 20.1.  


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Summary tables (number and % of patients) grouped by SOC and PT will be presented by dose and 
overall for Medical history firstly then for concomitant diseases. Medical histories are those "Not 
Ongoing" and concomitant diseases are those "Ongoing" at the screening visit. 
Listing of demographics, study disease characteristics and all diseases will be presented in CSR 
Appendix 16.2.4 with a flag for ongoing diseases. 
5.4.5. Clinical laboratory evaluation at baseline 
Laboratory data analysis will be done using the safety set by dose and overall. Blood samples will be 
performed during screening visit. 
 
Results will be presented in standard international (SI) units and conventional United States units 
(See Table 1 and Table 2 respectively). Original units will only be listed if different. Laboratory data 
will be analyzed quantitatively and qualitatively. Qualitative analyses will be done via comparison 
of laboratory data to their reference ranges. Quantitative analyses will be done by tabulating raw data. 
Summary statistics (number [n], mean, standard deviation [SD], median, minimum, and maximum) 
will be calculated for baseline serum creatinine and eGFR and displayed by dose and overall.  
Technique used to determine serum creatinine level and eGFR method will be presented. 
Table of locally eGFR and baseline serum creatinine will present the results in standard international 
units and conventional United States units.  
Qualitative analysis of eGFR will be done via comparison of data to the reference ranges (<60, ≥60 
and ≤90, >90).  
5.4.6. Vital signs, physical findings and other observations related to safety at baseline 
A routine physical examination will be performed at baseline, including the examination of general 
appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, 
lymph nodes, extremities, vascular and neurological.  
Physical examination will only be listed in CSR appendix 16.2.4.  
If any abnormality is detected among those parameters, it will be described in the Medical History 
section. 
5.4.7. Prior therapies 
Prior therapies are defined as therapies ended before administration. 
Prior medications will be coded using the WHODRUG dictionary version June 2015.  
The number and percent of patients taking prior therapies will be presented by dose and overall.  
Summary tables (number and % of patients) grouped by the first and the fourth level of ATC code 
will be presented by dose and overall for prior medication. 
5.4.8. Other baseline characteristics 
5.4.8.1 
Contrast agent history 
Data concerning contrast agent history will be only listed in section 16.2.4.  
 
5.4.8.2 
Suspected nodule detected 
Suspected nodules detection will be described by dose and overall using the FAS.  


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Frequency and percentage of procedure that first detected will be presented.  
Summary statistics (number [n], mean, standard deviation [SD], median, minimum, and maximum) 
will be calculated time between the procedure and IMP administration (days). 
 
5.4.8.3 
Suspected nodule characterization 
Suspected nodule(s) characterization will be displayed by procedure for each dose and overall using 
the FAS:  
 Procedure performed: Yes; No 
 If yes: 
o Number of suspected nodule(s)  
o Time between the procedure(s) and IMP administration (days). 
 
5.4.8.4 
Pregnancy test 
Pregnancy test will be only listed in section 16.2.4.  
 
5.4.8.5 
Histologic analysis 
Histologic analysis scheduled will only be listed in CSR appendix 16.2.4. 
 
5.4.8.6 
MRI Examination 
MRI examination and characteristics includes the following parameters and will be presented by dose 
using the FAS: 
 MRI performed: Yes; No. 
 If yes: 
o Time between the previous imaging, last date if several procedures performed, and 
trial MRI examination (days)  
o Magnetic field strength (Tesla): 1.5T; 3.0T 
o Occurrence of any deviation from the MRI procedures (Yes; No; If yes, Specification 
(multiple choices): Scanner-related deviation; Subject-related deviation 
 
 Unenhanced MRI and contrast-enhanced MRI sequences performed: Yes; No 
 If yes: 
o Time between the injection of contrast agent and each phase post-injection 
 Reasons for missing data at unenhanced MRI and contrast-enhanced MRI sequences as per expert 
reader by dose: Not available; Not assessable  
Subtraction sequences available at contrast-enhanced MRI sequence on arterial phase as per expert 
reader by dose if at least one hyperintensity for contrast intensity relative to parenchyma at 3D GRE 
T1-WI with fat saturation: Yes; No. 
 


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5.5. Efficacy evaluation 
Efficacy data will be summarized by dose using the FAS/FASN and PPSN for primary efficacy 
analysis and only using FAS/FASN for any other efficacy analysis. If there is a difference higher 
than 10% between the FAS and PPS then the secondary analysis will be repeated on the PPS. 
Listing of all efficacy data will be presented in CSR appendix 16.2.6. 
5.5.1. Primary analysis of the primary criteria 
P03277 imaging diagnosis (HCC or not HCC) will be presented at nodule level in a contingency table 
displaying number for each diagnosis category (HCC or not HCC) obtained with the standard of 
reference according to the following table: 
 
 
Standard of reference 
 
HCC 
Not HCC 
including uncertain 
cases 
P03277 
imaging 
expert 
reading 
results 
HCC 
(Typical features 
on this MR 
examination) 
True positive 
n1 
False positive 
n2 
Total 
n1 + n2 
Not HCC 
(No nodule/atypical 
features) 
False negative 
n3 
True negative 
n4 
Total 
n3 + n4 
 
Total 
n1 + n3 
Total 
n2 + n4 
All total 
N 
 
In case of nodules with a standard of reference but no detected by the experts, the diagnostic of expert 
reading will be considered Not HCC to complete the contingency table.   
 
The following parameters will be calculated: 
 Sensitivity: the number of nodules showing true positive HCC (i.e. HCC detected with both 
P03277 imaging and Standard of reference) divided by all nodules considered HCC according 
to standard of reference (n1 / n1 + n3) 
 Specificity: the number of nodules showing true negative HCC (i.e. HCC detected neither 
with P03277 imaging nor with Standard of reference) divided by all nodules considered as 
not HCC or uncertain according to standard of reference (n4 / n2 + n4) 
 Accuracy: the number of nodules showing true positive HCC and true negative HCC over all 
nodules (n1 + n4 / N) 
 Positive predictive value: the number of nodules showing true positive HCC /all nodules 
showing HCC according to P03277 imaging (n1 / n1 + n2) 
 Negative predictive value: the number of nodules showing true negative HCC /all nodules 
not showing HCC according to P03277 imaging (n4 / n3 + n4). 
Frequency and percentages of nodule diagnosis used for standard of reference (HCC/not HCC) will 
be presented.  


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5.5.2. Supportive analyses of primary criterion 
Nodule characterization from previous contrast enhanced imaging for diagnostic (CT and/or MRI), 
mapping and measurement will be described by dose:  
At nodule level, typical imaging hallmark and hyperintensity of parenchyma relative to the nodule 
will be presented. Frequency and percentages of suspected nodule(s) characterization depending the 
procedure will be described. 
Frequency and percentages of localization code of segment of suspected nodule(s) will be presented. 
Summary statistics (number [n], mean, standard deviation [SD], median, minimum, and maximum) 
will be calculated size of nodule (mm). 
Previous alpha-fetoprotein (AFP) value will be analyzed quantitatively and qualitatively. Frequency 
and percentages will be presented for previous AFP (≤200 ng/mL, >200 ng/mL). 
Diagnosis used for standard reference from previous contrast enhanced imaging and AFP will be 
described.  
Nodule characterization from histopathology will be presented for patients who performed a biopsy:  
 
time between MRI examination and the procedure(s) (days) 
 
nodule diagnosis by assessment, including final assessment. 
Nodule diagnosis (HCC, not HCC) according to histopathology and according to previous imaging 
will be presented. 
Nodule diagnosis based on experts reading or consensus will be described.  
5.5.3. Additional analyses of primary criterion 
Not Applicable. 
5.5.4. Analysis of secondary criteria 
Tables from expert reading will be displayed by expert readers.  
Results of consensus will be listed presenting patient number, dose, nodule number and diagnosis. 
Technical adequacy of images (on-site and/or expert reading) 
Technical adequacy will be presented by reading type, by displaying number and frequency of 
adequate and inadequate images and the categories for inadequacy. Number of cases not assessable 
and assessable will be presented. 
 
Visualization of biliary and liver vascular abnormalities (expert reading) 
Biliary and liver vascular abnormalities will be presented globally, by displaying number and 
frequency of portal thrombosis, hepatic venous thrombosis, biliary tract invasion, and visualization 
of arterio-portal fistula, and if yes, close to which nodule(s). 
 
Number of nodules evaluated (on-site and/or expert reading) 
Number of nodules evaluated by P03277 imaging will be presented quantitatively and qualitatively 
at patient level. 


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Localization and size of suspected nodule(s) (on-site and expert reading) 
Frequency and percentages of localization code of segment of suspected nodule(s) will be presented 
on-site and by expert readers. Summary statistics (number [n], mean, standard deviation [SD], 
median, minimum, and maximum) will be calculated size of nodule (mm). 
 
Qualitative evaluation of nodule intensity and nodule description (expert reading) 
Qualitative evaluation of nodule intensity (hypointensity, hyperintensity, isointensity and 
hetero/homogeneous) relative to parenchyma at each phase (T2, T1 unenhanced, arterial, portal, 
delayed) as well as, presence of capsule (portal and delayed phases), wash-out, visualization of fat 
and iron presence (T1 in and opposed phase) will be presented by displaying number and frequency 
for each standard of reference group (HCC or not HCC). 
 
Quantitative evaluation of nodule intensity (on-site) 
Quantitative evaluations of nodule intensity (SI, SNR, CNR and PE) will be presented at each phase 
(T1 unenhanced, arterial, portal, delayed, 15 ±5 minutes) for each standard of reference group (HCC 
or not HCC) by displaying number [n], mean, standard deviation [SD], median, minimum, maximum. 
 
Quantitative evaluation of vascular intensity (on-site) 
Quantitative evaluations of aorta intensity and portal vein intensity (SI and SNR) will be presented 
at patient level globally by displaying number [n], mean, standard deviation [SD], median, minimum, 
maximum. 
 
Qualitative evaluation at very delayed sequences for visualization of the parenchyma enhancement 
and nodule enhancement relative to parenchyma (expert reading) 
In case no more than 5 patients received very delayed sequences, data will be presented as listings 
only. 
Qualitative evaluation of parenchyma intensity relative to that on unenhanced GRE T1 sequence with 
fat-suppressed (hypointense, isointense or hyperintense) will be presented globally showing number 
and frequency at three available very delayed images and sequences (15 ±5 minutes, 1h, 2h). 
 
Qualitative evaluations for nodule enhancement relative to parenchyma (hypointense, isointense or 
hyperintense) will be presented by displaying number and frequency for each reference group (HCC 
or not HCC). 
 
5.6. Safety Evaluation 
Safety analysis will be done using the safety set presented by dose and overall. 
5.6.1. Extent of Exposure 
Duration from inclusion visit to IMP administration, summary of durations during the study, mode 
of injection, location of the injection site, volume theoretically administered, volume actually 
administered, dose administered, occurrence of an overdose, actual rate of administration and volume 
of saline flush will be tabulated.  
 
All durations will be computed in days as second date of interest - first date of interest + 1. 
 


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Listing of exposure will be presented in CSR appendix 16.2.5. 
5.6.2. Adverse Events 
Adverse events (AEs) will be coded using MedDRA version 20.1. 
The time period for the assessment of AEs will be divided into 3 mutually exclusive and exhaustive 
periods:  
 before start time of administration of P03277 
 after start time of administration of P03277 until day + 1 safety follow-up 
 after safety follow-up (> day +1) until biopsy if it is done 
 
Events will be classified as treatment-emergent adverse event (TEAE) if they occurred after the start 
time of P03277 administration. 
 
Partial start dates/times will be queried. If there is any doubt about treatment emergence, AEs will be 
classified as treatment emergent. 
 
Overall summary: 
The number (%) of patients and number of events will be presented in an overall summary for all 
AEs, AEs occurring before start time of P03277 administration and then all TEAEs according time 
periods by dose including: 
 Total number of AEs 
 Total number of patients with at least one AE 
 Distribution of the number of AEs reported by patients 
 Total number of TEAEs 
 Total number of patients with at least one TEAE 
 Total number of serious AEs  
 Total number of patients with at least one serious AE 
 Total number of AEs according to intensity 
 Total number of patients with at least one AE according to intensity 
 Total number of AEs according to outcome 
 Total number of patients with at least one AE according to outcome 
 Total number of AEs requiring AE-targeted medication 
 Total number of patients with at least one AE requiring AE-targeted medication 
 Total number of AEs requiring other AE-targeted action 
 Total number of patients with at least one AE requiring other AE-targeted action 
with the addition of the following information for TEAEs: 
 Total number of AEs with relationship to IMP/ a study procedure 
 Total number of patients with at least one AE with relationship to IMP/ a study procedure 
 Total number of AEs according to action taken with regard to administration of the IMP 
 Total number of patients with at least one AE according to action taken with regard to 
administration of the IMP 
 
The number (%) of serious events will be presented according to the following criteria: 
 Death 
 Life-threatening 


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 Hospitalisation or prolongation of hospitalisation 
 Persistent or significant disability or incapacity 
 Congenital anomaly or birth defect 
 Medically important. 
 
Distribution of AEs  
A table will present the total numbers and the distribution of AEs (number [%] of patients with 1, 2, 
etc… AEs).  
 
Summaries by SOC and PT 
The table of summaries of at least one TEAE will be displayed by SOC and PT by dose and overall. 
Same table of summaries will be displayed for at least one TEAE with relationship to IMP/a study 
procedure by dose and overall. 
 
 
Data listings will present all AEs reported, including non-TEAEs. Adverse event listings will be 
sorted by site, patient number and dose and will also display the SOC, and PT, time of onset, duration, 
intensity, seriousness, outcome, relationship to the IMP, relationship to a study procedure, action 
taken with IMP, AE-targeted medication, other AE-targeted action, date and time of IMP 
administration (presented in CSR appendix 16.2.7).  
 
AE Duration will be computed in days as Date of End of AE - Date of Onset of AE + 1. If the AE 
started before administration or after safety follow-up, no date and time of administration will be 
displayed. 
5.6.3. Deaths and other serious adverse events 
All serious adverse events experienced during the study will be separately listed per patient number 
and dose, presenting: description, SOC, PT, start and end date, duration, intensity, the relationship to 
study drug, the action taken, the outcome, the seriousness criteria, date and time of IMP 
administration, study period. 
5.6.4. Clinical laboratory evaluation 
All laboratory values recorded during the study will be individually listed and flagged for values 
outside reference ranges and clinically significant (presented in CSR appendix 16.2.8).  
 
Each hematology and biochemistry parameter will be tabulated for each visit presenting also 
abnormal values. 
 
Tables will present the results in standard international units and United States units (See Table 1 
Hematology parametersTable 1 and Table 2). Standard international units, United States units and 
original units (if different) will be listed.  
 
The baseline is defined as measure collected at visit 1 or visit 2. 
Laboratory data will be analyzed quantitatively and qualitatively. Qualitative analyses will be done 
via comparison of laboratory data to their reference ranges.  Any significance will be monitored and 
reported either as MH or AE. Quantitative analyses will be done by tabulating raw data and change 
from baseline. They will be displayed qualitatively as well as by means of shift tables for creatinine 


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(<60, ≥60 and <100, ≥100), eGFR (<30, ≥30 and <60, ≥60 and <90, ≥90) and BUN (<3, ≥3 and <8, 
≥8) for post-baseline visit as compared to the baseline value. 
 
Table 1 Hematology parameters 
Hematology parameters 
 
SI Units
US Units
Basophils 
BASO 
109/L
103/μL
Basophils/Leukocytes 
BASOLE
%
%
Eosinophils 
EOS 
109/L
103/μL
Eosinophils/Leukocytes 
EOSLE 
%
%
Hematocrit 
HCT 
v/v
%
Hemoglobin 
HGB 
g/L
g/dL
Lymphocytes 
LYM 
109/L
103/μL
Lymphocytes/Leukocytes 
LYMLE 
%
%
Mean red blood cells volume
MCV 
fL
fL
Monocytes 
MONO 
109/L
103/μL
Monocytes/Leukocytes 
MONOLE
%
%
Neutrophils 
NEUT 
109/L
103/μL
Neutrophils/Leukocytes 
NEUTLE
%
%
Platelet count 
PLAT 
109/L
103/μL
Red blood cells = Erythrocytes 
RBC 
1012/L
106/µL
White blood cells = Leukocytes 
WBC 
109/L
103/µL
 
Table 2 Biochemistry parameters 
Biochemistry parameters 
 
SI Units
US Units
Alpha fetoprotein 
AFP 
µg/L
ng/mL
Alkaline phosphatase 
ALP 
U/L
U/L
Aspartate amino transferase 
AST 
U/L
U/L
Alanine amino transferase  
ALT 
U/L
U/L
Direct bilirubin 
BILDIR 
µmol/L
mg/dL
Bilirubin 
BILI 
µmol/L
mg/dL
Indirect Bilirubin 
BILIND 
µmol/L
mg/dL
Blood Urea Nitrogen  
BUN 
mmol/L
mg/dL
Calcium 
CA 
mmol/L
mg/dL
Chloride 
CL 
mmol/L
mEq/L
Creatinine 
CREAT 
µmol/L
mg/dL
Cystatin C 
CYSTATC
mg/L
mg/L
Glucose 
GLUC 
mmol/L
mg/dL
Potassium 
K 
mmol/L
mEq/L
Lactate dehydrogenase 
LDH 
U/L
U/L
Phosphate 
PHOS 
mmol/L
mg/dL
Protein 
PROT 
g/L
g/dL
Sodium 
SODIUM 
mmol/L
mEq/L
Triglycerides 
TRIG 
mmol/L
mg/dL
eGFR 
GFRE 
mL/min/1.73m²
mL/min/1.73m²
 
5.6.5. Vital signs, physical findings and other observations related to safety 
Raw values and changes from baseline of Systolic/Diastolic Blood Pressure (mmHg) in supine 
position and Pulse Rate (beats/min) will be described according to the following schedules: 
 Immediately prior to contrast agent injection (baseline value) 


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 At 30±5 minutes following P03277 injection 
 One day after P03277 injection 
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. 
A clinically significant value is defined as follows:  
 Pulse Rate < 40 or >100 bpm;  
 Systolic Blood Pressure < 90 or >160 mmHg;  
 Diastolic Blood Pressure > 100 mmHg. 
Summary statistics (number [n], mean, standard deviation [SD], median, minimum, and maximum) 
will be calculated for these parameters, as well as change from baseline. Qualitative analysis will be 
done via comparison of vital signs data to their normal ranges. 
Listings of vital signs will be provided in CSR appendix 16.2.9, including Systolic/Diastolic Blood 
Pressure (mmHg), Pulse Rate (beats/min), and flag for clinically significant. 
Number of patients experiencing burning, pain, eruption, extravasation and inflammation at site 
injection will be tabulated by dose and overall. Pain at injection site will be measured using the Visual 
Assessment Scale (VAS) and VAS measurements for these patients will be tabulated. 
5.6.6. Concomitant medications 
The number and percentage of patients taking concomitant medications will be presented. Summary 
tables (number and % of patients) grouped by the first and the last level of ATC code (ATC4) will 
be presented by dose and overall for concomitant medications. Concomitant medications are those 
ongoing at or started after the P03277 injection.   
Listing of all concomitant medications will be presented in CSR appendix 16.2.4. 
 
Concomitant medications will be coded using the WHODRUG dictionary version June 2015.  
 
 
 


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 SHELLS FOR TABLES, FIGURES AND LISTINGS  
All outputs will be produced using SAS version 9.4 or a later version. 
All recorded data will be listed following the table order and structure of the case report form (CRF). 
In addition, all derived data used in the analyses will be listed. The listings will include all patients 
and will be ordered by site and patient. 
Unless otherwise indicated, in case of continuous or ordinal variables summary statistics are the n, 
mean, SD, median, minimum and maximum. The mean, median and SD will be reported to 1 decimal 
more 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. Clinical study report in-text tables, figures and listings 
7.2. Contents of clinical study report section 14 
7.3. Contents of clinical study report section 16.2 
 
 




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 APPENDICES 
Contents of clinical study report section 14: see attached document “GDX-44-008 - SAP - Attachment Tables - version 
1.0”. 
 
Contents of clinical study report section 16.2: see attached document “GDX-44-008 - SAP - Attachment Listings - version 
1.0”.