Conditions: Central Nervous System Indication Pediatric Patients Body Indication
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 80
Healthy volunteers: no

Brief summary:
This is a pharmacokinetics (PK), open-label, uncontrolled, multicenter phase II trial with age-staggered approach.

The primary objective is to evaluate the PK profile of gadopiclenol in plasma following single IV injection of 0.05 mmol/kg body weight (BW) in pediatric population aged from 2 to 17 years undergoing CNS contrast-enhanced MRI (CNS cohort).

Detailed description:
A population PK approach and an age-down staggered approach will be used. Patients will be recruited into 3 predefined age groups: 12-17, 7-11 and 2-6 years. The inclusions will start with the older group (Adolescents, 12-17 years), followed by Preadolescents (7-11 years) and finally Young Children (2-6 years of age).

Arms:
arm 1: Pediatric patients aged 2-6 years undergoing CNS contrast-enhanced MRI arm 2: Pediatric patients aged 7-11 years undergoing CNS contrast-enhanced MRI arm 3: Pediatric patients aged 12-17 years undergoing CNS contrast-enhanced MRI arm 4: Pediatric patients aged 2-6 years undergoing contrast-enhanced MRI of other body organs (head and neck, thorax, abdomen, pelvis or musculoskeletal system) arm 5: Pediatric patients aged 7-11 years undergoing contrast-enhanced MRI of other body organs (head and neck, thorax, abdomen, pelvis or musculoskeletal system) arm 6: Pediatric patients aged 12-17 years undergoing contrast-enhanced MRI of other body organs (head and neck, thorax, abdomen, pelvis or musculoskeletal system)

Interventions: intervention 1: P03277
Intervention descriptions: intervention 1: A dose of 0.05 mmol/kg body weight (0.1 mL/kg body weight) of P03277 will be administered to each patient in a single intravenous injection.

Protocol document:
Prot_000.pdf: 
Document Type 
Study Protocol 
Document Date 
April 24, 2020 
Official Title 
Pharmacokinetics, safety and efficacy of a new gadolinium-based 
contrast agent, gadopiclenol, in pediatric patients from 2 to 17 years 
of age undergoing contrast-enhanced MRI 
NCT Number 
NCT03749252 
 


 
 
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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-44-007 
Pharmacokinetics, safety and efficacy of a new gadolinium-based contrast agent, gadopiclenol, 
in pediatric patients from 2 to 17 years of age undergoing contrast-enhanced MRI. 
Phase II Clinical Trial 
 
Design 
Pharmacokinetics, open-label, uncontrolled, multicenter trial with 
age-staggered approach 
 
EudraCT No.: 2018-001516-30  
IND No.: 123673 
 
COORDINATING INVESTIGATOR  
 
 
 
 
SPONSOR 
GUERBET, B.P. 57400, 95943 Roissy CdG Cedex, FRANCE  
GUERBET MEDICAL EXPERT 
 
 
 
PHARMACOVIGILANCE 
 
 / e-mail: pharmacovigilance.headquarters@guerbet.com 
 
 
 


 
 
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TRIAL SYNOPSIS 
Trial Title: Pharmacokinetics, safety and efficacy of a new gadolinium-based contrast agent, 
gadopiclenol, in pediatric patients from 2 to 17 years of age undergoing contrast-enhanced MRI. 
Phase II Clinical Trial 
Trial Product(s): 
 Active Ingredient(s): gadopiclenol (P03277) 
EudraCT No.: 2018-001516-30 
IND No.: 123673 
Potential Participating countries (Potential Number of sites): 
Around 20 centers in approximately 5 European countries. 
Trial Objectives 
Primary objective: 
To evaluate the pharmacokinetic profile of gadopiclenol in plasma following single intravenous 
injection of 0.05 mmol/kg body weight (BW) in pediatric population aged from 2 to 17 years 
undergoing central nervous system (CNS) contrast-enhanced MRI (CNS cohort).  
Secondary objectives: 
1. To evaluate safety (clinical and biological) up to 3 months following single administration in 
both CNS and Body cohorts. 
2. To evaluate urinary excretion of gadopiclenol quantitatively up to 8 hours and in subsequent 
urine samples collected up to 3 months following single administration in both CNS and Body 
cohorts (or exceptionally up to 4 months if collection is delayed due to the COVID-19 
pandemic). 
3. To evaluate efficacy of gadopiclenol -enhanced MRI for CNS and body as assessed by on-
site Investigator. 
Trial design and methodology 
This Phase II open-label, uncontrolled, multicenter trial is designed to investigate the pharmacokinetic 
(PK) profile of gadopiclenol in plasma, in children aged from 2 to 17 years, using a population PK 
approach. This approach, allowing sparse blood sampling only is selected to minimize the clinical 
burden to children. Blood sampling will be performed via indwelling catheters rather than by repeated 
venipunctures. An optimized flexible design with 4 sampling windows (W) covering the first 8 hours 
following gadopiclenol injection will be used: 
 
W1: 1 min to 20 min 
 
W2: 30 min to 45 min 
 
W3: 2 to 3 hours 
 
W4: 7 to 8 hours 
A total of 4 blood samples per patient will be taken post-injection for PK analysis, one within each 
window.  
PK profile in plasma will only be investigated in the cohort of patients undergoing CNS contrast-
enhanced MRI (CNS cohort). 
Safety, urinary excretion and efficacy of gadopiclenol will be evaluated in both CNS cohort and in 
the cohort of patients undergoing contrast-enhanced MRI for diseases of other organs (Body cohort).  
When possible, total urine over 8 hours will be quantitatively collected following gadopiclenol 
injection in patients capable to control daytime urination to evaluate the concentration of urinary 


 
 
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excreted gadopiclenol. An age-down staggered approach will be used. Patients will be recruited into 
3 predefined age groups: 12-17, 7-11 and 2-6 years. The inclusions will start with the older group 
(Adolescents, 12-17 years), followed by Preadolescents (7-11 years) and finally Young Children (2-
6 years of age).  
The total sample size of 80 patients (60 in the CNS cohort and 20 in the Body cohort) will be balanced 
between 3 age groups as following:  
 
At least 15 patients and the number as close as possible to 20 patients will be included in each 
age group from the CNS cohort. The inclusion will be completed in parallel in all age groups to 
reach the overall number of 60 patients evaluable for the primary criterion.  
 
At least 3 patients from the Body cohort will be included per age group.  The inclusion will be 
completed in parallel in all age groups to reach the overall number of 20 patients in the Body 
cohort. 
The decision to start the next age group will be taken by Trial Safety Review Board (TSRB) based 
on safety assessment over one-day period after injection of the first 15 patients included in previous 
group from either CNS or both cohorts. 
The previous age group will be completed in parallel with the start of the next group.  
The children popPK model will be initiated with data from the first 15 patients in the adolescents’ 
group from CNS cohort and will be continuously upgraded at each 15 subsequent completed patients 
in each of the following age groups from the same cohort. 
Urine sampling to measure renal excretion of gadopiclenol will be performed 1 week and 3 months 
after gadopiclenol injection in patients with diseases in CNS and other body organs capable to control 
daytime urination. If the urine sampling is delayed at the visits V3-bis and V4-bis due to the COVID-
19 pandemic it can take place up to 1 month and 4 months after gadopiclenol injection respectively. 
Number of patients / sample size 
The sample size of the CNS cohort was determined in order to optimize the characterization of 
gadopiclenol pharmacokinetics in pediatric population through population PK modelling. Sample size 
determination was coupled with PK sampling time optimization in order to determine the best 
possible design for the population PK modelling. The best design (in terms of sample size and 
sampling points) was defined as the design minimizing model’s parameters root square error (RSE), 
hence providing the highest precision. 
According to adult’s data, a 2-compartment model with elimination from the central compartment 
described appropriately gadopiclenol pharmacokinetics. The design was evaluated for a sample size 
of 60 pediatric patients between 2 and 17 years old and predicted a correct estimation of all PK 
parameters. 
The total sample size of 80 patients was estimated sufficient for the satisfactory exploration of safety 
and efficacy of gadopiclenol in pediatric patients with diseases of CNS and other organs. 
Patient who has received an IMP injection and undergone an enhanced MRI examination in CNS 
without major deviations will be considered evaluable for the primary criterion. 
Eligibility criteria 
Inclusion criteria: 
1. Female or male pediatric patient aged 2 to 17 years, 
2. Patient with known or suspected lesion(s) scheduled to undergo routine contrast-enhanced 
MRI of CNS or of other organs including at least one organ among head and neck, thorax, 
abdomen, pelvis and musculoskeletal system (including extremities), 


 
 
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3. Patient whose parent(s) or legal guardian (where applicable) having read the information 
provided his/her/their consent to patient’s participation in writing by dating and signing the 
informed consent prior to any trial related procedure being conducted,  
4. Patient with capacity of understanding who received age- and maturity-appropriate 
information and provided his/her assent to participate in the trial (as required by national 
regulations), 
5. Patient affiliated to national health insurance according to local regulatory requirements. 
 
Non-inclusion criteria: 
1. Patient planned for treatment or procedure (e.g. surgery) that would prevent from obtaining 
the required blood samples or performing other trial procedures between the screening visit 
and up to 1 day after gadopiclenol administration, 
2. Patient undergoing treatment or procedure (e.g., diuretics, clinically significant blood loss or 
blood transfusion) preceding or subsequent to gadopiclenol administration that would alter 
gadopiclenol pharmacokinetic parameters, 
3. Patient with acute or chronic renal insufficiency defined as estimated Glomerular Filtration 
Rate (eGFR) out of age-adjusted normal ranges [eGFR must be calculated based on bedside 
Schwartz equation], 
4. Patients referred for MR Angiography. 
5. Patient with history of bleeding disorder, 
6. Patient with known severe liver disease,  
7. Patient with known cardiac disease (e.g., heart rhythm anomalies, long QT syndrome), 
8. Patient with any clinically significant abnormal 12-lead ECG that in the Investigator's opinion 
would affect the safety evaluation or place the patient at risk, 
9. Patient with electrolyte or fluid imbalance that at Investigator’s judgment presents undue risk 
assessed within 1 month prior to gadopiclenol administration, 
10. Patient undergoing a change in chemotherapy within 1 day prior to or 1 day after gadopiclenol 
administration, 
11. Patient who received or will receive any other contrast agent for CT and/or MRI within 1 
week prior to or 1 week  after gadopiclenol administration, 
12. Patient with contraindication for MRI such as iron metal implants (e.g., aneurysm clips, 
pacemaker), 
13. Patient with history of anaphylactoid or anaphylactic reaction to any allergen including drugs 
and contrast agents, 
14. Patient with history of hypersensitivity caused by any contrast media / agents (iodinated or 
gadolinium-based), 
15. Patient with known contraindication(s) to the use of any gadolinium-based contrast agent 
(GBCA), 
16. Pregnant or breast-feeding female patient [female patient with childbearing potential (who 
experienced menarche) must have a negative urine pregnancy test within 24 hours prior to 
gadopiclenol administration and must be using medically approved contraception* if sexually 
active], 
17. Patient with anticipated, current or past condition (medical, psychological, social or 
geographical) that would compromise the patient’s safety or her/his ability to participate to 
the whole trial, 
18. Patient unlikely to comply with the protocol, e.g., uncooperative attitude of parent(s) or legal 
guardian (where applicable), inability to return for follow-up visits and unlikelihood of 
completing the trial, 


 
 
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19. Having participated in a clinical trial and having received any investigational product within 
7 days prior to gadopiclenol administration or planned during the trial, 
20. Patient previously included in this trial, 
21. Patient related to the Investigator or any other trial staff or relative directly involved in the 
trial conduct. 
* medically approved contraception methods include: female sterilization, 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), barrier methods of contraception (condom or occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/ vaginal suppository). 
Investigational Medicinal Product administration 
Trial product: 
Name: gadopiclenol 
 
 
Pharmaceutical form: 20 ml vial of sterile, clear, ready-to-use aqueous solution for injection. 
Concentration: 0.5 M  
Route and method of administration: 
The IMP will be administered intravenously (IV) as a bolus injection at a recommended rate of 1-
2ml/sec. For dynamic contrast-enhanced studies the use of an injector is recommended. Contrast-
enhanced MRI can start shortly after the injection depending on the pulse sequences used and the 
protocol for the examination. Gadopiclenol injection will be followed with a normal saline flush to 
ensure complete administration of the contrast. 
 
Patients will be dosed according to their BW on the day of MRI examination. Gadopiclenol will be 
administered at a dose of 0.05 mmol/kg BW (0.1 ml/kg BW). A qualified professional according to 
local regulation will be responsible for preparing the dosing solutions. 
Trial duration for patients: 
Expected trial duration for each patient is about 3 months: 
Minimum trial duration for patients: 82 days 
Maximum trial duration for patients: 111 days (up to 134 days in case V4-bis) 
Each patient will undergo 4 visits:  
 V1 - Screening: up to 14 days before inclusion; 
 V2 - Inclusion:  between D1 (gadopiclenol administration) and D2, including confinement period 
(if not prevented by the constraints linked to the COVID-19 pandemic); 
 V3 – 1-week safety follow-up (followed by V3-bis: 1-month maximum safety follow-up if V3 
was done by phone or video); 
 V4 – 3-month safety follow-up (followed by V4-bis: 4-month maximum safety follow-up if V4 
was done by phone or video); 
MRI is performed prior to and after gadopiclenol administration on MR systems (1.5T or 3T). The 
start of administration is considered as IMP injection time point (T0). 4 blood samples for 
pharmacokinetic analysis are collected within 4 sampling windows in the CNS cohort.  


 
 
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The patient participation starts from the signing of the Informed Consent Form at V1 (screening) and 
ends at V4 (3-month safety follow-up) or V4-bis (4-month maximum safety follow-up) when 
applicable or earlier in case of premature discontinuation. 
Patients included and/or to be included in Body cohort may be impacted by COVID-19 pandemic 
related constraints. In this case following changes will be acceptable: 
 
V2-D1 – if 8 hour-confinement period cannot be respected, it may be shortened. The tasks or 
assessments planned up to 90 min after gadopiclenol injection are expected to be performed at 
site; 
 
V2-D2 - if the patient cannot come back to the site the investigator and other authorized trial staff 
are allowed to alternatively perform the visit at patient’s home. If impossible, at the very least a 
phone or video call should be placed;  
 
V3 – at the very least a phone or video call followed by additional on-site visit (Visit 3-bis) no 
later than 30 days after the IMP injection; V4 – at the very least a phone or video call followed 
by additional on-site visit (Visit 4-bis) no later than 120 days after the IMP injection. In this case, 
maximum trial duration will be extended up to 134 days. 
The date of the last visit (date of the last procedure related to the visit) of the last patient undergoing 
the trial will correspond to the end of the trial. 
 
Evaluation criteria 
Primary criteria: 
 
Gadopiclenol pharmacokinetics in plasma will be assessed in the CNS cohort both by age group 
and overall based on following pharmacokinetic parameters determined from the population PK 
model:  
o Simulated concentrations at 10, 20 and 30 minutes post injection 
o Area Under the Curve,  
o elimination half-life,  
o total clearance,  
o volume of distribution. 
Secondary criteria: 
Secondary criteria will be assessed in both CNS and Body cohorts. 
 
Clinical, biological and ECG safety 
o Vital signs (temperature, blood pressure, pulse rate and pulse oximetry), prior to IMP 
injection, 30-90 min after and 1 day after IMP injection, 
o 12-lead ECG recorded prior to IMP injection, 30-90 min after and 1 day after IMP 
injection. Heart rate, Intervals: RR, PR, QRS, QT, corrected QT (QTc Bazett and QTc 
Fridericia), ST segments, T-wave morphology, U-wave and global morphology will be 
analyzed, 
o Safety laboratory variables centrally analyzed (biochemistry and hematology) from 
blood samples collected prior to and 1 day after IMP injection, 
o Estimated glomerular filtration rate (eGFR) centrally calculated based on the bedside 
Schwartz equation prior to and 1 day after IMP injection, 
o Tolerance at the injection site (eruption, extravasation and inflammation) at T0, 30-90 
min after and 1 day after IMP injection, 


 
 
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o Adverse events (AE) occurred from the beginning of patient’s participation in the trial 
(Informed Consent Form signature) until the end of the participation (see Section 9.1.2 
Collection and recording of adverse event),  
o Clinical examination for active detection of Nephrogenic Systemic Fibrosis (NSF) at 3-
month follow-up safety visit. In case of suspicion of NSF a deep skin biopsy will be 
undertaken. 
 
Gadopiclenol urine concentration will be measured in patients capable to control daytime 
urination: 
o in total urine quantitatively collected over 8 hours after gadopiclenol injection (or less if 
the confinement is not possible over this period due to the COVID-19 pandemic),  
o in spot urine samples 1 week and 3 months after gadopiclenol injection (or up to 1 month 
and 4 months after gadopiclenol injection if the urine sampling is delayed to visits V3-
bis and V4-bis respectively due to the COVID-19 pandemic); 
 
Gadopiclenol-enhanced MRI (pre and pre+post comparison) efficacy evaluation in the CNS and 
Body cohorts will be performed by on-site radiologist based on following parameters:  
o Technical adequacy for diagnosis using a 4-point scale; 
o Assessment of contrast quality:  percentage of enhancement (E%) and Lesion to 
Background Ratio (LBR) for up to 3 most representative lesions;  
o Lesion visualization (lesion border delineation, internal morphology and contrast 
enhancement) using a 4-point scale for each parameter; 
o Change in diagnostic confidence following gadopiclenol administration.  
 
Statistical methods 
Descriptive statistical analysis for pharmacokinetic profile in plasma, urine excretion, clinical and 
biological safety and gadopiclenol-enhanced MR efficacy evaluation. 
A population PK approach will be used to characterize gadopiclenol pharmacokinetics in children 
and hence determine pharmacokinetic parameters (concentrations at 10, 20 and 30 minutes post 
injection, Area Under the Curve, elimination half-life, total clearance, volume of distribution).  




 
 
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(1) Confinement period can be reduced to 8 hours after the injection if patient remains close to the site 
and can easily come back for the D2 visit. In case of COVID-19 pandemic related constraints, if the 8 
hours confinement period cannot be respected, it may be shortened. The tasks or assessments planned 
up to 90min after Gadopiclenol injection are expected to be performed at site  
(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. Physical examination will 
include active detection of Nephrogenic Systemic Fibrosis (NSF) at 3-month follow-up safety visit. In 
case of suspicion of NSF a deep skin biopsy to be undertaken. 
(3) Vital signs, Injection site tolerance and ECG will be evaluated within the time window W2 and up to 
90 min after gadopiclenol injection. 
(4)Any medication, including homeopathic products, over-the-counter medications, as well as 
prescription drugs, on-going at D1 or administered until 1-week safety visit (D8) will be recorded in the 
patient’s eCRF. The concomitant medications/treatments started from D2 to D8 will be documented if 
the patient experienced at least one AE. 
Between D8 and D90 safety visits, any GBCA injection will be documented. Other concomitant 
medications/treatments will be documented if it is corrective treatment related to the reported AE. 
 (5) At screening, blood sample will be collected to analyse biochemistry and hematology in central lab 
and to measure serum creatinine. In order to enable the eligibility criteria assessment prior to MRI, sCr 
can be assessed locally as well. 
(6) At screening, locally or centrally calculated eGFR will be used to verify the non-inclusion criterion 
and centrally calculated eGFR will be used to assess safety. The height used for the local calculation 
must be specified in the source data along with the creatinine measured locally. 
(7) Contrast-enhanced MRI will correspond to the usual practice at site depending on the indication. 
(8) All Adverse Events occurring from the beginning of the patient’s participation in the trial (Informed 
Consent Form signature) and until 1-week safety visit (D8 or the day of Visit 3-bis), must be reported 
and followed even if no IMP was administered.  
Non-serious AE occurring before IMP administration and not related to the trial can be collected as 
medical history according to Investigator’s opinion. Non-serious AEs occurring after 1-week safety visit 
(D8) must be reported if related to the drug or to the trial and followed until recovery or sequelae 
stabilization.  
Serious Adverse Events (SAE) and Adverse Event of Special Interest (AESI) occurring from the 
beginning of the patient’s participation in the trial (ICF signature) and until 3-month safety visit (D90 
or the day of Visit 4-bis) must be reported and followed until recovery or sequelae stabilization (see 
Section 9.1.2). 
(9) Due to COVID-19 pandemic related constraints, patients included in Body cohort may not be allowed 
to stay at hospital for the full 8 hour-period. In this case the total urine collection will end when the 
patient is discharged from the hospital. 
(10) In case of COVID-19 pandemic related constraints, data collection at D2 will be insured as far as 
possible at site or at patient’s home by the investigating staff. At the very least a phone or video call will 
be placed to remotely enquire about new AE, follow up on previously reported AE, injection site 


 
 
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tolerance (eruption, extravasation and inflammation), any change in on-going medications/treatments 
and new concomitant medications/treatments.  
(11) In case of COVID-19 pandemic related constraints, data collection at V3 will be insured as far as 
possible. At the very least a phone or video call will be placed to remotely enquire about new AE, follow 
up on previously reported AE, any change in on-going medications/treatments since last visit and new 
concomitant medications/treatments if the patient experienced at least one AE.  
In case of remote Visit 3, an additional on-site visit (Visit 3-bis) should be scheduled whenever possible 
at the earliest possible timepoint and no later than 30 days after the IMP injection. All tasks or 
assessments planned for the Visit 3 at site will be performed during Visit 3-bis. 
(12) In case of COVID-19 pandemic related constraints, data collection at V4 will be insured as far as 
possible. At the very least a phone or video call will be placed to remotely enquire about new non-
serious AE related to the drug or to the trial, SAE and AESI since the last visit, follow up on previously 
reported AE, any GBCA injection since the last visit and other concomitant medications/treatments if 
related to the reported AE.  
In case of remote Visit 4, an additional on-site visit (Visit 4-bis) should be scheduled whenever possible, 
at the earliest possible timepoint and no later than 120 days after the IMP injection. All tasks or 
assessments planned for the Visit 4 at site will be performed during Visit 4-bis. 
 




 
 
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SIGNATURE PAGE 
GUERBET MEDICAL EXPERT 
 
Signature: 
 
 
Date:  
GUERBET CLINICAL PROJECT MANAGER 
 
Signature: 
 
 
Date:  
GUERBET BIOSTATISTICIAN 
 
Signature: 
 
 
Date:  
 
 
COORDINATING INVESTIGATOR 
 
 
Signature: 
 
 
Date:  
“Due to current sanitary conditions, wet ink signatures are temporarily replaced by electronic sign-off. 
Original signatures will be collected when permitted and document sent upon request. [March 20, 
2020]”. 
 
INVESTIGATOR STATEMENT 
I agree to conduct the clinical trial in accordance with the present protocol (and its amendments, if 
applicable) and to comply with the requirements of the Declaration of Helsinki, the Good Clinical 
Practice (GCP) guidelines of the International Conference on Harmonization (ICH) and all other laws 
and regulations in force on the use of investigational medicinal products. 
Name, Title 
 
Institution Name 
Address 
 
Telephone  
e-mail 
Signature: 
 
 
 
 
Date: DD Mon YYYY 


 
 
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ABBREVIATIONS  
AE 
 
Adverse Event 
AESI  
Adverse Event of Special Interest 
Body cohort 
Patients undergoing contrast-enhanced MRI for diseases of other than CNS organs 
BW 
 
Body Weight 
CNS cohort 
Patients undergoing CNS contrast-enhanced MRI 
CRA 
 
Clinical Research Associate (syn. Monitor) 
CRF/eCRF 
Case Report Form/ electronic Case Report Form 
CT 
 
Computed Tomography 
ECG 
 
Electrocardiography 
EMA  
European Medicine Agency 
FAS 
 
Full Analysis Set 
FDA 
 
Food and Drug Administration 
FIM 
 
Fisher Information Matrix 
GBCA  
Gadolinium-based contrast agent 
GCP 
 
Good Clinical Practice 
GFR 
 
Glomerular Filtration Rate 
IB 
 
Investigator’s Brochure 
ICF 
 
Informed Consent Form 
ICH 
 
International Conference on Harmonization 
IDMS  
Isotope Dilution Mass Spectroscopy 
IEC 
 
Independent Ethics Committee 
IMP 
 
Investigational Medicinal Product 
INN 
 
International Nonproprietary Name 
IRB 
 
Institutional Review Board 
ISF 
 
Investigator Site File 
IV 
 
Intravenous 
IWRS  
Interactive Web Response System 
LBR 
 
Lesion to Background Ratio 
MRI 
 
Magnetic Resonance Imaging 
PC-AKI 
Post-contrast acute kidney injury 
PK 
 
Pharmacokinetic/Pharmacokinetics 
PPS 
 
Per Protocol Set 
RSE 
 
Root Square Error 
SAE 
 
Serious Adverse Event 
SAP 
 
Statistical Analysis Plan 
SAR 
 
Serious Adverse Reaction 
sCr  
 
Serum Creatinine 
SD 
 
Standard deviation 
SOP 
 
Standard Operating Procedure 
SPC/SmPC 
Summary of Product Characteristics  
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE  
Treatment-Emergent Adverse Event 
TSRB  
Trial Safety Review Board 
W 
 
Window 
 
 


 
 
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TABLE OF CONTENTS 
TRIAL SYNOPSIS ................................................................................................................................. 2 
TRIAL FLOW CHART .......................................................................................................................... 8 
TRIAL DIAGRAM ............................................................................................................................... 11 
SIGNATURE PAGE ............................................................................................................................. 12 
ABBREVIATIONS ............................................................................................................................... 13 
TABLE OF CONTENTS ...................................................................................................................... 14 
AMENDMENT 3 .............................................................................................................................. 18 
1. 
INTRODUCTION AND TRIAL RATIONALE ........................................................... 25 
2. 
TRIAL OBJECTIVES ................................................................................................... 28 
2.1 
Primary Objective .......................................................................................................... 28 
2.2 
Secondary Objectives .................................................................................................... 28 
2.3 
Sub-Trial / Ancillary Trial Objectives ........................................................................... 28 
3. 
TRIAL DESCRIPTION ................................................................................................ 29 
3.1 
Protocol Design ............................................................................................................. 29 
3.2 
Trial Duration ................................................................................................................ 32 
3.3 
Interim Analysis ............................................................................................................ 33 
3.4 
Trial Committee(s) ........................................................................................................ 33 
4. 
PATIENT SELECTION ................................................................................................ 34 
4.1 
Inclusion Criteria ........................................................................................................... 34 
4.2 
Non-Inclusion Criteria ................................................................................................... 34 
4.3 
Patient Identification ..................................................................................................... 35 
5. 
INVESTIGATIONAL MEDICINAL PRODUCTS ...................................................... 36 
5.1 
Investigational Medicinal Product Description and Administration Modalities ........... 36 
5.2 
Packaging, Labeling, Storage ........................................................................................ 36 
5.3 
Condition of Investigational Medicinal Product Allocation .......................................... 37 
5.3.1 
Investigational Product(s) Allocation / Randomization ................................................ 37 
5.3.2 
Double-Blind Conditions ............................................................................................... 37 
5.3.3 
Individual Trial Treatment Unblinding ......................................................................... 37 
5.4 
Investigational Medicinal Product Management ........................................................... 37 
5.5 
Auxiliary Medicinal Product(s) and Other Trial Products ............................................ 38 
5.6 
Trial Product(s) Compliance and Accountability .......................................................... 38 
6. 
CONCOMITANT MEDICATIONS / PROCEDURES ................................................ 39 
6.1 
Concomitant Medications .............................................................................................. 39 
6.1.1 
Concomitant Medications of Special Attention ............................................................. 39 
6.1.2 
Prohibited Concomitant Medications ............................................................................ 39 


 
 
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6.2 
Procedures ..................................................................................................................... 39 
7. 
EVALUATION CRITERIA .......................................................................................... 41 
7.1 
Primary Criteria ............................................................................................................. 41 
7.2 
Secondary Criteria ......................................................................................................... 41 
7.2.1 
Clinical, biological and ECG safety data ...................................................................... 41 
7.2.2 
Gadopiclenol  urine concentration ................................................................................ 42 
7.2.3 
Gadopiclenol-enhanced MRI (pre and pre+post comparison) efficacy evaluation in the 
CNS and Body cohorts by on site radiologist ................................................................ 42 
8. 
TRIAL SCHEDULE AND PROCEDURES ................................................................. 45 
8.1 
Trial Schedule ................................................................................................................ 45 
8.1.1 
Screening – Visit 1 – Day - 14 to Day 1 ........................................................................ 45 
8.1.2 
Inclusion – Visit 2 – From Day 1 to Day 2 .................................................................... 46 
8.1.3 
Safety Follow-up – Visit 3 – Day 8 ................................................................................ 48 
8.1.4 
Safety Follow-up – Visit 4 – Day 90 .............................................................................. 49 
8.2 
Imaging Characteristics ................................................................................................. 50 
8.2.1 
Equipment ...................................................................................................................... 50 
8.2.2 
Sequences ...................................................................................................................... 50 
8.3 
On Site Reading of Images ............................................................................................ 50 
8.4 
Off Site Reading of Images ........................................................................................... 50 
8.5 
Other Centralized Trial Procedures ............................................................................... 50 
8.5.1 
Pharmacokinetic procedures and assessments.............................................................. 50 
8.5.2 
Central Laboratory for biological assessments............................................................. 51 
9. 
SAFETY REPORTING ................................................................................................ 53 
9.1 
Adverse Event ............................................................................................................... 53 
9.1.1 
Definition of Adverse Event ........................................................................................... 53 
9.1.2 
Collection and recording of Adverse Events ................................................................. 53 
9.1.3 
Description of Adverse Events....................................................................................... 54 
9.2 
Serious Adverse Event .................................................................................................. 55 
9.2.1 
Definition of Serious Adverse Event (SAE) ................................................................... 55 
9.2.2 
Reporting Serious Adverse Events (SAE) ...................................................................... 56 
9.3 
Special situations ........................................................................................................... 57 
9.3.1 
Cases of overdose, lack of efficacy, drug-drug interaction, medication errors or misuses
 ....................................................................................................................................... 57 
9.3.2 
Pregnancy ...................................................................................................................... 57 
9.3.3 
Adverse Events of Special Interest ................................................................................ 57 
9.3.4 
Any suspicion of transmission of an infectious agent via an IMP ................................. 58 
9.4 
Other important safety issue /New fact ......................................................................... 58 


 
 
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9.5 
Unblinding Procedures .................................................................................................. 58 
10. 
PREMATURE DISCONTINUATION OF THE TRIAL ............................................. 59 
10.1 
Premature Discontinuation of the Trial per GUERBET Decision................................. 59 
10.2 
Reasons for patient’s premature discontinuation ........................................................... 59 
11. 
STATISTICAL CONSIDERATIONS .......................................................................... 60 
11.1 
Statistical Method (null and alternative hypotheses) ..................................................... 60 
11.2 
Sample Size for primary criterion assessment ............................................................... 60 
11.3 
Planned Analysis ........................................................................................................... 61 
11.3.1 
Disposition of Patients .................................................................................................. 61 
11.3.2 
Data Sets Analyzed ........................................................................................................ 61 
11.3.3 
Protocol Deviations ....................................................................................................... 61 
11.3.4 
Demographics and Baseline Characteristics ................................................................ 62 
11.3.5 
PK .................................................................................................................................. 62 
11.3.5.1 Population PK ............................................................................................................... 62 
11.3.5.2 Urinary PK .................................................................................................................... 63 
11.3.6 
Efficacy Analysis ........................................................................................................... 63 
11.3.7 
Adverse Event ................................................................................................................ 63 
11.3.8 
Laboratory data ............................................................................................................. 64 
11.3.9 
Other safety observations .............................................................................................. 64 
11.4 
Statistical/Analytical issues ........................................................................................... 65 
11.4.1 
Adjustments for Covariates ........................................................................................... 65 
11.4.2 
Handling of Dropouts or Missing Data ......................................................................... 66 
11.4.3 
Interim Analyses and Data Monitoring ......................................................................... 66 
11.4.4 
Multicenter Trials .......................................................................................................... 66 
11.4.5 
Multiple Comparisons/Multiplicity ............................................................................... 66 
11.4.6 
Use of an "Efficacy Subset" of Patients ......................................................................... 66 
11.4.7 
Active-Control Trials Intended to Show Equivalence ................................................... 66 
11.4.8 
Examination of Subgroups ............................................................................................ 67 
12. 
TRIAL COMMITTEES ................................................................................................ 68 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS ............................................. 69 
13.1 
References ..................................................................................................................... 69 
13.2 
Institutional Review Board/Independent Ethics Committee and Regulatory/Competent 
Authorities ..................................................................................................................... 70 
13.3 
Patient Parent(s) or Legal Guardian (where applicable) Informed Consent .................. 70 
13.4 
Trial Records and Archiving ......................................................................................... 71 
14. 
QUALITY CONTROL / QUALITY ASSURANCE .................................................... 72 
14.1 
Direct Access to Source Data/Documents ..................................................................... 72 


 
 
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14.2 
Clinical Monitoring ....................................................................................................... 72 
14.3 
Clinical Data Handling .................................................................................................. 72 
14.3.1 
Data Reported in the eCRF ........................................................................................... 72 
14.3.2 
Data Reported in the eCRF according to Patient Status ............................................... 73 
14.3.3 
Data Management System ............................................................................................. 73 
14.4 
Audits and Inspections .................................................................................................. 73 
 
 
16. 
REFERENCES .............................................................................................................. 76 
17. 
COMPANY LIABILITY INSURANCE ...................................................................... 78 
18. 
APPENDICES ............................................................................................................... 79 
LIST OF FIGURES 
 
Figure 2: Age-down staggered enrollment ............................................................................................ 31 
 
 
 


 
 
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1. 
INTRODUCTION AND TRIAL RATIONALE 
Magnetic Resonance Imaging (MRI) is an important modality used in children for detection, evaluation, 
staging, and follow-up of lesions mostly in the central nervous system (CNS) diseases. MRI is applied 
for a range of CNS disease processes such as tumors (eg, ependymoma, medulloblastoma, cerebellar 
low-grade astrocytoma), congenital malformations, demyelinating diseases, neurodegenerative 
diseases, inflammatory diseases, epilepsy and infections. In addition to CNS imaging, MRI is also very 
helpful in anatomic imaging of chest, abdomen, pelvis, cardiovascular and musculoskeletal systems for 
disorders including congenital malformations, tumors, infections, metabolic disorders, and 
inflammatory diseases. Comparing to other imaging modalities (such as ultrasound, X-ray, computed 
tomography [CT]) available in children, MRI offers the major safety advantage of a lack of ionizing 
radiation, combined with efficacy benefits of excellent three-dimensional anatomic representation, 
tissue characterization, and quantitative/functional capabilities [1]. 
Gadolinium-based contrast agents (GBCA) provide reliable enhancement on T1-weighted images and 
represent the clinical standard in many pediatric MRI protocols. MRI with GBCAs improves the 
localization, characterization, and staging of tumors/lesions, the differentiation of inflammatory and 
infective disorders.   
For GBCAs, r1-relaxivity is the primary determining factor for contrast efficacy. Most of the GBCAs 
available have similar T1 relaxivity, except for gadobenate dimeglumine (MultiHance®), its r1-
relaxivity is approximately 1.5 to 2 fold higher than other agents with standard relaxivity. A series of 
intra-individual comparative studies have demonstrated measurable differences in image preference and 
diagnostic performance for gadobenate dimeglumine [2-6].  
However, gadobenate dimeglumine is belonging to linear GBCAs, and some of the recently published 
studies showed gadolinium retention in the brain related to linear agents [7-12] even though clinical 
consequence of this finding is still under investigation. However, gadolinium retention raise special 
concern in the potentially vulnerable pediatric patient population.  There is thus a medical need to have 
a macrocyclic agent with a high relaxivity for diagnosing and monitoring a wide range of childhood 
diseases. 
Gadopiclenol (P03277) is a new paramagnetic, macrocyclic, non-ionic GBCA developed for 
intravenous (IV) use during MRI. Its molecular weight is 970.11 g/mol 
 
.  
Gadopiclenol is used as an aqueous injectable solution for injection at a concentration of 0.5M. 
Gadopiclenol has demonstrated at least two-fold higher T1 relaxivity compared to other available 
GBCAs including gadobenatedimeglumine and therefore is expected to have better contrast efficacy, 


 
 
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i.e. clinically relevant increases in signal enhancement or meaningful increase in lesion number or lesion 
extent compared with other “standard relaxivity” GBCAs.  
In contrast to linear chelates, the macrocyclic chelates offer a strong binding to Gd3+ by the virtue of 
being preorganized rigid rings of almost optimal size to cage the gadolinium atom [13]. Therefore the 
macrocyclic structure of gadopiclenol makes it a more stable complex than the linear ones. This is 
supported by stability studies. As a macrocyclic GBCA, gadopiclenol is expected to have a very low 
risk for brain retention of gadolinium [14]. Therefore a good long-term safety is anticipated. 
Several published studies documented the pharmacokinetic profiles of GBCAs in children. All patients 
received a single intravenous injection of 0.1 mmol/kg of GBCA; serum and urine (whenever applicable) 
samples were analyzed for total gadolinium to describe their pharmacokinetic profile. The results show 
similar pharmacokinetic values obtained in pediatric population to those observed in adults [15-20]. The 
trial will analyze the PK profiles of gadopiclenol after a single injection of 0.05 mmol/kg BW, a half as 
high as dosage of other GBCAs used in children. Based on preliminary data in adults this dosage is 
expected to provide satisfactory efficacy. 
Extensive non-clinical study program already performed on gadopiclenol showed a very satisfactory 
safety profile supporting the clinical development in adults and pediatric patients.  
At the time of this protocol submission, the following clinical data in adults are already available: 
A Phase I/IIa PK single center, ascending dose trial (GDX-44-003) has been conducted on 54 healthy 
volunteers (gender balanced) and 12 patients with CNS disorders. Primary objective of the trial was to 
evaluate the safety (clinical and biological) and pharmacokinetics (plasma and urine) of gadopiclenol 
through a 2 days post dosing confinement period and 7 days follow-up. 
For the phase I trial, six intravenous doses ranged from 0.025 to 0.3 mmol/kg were tested in successive 
cohorts of 9 healthy volunteers (6 active and 3 placebo). No serious adverse events were reported. The 
pharmacokinetics of gadopiclenol were considered linear dose-independent. The elimination half-life of 
gadopiclenol ranged from 1.5 to 2 hours and urinary excretion in the unchanged form showed to be the 
major route of elimination for gadopiclenol. 
For the Phase IIa trial, 4 doses were tested in successive cohorts of 3 subjects:  0.05, 0.075, 0.1, and 0.2 
mmol/kg, administered as single dose. All of them underwent MRI examination. Similar gadopiclenol 
concentrations and pharmacokinetics were observed in patients versus healthy subjects at corresponding 
doses. One SAE not related to gadopiclenol was reported (see Investigator Brochure for detailed 
information). 
Another Phase IIa proof of concept trial (GDX-44-008) enrolled 40 patients, aimed to evaluate the 
diagnostic value for hepatocellular carcinoma of gadopiclenol in patients with suspected small nodules 
and chronic liver disease. 30 patients have been injected with the dose of 0.1 mmol/kg BW and 10 
patients with the dose of 0.05 mmol/kg BW. No safety concerns have been raised from the trial.  
A Phase IIb trial (GDX-44-004) has been conducted in 280 adults with CNS diseases. This was a dose-
response trial with a cross-over design allowing the comparison of contrast quality provided by each of 
the 4 tested gadopiclenol doses (0.025, 0.05, 0.1 and 0.2 mmol/kg) towards gadobenate dimeglumine at 
the standard dose of 0.1 mmol/kg BW. No safety concern arose from the study. Dose 0.05 mmol/kg was 
identified as the lowest dose showing efficacy similar to the reference product. 
A phase I QT/QTc trial (GDX-44-006) has been conducted in 48 volunteers to assess the cardiac safety 
of gadopiclenol tested at 2 doses (0.1 mmol/kg BW and 0.3 mmol/kg BW) with positive control. Urinary 
and blood long term elimination was evaluated up to 3 months after the injection. The trial demonstrated 
that gadopiclenol did not prolong the QT interval neither at the dose of 0.1 mmol/kg nor at the dose of 
0.3 mmol/kg in healthy volunteers. The clinical and biological safety profile of the product observed 
during the study did not raise any concern. 


 
 
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Another trial is ongoing without safety concerns having been raised so far. 
Phase I trial in patients with renal insufficiency (GDX-44-005) is designed to include 5 successive 
cohorts of 8 subjects: volunteers and patients with mild, moderate, severe and end stage renal disease. 
Urinary and blood long term elimination will be evaluated up to 6 months following gadopiclenol IV 
injection at a dose of 0.1 mmol/kg BW. 
The current trial population will be limited to pediatric patients with normal renal function scheduled to 
undergo routine contrast-enhanced MRI of CNS and body. This trial is part of the Pediatric Investigation 
Plan (PIP) and Pediatric Study Plan (PSP) agreed with EMA and FDA respectively. 
 
 


 
 
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2. 
TRIAL OBJECTIVES 
2.1 Primary Objective 
To evaluate the pharmacokinetic profile of gadopiclenol in plasma following single intravenous 
injection of 0.05 mmol/kg body weight (BW) in pediatric population aged from 2 to 17 years undergoing 
central nervous system (CNS) contrast-enhanced MRI (CNS cohort).  
2.2 Secondary Objectives 
1. To evaluate safety (clinical and biological) up to 3 months following single administration in both 
CNS and Body cohorts. 
2. To evaluate urinary excretion of gadopiclenol quantitatively up to 8 hours and in subsequent urine 
samples collected up to 3 months following single administration in both CNS and Body cohorts (or 
exceptionally up to 4 months if collection is delayed due to the COVID-19 pandemic). 
3. To evaluate efficacy of gadopiclenol-enhanced MRI for CNS and body as assessed by on-site 
Investigator. 
2.3 Sub-Trial / Ancillary Trial Objectives 
Not applicable. 
 
 


 
 
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3. 
TRIAL DESCRIPTION 
3.1 Protocol Design 
This phase II open-label, uncontrolled, multicenter international trial is designed to investigate the 
pharmacokinetic (PK) profile of gadopiclenol in plasma, in children aged from 2 to 17 years, using a 
population PK approach. This approach, allowing sparse blood sampling is selected to minimize the 
clinical burden to children. The 2-compartment model with elimination from the central compartment 
validated in adults was used to optimize the trial design and PK sampling time.  
Blood sampling will be performed via indwelling catheters rather than by repeated venipunctures. An 
optimized flexible design with 4 sampling windows (W) covering the first 8 hours (at least 4 elimination 
half-lives of gadopiclenol following the injection will be used: 
 
W1: 1 min to 20 min 
 
W2: 30 min to 45 min 
 
W3: 2 to 3 hours 
 
W4: 7 to 8 hours 
A total of 4 blood samples per patient will be taken post-injection for PK analysis, one within each 
window. 
PK profile in plasma will only be investigated in the cohort of patients undergoing CNS contrast-
enhanced MRI (CNS cohort). Safety, urinary excretion and efficacy of gadopiclenol will be evaluated 
in both CNS cohort and in the cohort of patients undergoing contrast-enhanced MRI for diseases of 
other organs (Body cohort).  
When possible, total urine over 8 hours will be quantitatively collected following gadopiclenol injection 
in patients capable to control daytime urination to evaluate the concentration of urinary excreted 
gadopiclenol. 
 An age-down staggered approach will be used. Patients will be recruited into 3 predefined age groups: 
12-17, 7-11 and 2-6 years. The inclusions will start with the older group (Adolescents, 12-17 years), 
followed by Preadolescents (7-11 years) and finally Young Children (2-6 years).  
The total sample size of 80 patients (60 in the CNS cohort and 20 in the Body cohort) will be balanced 
between 3 age groups as following: 
 At least 15 patients and the number as close as possible to 20 patients will be included in each age 
group from the CNS cohort. The inclusion will be completed in parallel in all age groups to reach 
the overall number of 60 patients evaluable for the primary criterion. 
 At least 3 patients from the Body cohort will be included per age group. The inclusion will be 
completed in parallel in all age groups to reach the overall number of 20 patients in the Body cohort. 
The decision to start the next age group will be taken by Trial Safety Review Board (TSRB) based on 
safety assessment over one-day period after injection of the first 15 patients included in previous group 
from either CNS or both cohorts. The previous age group will be completed in parallel with the start of 
the next group (Figure 2).  
The children popPK model will be initiated with data from the first 15 patients in the adolescents’ group 
from the CNS cohort and will be continuously upgraded at each 15 completed patients from the same 
cohort in each of the following age groups to simulate expected exposure.  
Any patient who has received an IMP injection and undergone an enhanced MRI examination in CNS 
without major deviations, will be considered evaluable for the primary criterion.  
Urine sampling to assess potential long term excretion of gadopiclenol, by measuring concentration of 
gadopiclenol, will be performed 1 week and 3 months after gadopiclenol injection in patients with 
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delayed at the visits V3-bis and V4-bis due to the COVID-19 pandemic it can take place up to 1 month 
and 4 months after gadopiclenol injection respectively. 
  
 


 
 
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Figure 2: Age-down staggered enrollment 
 
 
 
   
 
 


 
 
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3.2 Trial Duration 
Each patient will undergo 4 visits:  
 
V1 - Screening: up to 14 days before inclusion; 
 
V2 - Inclusion:  between D1 (gadopiclenol administration) and D2, including confinement period 
(if not prevented by the constraints linked to the COVID-19 pandemic); 
 
V3 – 1-week safety follow-up (followed by V3-bis: 1-month maximum safety follow-up if V3 was 
done by phone or video); 
 
V4 – 3-month safety follow-up (followed by V4-bis: 4-month maximum safety follow-up if V4 was 
done by phone or video); 
Patient eligibility is appraised at screening visit and takes place up to 14 days before inclusion. The 
screening visit can be performed the same day as V2 if all inclusion/non-inclusion criteria are met. 
MRI is performed prior to and after gadopiclenol administration on MR systems (1.5T or 3T). The start 
of administration is considered as IMP injection time point (T0), and blood samples for pharmacokinetic 
analysis in CNS cohort are collected within 4 sampling windows (W) covering the first 8 hours following 
gadopiclenol injection: 
 
W1: 1 min to 20 min 
 
W2: 30 min to 45 min 
 
W3: 2 to 3 hours 
 
W4: 7 to 8 hours 
Overall expected trial duration for each patient is about 3 months: 
Minimum trial duration for each patient: 82 days 
Maximum trial duration for each patient: 111 days (up to 134 days in case of V4-bis) 
 
Patient participation starts from the signing of the Informed Consent Form at V1 (screening) and ends 
at V4 (3-month safety follow-up) or V4-bis (4-month maximum safety follow-up) or earlier in case of 
premature discontinuation. 
Patients included and/or to be included in Body cohort may be impacted by COVID-19 pandemic related 
constraints. In this case following changes will be acceptable: 
 
V2-D1 – if 8 hour-confinement period cannot be respected, it may be shortened. The tasks or 
assessments planned up to 90 min after gadopiclenol injection are expected to be performed at site; 
 
V2-D2 – if the patient cannot come back to the site the investigator and other authorized trial staff 
are allowed to alternatively perform the visit at patient’s home. If impossible, at the very least a 
phone or video call should be placed  
 
V3– at the very least a phone or video call followed by additional on-site visit (Visit 3-bis) no later 
than 30 days after the IMP injection;  
 
V4 – at the very least a phone or video call followed by additional on-site visit (Visit 4-bis) no later 
than 120 days after the IMP injection. In this case, maximum trial duration will be extended up to 
134 days.  
The date of the last visit (date of the last procedure related to the visit) of the last patient undergoing the 
trial will correspond to the end of the trial. 


 
 
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3.3 Interim Analysis 
Not applicable.  
3.4 Trial Committee(s) 
Trial Safety Review Board (TSRB) described in Section 12 is established for: 
 
assessing the safety data at intervals and to decide whether to continue, modify, or stop the trial;  
 
taking a decision to start the enrollment of the next age down group based on the safety 
assessment in the previous groups (Adolescents and Preadolescents). 
 
 


 
 
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4. 
PATIENT SELECTION 
4.1 Inclusion Criteria 
To be included in the trial, the patient must meet all these inclusion criteria. 
1. Female or male pediatric patient aged 2 to 17 years, 
2. Patient with known or suspected lesion(s) scheduled to undergo routine contrast-enhanced MRI 
of CNS or of other organs including at least one organ among head and neck, thorax, abdomen, 
pelvis and musculoskeletal system (including extremities), 
3. Patient whose parent(s) or legal guardian (where applicable) having read the information 
provided his/her/their consent to patient’s participation in writing by dating and signing the 
informed consent prior to any trial related procedure being conducted,  
4. Patient with capacity of understanding who received age- and maturity-appropriate information 
and provided his/her assent to participate in the trial (as required by national regulations), 
5. Patient affiliated to national health insurance according to local regulatory requirements. 
4.2 Non-Inclusion Criteria 
1. Patient planned for treatment or procedure (e.g., surgery) that would prevent from obtaining the 
required blood samples or performing other trial procedures between the screening visit and up 
to 1 day after gadopiclenol administration, 
2. Patient undergoing treatment or procedure (e.g., diuretics, clinically significant blood loss or 
blood transfusion) preceding or subsequent to gadopiclenol administration that would alter 
gadopiclenol pharmacokinetic parameters, 
3. Patient with acute or chronic renal insufficiency defined as estimated Glomerular Filtration Rate 
(eGFR) out of age-adjusted normal ranges [eGFR must be calculated based on bedside Schwartz 
equation],  
4. Patients referred for MR Angiography. 
5. Patient with history of bleeding disorder, 
6. Patient with known severe liver disease, 
7. Patient with known cardiac disease (e.g., heart rhythm anomalies, long QT syndrome), 
8. Patient with any clinically significant abnormal 12-lead ECG that in the Investigator's opinion 
would affect the safety evaluation or place the patient at risk, 
9. Patient with electrolyte or fluid imbalance that at Investigator’s judgment presents undue risk 
assessed within 1 month prior to gadopiclenol administration, 
10. Patient undergoing a change in chemotherapy within 1 day prior to or 1 day after gadopiclenol 
administration, 
11. Patient who received or will receive any other contrast agent for CT and/or MRI within 1 week 
prior to or 1 week after gadopiclenol administration, 
12. Patient with contraindication for MRI such as iron metal implants (e.g., aneurysm clips, 
pacemaker), 
13. Patient with history of anaphylactoid or anaphylactic reaction to any allergen including drugs, 
14. Patient with history of hypersensitivity caused by any contrast media / agents (iodinated or 
gadolinium-based), 
15. Patient with known contraindication(s) to the use of any gadolinium-based contrast agent 
(GBCA), 
16. Pregnant or breast-feeding female patient [female patient with childbearing potential (who 
experienced menarche) must have a negative urine pregnancy test within 24 hours prior to 
gadopiclenol administration and must be using medically approved contraception* if sexually 
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17. Patient with anticipated, current or past condition (medical, psychological, social or 
geographical) that would compromise the patient’s safety or her/his ability to participate to the 
whole trial, 
18. Patient unlikely to comply with the protocol, e.g., uncooperative attitude of parent(s) or legal 
guardian (where applicable), inability to return for follow-up visits and unlikelihood of 
completing the trial, 
19. Having participated in a clinical trial and having received any investigational product within 7 
days prior to gadopiclenol administration or planned during the trial, 
20. Patient previously included in this trial, 
21. Patient related to the Investigator or any other trial staff or relative directly involved in the trial 
conduct. 
* medically approved contraception methods include: female sterilization, 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), barrier methods of contraception (condom or occlusive cap (diaphragm or cervical/vault caps) 
with spermicidal foam/gel/film/cream/ vaginal suppository).  
4.3 Patient Identification 
After having obtained the written informed consent and verified that all eligibility criteria are met, 
Patients will be enrolled in the trial and will be allocated a unique Identification Number (Patient ID). 
This Patient ID will contain 8 digits: the first three digits corresponding to the country number, the 
following two digits corresponding to the site number, which are attributed at the beginning of the trial, 
and the last three digits being chronologically implemented depending on patient enrollment. The lowest 
enrollment number will correspond to the first patient enrolled at this site and the highest number to the 
last patient enrolled.  
 


 
 
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5. 
INVESTIGATIONAL MEDICINAL PRODUCTS 
Investigational Medicinal Product(s) will be manufactured, labeled, packaged and released in 
accordance with: 
- 
European Directive 2003/94/EC laying down the principles and guidelines of good 
manufacturing practice in respect of medicinal products for human use and investigational 
medicinal products for human use 
- 
EudraLex, The Rules Governing Medicinal Products in the European Union, Volume 4, EU 
Guidelines to Good Manufacturing Practice - Medicinal Products for Human and Veterinary 
Use, Annex 13 Investigational Medicinal Products 
- 
US Food and Drug Administration, Title 21 Code of Federal Regulations Part 211 on Current 
Good Manufacturing Practice for Finished Pharmaceuticals 
In addition, the IMP manufacturing, packaging, labeling and release will comply with any local 
applicable regulatory requirement. 
The IMP will consist of a vial individually packaged in a carton box with a single use detachable label 
that will allow ensuring accuracy of IMP allocation per patient. 
5.1 Investigational Medicinal Product Description and Administration 
Modalities 
Gadopiclenol 
 
 is a sterile, clear, ready-to-use aqueous solution for injection contained in vials of 20 
ml, concentrated at 0.5 M  
Gadopiclenol is administered intravenously (IV) as a bolus injection at a recommended rate of 1-2 
ml/sec. For dynamic contrast-enhanced studies the use of an injector is recommended. Contrast-
enhanced MRI can start shortly after the injection depending on the pulse sequences used and the 
protocol for the examination. Gadopiclenol injection will be followed with a normal saline flush to 
ensure complete administration of the contrast. 
A patient IV line should be established and maintained throughout the examination. General sedation or 
topical anesthesia will be considered to minimize discomfort and distress.  
Wherever possible trial specific blood sampling will be performed when routine clinical samples are 
obtained. Patients who might be at risk for a particular reaction during the contrast agent injection should 
receive added surveillance (e.g., carefully monitored pulse and blood pressure). 
Examination of the patient will be immediately discontinued if a serious adverse event (SAE) occurs 
during or just after injection of the contrast agent (preventing post-contrast imaging sequences). 
Patients will be dosed according to their BW on the day of MRI examination. Gadopiclenol will be 
administered at a dose of 0.05 mmol/kg BW (0.1 ml/kg BW). A qualified professional according to local 
regulation (study nurse or technician) will be responsible for preparing the dosing solutions. 
Patients will receive a single dose of gadopiclenol on the day of MRI examination at T0.  
For more information on gadopiclenol please refer to the Investigator Brochure. 
5.2 Packaging, Labeling, Storage 
Packaging and labeling will be performed in strict accordance with the local regulatory specifications 
and requirements. 


 
 
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The packaging and labeling of gadopiclenol will be performed by GUERBET.  
In addition to the usual and regulatory labeling for clinical studies, each IMP will have a white 
detachable sticker indicating the protocol number, batch ID, IMP number and patient ID number. This 
label will be stuck on the patient file or trial documentation. 
IMP will consist in a box that contains one 20 ml vial of gadopiclenol.  
In case of damaged IMP, a new IMP will be allocated to the patient via the IWRS. 
All IMPs will be stored in a secure place, under the responsibility of the Investigator or other authorized 
individual and under the conditions described in Investigator’s Brochure. The IMPs should be stored at 
a temperature of 25°C or below in the original package, protected from light and not frozen. 
At the time of the trial completion, all used (including empty vials) and unused IMPs should have been 
returned to 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 
A central web randomization system or IWRS (Interactive Web Response System) will be used to 
manage inclusion of patients in the trial and IMP allocation. Once eligibility criteria are confirmed, 
Patient Identification Number will be recorded into the system.  
IWRS will ensure a balanced distribution of the trial population between 3 predefined age groups: 
Adolescents (12-17 years), Preadolescents (7-11 years) and Young Children (2-6 years).  
Although a total number of 20 patients evaluable for the primary criterion (CNS cohort) is targeted in 
each age group, a slight imbalance between the groups is acceptable with a minimum of 15 patients in 
each age group and a maximum of 25 in the group with quicker enrollment in order to facilitate the 
inclusion of the last 5 patients. 
At least 3 patients from the Body cohort will be included per age group.  
First enrollment in the next age group will be conditioned by the decision of the TSRB. The inclusion 
will continue until the overall number reaches 60 patients evaluable for the primary criterion in the CNS 
cohort and 20 patients included in the Body cohort.  
IMP number will be independent from the Patient Identification Number. 
5.3.2 Double-Blind Conditions 
Not applicable. The IMP will be administered in an open-label fashion. 
5.3.3 Individual Trial Treatment Unblinding 
Not applicable. 
5.4 Investigational Medicinal Product Management 
The Investigator, the hospital pharmacist, or other personnel allowed to store and dispense IMP(s) is 
responsible for ensuring that the IMP used in the clinical trial is securely maintained as specified by 
GUERBET and in accordance with the applicable regulatory requirements. 
Any quality issue noticed with the receipt or use of an IMP (deficient IMP in condition, appearance, 
pertaining documentation, labeling, expiry date, etc.) should be promptly notified to GUERBET, who 
will initiate a complaint procedure. 


 
 
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Under no circumstances shall the Investigator supply IMP to a third party, allows the IMP to be used 
other than as directed by this clinical trial protocol, or dispose of IMP in any other manner. 
5.5 Auxiliary Medicinal Product(s) and Other Trial Products 
Not applicable. 
5.6 Trial Product(s) Compliance and Accountability 
The Investigator, the hospital pharmacist, or other allowed personnel 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 patient.  
The dosing information will be recorded in individual patient’s records. When protocol required IMP 
administration conditions are not followed, reason(s) will be given and recorded by the Investigator.


 
 
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6. 
CONCOMITANT MEDICATIONS / PROCEDURES 
6.1 Concomitant Medications 
Any medication, including homeopathic products, over-the-counter medications, as well as prescription 
drugs, on-going at D1 or administered until 1-week safety visit (D8) will be recorded in the patient’s 
eCRF. The concomitant medications/treatments started from D2 to D8 will be documented if the patient 
experienced at least one adverse event.  
Between D8 and D90 safety visits, any GBCA injection will be documented. Other concomitant 
medications/treatments will be documented if it is a corrective treatment related to the reported AE. 
The following information must be provided:  
- 
Drug (brand name or generic name) 
- 
Route of administration 
- 
Purpose (medical history/AE/pre-medication/contraception/prophylaxis) 
- 
Indication  
- 
Start/end of treatment  
6.1.1 Concomitant Medications 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 
GBCA. Thus, no pre-treatment of any nature will be recommended before contrast-enhanced MRI. 
Nevertheless, if the Investigator decides to premedicate a patient, the treatment must be documented in 
the medical file and then in the eCRF. 
In general, there are no specific recommendations regarding GBCA, and therefore, no specific hydration 
procedure is defined in this protocol. Nonetheless, whenever possible, the patient should be encouraged 
to drink water and other non-alcoholic fluids liberally before and after the injection. 
According to current knowledge, there is no other concomitant treatment of special attention in that trial. 
However warnings and precautions for use of the concomitant treatments taken by the patient should be 
considered. 
6.1.2 Prohibited Concomitant Medications 
A minimum of 1 week wash-out is required between any other contrast agent administration for CT 
and/or MRI and gadopiclenol injection. At least 1 week must elapse between trial contrast-enhanced 
MRI and any subsequent contrast agent administration. 
Any medication preceding or subsequent to the gadopiclenol administration that would alter 
gadopiclenol pharmacokinetic parameters (e.g., treatment with diuretics), is not permitted. 
Any change in chemotherapy is prohibited within 1 day prior to and 1 day after gadopiclenol 
administration.  
6.2  Procedures 
Any procedure performed during the trial and related to any reported AE will be recorded in the 
patient eCRF. At least the following information must be provided:  
- 
Name of procedure 
- 
Indication  
- 
Duration  


 
 
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Any intervention that would prevent from obtaining the required blood samples or performing other 
trial procedures (e.g., surgery) is prohibited between the screening visit and up to 1 day after 
gadopiclenol administration. 
Any procedure preceding or subsequent to the gadopiclenol administration that would alter gadopiclenol  
pharmacokinetic parameters (e.g., blood transfusion), is not permitted. 
 
 


 
 
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7. 
EVALUATION CRITERIA 
7.1 Primary Criteria 
Gadopiclenol pharmacokinetics in plasma will be assessed in the CNS cohort both by age group and 
overall based on following pharmacokinetic parameters determined from the population PK model:  
 
Simulated concentrations at 10, 20 and 30 minutes post injection 
 
Area Under the Curve,  
 
elimination half-life,  
 
total clearance,  
 
volume of distribution. 
Gadopiclenol concentrations in plasma and urine will be determined using a validated liquid 
chromatography coupled with tandem mass spectrometry LC-MS/MS method. 
A separate analytical protocol will describe the gadopiclenol assays in plasma and urine samples. 
 
 
 
7.2 Secondary Criteria 
Secondary criteria will be assessed in both CNS and Body cohorts. 
7.2.1 Clinical, biological and ECG safety data 
 
Vital signs (temperature, systolic and diastolic blood pressure, pulse rate and pulse oximetry), 
prior to IMP injection, 30-90 min after and 1 day after IMP injection,  
Blood pressure and pulse rate will be measured after a rest for at least 5 minutes in supine 
position. Blood pressure will not be measured on the arm used for the injection. 
Blood oxygen saturation SpO2 (pulse oximetry) will be measured using a transcutaneous non-
invasive light emitter.   
 
12-lead ECG recorded prior to IMP injection, 30-90 min after and 1 day after IMP injection. 
o Heart rate  
o Intervals: RR, PR, QRS, QT [corrected QT (QTc) will be calculated according to 
Fridericia and Bazett methods]  
o ST segments, T-wave morphology, U-wave 
o Global morphology 
 
ECG will be recorded after a rest for at least 5 minutes in supine position. A notable QTc change 
is defined as a QTc (Fridericia’s or Bazett’s) interval > 450 ms for males and females or an 
increase of >30 ms from baseline. All ECGs changes considered as abnormal and clinically 
significant according to Investigator’s judgment will be reported as AEs.  
 
Safety laboratory variables centrally analyzed (hematology and biochemistry) from blood 
samples collected prior to and 1 day after IMP injection: 


 
 
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o Hematology: red blood cells (RBCs), white blood cells (WBCs) counts: neutrophils, 
eosinophils, basophils, lymphocytes and monocytes, platelet count, hemoglobin, 
hematocrit, mean red blood cells volume (MCV);  
o Biochemistry: sodium, potassium, chloride, glucose, blood urea nitrogen (BUN), 
creatinine, total protein, calcium, phosphorus, total bilirubin, conjugated bilirubin, 
aspartate amino transferase (AST), alanine amino transferase (ALT), alkaline 
phosphatase, lactate dehydrogenase (LDH), PT (prothrombin time) / INR (International 
Normalised Ratio); 
 
Estimated glomerular filtration rate (eGFR) centrally calculated based on the bedside Schwartz 
equation prior to and 1 day after IMP injection, 
Bedside Schwartz equation [21-23] is used with creatinine methods with calibration traceable 
to isotope dilution mass spectroscopy (IDMS): 
 
eGFR (ml/min/1.73 m2 ) = (0.413 × Height in cm) / Standardized Serum creatinine (mg/dl) 
Post-contrast acute kidney injury (PC-AKI) is defined as an increase in sCr of ≥ 0.3 mg/dl or 
sCr ≥1.5 times baseline. Such changes will be monitored and additional information may be 
requested to the investigator.  
 
Tolerance at the injection site (eruption, extravasation and inflammation) at T0, 30-90 min after 
and 1 day after IMP injection.  
 
Adverse events (AE) occurred from the beginning of patient’s participation in the trial 
(Informed Consent Form signature) until the end of the participation (see Section 9.1.2).  
 
Clinical examination for active detection of Nephrogenic Systemic Fibrosis (NSF) at 3-month 
follow-up safety visit (or 4-month follow-up safety visit in case of V4-bis).  
Following symptoms will be recorded: burning, itching, swelling, scaling, hardening and 
tightening of the skin; red or dark patches on the skin; stiffness in joints with trouble moving, 
bending or straightening the arms, hands, legs or feet; pain in the hip bones or ribs; or muscle 
weakness.  
In case of suspicion of NSF a deep skin biopsy will be undertaken and results reported to the 
eCRF. 
7.2.2 Gadopiclenol  urine concentration  
Gadopiclenol urine concentration will be measured in patients capable to control daytime urination: 
 
in total urine quantitatively collected over 8 hours after gadopiclenol injection (or less if the 
confinement is not possible over this period due to the COVID-19 pandemic) 
 
in spot urine samples 1 week and 3 months after gadopiclenol injection (or up to 1 month and 4 
months after gadopiclenol injection if the urine sampling is delayed to visits V3-bis and V4-bis 
respectively due to the COVID-19 pandemic). 
7.2.3 Gadopiclenol-enhanced MRI (pre and pre+post comparison) efficacy 
evaluation in the CNS and Body cohorts by on site radiologist 
 
Technical adequacy for diagnosis using a 4-point scale: nondiagnostic, poor, fair and good. 


 
 
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 
Assessment of contrast quality: percentage of enhancement (E%) and Lesion to Background 
Ratio (LBR): for up to 3 most representative lesions. 
o Measurements of the signal intensity (SI) of the lesion will be performed on the pre and 
post-injection identical T1 weighted sequences.  
o Measurements of the SI of background tissue (SIb) will be performed on post-injection 
T1 weighted sequence.  
o Measurements of the SI of the lesion are to be made on the best representative images 
of the pathology.  These images will be selected according to the following:  
 
Up to 3 most representative lesions (largest enhancing lesion) will be measured 
separately,  
 
The ROI for a lesion will encompass a homogeneous area within the lesion as 
large as possible.  
o Measurements of the background tissue’s SI are to be placed in the target region on the 
slice where corresponding lesion is located. The ROI should be as large as possible. 
 
Percentage of enhancement (E%) of lesion will be calculated by using the equations below: 
E% = 𝑆𝐼𝑝𝑜𝑠𝑡− 𝑆𝐼𝑝𝑟𝑒
𝑆𝐼𝑝𝑟𝑒
x100 
where  SIpost = SI of lesion on post injection images 
SIpre = SI of lesion on pre injection images. 
 
Lesion to Background Ratio (LBR) will be calculated by using the equations below: 
𝐿𝐵𝑅𝑝𝑜𝑠𝑡= 𝑆𝐼𝑝𝑜𝑠𝑡
𝑆𝐼𝑏
 
where  SIpost = SI of lesion on post injection images 
SIb = SI of background (surrounding healthy tissue of the lesion) on post injection 
images. 
 
Lesion visualization (lesion border delineation, internal morphology and contrast enhancement) 
assessed using a 4-point scale for each parameter. 
The Investigator will record each of lesion visualization variables (lesion border delineation, 
internal morphology and degree of contrast enhancement) for up to 3 most representative 
enhancing lesions.  
o Border delineation: 
Delineation of the lesion border is defined as the distinction of lesion from surrounding 
tissues, structures, or edema; and the detection of extent of the lesion (for extra-axial lesions, 
this pertains to the definition of the space in which the lesion is present, and for intra-axial 
lesions, it pertains to the invasion of white matter, gray matter, or both; the neuroanatomical 
distribution of the lesion; and its mass effect). This criterion will be assessed through the 
following scale: 
 
1 = none: no or unclear delineation 
 
2 = moderate: some areas of clear delineation but also with some significant 
areas of non-distinct delineation 


 
 
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 
3 = good: almost clear but not complete delineation 
 
4 = excellent: border outline is sharp with clear and complete delineation  
o Internal morphology: 
Internal morphology of the lesion includes an identification of lesion architecture and the 
intra-lesion features such as necrosis, hemorrhage and vascularity. This criterion will be 
assessed through the following scale: 
 
1 = poor: poorly seen 
 
2 = moderate: majority of lesion is poorly seen but with minor parts of lesion 
visible 
 
3 = good: majority of lesion is clearly seen but with minor parts of lesion 
invisible 
 
4 = excellent: lesion is well seen and can see “through” lesion to observe any 
complex areas of necrosis or hemorrhage or cyst formation.  
o Degree of contrast enhancement:  
This criterion will be a qualitative assessment according to the following scale: 
 
1 = no: no enhancement  
 
2 = moderate: weakly enhanced 
 
3 = good: clearly enhanced 
 
4 = excellent: clearly and brightly enhanced 
 
Change in diagnostic confidence: following gadopiclenol administration, the Investigator’s 
diagnostic confidence is improved or remains unchanged or getting worse. 
 
 


 
 
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8. 
TRIAL SCHEDULE AND PROCEDURES 
8.1 Trial Schedule 
Day 1 is defined as the day of IMP injection. 
8.1.1 Screening – Visit 1 – Day - 14 to Day 1 
During this visit, the following tasks or assessments will be performed in patients from both CNS and 
Body cohorts: 
 
The patient with capacity of understanding will receive age- and maturity-appropriate 
information about his/her participation in the trial and his/her assent to participate in the 
trial will be obtained (as required by national regulations); 
 
Written informed consent for the participation of the child in the trial prior to any trial 
related procedure will be obtained from parent(s) or legal guardian (where applicable) 
as described in Section 13.3; 
 
Verification of all eligibility (inclusion/non-inclusion) criteria will be done by the 
Investigator; 
 
The patient will be attributed an Identification Number in chronological order; 
 
Demographic data will be recorded: sex, race/ethnicity and age (years and months);  
 
Medical/Surgical history and current medical condition will be obtained. The 
Investigator will question on any possible previous contrast agents injection (type of 
contrast agent injected and tolerance will be recorded); 
 
A physical examination will be performed. Physical examination will include: general 
appearance, skin, neck (including thyroid), eyes, ENT (ears, nose, throat), lungs, heart, 
abdomen, back, lymph nodes, extremities, peripheral vascular and neurological 
examination;  
 
Medications and treatments on-going at the time of signing informed consent will be 
documented; 
 
Blood sample will be collected and analyzed : 
o In Local or Central Lab for serum creatinine measurement. The result must be 
available at the time of the inclusion and will be used to estimate glomerular filtration 
rate (eGFR) for the inclusion criterion. eGFR will be calculated based on the bedside 
Schwartz equation.  
o In Central Lab:  
o Hematology: red blood cells (RBCs), white blood cells (WBCs) 
counts: neutrophils, eosinophils, basophils, lymphocytes and 
monocytes, platelet count, hemoglobin, hematocrit, mean red blood 
cells volume (MCV);  
o Biochemistry: sodium, potassium, chloride, glucose, blood urea 
nitrogen (BUN), creatinine, total protein, calcium, phosphorus, total 
bilirubin, conjugated bilirubin, aspartate amino transferase (AST), 
alanine amino transferase (ALT), alkaline phosphatase, lactate 


 
 
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dehydrogenase (LDH), PT (prothrombin time) / INR (International 
Normalised Ratio). 
8.1.2 Inclusion – Visit 2 – From Day 1 to Day 2 
Patients will be hospitalized for a confinement period of 1 day. Confinement period can be reduced to 8 
hours after the injection if patient remains close to the site and can easily come back for the D2 visit. 
Images acquisition before and after gadopiclenol injection will be performed according to the Imaging 
Manual. Diagnostic will be recorded. Total urine will be collected over 8 hours after the injection to 
measure concentration of the urinary excreted gadopiclenol in patients capable to control daytime 
urination.  
Due to COVID-19 pandemic related constraints, patients included in Body cohort may not be allowed 
to stay at hospital for the full 8 hour-period. In this case the total urine collection will end when the 
patient is discharged from the hospital. Actual duration of total urine collection will be recorded. The 
tasks or assessments planned up to 90 min after gadopiclenol injection are expected to be performed at 
site. 
 
8.1.2.1 
Day 1 
Throughout the Day 1, the following other tasks or assessments will be performed in patients from both 
cohorts: 
8.1.2.1.1 
Prior to gadopiclenol injection 
 
Verification of all eligibility (inclusion/non-inclusion) criteria will be done by the 
Investigator;  
 
Indication for current contrast-enhanced MRI will be recorded; 
 
Demographic data will be recorded: age (years and months);  
 
Other baseline characteristics will be recorded: childbearing potential for female patient 
(experienced menarche) and ability to control daytime urination; 
 
Vital signs (temperature, blood pressure, pulse rate and transcutaneous non-invasive 
pulse oximetry using a light emitter) will be measured;  
 
Body weight and height will be measured; 
 
Standard 12-lead electrocardiogram (ECG) will be recorded and assessed; 
 
Any change in on-going or new medication and treatment since last visit will be 
documented;  
 
Urine pregnancy test will be performed for female patient with childbearing potential; 
 
AEs occurred since screening visit will be recorded and assessed.  
8.1.2.1.2 
Time point T0 
The start of gadopiclenol administration is set as time point 0 (T0). IV catheters will be inserted (a 
patient IV line will be established) in patients from the CNS cohort in order to have contrast agent 
administration and blood samples collection. 


 
 
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 
Injection site tolerance (eruption, extravasation and inflammation) will be evaluated 
and any event will be reported as adverse event in patients from both cohorts; 
 
 Start of total urine collection over 8 hours in patients from both cohorts capable to 
control daytime urination. 
8.1.2.1.3 
Time window W1 
The following task will be performed within first time window (1-20 min) after gadopiclenol  injection: 
 
Blood sample will be collected for PK analysis in patients from the CNS cohort. Actual 
sampling time must be recorded; 
8.1.2.1.4 
Time window W2 
The following task will be performed within second time window (30-45 min) after gadopiclenol 
injection: 
 
Blood sample will be collected for PK analysis in patients from the CNS cohort. Actual 
sampling time must be recorded. 
The following tasks or assessments will be performed within W2 and up to 90 min after gadopiclenol 
injection in patients from both cohorts: 
 
Vital signs (temperature, blood pressure, pulse rate and transcutaneous non-invasive  
pulse oximetry using a light emitter) will be measured;  
 
Injection site tolerance (eruption, extravasation and inflammation) will be evaluated 
and any event will be reported as adverse event; 
 
Standard 12-lead ECG will be recorded and assessed; 
8.1.2.1.5 
Time window W3 
The following task will be performed within third time window (2-3h) after gadopiclenol injection: 
 
Blood sample will be collected for PK analysis in patients from the CNS cohort. Actual 
sampling time must be recorded.  
8.1.2.1.6 
Time window W4 
The following task will be performed within fourth time window (7-8h) after gadopiclenol injection: 
 
Blood sample will be collected for PK analysis in patients from the CNS cohort. Actual 
sampling time must be recorded. 
8.1.2.1.7 
Time point T8h 
 
End of total urine collection in patients from both cohorts capable to control daytime 
urination. 
8.1.2.2 
Day 2  
The following tasks or assessments will be performed 1 day after gadopiclenol injection in patients from 
both cohorts: 
 
A physical examination will be performed. 


 
 
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 
Vital Signs (temperature, blood pressure, pulse rate and transcutaneous non-invasive 
pulse oxymetry using a light emitter) will be measured; 
 
Standard 12-lead ECG will be recorded and assessed; 
 
Blood sample will be collected and following laboratory parameters will be analysed in 
the Central Lab:  
o Hematology: red blood cells (RBCs), white blood cells (WBCs) counts: neutrophils, 
eosinophils, basophils, lymphocytes and monocytes, platelet count, hemoglobin, 
hematocrit, mean red blood cells volume (MCV);  
o Biochemistry: sodium, potassium, chloride, glucose, blood urea nitrogen (BUN), 
creatinine, total protein, calcium, phosphorus, total bilirubin, conjugated bilirubin, 
aspartate amino transferase (AST), alanine amino transferase (ALT), alkaline 
phosphatase, lactate dehydrogenase (LDH), PT (prothrombin time) / INR 
(International Normalised Ratio); 
 
Estimated glomerular filtration rate (eGFR), calculated based on the Bedside Schwartz 
equation; 
 
Injection site tolerance (eruption, extravasation and inflammation) will be evaluated 
and any event will be reported as adverse event; 
 
Any change in on-going medication and treatment since Day 1 will be documented. 
New concomitant medications/treatments will be documented if the patient experienced 
at least one AE; 
 
All AEs occurred since Day 1-T0 will be recorded and assessed. 
If it is not possible to perform the corresponding assessments on site due to COVID-19 pandemic related 
constraints, the investigator and other authorized trial staff are allowed to alternatively perform the visit 
at patient’s home to insure data collection as far as possible. If this option is also impossible, at the very 
least a phone or video call should be performed by investigator to ensure follow-up of patient’s safety 
and remotely enquire about:  
 
New AE occurred since Day 1-T0; 
 
Follow up on previously reported AE; 
 
Injection site tolerance (eruption, extravasation and inflammation) will be evaluated 
and any event will be reported as adverse event; 
 
Any change in on-going medication and treatment since Day 1; 
 
New concomitant medications/treatments. 
8.1.3 Safety Follow-up – Visit 3 – Day 8 
During this visit, the following tasks or assessments will be performed in patients from both cohorts: 
 
A physical examination will be performed; 
 
Any change in on-going medication/treatment since last visit will be documented. Other 
new concomitant medications/treatments will be documented if the patient experienced 
at least one AE; 
 
Spot urine sample will be collected to measure concentration of the excreted 
gadopiclenol in patients capable to control daytime urination; 


 
 
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 
All AEs since last visit will be recorded and assessed. 
If it is not possible to perform the visit at site due to COVID-19 pandemic related constraints, at the very 
least a phone or video call should be placed by investigator to remotely enquire about:  
 
New AE occurred since last visit; 
 
Follow-up on previously reported AE; 
 
Any change in ongoing medication and treatment since last visit; 
 
Other new concomitant medications/treatments if the patient experienced at least one 
AE  
The possibility to perform urine sampling at patient’s home will be assessed on case by case basis by 
the site staff and documented. 
In case of remote Visit 3, an additional on-site visit (Visit 3-bis) should be scheduled whenever possible, 
at the earliest possible timepoint and no later than 30 days after the IMP injection. All tasks or 
assessments planned for the Visit 3 at site will be performed during Visit 3-bis. 
8.1.4 Safety Follow-up – Visit 4 – Day 90 
During this visit, the following tasks or assessments will be performed in patients from both cohorts: 
 
A physical examination will consist in active detection of Nephrogenic Systemic 
Fibrosis (NSF)-related symptoms including: burning, itching, swelling, scaling, 
hardening and tightening of the skin; red or dark patches on the skin; stiffness in joints 
with trouble moving, bending or straightening the arms, hands, legs or feet; pain in the 
hip bones or ribs; or muscle weakness. In case of suspicion of NSF a deep skin biopsy 
will have to be undertaken. In case of the detection of one or more of the listed 
symptoms that lead to suspect NSF, a report form for SAE, AESI or pregnancy must be 
completed and reported.  
 
Any GBCA injection since the last visit will be documented; 
 
Other concomitant medications/treatments will be documented if related to the reported 
AE. 
 
Spot urine sample will be collected to measure concentration of the excreted 
gadopiclenol in patients able to control daytime urination; 
 
Non-serious AE related to the drug or to the trial, Serious Adverse Event (SAE) and 
Adverse Event of Special Interest (AESI) since the last visit will be recorded and 
assessed. 
If it is not possible to perform the visit at site due to COVID-19 pandemic related constraints, at the very 
least a phone or video call should be placed by investigator to remotely enquire about:  
 
Non-serious AE related to the drug or to the trial, Serious Adverse Event (SAE) and 
Adverse Event of Special Interest (AESI) since the last visit;  
 
Any GBCA injection since the last visit; 
 
Other concomitant medications/treatments if related to the reported AE  
The possibility to perform urine sampling at patient’s home will be assessed on case by case basis by 
the site staff and documented. 


 
 
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In case of remote Visit 4, an additional on-site visit (Visit 4-bis) should be scheduled whenever possible, 
at the earliest possible timepoint and no later than 120 days after the IMP injection. All tasks or 
assessments planned for the Visit 4 at site will be performed during Visit 4-bis. 
8.2 Imaging Characteristics 
8.2.1 Equipment 
MRI units with 1.5T or 3T magnetic field will be used, regardless of the manufacturer.  
MRI scans will be acquired before and after gadopiclenol injection. The imaging 
sequences/parameters will be performed according to site’s standard imaging protocol.  
8.2.2 Sequences 
For every patient, pre and post gadopiclenol T1-weighted SE/TSE/GRE images must be performed, and 
the same parameter setting must be used for unenhanced images and for gadopiclenol-enhanced images 
in each patient. 
8.3 On Site Reading of Images 
For each investigational site, a radiologist will be appointed at the start of the trial to read all images of 
patients included at the site. 
GUERBET will document the imaging tasks and obligations of the investigational site in an Imaging 
Manual. GUERBET’s representative will ensure that the imaging can be performed by the site and that 
the Imaging Manual will be accurately followed by the Investigator. 
The Investigator will report required evaluation results in the eCRF.  
8.4 Off Site Reading of Images 
Not applicable. However GUERBET’s representative will request that investigational site submit 
anonymous images to GUERBET in a format agreed prior to trial start.   
8.5 Other Centralized Trial Procedures 
8.5.1 Pharmacokinetic procedures and assessments 
Details on handling blood and urine samples for gadopiclenol assay will be provided to the site in a trial 
specific manual. 
8.5.1.1 
Blood sampling for PK (for patients from the CNS cohort) 
A peripheral catheter will be placed for blood collection during the confinement period in the forearm 
(contralateral to the injection site) or in the feet (only for blood samplings performed during MRI 
sequences). During the ambulatory period, blood samples will be collected by direct venipuncture. As 
far as possible a venous line already in place for the current care (central or peripheral venous catheter) 
will be used for blood collection. Blood samples of 1 mL each will be collected at each time point for 
analysis. In any case the overall trial-related blood loss will not exceed 3% of the total blood volume 
during a period of four weeks and will not exceed 1% for any single blood draw. 
For gadopiclenol analysis, blood will be collected into lithium heparin tubes. 


 
 
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Plasma will be obtained within 30 minutes after blood collection by centrifugation at approximately 
3000 rpm for 10 minutes and aliquots stored into polypropylene tubes at -20ºC (±5°C) for analysis. 
Plasma will be divided into two different aliquots of at least 250 µL for gadopiclenol analysis. 
The labelling of the tubes will include: 
 
Study number 
 
Patient number 
 
Theoretical and actual time of blood collection 
 
Plasma 
In case of remaining blood collected, it will be discarded. 
The 1st aliquot for gadopiclenol determination will be sent on dry ice to the analytical centre. The second 
aliquot collected will be kept in the clinical centre and will be sent to the analytical centre only if 
necessary. 
8.5.1.2 
Urine sampling for PK (for patients from both cohorts) 
Total urine will be collected quantitatively over 8 hours (or less if the confinement is not possible over 
this period due to the COVID-19 pandemic) after gadopiclenol injection in patients capable to control 
daytime urination to evaluate concentration of the urinary excreted gadopiclenol. The total volume of 
collected urine will be measured and recorded by the site. 
Spot urine samples will be collected 1 week and 3 months after gadopiclenol injection to measure 
concentration of gadopiclenol in patients able to control daytime urination. If the urine sampling is 
delayed to visits V3-bis and V4-bis due to the COVID-19 pandemic the collection can take place up to 
1 month and 4 months after gadopiclenol injection respectively. 
After homogenization of the collected sample, urine will be divided in 2 aliquots (of maximum 5 mL 
each) and stored at -20°C (±5°C) until shipment to the analytical center. The 1st aliquot will be sent to 
the analytical center. The second aliquot collected will be kept in the clinical center and will be sent on 
dry ice to the analytical center only if necessary. Aliquots will be placed into polypropylene tubes, will 
be tightly capped and stored at -20ºC (±5°C) until shipment for analysis. 
The labelling of the tubes will be as follows: 
 
Study number 
 
Patient number 
 
Urine 
 
Period of collection 
After having aliquoted the samples, the remaining urine will be destroyed.  
8.5.2 Central Laboratory for biological assessments 
A central laboratory will be used for all scheduled laboratory tests in this trial except for the pregnancy 
test which will be done locally and eGFR which can be assessed locally for non-inclusion criteria 
verification and centrally for safety evaluation. Bedside Schwartz equation will be used for calculation 
of the estimated Glomerular Filtration Rate (eGFR). This formula is for use with creatinine methods 
with calibration traceable to isotope dilution mass spectroscopy (IDMS): 
eGFR (ml/min/1.73 m2 ) = (0.413 × Height in cm) / Standardized Serum creatinine (mg/dl) 


 
 
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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 patient’s source document.  
All laboratory reports must be promptly reviewed by the Investigator, and upon review, initialed and 
dated by the Investigator. All abnormal values considered clinically significant according to 
investigator’s judgment will be reported as AEs and documented in the patient’s source document. 
Laboratory samples obtained for this trial will be used only for this trial. Samples obtained in this trial 
will not be retained or used for any other purposes. 


 
 
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9. 
SAFETY REPORTING 
The Investigator will report to the sponsor any adverse event whether related or not to the investigational 
medicinal product, serious or not, that occurred in a trial patient depending on the period of the trial. 
Special situations such as treatment errors, suspicion of transmission of an infectious agent via an IMP, 
unusual failure in efficacy, overdose (symptomatic or not), drug exposure during pregnancy or 
breastfeeding even if uneventful, suspected drug-drug interaction with another product (symptomatic or 
not) will also be reported to the sponsor.   
The definition, modalities of collection and reporting are provided below. 
9.1 Adverse Event 
9.1.1 Definition of Adverse Event 
An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a causal relationship 
with this treatment.  
An adverse event (AE) can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product (ICH E2A).  
Any disease identified and diagnosed by trial contrast-enhanced MRI with injection of trial contrast 
agent will not be considered as AE. It may be collected in eCRF as medical history or trial disease.  
The trial disease of the patient that met inclusion criteria or any pre-existing disease is not reported as 
AE, nevertheless, any worsening of such pathologies during the course of the trial has to be considered 
as an AE. 
9.1.2 Collection and recording of Adverse Events 
The Investigator or his/her designee will invite the patient’s parent(s) or legal guardian (where 
applicable) to report any experienced abnormality as part of the usual clinical follow-up. In addition, 
any biological value assessed as significant by the Investigator should be considered as AE. 
In order to ensure complete safety data collection, all Adverse Events occurring from the beginning of 
the patient’s participation in the trial (Informed Consent Form signature) and until 1-week safety visit 
(D8), must be reported and followed even if no IMP was administered. Non-serious AE occurring before 
IMP administration and not related to the trial can be collected as medical history according to 
Investigator’s opinion. Non-serious AEs occurring after 1-week safety visit must be reported if related 
to the drug or to the trial and followed until recovery or sequelae stabilization. Serious Adverse Events 
(SAE) and Adverse Event of Special Interest (AESI) occurring from beginning of the patient’s 
participation in the trial (ICF signature) and until 3-month safety visit (D90 or the day of Visit 4-bis) 
must be reported and followed until recovery or sequelae stabilization. 
 
In addition, if occurring after the end of the patient’s follow-up period defined for this trial, adverse  
events that the Investigator thinks may be associated with the trial medication/procedure must be 
reported to the sponsor regardless of the time between the event and the end of the trial.  
 
As reminder the patient’s participation is defined as the period from the screening visit (ICF signature) 
to the last trial visit in the general case and defined in Section 10 in case of premature discontinuation. 


 
 
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The information relative to AE should be reported and documented in the medical file and the 
appropriate section of the eCRF. In case of AE remotely collected, every effort should be made to collect 
source documents, at least electronically, if any. 
Any AE is followed up from onset to recovery or stabilization of sequelae. If no follow-up is performed, 
the Investigator must provide a justification in the medical file. 
 
9.1.3 Description of Adverse Events 
The following guidelines and definitions should be used by the Investigator for the description of an AE 
when reporting information in eCRF and any specific AE report forms: 
 
Nature of AE: preferably an overall diagnosis or syndrome, rather than individual symptoms 
or signs. The Investigator must report AE using standard medical terminology. The same terms 
should be used in the source documentation and in the eCRF. 
 
Date and time of onset: date and clock time of the AE start 
 
Intensity: 
o Mild: the patient is aware of the sign or symptom, but it does not interfere with her/his 
usual daily activities and/or it is of no clinical consequence 
o Moderate: the AE interferes with the usual daily activities of the patient or it is of some 
clinical consequence 
o Severe: the patient is unable to work normally or to carry out his/her usual daily 
activities, and/or AE is of definite clinical consequence. 
 
Date of the event end (or consolidation): The real date of event end will be entered if the event 
has come to its end. If the AE is still ongoing by the time of end of trial follow-up for the patient 
(i.e. last trial visit), the patient should be followed up until AE resolution or a justification should 
be provided by the Investigator (i.e. chronic disease) in the medical file. 
 
Causal relationship to the 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 trial drug and the event, but an 
obvious alternative cause exists (e.g., the patient’s underlying medical condition or 
concomitant therapy). 
 
Causal relationship to a trial procedure – apart from imaging procedure: 
o Related 
o Not related 
 
Outcome: 
o Recovered/Resolved: the AE is no longer present at any intensity or return to baseline 
intensity (for pre-existing disorders) or values for biological data. 
o Recovered/Resolved with sequelae: the AE is resolved but residual effects are still 
present. 
o Not recovered/Not Resolved: the AE is still present at the last contact with the patient. 
o Fatal: this AE caused or directly contributed to the patient’s death. 
 
Action taken with regard to administration of the IMP: 
No Action: for AE occurring prior or after IMP administration, or if the Investigational 
Medicinal Product dosing/administration remained the same in spite of AE being 
present. 


 
 
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o IMP interrupted: the IMP administration is interrupted during the administration (e. g. 
extravasation…).  
o IMP definitively discontinued: the event leads to a definite contra-indication to the drug 
(e.g. confirmed hypersensitivity…). 
 
 
Other action taken:  
o AE-targeted medication: the patient took a medication (either prescription or non-
prescription) specifically for this AE. The drug(s) should be reported in the appropriate 
section of the eCRF (“concomitant drug” section). 
o Other AE-targeted action: therapeutic measures other than corrective drug 
administration (e.g., ice, heating pad, brace, cast…) or patient underwent a procedure 
(surgery, physiotherapy, additional laboratory test…) for this AE. The therapeutic 
measure(s) should be reported in the appropriate section of the eCRF. 
o Trial discontinuation: AE leads to a trial discontinuation 
 
 
Assessment of the seriousness of the AE: see Section 9.2 for SAE definition. 
9.2 Serious Adverse Event 
9.2.1 Definition of Serious Adverse Event (SAE) 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose (ICH E2A):  
- 
Results in death 
- 
Is life-threatening 
- 
Requires inpatient hospitalization or prolongation of existing hospitalization 
- 
Results in persistent or significant disability / incapacity 
- 
Is a congenital anomaly / birth defect 
- 
Is an important medical event 
Important medical event: medical and scientific judgement should be exercised in deciding whether 
expedited reporting is appropriate in situations such as important medical event that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardise the patient or may 
require intervention to prevent one of the other outcomes listed in the definition above. These should 
also usually be considered serious.  
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or development of 
drug dependency or drug abuse.  
Note: Life-threatening in the definition of a serious adverse event refers to an event in which the patient 
was at risk of death at the time of the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe.  
Hospitalization refers to an admission and overnight stay at the hospital due to the adverse event. 
Emergency room visits that do not result in admission to the hospital should be evaluated for one of the 
other serious outcomes. 
In case of a SAE, the Investigator is responsible for the measures to be taken to ensure the safety of the 
trial participants. 
Severe / Serious: the term “severe” is used to describe the intensity (severity) of a specific event (within 
the scale mild, moderate, severe). This is not the same as “serious”, which is based on patient/event 
outcome or action criteria. The event itself may be severe but of relatively minor medical significance.  




 
 
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According to local requirements, GUERBET or its representatives will communicate relevant safety 
information to the appropriate agency(ies), IEC and/or all active Investigators, as it becomes available. 
The transmission of the information to the sponsor does not release the Investigator from his 
responsibility to inform the regulatory authorities, if applicable. 
9.3 Special situations  
9.3.1 Cases of overdose, lack of efficacy, drug-drug interaction, medication errors 
or misuses 
The safety information regarding the following special situations has to be collected and reported by the 
Investigator with the same procedure as for AE, even if uneventful:  
 
Unintentional treatment errors (e.g., wrong route of administration),  
 
Misuse: where the medicinal product is intentionally and inappropriately used not in accordance 
with the protocol, 
 
Occupational exposure to an IMP, 
 
Overdose: administered dose above the 0.3 mmol/kg for gadopiclenol. 
If one of these situations leads to an AE or SAE, the safety information will be managed as for AE or 
SAE accordingly and will follow the appropriate reporting procedure. 
9.3.2 Pregnancy 
Any participating patient who becomes pregnant or is aware of a pregnancy (patient’s partner) during 
trial participation should inform immediately the investigational site. The female patient should be 
immediately withdraw from the trial and must not receive any IMP. 
Any pregnancy (with or without an Adverse Event) of female adolescent participating in the trial or of 
partners of male adolescent participating in the trial, that is discovered after the ICF signature must be 
reported to GUERBET Pharmacovigilance via the Report Form for SAE, AESI or pregnancy 
 
(see Section 9.2.2) unless the conception date is over one week (for GBCAs) after the last trial drug 
administration. In this case, there is no need to report the pregnancy to Guerbet except in case of noxious 
effect related to the trial drug according to investigator’s opinion.  
Pregnancy will be monitored until delivery (health of infant up to 8 weeks of age) or early termination.  
Specific forms “history and start of pregnancy” and “course and outcome of pregnancy” will be provided 
to the investigational sites. These forms will be used to collect information on the medical history of the 
pregnant adolescent and any risk factor of pregnancy complication, and on the follow-up and outcome 
of the pregnancy.  
Any complication of pregnancy will be reported as an AE or SAE, as appropriate.  
9.3.3 Adverse Events of Special Interest 
An adverse event of special interest (serious or non-serious) is one of scientific and medical concern 
specific to the sponsor’s product or program, for which ongoing monitoring and rapid communication 
by the investigator to the sponsor could be appropriate. Such an event might require further investigation 
in order to characterize and understand it.  
For GUERBET, the transmission of an AESI to the Guerbet Pharmacovigilance Department respects 
the same time frame as an SAE and must be reported to GUERBET Pharmacovigilance via the Report 
Form for SAE, AESI or pregnancy 
 (see Section 9.2.2). 


 
 
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AESI for this protocol is the following: suspected or confirmed Nephrogenic Systemic Fibrosis (NSF). 
9.3.4 Any suspicion of transmission of an infectious agent via an IMP 
Any suspicion of transmission of an infectious agent via an IMP should be considered as serious and 
processed as an SAE. 
9.4 Other important safety issue /New fact 
Any safety issues that may alter the current benefit-risk assessment of an investigational medicinal 
product, or would be sufficient to consider changes in the trial drug administration or  would involve 
any update of trial documents or in the overall conduct of the trial should be evaluated by the sponsor. 
It includes any new event likely to affect the safety of the patients and that may be related to the conduct 
of the trial or the development of the trial drug such as: 
 
A SAE which could lead to the modification of the conduct of the trial 
 
A significant hazard to the patient 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 trial, 
 
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 TSRB, if any, where relevant for the safety of patients, 
 
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/IRB and/or all active Investigators, as it becomes 
available. 
Consequently, this type of important safety issue might lead also to:  
 
Urgent safety measures and their notification 
 
Substantial modifications 
 
Premature discontinuation of the trial  
 
Premature discontinuation of the patient 
9.5 Unblinding Procedures 
Not applicable. 
 
 


 
 
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10. 
PREMATURE DISCONTINUATION OF THE TRIAL 
10.1 Premature Discontinuation of the Trial per GUERBET Decision 
GUERBET reserves the right to discontinue the trial at any time for medical, administrative or other 
reasons. 
GUERBET will inform the relevant authorities in each country, the ethics committees, the trial site 
Investigators, pharmacists and hospital authorities according to the regulatory texts in force. 
10.2 Reasons for patient’s premature discontinuation 
Screening Failure:  
A patient whose parent(s) or legal guardian (where applicable) have signed the informed consent and 
who discontinue the trial before gadopiclenol injection will be considered screening failure. The reason 
for screening failure will be documented. Such patient can be re-screened according to the same 
modalities as for the new patient. A new patient number will be allocated to the patient. 
Premature discontinuation of patients: 
Patient may discontinue the trial after gadopiclenol injection for following reasons: 
- 
Adverse Event (according to the Investigator’s judgement); 
- 
Withdrawal of patient’s parent(s) or legal guardian (where applicable) consent; 
- 
Patient lost to follow-up (date of last contact will be documented in the medical file and the eCRF). 
Any effort will be undertaken to know the reason for this loss to follow-up and/or to exclude any 
adverse reaction as this reason. This will be documented in the medical file; 
- 
Discovery of an unexpected, significant, or unacceptable risk to the patients enrolled in the trial; 
- 
At the discretion of the Investigator if the patient safety or well-being is not compatible with trial 
continuation. 
- 
Other reason (to be specified). 
A reason for trial discontinuation will be documented. 
Enrollment of additional patients: 
Patients prematurely discontinuing the trial will not be replaced. However, if the threshold of 15 patients 
per age group, evaluable for the primary criterion is not reached, the enrollment will continue in order 
to ensure a minimum number of evaluable patients per group. 
In the event of premature discontinuation, patients will receive adequate follow-up and usual medical 
care from site Investigators.  
 
 
 


 
 
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11. 
STATISTICAL CONSIDERATIONS 
The following sections summarize the statistical considerations, which are fully described in the 
Statistical Analysis Plan (SAP).  
Two separate SAPs will be provided: 
- 
a SAP for safety and efficacy 
- 
and a SAP for population PK analysis. 
Summary statistics will be presented for continuous variables, by way of n, n missing (if any), mean, 
standard deviation (SD), median, minimum and maximum and by way of cohort frequencies and 
percentages for categories of categorical variables. Percentages will be calculated using the total patients 
per cohort excluding missing. 
Descriptive statistics for parameters of interest will be provided by age group and overall. 
11.1  Statistical Method (null and alternative hypotheses) 
The trial aims to evaluate the pharmacokinetic profile of gadopiclenol in plasma. So, a population PK 
analysis will be performed through modeling to determine primary pharmacokinetic parameters. These 
parameters will be then summarized through descriptive statistics.  
Therefore, no inference will be done from this trial and therefore no null or alternative hypotheses are 
needed. 
11.2 Sample Size for primary criterion assessment 
The sample size was determined in order to optimize the characterization of gadopiclenol 
pharmacokinetics in pediatric population through population PK modelling. Sample size determination 
was coupled with PK sampling time optimization in order to determine the best possible design for the 
population PK modelling. The best design (in terms of sample size and sampling points) was defined as 
the design minimizing model’s parameters root square error (RSE), hence providing the highest 
precision. 
According to adult’s data, a 2-compartment model with elimination from the central compartment 
described appropriately gadopiclenol pharmacokinetics. The design was evaluated for a sample size of 
60 pediatric patients between 2 and 17 years old and predicted a correct estimation of all PK parameters. 
As a first step, an optimization was performed on 60 children between 2 and 17 years of age. As no 
structural modification in the PK of children between 2 and 17 years of age was expected, a single design 
was optimized for a typical child of 10 years old with a body weight of 33 kg. The amount injected was 
calculated as following: 
n = 0,1 mmol/kg × 33 kg = 3,3 mmol 
m = 3,3 mmol × 970.11 mg/mmol (gadopiclenol molecular weight) = 3201 mg 
A balanced sample size within each of the age group was targeted, leading to a total sample size multiple 
of 3. The PK sampling time and number of patients was optimized using approaches based on the Fisher 
Information Matrix (FIM) for nonlinear mixed effect models, which consist in determining a balance 
between the number of patients and the number of samples per patient, as well as the allocation of times, 
according to experimental conditions 
  
Different designs were investigated and were compared in term of RSE and the selected design needed 
to provide reasonable RSE and flexibility. The predicted RSE for this design were very good and the 
inclusion of additional patients was not expected to impair the performance of an overall model built on 
all children. Thus the design with additional 20 patients aged between 0-23 months was investigated. 
. 


 
 
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A minimum of 15 patients will be included in each of the three age groups (12-17, 7-11 and 2-6 years) 
in order to balance the sample size between the groups. The inclusion will be completed in parallel in 
all groups to reach the overall number of 60 patients evaluable for the primary criterion. 
11.3 Planned Analysis  
11.3.1 Disposition of Patients 
Number of patients and reasons for screening failure before injection will be provided per age group 
and overall.  
Number of injected patients prematurely discontinued from the trial and reasons for trial discontinuation 
will be provided according to the age group and overall. 
11.3.2 Data Sets Analyzed 
There will be four patient sets defined for this trial: All enrolled patients set, the Full Analysis Set (FAS), 
the Safety Set and the Per Protocol Set (PPS). 
 
All enrolled Patients Set: all patients having the inform consent form signed by their 
parent(s)/legal guardian. This set will be used for patient disposition summaries and individual 
listings.  
 
The FAS will include all patients undergoing an enhanced MRI examination in CNS and other 
organs. This set will be used for the Efficacy Analysis. 
 
Safety Set will include all patients, receiving at least one administration of study drug. This set 
will be used for evaluation of safety, urinary PK and gadopiclenol excretion and description of 
demographic data and baseline characteristics. 
 
The PPS will include all patients in the Safety Set undergoing an enhanced MRI examination in 
CNS without major deviations likely to impact the population PK model. This set will be used 
for population PK analysis and description of demographic data and baseline characteristics.  
11.3.3 Protocol Deviations 
Any deviation(s) from the original statistical plan will be described and justified in the final report. At 
minimum following protocol deviations will be stated as major in the trial (a major deviation being 
defined as a deviation having an impact on the primary criterion): 
 
No plasma PK sample was obtained 
 
Concomitant treatment or procedure (e.g., diuretics, clinically significant blood loss or blood 
transfusion) that may altered gadopiclenol pharmacokinetic parameters 
 
Missing information regarding time of injection and times of PK sampling (all missing) 
Patients with major deviations (final list will be available prior to the analysis) will be excluded from 
the pharmacokinetic population analysis. All other deviations will be classified as non-major deviations. 
COVID-19 pandemic-related deviations will be clearly identified. 
Modeling is done using all patients and sensitivity analyses could be conducted without data/patient 
identified as outliers.  
Frequency and percentages of patients with non-major protocol deviations will be presented using the 
All enrolled Patients Set. 


 
 
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The actual period of quantitative urine collection will be provided and the period below 8 hours will not 
be considered as a deviation. 
11.3.4 Demographics and Baseline Characteristics 
All demographic and other baseline characteristics parameters will be summarised by age group and 
overall in the Safety Set and in PPS if different. 
 
Demographic parameters: age, sex, body weight, height, race/ethnicity.  
 
Other baseline characteristics: childbearing potential, urinary continence, medical history, 
contrast media intolerance history and the prior medications / procedures defined as medications 
/ procedures which stopped before IMP administration.  
Patient's medical history will be coded using the MedDRA dictionary and tabulated by body system, 
preferred term and status (concomitant or not). 
Patient's prior medications will be coded using the Anatomical Therapeutic Chemical (ATC) Drug 
dictionary and tabulated by ATC code. 
Patient's prior procedures will be coded using the MedDRA dictionary and tabulated by body system, 
and preferred term. 
11.3.5 PK 
11.3.5.1 
Population PK 
The population PK analysis will be performed on the PPS using a dedicated software modelling and 
including pharmacokinetic models library. 
The structural model describing the gadopiclenol concentrations profile as a function of time and amount 
of product injected will be first determined. Structural PK model parameters will enter the model either 
as fixed or random effects (when supporting a between-patient variability). 
Covariates potentially influencing the PK of gadopiclenol will be tested using a backward sequential 
approach in order to prevent inflation of the type I error over the number of statistical tests. 
Quality of the model will be assessed using goodness of fit plots and an internal validation will be 
performed using visual predictive checks. 
gadopiclenol plasma concentrations below the limit of quantification will be considered as missing, 
unless their proportion represent more than 15% of the total concentrations. In that case, alternative 
methods, such as left-censoring, will be considered for their contribution to the likelihood. 
Empirical Bayes estimates (EBEs) of PK parameters (basically clearance and volume of distribution) 
will be obtained from the final model and summarized per age group and overall. In addition, the 
following parameters will be derived from the EBEs, depending on the structural model retained for 
gadopiclenol: 
- 
Area Under the Curve,  
- 
elimination half-life, 
In addition, gadopiclenol plasma concentrations at 10, 20 and 30 minutes post-injection will be 
simulated from the final model and their distribution will be summarized using box-plots and descriptive 
statistics by age group and overall. 
All methods to be applied for the population modelling will be fully detailed in a dedicated analysis 
plan. 


 
 
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11.3.5.2 
Urinary PK 
Percentage of urinary excreted gadopiclenol injected dose over 8 hours and concentration of 
gadopiclenol excreted in spot urine samples collected at D8 (or up to D30 in case of collection at V3-
bis) visit and D 90 (or up to D120 in case of collection at V4-bis) visit will be provided by age group 
and overall using the Safety Set. 
11.3.6 Efficacy Analysis 
All efficacy analyses will be done using the FAS: 
o Technical adequacy for diagnosis: patient score will be tabulated qualitatively for pre and 
pre+post contrast images per age group, cohort and overall. Shift tables between pre and 
post scores will be provided. 
o Assessment of contrast quality:  percentage of enhancement (E%) and LBR for up to 3 
most representative lesions will be tabulated quantitatively per age group, cohort and 
overall.  
o Lesion visualization (lesion border delineation, internal morphology and contrast 
enhancement): for each parameter patient score will be tabulated qualitatively for pre and 
pre+post contrast images per age group, cohort and overall. For each MRI evaluation (“pre-
contrast” and “pre+post contrast”), the number and percentage of each score of the 
parameter (border delineation, internal morphology, degree of contrast enhancement) will 
be described. A shift tables between pre and pre+post scores will be provided. The sum 
and variation of lesions scores and variation will be described quantitatively per age group, 
cohort and overall.  
o Change in diagnostic confidence: following administration, the Investigators’ diagnostic 
confidence is improved or remains unchanged or getting worse. Investigator’s diagnostic 
confidence will be tabulated qualitatively for pre and pre+post contrast images per age 
group, cohort and overall. 
11.3.7 Adverse Event 
Adverse event analysis will be done using the Safety Set except otherwise specified. 
All analyses of AEs will be based on the number of patients with AEs (and not on the number of AEs) 
except otherwise specified. 
Events will be classified as treatment-emergent (TEAE) if they started after drug administration. 
A serious AE is defined as an AE with serious classified as ‘yes’ or missing with each of the criteria for 
seriousness. 
o Overall overview of Treatment Emergent AE (TEAE) 
The number (%) of patients having at least one Treatment Emergent AE (TEAE) will be summarized 
for each age group and overall for: 
- 
At least one TEAE 
- 
At least one TEAE with each of the following classifications of intensity 
o Mild 
o Moderate 
o Severe 
 
At least one TEAE with each of the following classifications of action taken with regard to 
administration of the IMP: 
o No action 
o IMP interrupted 


 
 
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o IMP definitively discontinued 
- 
At least one TEAE related to trial procedure 
- 
At least one adverse reaction (relationship to study IMP classified as ‘Related’) 
- 
At least one TEAE with each of the following classifications of outcome: 
o Recovered/resolved 
o Recovered/resolved with sequelae 
o Not recovered/Not resolved 
o Fatal 
- 
At least one TEAE leading to AE-targeted medication 
- 
At least one TEAE leading to other AE-targeted action 
- 
At least one serious TEAE 
 
The table will be repeated for all Non Treatment Emergent AE (NTEAE) without presenting the adverse 
reaction and using the All enrolled Patients Set. 
o Distribution of AEs, AESI and SAEs 
A table will be presented showing the total numbers and the distribution of AEs (number [%] of patients 
with 0, 1, 2 etc… AEs) for each age group and overall. The table will also show the same information 
for SAEs and AESI, unless the number of SAEs or AESI make this uninformative. 
o Summaries by System Organ Classes (SOC) and Preferred Term (PT)  
Summaries by SOC and PT will be presented for all TEAE and all related treatment-emergent events, 
for each age group and overall. 
11.3.8 Laboratory data 
Laboratory data are defined as safety laboratory variables centrally analyzed (hematology and 
biochemistry) from blood samples, estimated glomerular filtration rate (eGFR) centrally calculated 
based on the bedside Schwartz equation and urinalysis with dipstick (see Section 7.2). Laboratory data 
analysis will be done using the Safety Set. 
The baseline is defined as the last measure before the IMP administration 
The statistical analysis will present results in standard international units and conventional United States 
units. Original units will be only listed. Laboratory data will be analyzed quantitatively and qualitatively 
for each age group and overall. 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. 
Summary of laboratory values and change from baseline will be summarized by age group and overall. 
The incidence of out-of-range results as well as shifts from baseline will also be presented by age group 
and overall.  
11.3.9 Other safety observations 
Other safety observations analysis will be done using the Safety Set. 
11.3.9.1 
Vital signs (blood pressure, pulse rate and Blood oxygen saturation 
SpO2) 
The baseline is defined as the last measure before the IMP administration  


 
 
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Vital signs will be analyzed quantitatively and qualitatively for each age group and overall. Qualitative 
analyses will be done via comparison of vital signs data to their normal ranges and according to their 
clinical significant changes. Quantitative analyses will be done by tabulating raw data and change from 
baseline. 
11.3.9.2 
ECG 
The baseline is defined as the last measure before the IMP administration  
ECG data will be analyzed quantitatively and qualitatively for each age group and overall. Qualitative 
analyses will be done via comparison of ECG data to their normal ranges (by parameter). Quantitative 
analyses will be done by tabulating raw data and change from baseline. 
11.3.9.3 
Injection site tolerance  
Number of patients experiencing eruption, extravasation and inflammation at site injection will be 
tabulated per age group and overall. 
11.3.9.4 
NSF Monitoring (clinical examination)  
Number of patients with or without Nephrogenic Systemic Fibrosis (NSF) symptoms at 3 months will 
be provided for each age group and overall. In case of NSF, clinical evidence and results of the biopsy 
will be displayed for each age group and overall. 
11.3.9.5 
Extent of exposure 
Duration between IMP administrations and end of trial, volume theoretically administered (ml), volume 
actually administered (ml), site of administration, manual / power injector administration. If power 
injector administration actual rate of administration (ml/s) and theoretical rate of administration (ml/s) 
will be tabulated. Frequency tabulation of theoretical volume actually administered and theoretical rate 
of administration actually performed (yes/no) will be also displayed. 
11.3.9.6 
Concomitant medications / procedures 
Frequency and percentages will be calculated for concomitant medications / procedures. 
Concomitant medications / procedures are defined as medications / procedures which continue or start 
after IMP administration.  
Patient's concomitant medications will be coded using the Anatomical Therapeutic Chemical (ATC) 
Drug dictionary and tabulated by ATC code. 
Patient's concomitant procedures will be coded using the MedDRA dictionary and tabulated by body 
system, and preferred term. 
11.4 Statistical/Analytical issues  
11.4.1 Adjustments for Covariates  
Identification of covariates that are predictive of pharmacokinetic variability will be an important part 
of the modelling strategy. 
Two sets of covariates will be considered. First, covariates know a priori to be highly influential for 
physiologic reasons will be considered during the structural model building in order to ensure model 
stability. These covariates may include for pediatric population body weight, age or eGFR for example. 


 
 
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In a second step, variability in PK may be identified and characterized by addition of covariates to the 
model. The inclusion of these covariates will follow a two steps approach. The first step will consist on 
an univariate screening of each covariate and the second step as a backward deletion procedure of each 
covariate from a full model including all covariates found significant during the first step. 
Typically, both steps will be based on likelihood ratio tests, performed at the 5% level for the univariate 
step and at the 0.5% for the second step. 
All covariates to be investigated will be pre-defined in the PK statistical analysis plan. 
11.4.2 Handling of Dropouts or Missing Data  
As a general rule, missing concentration data will not be imputed for the population PK modeling and 
values below the limit of quantification (BLQ) will be considered as missing unless they represent more 
than 15% of the total number of concentrations. In that case, an alternative method considering the 
values BLQ as censored will be considered. 
Missing information regarding product administration will not be imputed and will lead to patient 
removal from the analysis. 
In case of missing date or time for sampling, no imputation will be performed and the sample will not 
be considered for the analysis. 
In case of missing covariate value, the population median or the most reported category (for categorical 
covariate) will be imputed. If more than 15% of the patients present a missing value for a covariate, it 
will not be considered for the analysis. 
For efficacy and safety data, Missing Data will not be imputed and only observed data will be described. 
11.4.3 Interim Analyses and Data Monitoring  
No formal interim analysis is planned for this trial. However, after the injection of the first 15 patients 
included in age groups of Adolescents and Preadolescents, Trial Safety Review Board (TSRB) will be 
planned in order to assess safety data and to decide trial continuation. 
11.4.4 Multicenter Trials 
Potential differences between centers that may impact the pharmacokinetics of gadopiclenol are not 
expected in this trial, therefore the center will not be considered for the population PK model unless 
there is sufficient evidence to invalidate this assumption. In that case, the center will be considered as a 
covariate. 
11.4.5 Multiple Comparisons/Multiplicity  
Multiplicity will affect only the covariates model building in the modeling process. In order to protect 
the overall type I error, the backward deletion process will be performed at the 0.5% level.  
11.4.6 Use of an "Efficacy Subset" of Patients 
Efficacy is a secondary analysis and will be analyzed using FAS which will include all patients 
undergoing contrast-enhanced MRI examination in CNS and other organs. 
11.4.7 Active-Control Trials Intended to Show Equivalence  
Not-applicable. 


 
 
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11.4.8 Examination of Subgroups 
No subgroup analysis will be performed in this trial. The 3 age groups specificities will be considered 
in the population PK model through representative structural covariates (for example weight, age, 
eGFR). 
 
 


 
 
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12. 
TRIAL COMMITTEES 
 Trial Safety Review Board (TSRB) 
Trial Safety Review Board (TSRB) is set up to perform a risk/benefit assessment in order to weight 
possible safety disadvantages against a possible gain in efficacy during the recruitment period and for 
monitoring the overall conduct of the clinical trial as well as ensuring that criteria for early stopping are 
met.  
TSRB  is responsible for the careful review of the safety data of first 15 patients recruited in each age 
group from either CNS or both cohorts. Review of safety will be based on disposition demography and 
other baseline characteristics as well as all safety parameters (AE, laboratory data and other safety 
observation such as vital signs and ECG data).  
The decision to start the inclusion in the group of patients aged 7-11 and 2-6 years will be taken based 
on safety assessment over one-day period after injection of the respective previous group. TSRB will 
not monitor the primary pharmacokinetic parameters. 
The TSRB is composed as following: the international coordinator (or other identified medical expert 
in pediatric radiology) and GUERBET team (drug safety physician, medical expert, clinical project 
manager and ad-hoc team members).  
The role and responsibilities of the TSRB will be described in a separate document (TSRB Plan) that 
will be written before first patient in. 
 
 
 


 
 
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13. 
ETHICAL AND REGULATORY CONSIDERATIONS 
13.1 References 
The trial will be conducted in accordance with the following regulatory / guidance texts: 
- 
World Medical Association Declaration of Helsinki, Ethical Principles for Medical Research 
Involving Human Subjects, June 1964, and amended in: October 1975 (Tokyo), October 1983 
(Venice), September 1989 (Hong Kong), October 1996 (Somerset West), Scotland, October 
2000 (Edinburgh), 2002 (Washington), 2004 (Tokyo), October 2008 (Seoul), October 2013 
(Fortaleza) 
- 
International Conference on Harmonisation (ICH) of Technical Requirements for Registration 
of Pharmaceuticals for Human Use: Integrated Addendum to ICH E6(R1): Guideline for Good 
Clinical Practice E6 (R2) Current Step 5 version dated 15  Decembre 2016 
- 
International Conference on Harmonisation (ICH) of Technical Requirements for Registration 
of Pharmaceuticals for Human Use: Clinical Safety Data Management: Definitions and 
Standards for Expedited Reporting E2A Current Step 4 version dated 27 October 1994 
- 
International Conference on Harmonisation (ICH) of Technical Requirements for Registration 
of Pharmaceuticals for Human Use: General Considerations for Clinical Trials E8 Current Step 
4 version dated 17 July 1997 
- 
Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the 
approximation of the laws, regulations and administrative provisions of the Member States 
relating to the implementation of good clinical practice in the conduct of clinical trials on 
medicinal products for human use 
- 
Commission Directive 2003/94/EC of 8 October 2003 laying down the principles and guidelines 
of good manufacturing practice in respect of medicinal products for human use and 
investigational medicinal products for human use 
- 
Commission Directive 2005/28/EC of 8 April 2005 laying down principles and detailed 
guidelines for good clinical practice as regards investigational medicinal products for human 
use, as well as the requirements for authorisation of the manufacturing or importation of such 
products 
- 
International Conference on Harmonisation (ICH) of Technical Requirements for Registration 
of Pharmaceuticals for Human Use: Ethnic Factors in the Acceptability of Foreign Clinical Data 
E5(R1) Current Step 4 version dated 5 February 1998 
- 
International Conference on Harmonisation (ICH) of Technical Requirements for Registration 
of Pharmaceuticals for Human Use: Clinical Investigation of Medicinal Products in the Pediatric 
Population E11 Current Step 4 version dated 20 July 2000 and E11 (R1) Addendum dated 20 
July 2017 
- 
Regulation (Eu) 2016/679 Of The European Parliament And Of The Council of 27 April 2016 
on the protection of natural persons with regard to the processing of personal data and on the 
free movement of such data, and repealing Directive 95/46/EC (General Data Protection 
Regulation) 
- 
EudraLex, The Rules Governing Medicinal Products in the European Union, Volume 4, EU 
Guidelines to Good Manufacturing Practice - Medicinal Products for Human and Veterinary 
Use, Annex 13 Investigational Medicinal Products 


 
 
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- 
US Food and Drug Administration, Title 21 Code of Federal Regulations Part 11 on Electronic 
Records; Electronic Signatures 
- 
US Food and Drug Administration, Title 21 Code of Federal Regulations Part 211 on Current 
Good Manufacturing Practice for Finished Pharmaceuticals 
- 
Regional / local regulations and other specific populations regulations 
- 
EMA/141885/2020 Guidance on the Management of Clinical Trials during the COVID-19 
(Coronavirus) pandemic version 2 dated 27 March 2020 
- 
EMA/158330/2020, Points to consider on implications of Coronavirus disease (COVID-19) on 
methodological aspects of ongoing clinical trials Draft dated 25 March 2020 
- 
FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public 
Health Emergency. Guidance for Industry, Investigators, and Institutional Review Boards dated 
March 2020 Updated on April 16, 2020 
13.2 Institutional 
Review 
Board/Independent 
Ethics 
Committee 
and 
Regulatory/Competent Authorities 
As per international regulation, the clinical trial may be initiated only after having received the approval 
by and Institutional Review Board/Independent Ethics Committee (IRB/IEC) and the authorization by 
the national Regulatory/Competent Authority. The final written approval and authorization must be 
available for a given investigational site when initiating the trial conduct at this particular site. Amongst 
all documents required locally, the approval and authorization must be obtained for the protocol, 
Investigator’s brochure, the patient parent(s) or legal guardian  (where applicable) Informed Consent 
Form and any other written information or document to be provided to the patient or patient parent(s) 
or legal guardian (where applicable). 
In case of modifications to the trial protocol, patient parent(s) or legal guardian (where applicable) 
Informed Consent Form or any other written information provided to the patients or patients parent(s) 
or legal guardian (where applicable), or to any trial procedure; the modified documents will be submitted 
to IRB/IEC and Regulatory/Competent Authority opinions. Modifications may be implemented when 
the final approval and authorization are available. 
In case of an emergency situation when the patients’ safety may be at risk, GUERBET may implement 
emergency safety measures prior to obtaining IRB/IEC approval and Regulatory/Competent Authority 
opinion. In parallel to implementing these measures, GUERBET will immediately notify the concerned 
IRB/IEC and Regulatory/Competent Authorities of such implementation. 
The documentation related to the approvals and authorizations must be filed in the Trial Master File at 
GUERBET and at the investigational sites in their respective Investigational Site File (ISF) 
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 9 of the 
present protocol. 
Notifications of non-compliances / deviations to IRB/IEC and Regulatory/Competent Authority will be 
made according to national requirements of participating countries and according to individual IRB/IEC 
requirements when applicable 
13.3 Patient Parent(s) or Legal Guardian (where applicable) Informed Consent 
Prior to participation, all patients parent(s) or legal guardian (where applicable) must confirm their free 
and voluntary willingness to involve their child in the trial. This confirmation is obtained in writing after 
having received a full oral and written explanation on the trial: 


 
 
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- 
Blood sampling, methodology and duration of the trial; 
- 
Potential benefits, foreseeable risks and inconveniencies related to the trial; 
- 
Rights and responsibilities of patients parent(s) or legal guardian (where applicable), with 
particular emphasis on the right to refuse trial participation or to withdraw consent to 
participation at any time without consequences or penalties; 
- 
Information on IMP and its administration; 
- 
Contact details of persons dedicated to the trial at the investigational site. 
The child should participate in the informed consent process together with the parent(s) or legal guardian 
(where applicable), in a way that is appropriate to his or her age and maturity.  
The language used when informing the patients and their parents or legal guardian and answering their 
questions must be as understandable as possible and shall not induce any misunderstanding or feeling 
to be influenced to participate. Patients and their parents or legal guardian must be given ample time to 
decide whether they agree to participate or not. 
Parent(s) or legal guardian (where applicable) may consent to participation of their child 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. 
The information of patients and parent(s) or legal guardian (where applicable) may only be conducted 
by qualified investigational site personnel, whose involvement and responsibility for patient information 
has been fully documented and approved by the Principal Investigator. 
The Principal Investigator must ensure that local applicable regulations/requirements are fully observed 
by the staff under her/his responsibility. 
In case of modifications of the patient parent(s) or legal guardian informed consent or of any other 
document to be provided to them or to the patient, the IRB/IEC approval must be obtained prior to 
implementing the new document(s). Parent(s) or legal guardian (where applicable) who already 
consented may be asked to confirm their willingness to continue participating in writing. In any case, 
the same information and consent process as described above must be followed. 
13.4 Trial Records and Archiving 
During the course of the clinical trial, investigational sites must ensure completeness and accuracy of 
the trial records that are to be filed in the Investigator Site File (ISF) provided by GUERBET at the 
initiation visit. The completeness and accuracy of such files will be checked regularly by GUERBET 
representative (Clinical Research Associate or Monitor). The final check will occur at the close out visit 
when investigational site participation is over. 
At the end of the trial, investigational sites must ensure the ISF will be archived in an appropriate way 
that allows timely access and proper retention of documents. Retention period will be of at least 15 years 
after trial completion. Sites should obtained GUERBET written approval before destroying trial 
documents. 
 
 


 
 
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14. 
QUALITY CONTROL / QUALITY ASSURANCE 
14.1 Direct Access to Source Data/Documents 
The Investigator will allow GUERBET representatives, the persons responsible for the audit, the 
representatives of the Ethics Committees and of the Regulatory Authorities to have direct access to 
source data/documents. 
The Investigator must guarantee the safety of the trial data in the medical files by implementing security 
measures to prevent unauthorised access to the data. 
The Investigator undertakes, in accordance with the regulation in force, to make anonymous any patient 
data before collection by GUERBET. Especially the name and address of the patients will be deleted 
from any medium such as eCRF, document for biological results, MR images or digital supports. 
- 
For this trial, the following will be considered as source data (as a minimum): patients medical 
files, MR images, ECG records. 
- 
If computerized medical files are used, the system must be evaluated by GUERBET (or 
representative): In case printing of files is not possible, the computerized system must be 
validated and access should be granted to GUERBET or its representative. 
If the computerized system is not validated, the Investigator must, at the start of the trial, print, sign and 
date all the medical files of all patients and during the trial, print, sign and date in real time each data 
entry and each data change, 
14.2 Clinical Monitoring 
Before the trial is conducted at a given investigational site and until the trial is completed/terminated at 
the same given investigational site, GUERBET will mandate a representative to perform a close 
monitoring of the trial conduct that will ensure that the investigational site is properly equipped; the 
staff is adequately experienced and knowledgeable of regulatory and ethical requirements. Monitors 
contact details will be listed on the trial team list. 
The representative will perform regular investigational site visits and report all discussions, patient and 
IMP data verification performed with particular attention to patients’ safety and well-being and trial data 
accuracy and completeness. 
14.3 Clinical Data Handling 
14.3.1 Data Reported in the eCRF 
The eCRF 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 eCRF, at each patient 
visit, and all other documents provided by GUERBET (e.g., documents relating to the IMP management) 
and to reply to any data clarifications raised in a timely manner. 
The Investigator must attest: 
- 
The authenticity of the data collected in the eCRF;  
- 
The consistence between the data in the eCRF and those in the source documents, with the 
exception of those data recorded directly in the eCRF and considered as source data. 
Results of evaluation of MR images and ECG can be recorded directly on the eCRF (i.e., no prior written 
or electronic record of data), and to be considered to be source data. 


 
 
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14.3.2 Data Reported in the eCRF according to Patient Status  
For screening failure/non selected patients, only the date of visit, the date of informed consent signature, 
demographic data, eligibility criteria, the adverse event, the reason for non-selection and the date of 
study end will be reported. 
For included patients, withdrawn before the administration of the IMP, only the selection data, the safety 
data, the reason for discontinuation and the date of study end will be reported. 
For patients withdrawn from the trial after the administration of the IMP, all data available at the time 
of discontinuation will be reported in the medical file and the eCRF (e.g., inclusion data, safety data, 
administration data, PK data, imaging data, reason for premature discontinuation, etc.). The Investigator 
must make every effort to collect and record all follow-up safety information (i.e., adverse events, 
injection-site tolerance, as appropriate), unless the patient’s parent(s) or legal guardian (where 
applicable) withdraws consent for further data collection/participation for/in the trial. 
14.3.3 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. 
14.4 Audits and Inspections 
At any time during the trial conduct, GUERBET may mandate a representative to perform an audit of 
investigational sites in order to assess compliance with the regulatory and ethical requirements, the trial 
protocol and related instructions and to assess the accuracy and completeness of data generated by the 
investigational sites. 
In parallel, at any time during the trial conduct, Competent/Regulatory Authorities may also carry out 
an inspection in the facilities of GUERBET and/or the investigational sites. GUERBET will inform all 
the Investigators immediately upon notification of a pending inspection. Likewise, the Investigator will 
inform GUERBET of any pending inspection. 
Whether for an audit or for a regulatory inspection, GUERBET and the investigational sites both agree 
to cooperate in full transparency, confidentiality and professional secrecy. 
The Investigator must allow the representatives of GUERBET (audit) and/or of the 
Competent/Regulatory Authorities (inspection):  
- 
To inspect the site, facilities and trial material, 
- 
To meet all members of his/her team involved in the trial, 
- 
To have direct access to trial data and source documents, 
- 
To consult all of the documents relevant to the trial. 
 
 


 
 
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Radiol.2016;51:50–57. 
20. Scala M, Koob M, de Buttet S, Bourrinet P, Felices M, Jurkiewicz E. A. Pharmacokinetics, 
Efficacy, and Safety Study of Gadoterate Meglumine in Pediatric Subjects Aged Younger Than 2 
Years. Invest Radiol.2017. DOI: 10.1097/RLI.0000000000000412[Epub ahead of print] 
21. Schwartz GJ, Munoz A, Schneider MF, et al. New equations to estimate GFR in children with 
CKD. J Am Soc Nephrol.2009;20:629-37. 
22. Schwartz GJ and Work DF. Measurement and estimation of GFR in children and adolescents. J 
Am Soc Nephrol.2009; 4(11):1832-43. 
23. Staples A, LeBlond R, Watkins S, Wong C, Brandt J. Validation of the revised Schwartz 
estimating 
equation 
in 
a 
predominantly 
non-CKD 
population. 
Pediatr 
Nephrol.2010;Nov;25(11):2321-6. 
 
 
 
 
 
 
 
 
 


 
 
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Protocol No. GDX-44-007 
Version No. 4.0 
 
Date 24 Apr 2020 
 
Page 78 / 79 
 
 
17. 
COMPANY LIABILITY INSURANCE 
GUERBET’s liability, as well as the liability of the Investigators participating to this trial, is covered by 
an insurance policy, a copy of the certificate being submitted to the Investigator. 
Furthermore, GUERBET and the Investigator undertake to comply with the locally applicable legal 
requirements with respect to insurance. 
However, GUERBET and its insurer reject all liability in the following cases, which are merely 
indicative and not exhaustive: 
 
An accident due to a cause other than the investigational medicinal product administered, 
 
An accident occurring during use of the investigational medicinal product differently from the 
instructions given in the trial protocol, 
 
An accident occurring for a patient whose consent to participation was not adequately collected. 
 
 


 
 
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Protocol No. GDX-44-007 
Version No. 4.0 
 
Date 24 Apr 2020 
 
Page 79 / 79 
 
 
18. 
APPENDICES 
Not applicable. 

SAP_001.pdf: 
Document Type 
Statistical Analysis Plan 
Document Date 
January 27, 2021 
Official Title 
Pharmacokinetics, safety and efficacy of a new gadolinium-based 
contrast agent, gadopiclenol, in pediatric patients from 2 to 17 years 
of age undergoing contrast-enhanced MRI 
NCT Number 
NCT03749252 
 




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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine amino Transferase 
AST 
Aspartate amino Transferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the Curve 
BPM 
Beats Per Minute 
BUN 
Blood Urea Nitrogen 
BW 
Body Weight 
eCRF 
electronic Case Report Form 
CRO 
Contract Research Organization 
CNS 
Central Nervous System 
CSR 
Clinical Study Report 
CT 
Computed Tomography 
D 
Day  
DBP 
Diastolic Blood Pressure 
ECG 
Electro Cardio Gram 
eGFR 
Estimated Glomerular Filtration Rate 
FAS 
Full Analysis Set 
GBCA 
Gadolinium-Based Contrast Agent 
GCP 
Good Clinical Practice 
HR 
Heart Rate 
ICH 
International Conference on Harmonization 
ICF 
Informed Consent Form 
IMP 
Investigational Medicinal Product 
INR 
International Normalized Ratio 
IWRS 
Interactive Web Response System 
LBR 
Lesion to Background Ratio 
LC-MS/MS 
Liquid Chromatography with tandem Mass Spectrometry 
LDH 
Lactate Dehydrogenase 
LLN 
Lower Limit of Normal range 
MedDRA 
Medical Dictionary For Regulatory Activities 
MCV 
Mean red blood Cells Volume 
MR 
Magnetic Resonance 
MRI 
Magnetic Resonance Imaging 
NSF 
Nephrogenic Systemic Fibrosis 
PK 
Pharmacokinetics 
PPS 
Per Protocol Set 
PT 
Preferred Term / Prothrombin Time 
RBC 
Red Blood Cell 
ROI 
Region Of Interest 
SAE 
Serious Adverse event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SI 
Standard International 
SOC 
System organ Class 
SpO2 
Pulse Oxymetry 
SS 
Safety Set 
TEAE 
Treatment Emergent Adverse Event 


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TSRB 
Trial Safety Review Board 
ULN 
Upper Limit of Normal Range 
US 
United States 
W 
Window 
WBC 
White Blood Cells 
WHO 
World Health Organization 


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TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ........................................................................ 3 
 
SUMMARY OF THE STUDY PROTOCOL ................................................................................................ 7 
1.1. 
STUDY OBJECTIVES ..................................................................................................................................... 7 
1.2. 
STUDY DESIGN ............................................................................................................................................ 7 
 
EVALUATION CRITERIA ............................................................................................................................ 8 
2.1. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ......................................................................... 8 
2.2. 
PK DATA (PRIMARY CRITERIA AND SECONDARY CRITERIA) ...................................................................... 9 
2.3. 
SAFETY CRITERIA (SECONDARY CRITERIA) .............................................................................................. 10 
2.3.1. 
Extent of Exposure ............................................................................................................................. 10 
2.3.2. 
Adverse Events ................................................................................................................................... 11 
2.3.3. 
Clinical laboratory evaluation ........................................................................................................... 11 
2.3.4. 
Vital signs, physical findings and other observations related to safety ............................................. 13 
2.3.5. 
Concomitant medications and procedures......................................................................................... 14 
2.4. 
EFFICACY CRITERIA .................................................................................................................................. 14 
 
STATISTICAL METHODS .......................................................................................................................... 16 
3.1. 
GENERAL CONSIDERATIONS ...................................................................................................................... 16 
3.2. 
NULL AND ALTERNATIVE HYPOTHESIS ..................................................................................................... 17 
3.3. 
DETERMINATION OF SAMPLE SIZE ............................................................................................................. 17 
3.4. 
ADJUSTMENT FOR COVARIATES ................................................................................................................ 17 
3.5. 
HANDLING OF DROPOUTS OR MISSING DATA ............................................................................................ 17 
3.6. 
INTERIM ANALYSES AND DATA MONITORING ........................................................................................... 17 
3.7. 
MULTICENTER STUDIES ............................................................................................................................. 17 
3.8. 
MULTIPLE COMPARISONS/MULTIPLICITY ................................................................................................. 17 
3.9. 
USE OF AN “EFFICACY SUBSET” OF PATIENTS ........................................................................................... 18 
3.10. 
ACTIVE CONTROL STUDIES INTENDED TO SHOW EQUIVALENCE ........................................................... 18 
3.11. 
EXAMINATIONS OF SUBGROUPS ............................................................................................................ 18 
 
STATISTICAL AND ANALYTICAL PLANS ........................................................................................... 20 
5.1. 
DISPOSITION OF PATIENTS ......................................................................................................................... 20 
5.2. 
DATA SETS ANALYZED AND PROTOCOL DEVIATIONS............................................................................... 20 
5.3. 
MEASUREMENTS OF COMPLIANCE WITH GADOPICLENOL ......................................................................... 26 
5.4. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ...................................................................... 26 
5.4.1. 
Demographic data ............................................................................................................................. 26 
5.4.2. 
Study disease ...................................................................................................................................... 26 
5.4.3. 
Risk factors ........................................................................................................................................ 26 
5.4.4. 
Medical history and concomitant diseases ........................................................................................ 26 
5.4.5. 
Prior medications and procedures .................................................................................................... 26 
5.5. 
PK EVALUATION ....................................................................................................................................... 27 
5.6. 
SAFETY EVALUATION ............................................................................................................................... 27 
5.6.1. 
Extent of Exposure ............................................................................................................................. 27 
5.6.2. 
Adverse Events ................................................................................................................................... 27 
5.6.3. 
Deaths, serious adverse events and other significant adverse events ................................................ 28 
5.6.4. 
Clinical laboratory evaluation ........................................................................................................... 28 


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5.6.5. 
Vital signs, physical findings and other observations related to safety ............................................. 29 
5.6.5.1 
Vital signs ................................................................................................................................... 29 
5.6.5.2 
ECG ............................................................................................................................................ 29 
5.6.5.3 
Injection Site Tolerance .............................................................................................................. 29 
5.6.5.4 
Physical examination .................................................................................................................. 29 
5.6.6. 
Concomitant medications and procedures......................................................................................... 29 
5.7. 
EFFICACY EVALUATION ............................................................................................................................ 30 
 
LIST OF TABLES, FIGURES AND LISTINGS ........................................................................................ 31 
6.1. 
CONTENTS OF CLINICAL STUDY REPORT SECTION 14 ................................................................................ 31 
6.1.1. 
Demographic data ............................................................................................................................. 31 
6.1.1.1 
Disposition of Patients ................................................................................................................ 31 
6.1.1.2 
Protocol Deviations .................................................................................................................... 31 
6.1.1.3 
Data Sets Analysed ..................................................................................................................... 31 
6.1.1.4 
Demographics and Baseline Characteristics ............................................................................... 31 
6.1.1.5 
Compliance with gadopiclenol administration ........................................................................... 32 
6.1.2. 
PK data .............................................................................................................................................. 32 
6.1.3. 
Safety data ......................................................................................................................................... 32 
6.1.3.1 
Extent of exposure ...................................................................................................................... 32 
6.1.3.2 
Adverse events............................................................................................................................ 32 
6.1.3.3 
Deaths, serious adverse events and other significant adverse events ......................................... 32 
6.1.3.4 
Laboratory data ........................................................................................................................... 32 
6.1.3.5 
Vital Signs, physical findings and other observations related to safety ..................................... 33 
6.1.3.6 
Concomitant medications / Procedures ...................................................................................... 33 
6.1.4. 
Efficacy data ...................................................................................................................................... 33 
6.2. 
CONTENTS OF CLINICAL STUDY REPORT SECTION 16.2 ............................................................................. 34 
6.2.1. 
Demographic Data ............................................................................................................................ 34 
6.2.1.1 
Disposition of Patients ................................................................................................................ 34 
6.2.1.2 
Protocol Deviations .................................................................................................................... 34 
6.2.1.3 
Data Sets Analysed ..................................................................................................................... 34 
6.2.1.4 
Demographics and Baseline Characteristics ............................................................................... 34 
6.2.2. 
PK Data ............................................................................................................................................. 34 
6.2.3. 
Safety Data ......................................................................................................................................... 34 
6.2.3.1 
Extent of exposure ...................................................................................................................... 34 
6.2.3.2 
Adverse Events ........................................................................................................................... 35 
6.2.3.3 
Death .......................................................................................................................................... 35 
6.2.3.4 
Laboratory Data .......................................................................................................................... 35 
6.2.3.5 
Vital Signs, physical findings and other observations ................................................................ 35 
6.2.4. 
Efficacy Data ..................................................................................................................................... 35 
 
 
 


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 SUMMARY OF THE STUDY PROTOCOL  
This document presents the statistical analysis plan (SAP) for safety and efficacy for Guerbet, Protocol No. GDX-
44-007: “Pharmacokinetics, safety and efficacy of a new gadolinium-based contrast agent, gadopiclenol, in 
pediatric patients from 2 to 17 years of age undergoing contrast-enhanced MRI”. 
This analysis plan is based on the final protocol Version 4.0
 
  
This document does not include the statistical analyses that meet the pharmacokinetics (PK) objectives. A specific 
SAP for population PK analysis will be written separately, as well as, a specific analytical PK report for 
concentrations data and urinary excretion. 
 
1.1. Study objectives 
The objectives of the study are defined for two cohorts of pediatric population aged from 2 to 17 years. The first 
one includes patients undergoing central nervous system (CNS) contrast-enhanced Magnetic Resonance Imaging 
(MRI): CNS cohort. The second one includes patients undergoing contrast-enhanced MRI for diseases of other 
organs: Body cohort. 
The primary objective of the trial is to evaluate the PK profile of gadopiclenol in plasma following single 
intravenous injection of 0.05 mmol/kg body weight (BW) in pediatric population aged from 2 to 17 years 
undergoing CNS MRI (CNS cohort). 
The secondary objectives are: 
 
To evaluate the safety (clinical and biological) of gadopiclenol up to 3 months following single 
administration in both CNS and Body cohorts 
 
To evaluate the urinary excretion of gadopiclenol quantitatively up to 8 hours and in subsequent urine 
samples collected up to 3 months following single administration in both CNS and Body cohorts (or 
exceptionally up to 4 months if collection is delayed due to the COVID-19 pandemic). 
 
To evaluate the efficacy of gadopiclenol-enhanced MRI for CNS and Body cohorts as assessed by on-site 
Investigator. 
 
1.2. Study design 
GDX-44-007 is an open-label, uncontrolled, multicenter international, non-randomized, single dose design phase 
II trial. 
 
The design is evaluated for a sample size of 60 patients in CNS cohort between 2 and 17 years old and predicted a 
correct estimation of all PK parameters. Patients are recruited into 3 predefined age groups:  
- 
Age group 1: Adolescents 12-17,  
- 
Age group 2: Preadolescents 7-11  
- 
Age group 3: Young Children 2-6 years.  
 
The total sample size of 80 patients (60 patients in CNS cohort and 20 patients in Body cohort) was estimated 
sufficient for the satisfactory exploration of safety and efficacy of gadopiclenol in pediatric patients with diseases 
of CNS and other organs. 
 
The total sample size is balanced between 3 age groups in such a way that: 


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- 
At least 15 patients and the number as close as possible to 20 patients are included in each age group 
from the CNS cohort. The inclusion is completed in parallel in all age groups to reach the overall 
number of 60 patients evaluable for the primary criterion 
- 
At least 3 patients from the Body cohort are included per age group. The inclusion is completed in 
parallel in all age groups to reach the overall number of 20 patients in the Body cohort. 
 
 
The duration of the trial for a patient is about 3 months with a minimum of 82 days and maximum of 111 days (up 
to 134 days in case V4-bis)  
. Each patient will undergo 4 visits: 
- 
The screening visit (Visit 1): up to 14 days before inclusion 
- 
The inclusion visit (Visit 2) and the confinement period: 
o The inclusion visit between the following days (D): D1 (gadopiclenol administration) and D2 
including the confinement period (if not prevented by the constraints linked to the COVID-19 
pandemic) 
o 4 sampling windows (W) covering the first 8 hours after gadopiclenol administration 
 
W1: 1 to 20 min 
 
W2: 30 to 45 min 
 
W3: 2 to 3 hours 
 
W4: 7 to 8 hours 
- 
The 1-week safety follow-up (D8 – Visit 3) followed by V3-bis: 1-month maximum safety follow-up 
if V3 was done by phone or video) 
- 
The 3-month safety follow-up (D90 – Visit 4) (followed by V4-bis: 4-month maximum safety follow-
up if V4 was done by phone or video); 
 
 EVALUATION CRITERIA 
2.1. Demographic and other baseline characteristics 
At screening visit, the following demographic data are collected: 
- 
Age: Years and Months 
- 
Gender: Male, Female 
- 
Ethnicity: Hispanic or Latino, Not Hispanic nor Latino 
- 
Race (multiple choices): American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or other Pacific islander, White, Other (specify) 
 
At inclusion visit, additional demographic variables are collected: 
- 
Age: Years and Months (if the dates of screening visit and inclusion visit are different) 
- 
Weight (kg) 
- 
Height (cm) 
 
Baseline characteristics are: 
- 
Physical examination (at screening visit) 
o Examination performed: Yes, No (and Reason in case of No) 
o If examination performed, abnormalities: 
 
Yes, No 
 
If yes, type of abnormalities (multiple choices): General appearance, Skin, Neck, Eyes, 
Ears, Nose, Throat, Lungs, Heart, Abdomen, Back, Lymph nodes, Extremities, Peripheral 
vascular and neurological examination, other (specify) 
- 
Patient’s medical/surgical history and concomitant diseases at screening visit  
o They will be coded using the MedDRA dictionary, version 23.0 – Apr 2020.  


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o Medical histories are those "Not Ongoing" and concomitant diseases are those "Ongoing" at the 
screening visit. 
- 
Urine collection data 
o Ability to control daytime urination at inclusion visit: Yes, No 
o Total urine collection over 8 hours after gadopiclenol injection: Yes, No 
o If total urine over 8 hours collected, volume of collected urine (mL) 
- 
Childbearing potential for female patient (at inclusion visit): Yes, No 
o Pregnancy test performed (only for female patient with childbearing potential): Yes, No 
o Result of test: Negative, Positive 
- 
Prior medications and procedures 
o Previous medications are medications ended before the gadopiclenol administration. They 
correspond to medications with the start period and end of treatment entered in categories: 1 = 
“More than 7 days before gadopiclenol administration”, 2 = “Between 2 and 7 days before 
gadopiclenol administration, 3 = “1 day before gadopiclenol administration”. 
o Patient’s previous medications will be coded using the World Health Organization (WHO) Drug 
dictionary at least version B3 WHO DDE mars 2020 
o Patient’s prior procedures related to a reported adverse event (AE) will be coded using the 
MedDRA dictionary version 23.0 – Apr 2020 
 
- 
Previous experience with contrast agent administration (inclusion visit): Yes, No 
o Number of examinations per type of product 
o Adverse reaction during these examinations: Yes, No 
o Administration received within 7 days before the inclusion visit: Yes, No 
 
MRI examination is described by: 
- 
Examination performed: Yes, No 
- 
Brand name 
- 
MRI machine field strength: 1.5T, 3T 
- 
Date of MRI examination 
- 
Reader’s name 
- 
MRI examination 
o CNS Cohort: Brain / Spine 
o Body Cohort: Head and neck / Thorax / Abdomen / Pelvis / Musculoskeletal system (including 
extremities)  
- 
Pre-injection and post-injection MRI sequence performed: Yes, No by MRI sequence: 
o Brain T1-weighted axial 
o Spine T1-weighted sagittal 
o Head and neck T1-weighted 
o Thorax T1-weighted 
o Abdomen T1-weighted 
o Pelvis T1-weighted 
o Musculoskeletal T1-weighted 
 
2.2. PK data (Primary criteria and secondary criteria) 
Gadopiclenol PK profile in plasma will be assessed in the CNS cohort both by age group and overall based on the 
following PK parameters determined from the population PK model:  
 
- 
Simulated concentrations at 10, 20 and 30 minutes post injection 
- 
Area Under the Curve (AUC) 


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- 
Elimination half-life (T1/2) 
- 
Total clearance (CT) 
- 
Volume of distribution (Vd) 
 
Gadopiclenol concentrations in plasma and urine will be determined using a validated liquid chromatography 
coupled with tandem mass spectrometry (LC-MS/MS) method.  
 
A separate analytical protocol describes the gadopiclenol assays in plasma and urine samples and urinary excretion. 
 
 
  
 
2.3. Safety criteria (Secondary criteria) 
2.3.1. Extent of Exposure 
 
Extent of exposure will be described by a summary of durations in the study and a display of study contrast agent 
administration modalities. 
 
The study participation durations are as follows: 
- 
Duration between the ICF signature and the gadopiclenol injection (in days): date of gadopiclenol 
injection – date of ICF signature + 1 
- 
Duration between the gadopiclenol injection and the end of the confinement period (in days): date of 
the day 2 visit 2– date of gadopiclenol injection + 1 
- 
Duration between the gadopiclenol injection and the one-week follow-up date visit (in days): date of 
the one-week follow-up visit – date of gadopiclenol injection + 1 
- 
Duration between the gadopiclenol injection and the three-month follow-up date visit (in days): date of 
the three-month follow-up visit – date of gadopiclenol injection + 1 
 
The study contrast agent administration modalities are defined by the following parameters: 
 
Gadopiclenol administered (Yes/No) 
 
Overdose occurred (Yes/No) 
 
Administered treatment number  
 
Mode of injection (Manual/Power injector) 
 
Injection rate (mL/s) 
 
Volume of saline flush (mL) 
 
Volume actually administered (mL) 
 
The patient’s theoretical dose of contrast agent is calculated for each patient and is provided by the IWRS. The 
patient’s actual dose administered is recorded in the eCRF. When the actual dose is different from the theoretical 
dose, the reason has to be given and recorded in the eCRF. The difference in mL and in % will be calculated: 
 
Difference (mL) = Volume actually administered (mL) – Theoretical calculated volume (mL) 
 
𝐷𝑖𝑓𝑓𝑒𝑟𝑒𝑛𝑐𝑒 (%) = 𝑉𝑜𝑙𝑢𝑚𝑒 𝑎𝑐𝑡𝑢𝑎𝑙𝑙𝑦 𝑎𝑑𝑚𝑖𝑛𝑖𝑠𝑡𝑒𝑟𝑒𝑑 (𝑚𝐿) −𝑡ℎ𝑒𝑜𝑟𝑒𝑡𝑖𝑐𝑎𝑙 𝑐𝑎𝑙𝑐𝑢𝑙𝑎𝑡𝑒𝑑 𝑣𝑜𝑙𝑢𝑚𝑒 (𝑚𝐿)
𝑡ℎ𝑒𝑜𝑟𝑒𝑡𝑖𝑐𝑎𝑙 𝑐𝑎𝑙𝑐𝑢𝑙𝑎𝑡𝑒𝑑  𝑣𝑜𝑙𝑢𝑚𝑒 (𝑚𝐿)
∗100 
 
 


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2.3.2. Adverse Events 
 
Adverse events (AEs) are coded using the Medical Dictionary for Regulatory Activities (MedDRA),version 23.0 – 
Apr 2020.  
 
All AEs occurring from the beginning of the patient’s participation in the trial (signature of Informed Consent Form 
(ICF) and until 1-week safety visit (D8)), must be reported and followed even if no gadopiclenol was administered. 
Non-serious AEs occurring before gadopiclenol administration and not related to the trial can be collected as 
medical history according to Investigator’s opinion. Non-serious AEs occurring after 1-week safety visit (D8) must 
be reported if related to the drug or to the trial and followed until recovery or sequelae stabilization.  
 
Serious Adverse Events (SAE) and Adverse Event of Special Interest (AESI) occurring from the beginning of the 
patient’s participation in the trial (ICF signature) and until 3-month safety visit (D90 or the day of Visit 4-bis) must 
be reported and followed until recovery or sequelae stabilization.  
- 
A serious AE is defined as an event serious AE with seriousness classified as “Yes” 
- 
An AESI for this protocol is defined by suspected or confirmed Nephrogenic Systemic Fibrosis (NSF). 
The MedDRA code 10067467 corresponding to the PT “Nephrogenic systemic fibrosis” will be used 
to identify these AESI. 
 
Events will be classified as treatment-emergent (TEAE) if they occurred after the start time of gadopiclenol 
administration. If the date of the event is incomplete or missing, the event will be considered as TEAE. 
 
2.3.3. Clinical laboratory evaluation 
 
Safety laboratory variables centrally analyzed from blood samples are collected: 
- 
at screening visit 
- 
1 day after gadopiclenol injection 
 
The following tables list in order all parameters in both standard international units (SI) and conventional United 
States units (US): 
Table 1 Hematology parameters 
Hematology parameters 
US Units 
SI Units 
Erythrocytes 
106/µL 
1012/L 
Hemoglobin 
g/dL 
g/L 
Hematocrit 
% 
L/L 
Mean red blood cell volume (MCV) 
fL 
fL 
Leukocytes 
103/µL 
109/L 
Neutrophils 
103/μL 
109/L 
Neutrophils/Leukocytes 
% 
% 
Lymphocytes 
103/μL 
109/L 
Lymphocytes/Leukocytes 
% 
% 
Monocytes 
103/μL 
109/L 
Monocytes/Leukocytes 
% 
% 
Eosinophils 
103/μL 
109/L 
Eosinophils/Leukocytes 
% 
% 
Basophils 
103/μL 
109/L 
Basophils/Leukocytes 
% 
% 
Platelet count 
103/μL 
109/L 


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Table 2 Biochemistry parameters 
Biochemistry parameters 
US Units 
SI Units 
Sodium 
mEq/L 
mmol/L 
Potassium 
mEq/L 
mmol/L 
Chloride 
mEq/L 
mmol/L 
Calcium 
mg/dL 
mmol/L 
Phosphorus 
mg/dL 
mmol/L 
Glucose 
mg/dL 
mmol/L 
Total proteins 
g/dL 
g/L 
Creatinine 
mg/dL 
µmol/L 
eGFR* 
mL/min/1.73m² 
mL/min/1.73m² 
Blood Urea Nitrogen (BUN) 
mg/dL 
mmol/L 
Aspartate amino transferase (AST) 
U/L 
U/L 
Alanine amino transferase (ALT) 
U/L 
U/L 
Alkaline phosphatase 
U/L 
U/L 
Total bilirubin 
mg/dL 
µmol/L 
Conjugated/Direct bilirubin 
mg/dL 
µmol/L 
Lactate dehydrogenase (LDH) 
U/L 
U/L 
*eGFR centrally calculated based on the bedside Schwartz equation  
 
Table 3 Coagulation parameters 
Coagulation parameters 
US Units 
SI Units 
Prothrombin Time (PT) / International Normalised Ratio (INR) 
NA 
NA 
PT 
Sec 
Sec 
 
 
 
 


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2.3.4. Vital signs, physical findings and other observations related to safety 
 
Vital signs include the following parameters: 
- 
Temperature (°C) 
- 
Systolic Blood Pressure (SBP) (mmHg) 
- 
Diastolic Blood Pressure (DBP) (mmHg) 
- 
Pulse Rate (bpm) 
- 
Blood oxygen saturation (pulse oximetry) (SpO2) 
 
ECG data include: 
- 
Heart Rate (HR) (bpm) 
- 
ST segments 
 
Isoelectric 
 
Elevation 
 
Depression 
- 
T-wave morphology 
 
Normal 
 
Abnormal 
- 
U-wave morphology 
 
Normal 
 
Abnormal 
- 
Global morphology 
 
Normal 
 
Abnormal 
and the following intervals:  
- 
RR (ms) 
- 
PR (ms) 
- 
QRS (ms) 
- 
QT (ms) 
- 
QTc Fridericia’s 
- 
QTc Bazett’s 
A notable QTc change is defined as a 
 
QTC (Fridericia’s or Bazett’s) interval > 450 ms  
or 
 
An increase of > 30 ms from baseline 
 
Vital signs and ECG data are measured at several time points: 
- 
Prior to gadopiclenol injection 
- 
30-90 min after gadopiclenol injection 
- 
1 day after gadopiclenol injection 
 
Tolerance at the injection site (eruption, extravasation, inflammation and/or other) is evaluated during the 
gadopiclenol injection, 30-90 min after the injection and 1 day after gadopiclenol injection. 
 
Physical examination is performed (Yes/No) at 
- 
1 day after gadopiclenol injection 
- 
1-week follow-up safety visit (D8 or up to D30 in case of V3-bis) 
If yes, only new abnormalities are reported since the last visit. 
Additionally, a specific physical examination for active detection of Nephrogenic Systemic Fibrosis (NSF) is 
performed at 3-month follow-up visit (D 90 or up to D120 in case of V4-bis) (Yes/No) using a specific checklist 
of clinical symptoms potentially related to NSF. 


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2.3.5. Concomitant medications and procedures 
 
Patient’s concomitant medications / procedures are treatments / procedures on-going at D1 or administered until 1-
week safety visit (D8). A treatment who started before the gadopiclenol administration and ongoing after 
gadopiclenol administration is considered as a concomitant medication.  
 
Patient’s concomitant medications will be coded using the World Health Organization (WHO) Drug dictionary at 
least version B3 WHO DDE mars 2020 and tabulated by ATC code. 
 
Patient’s concomitant procedures related to a reported AE will be coded using the MedDRA dictionary version 23.0 
– Apr 2020. 
 
2.4. Efficacy criteria 
Unenhanced MRI (pre) and Gadopiclenol-enhanced MRI (post) in the CNS and Body cohorts will be evaluated by 
on site radiologist on following parameters: 
 
- 
Images adequacy  
o Technical adequacy for diagnosis using a 4-point scale 
 
Non-diagnostic 
 
Poor 
 
Fair 
 
Good 
o Assessment of images 
 
Images assessable: Yes, No 
 
If no, reasons 
 
Artifacts due to patient 
 
Artifacts due to machine 
 
Injection technical failure 
 
Inadequate anatomic coverage 
 
Other 
o Total number of detected lesions 
 
- 
Evaluation of lesions (3 most representatives lesions) 
o Location (multiples choices)  
o Largest diameter of the legion  
o Signal Intensity (SI) of the lesion  
o SI of background (SIb) (post only) 
 
- 
Assessment of contrast quality through the percentage of enhancement (E%) and the Lesion to Background 
Ratio (LBR) for up to 3 most representative lesions will be calculated: 
o Percentage of enhancement (E%) of lesion will be calculated by using the equation below: 
 
𝐸% = 𝑆𝐼𝑝𝑜𝑠𝑡− 𝑆𝐼𝑝𝑟𝑒
𝑆𝐼𝑝𝑟𝑒
∗100 %   𝑤𝑖𝑡ℎ  {     𝑆𝐼𝑝𝑜𝑠𝑡= 𝑆𝐼 𝑜𝑓 𝑙𝑒𝑠𝑖𝑜𝑛 𝑜𝑛 𝑝𝑜𝑠𝑡 𝑖𝑛𝑗𝑒𝑐𝑡𝑖𝑜𝑛 𝑖𝑚𝑎𝑔𝑒𝑠
    𝑆𝐼𝑝𝑟𝑒= 𝑆𝐼 𝑜𝑓 𝑙𝑒𝑠𝑖𝑜𝑛 𝑜𝑛 𝑝𝑟𝑒 𝑖𝑛𝑗𝑒𝑐𝑡𝑖𝑜𝑛 𝑖𝑚𝑎𝑔𝑒𝑠 
 
o Lesion to Background Ratio (LBR) will be calculated by using this formula: 
 
𝐿𝐵𝑅𝑝𝑜𝑠𝑡= 𝑆𝐼𝑝𝑜𝑠𝑡
𝑆𝐼𝑏
    


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𝑤𝑖𝑡ℎ {
𝑆𝐼𝑝𝑜𝑠𝑡= 𝑆𝐼 𝑜𝑓 𝑙𝑒𝑠𝑖𝑜𝑛 𝑜𝑛 𝑝𝑜𝑠𝑡 𝑖𝑛𝑗𝑒𝑐𝑡𝑖𝑜𝑛 𝑖𝑚𝑎𝑔𝑒𝑠
 𝑆𝐼𝑏= 𝑆𝐼 𝑜𝑓 𝑏𝑎𝑐𝑘𝑔𝑟𝑜𝑢𝑛𝑑 (𝑠𝑢𝑟𝑟𝑜𝑢𝑛𝑑𝑖𝑛𝑔 ℎ𝑒𝑎𝑙𝑡ℎ𝑦 𝑡𝑖𝑠𝑠𝑢𝑒 𝑜𝑓 𝑡ℎ𝑒 𝑙𝑒𝑠𝑖𝑜𝑛) 𝑜𝑛 𝑝𝑜𝑠𝑡 𝑖𝑛𝑗𝑒𝑐𝑡𝑖𝑜𝑛 𝑖𝑚𝑎𝑔𝑒𝑠 
 
 
- 
Lesion visualization trough the following parameters: lesion border delineation, internal morphology and 
contrast enhancement. Each parameter is assessed using a 4-point scale. The Investigator will record each 
of lesion visualization variables for up to 3 most representative enhancing lesions. 
o Lesion border delineation will be assessed through the following scale 
 
1 = none: no or unclear delineation 
 
2 = moderate: some areas of clear delineation but also with some significant areas of non-
distinct delineation 
 
3 = good: almost clear but not complete delineation 
 
4 = excellent: border outline is sharp with clear and complete delineation 
o Internal morphology will be assessed through the following scale: 
 
1 = poor: poorly seen 
 
2 = moderate: majority of lesion is poorly seen but with minor parts of lesion visible 
 
3 = good: majority of lesion is clearly seen but with minor parts of lesion invisible 
 
4 = excellent: lesion is well seen and can see “through” lesion to observe any complex 
areas of necrosis or hemorrhage or cyst formation 
o Degree of contrast enhancement will be assessed through the following scale: 
 
1 = no: no enhancement  
 
2 = moderate: weakly enhanced 
 
3 = good: clearly enhanced 
 
4 = excellent: clearly and brightly enhanced 
 
- 
Change in diagnostic confidence: following gadopiclenol administration, the Investigator’s diagnostic 
confidence is assessed using following description: 
o Improved  
o Remains unchanged 
o Getting worse 
 
- 
Following contrast-enhanced MRI, the main diagnosis is also described: 
o Primary tumor 
o Secondary tumor 
o Inflammatory disease 
o Infectious disease 
o Vascular disease 
o Congenital malformation 
o Neurodegenerative diseases 
o Other 
 
 
 
 
 


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This document is the exclusive property of Guerbet. It may not be forwarded or reproduced  
 STATISTICAL METHODS 
This plan presents only the statistical method of safety and efficacy evaluation.  
3.1. General considerations 
With regards to the ICH topic E9, it has been decided that this study does not enter in the scope of the addendum. 
Indeed, efficacy is a secondary analysis and PK primary analysis does not aim to show treatment effect. 
After the database lock, the statistical analysis will be performed by the CRO,
 
 under the supervision of the Guerbet Biostatistician, based on the present 
document. 
A quality control of the statistical analysis will be performed to ensure the reliability of the results.  
Thorough description of all parameters reported will be presented separately by age group (CNS and Body cohorts 
confounded), overall in the CNS cohort, overall in the Body cohort, and overall (CNS and Body cohorts 
confounded) unless otherwise specified (particularly for efficacy data). Summary tabulated results will be provided 
by assessment time, if relevant, or they will be replaced by the corresponding individual data listings if too few 
patients are concerned. 
 
Baseline definition 
The baseline is defined as the last measure before the gadopiclenol administration. 
Unscheduled measures after the gadopiclenol administration will not be taken into account in the descriptive 
statistical analysis. These will only be listed. 
 
Quantitative parameters 
Summary statistics (Number [n], Mean, Standard Deviation (SD), Median, Minimum, Maximum and Missing) will 
be calculated for quantitative variables. If for a given parameter, the raw value has been collected with x decimal 
places, the mean, median and SD will be rounded to x+1 decimal places, while the minimum and maximum values 
will be tabulated as reported with x decimal places. 
 
Qualitative parameters 
Number of patients and percentages will be presented for categorical variables. Percentages will be rounded to one 
decimal place. The denominator will be the number of patients (excluding missing) in the set presented. 
For laboratory data, the comparison of parameter values to their normal ranges will be done based on the following 
categories: 
- 
< LLN (Lower Limit of Normal range) 
- 
> ULN (Upper Limit of Normal range) 
 
Software 
SAS® Version 9.4 will be used for all descriptive summaries and statistical analyses. 
 
 


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3.2. Null and alternative hypothesis 
No inference will be drawn from this trial which is only descriptive. Therefore, neither null nor alternative 
hypotheses will be carried out. 
 
3.3. Determination of sample size 
The sample size of the CNS cohort was determined in order to optimize the characterization of gadopiclenol 
pharmacokinetics in pediatric population through population PK modelling.  
 
A sample size of 60 pediatric patients between 2 and 17 years old was determined to be adequate for this design 
and to predict a correct estimation of all PK parameters. The total sample size of 80 patients was estimated enough 
for the satisfactory exploration of safety and efficacy of gadopiclenol in pediatric patients with diseases of CNS 
and other organs. 
 
The decision to start the next age group is taken by Trial Safety Review Board (TSRB) based on safety 
assessment over one-day period after injection of the first 15 patients included in previous group from either CNS 
or both cohorts. The previous age group is completed in parallel with the start of the next group.  
 
3.4. Adjustment for covariates 
The statistical analysis for the safety and efficacy evaluation of the gadopiclenol is only descriptive. No adjustment 
is necessary. (Not applicable) 
 
3.5. Handling of dropouts or missing data 
No imputation will be performed in this trial for efficacy and safety data. 
 
3.6. Interim analyses and data monitoring 
No interim analysis is planned for this trial. 
 
However, TSRB is planned after injection of the first 15 patients recruited in each age group (leading to 4 TSRB) 
to assess safety data and to decide the trial continuation. One final TSRB is planned at the end of recruitment to 
assess safety. Review of safety is based on disposition demography and other baseline characteristics as well as all 
safety parameters (AE, laboratory data and other safety observation such as vital signs and ECG data). 
 
3.7. Multicenter studies 
No formal analyses by center will be performed; however, the number of exposed patients will be described by 
center.  
 
3.8. Multiple comparisons/Multiplicity 
Not applicable. 
 


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3.9. Use of an “efficacy subset” of patients 
Efficacy is a secondary analysis and will be analyzed using the Full Analysis Set (FAS).  
 
3.10. 
Active control studies intended to show equivalence 
Not applicable. 
 
3.11. 
Examinations of subgroups 
Not applicable 
 
 


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 STATISTICAL AND ANALYTICAL PLANS 
This SAP concerns only the evaluation of safety up to 3-months following single administration and efficacy of 
gadopiclenol-enhanced MRI for CNS and Body cohorts. The statistical analysis of PK data (including excretion of 
gadopiclenol) is not be presented in this document.  
 
5.1. Disposition of patients 
Number (%) of patients screened, receiving gadopiclenol injection, completed the study and prematurely 
discontinued will be presented by age group and overall, in each cohort and globally. 
The following descriptions (number and percentage of patients) will be performed per age group (CNS and Body 
confounded), cohort and overall with regards to the disposition of patients: 
 
Patients present at each study visit  
 
Patients by center  
 
Patients and reasons for screening failure before injection 
o A patient who signed the ICF and discontinue at screening visit or at inclusion visit before 
gadopiclenol injection will be considered screening failure 
 
Injected patients and reasons for prematurely discontinuation  
o A patient who received the gadopiclenol injection and discontinue before the end of the study will 
be considered discontinued 
Reasons for screening failure or for premature discontinuation will be presented separately if they are due to the 
COVID-19 pandemic. 
 
If a patient withdrew for Adverse Event and at least one adverse event is coded with PT=« COVID-19 » then the 
reason of premature withdrawal will be put at COVID-19 but if no AE is coded with PT=« COVID-19 » then the 
reason of premature withdrawal will be put at Adverse Event other than COVID-19 
 
If a patient withdrew for other reason and it is written in the specify field : “COVID-19 crisis preventing patient to 
follow protocol schedule” then the reason of premature withdrawal will be put at COVID-19 pandemic preventing 
patient from following protocol schedule but if the specify field is filled with other texts then the reason of premature 
withdrawal will be put at Other reason 
 
5.2. Data Sets Analyzed and protocol deviations 
There will be four patients sets defined for this study: All enrolled patients Set, the Safety Set (SS), the Full Analysis 
Set (FAS), and the Per Protocol Set (PPS). 
 
All enrolled patients set will include all patients whose parent(s)/legal guardian have signed the ICF. This set will 
be used for patient disposition summaries and individual listings including AEs. 
 
The SS will include all patients receiving at least one administration of study drug. This set will be used for 
evaluation of safety, description of demographic data and baseline characteristics. 
 
 
The FAS will include all patients undergoing an enhanced (i.e., after gadopiclenol administration) MRI examination 
in CNS and other organs. This set will be used for the efficacy analysis. 
 
The PPS will include all patients in the SS undergoing an enhanced MRI examination in the CNS cohort only 
without major deviations likely to impact the population PK model. This set will be used for description of 
demographic data and baseline characteristics. 
 
 


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The following table describes how the above defined patients sets will be used in the different analyses conducted.  
 
Analyses Sets 
All enrolled 
patients Set 
Safety Set 
FAS 
PPS 
Disposition of patients 
 
 
 
 
Individual listings 
 
 
 
 
Description of demographic data 
 
 
 
* 
Baseline characteristics 
 
 
 
* 
Efficacy assessment 
 
 
 
 
Safety assessment 
** 
 
 
 
 
* If the PPS is different from the SS 
             ** Only for overall summary of all AEs  
 
 
Protocol deviations 
 
As per International Conference on Harmonization (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 displayed in the Clinical Study Report (CSR) as 
a metric of the feasibility and reliability of the study. The list of protocol deviations is presented in the table below 
and can be updated if necessary. Protocol deviations will be gathered from monitoring files, clinical database, 
external vendors of off-site data (Laboratory data and PK data) and PK experts 
 
 
Protocol deviations will be split in major and non-major deviations. A major deviation is defined as a deviation 
having an impact on the primary criteria. A first categorization is done in this document. It will be refined during 
the statistical data review meeting that will be held before database lock. The decisions will be duly described in 
the meeting minutes.  
 
All deviations will be reviewed during the statistical data review meeting and if the cause of the deviation is related 
to the COVID-19 pandemic then the deviation will be presented apart with the addition of “due to COVID-19” in 
the corresponding description. 
 
The deviations are listed in the table below: 
 
Category 
 
Description 
Source 
Status 
Inclusion Criteria not met and patient included 
 
 
Female or Male pediatric patient not aged from 2 to 17 
years 
Clinical data base 
Non major 
 
Patient with known or suspected lesion(s) scheduled to 
undergo routine contrast-enhanced MRI of CNS or of 
other organs 
Clinical data base 
Non major 
 
Patient whose parent(s) or legal guardian (where 
applicable) did not provide his/her/their consent to 
patient’s participation in writing by dating and signing 
the informed consent prior to any trial related 
procedure being conducted  
Monitoring/ 
Clinical data base 
Major 


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Patient with capacity of understanding who did not 
receive age- and maturity-appropriate information and 
did not provide his/her assent to participate in the trial 
(as required by national regulations) 
Monitoring / 
Clinical data base 
Major 
 
Patient not affiliated to national health insurance 
according to local regulatory requirements 
Clinical data base 
Non major 
Non-inclusion criteria met and patient included 
 
 
Patient planned for treatment or procedure (e.g. 
surgery) that would prevent from obtaining the required 
blood samples or performing other trial procedures 
between the screening visit and up to 1 day after 
gadopiclenol administration 
Clinical data base 
Major 
 
Patient whose treatment or procedure (e.g., diuretics, 
clinically significant blood loss or blood transfusion) 
preceding or subsequent to gadopiclenol administration 
would alter gadopiclenol pharmacokinetic parameters 
Clinical data base 
Major 
 
Patient with acute or chronic renal insufficiency defined 
as estimated Glomerular Filtration Rate (eGFR) out of 
age-adjusted normal values [eGFR must be calculated 
based on bedside Schwartz equation] 
Clinical data base 
Non major 
 
Patients referred for MR angiography 
Clinical data base 
Non major 
 
Patient with history of bleeding disorder 
Clinical data base 
Non major 
 
Patient with known severe liver disease 
Clinical data base 
Non major 
 
Patient with known cardiac disease (e.g., heart rhythm 
anomalies, long QT syndrome) 
Clinical data base 
Non major 
 
Patient with any clinically significant abnormal 12-lead 
ECG that in the Investigator's opinion would affect the 
safety evaluation or place the patient at risk 
Clinical data base 
Non major 
 
Patient with electrolyte or fluid imbalance that at 
Investigator’s judgment presents undue risk assessed 
within 1 month prior to gadopiclenol administration 
Clinical data base 
Non major 
 
Patient undergoing a change in chemotherapy within 1 
day prior to or 1 day after gadopiclenol administration 
Clinical data base 
Non major 
 
Patient who received or will receive any other contrast 
agent for CT and/or MRI within 1 week prior to or 1 
week after gadopiclenol administration  
Monitoring/Clinical 
data base 
Major 
 
Patient with contraindication for MRI such as iron 
metal implants (e.g., aneurysm clips, pacemaker) 
Clinical data base 
Non major 
 
Patient with history of anaphylactoid or anaphylactic 
reaction to any allergen including drugs and contrast 
agents 
Clinical data base 
Non major 
 
Patient with history of hypersensitivity caused by any 
contrast media / agents (iodine or gadolinium) 
Clinical data base 
Non major 
 
Patient with known contraindication(s) to the use of any 
gadolinium-based contrast agent (GBCA) 
Clinical data base 
Non major 
 
Pregnant or breast-feeding female patient [female 
patient with childbearing potential (who experienced 
menarche) must have a negative urine pregnancy test 
within 24 hours prior to gadopiclenol administration 
Clinical data base 
Non major 


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and must be using medically approved contraception* 
if sexually active] 
 
Patient with anticipated, current or past condition 
(medical, psychological, social or geographical) that 
would compromise the patient’s safety or her/his ability 
to participate to the whole trial 
Clinical data base 
Non major 
 
Patient unlikely to comply with the protocol, e.g., 
uncooperative attitude of parent(s) or legal guardian 
(where applicable), inability to return for follow-up 
visits and unlikelihood of completing the trial 
Clinical data base 
Non major 
 
Patient having participated in a clinical trial and having 
received any investigational product within 7 days prior 
to gadopiclenol administration or planned during the 
trial  
Clinical data base 
Non major 
 
Patient previously included in this trial 
Clinical data base 
Non major 
 
Patient related to the Investigator or any other trial staff 
or relative directly involved in the trial conduct 
Clinical data base 
Non major 
Patient not withdrawn as per protocol 
 
 
Patient becoming pregnant or discovering her 
pregnancy 
during 
trial 
participation 
(urine 
pregnancy test positive) and not withdrawn 
Monitoring/Clinical 
data base 
Non major 
 
Patient with calculated eGFR missing or out of age-
adjusted normal values and not withdrawn 
Clinical data base 
Non major 
Missing data 
 
 
PK blood sample not performed, or results are missing 
Clinical data base/ 
PK database 
Non major 
 
No plasma PK sample was obtained 
Clinical data base/ 
PK database 
Major 
 
PK urine sample not performed, or results are missing 
Clinical 
data 
base/PK database 
Non major 
 
PK total urine collection not performed, or results are 
missing 
Clinical 
data 
base/PK database 
Non major 
 
Vital signs not measured, or results are missing 
Clinical data base 
Non major 
 
Standard 12-lead ECG not performed or results missing Clinical data base 
Non major 
 
Biochemistry sample not performed, or results are 
missing 
Clinical 
data 
base/Laboratory 
database 
Non major 
 
Hematology sample not performed, or results are 
missing 
Clinical 
data 
base/Laboratory 
database 
Non major 
 
Tolerance at injection site is not filled in for patient 
receiving gadopiclenol 
Clinical data base 
Non major 
 
Ability to control daytime urination is missing 
Clinical data base 
Non major 
 
Age is missing 
Clinical data base 
Non major 
 
Sex is missing 
Clinical data base 
Non major 
 
Weight is missing 
Clinical data base 
Non major 


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Height is missing 
Clinical data base 
Non major 
 
Ethnicity is missing 
Clinical data base 
Non major 
 
Race is missing 
Clinical data base 
Non major 
 
Physical examination not performed 
Clinical data base 
Non major 
 
Physical examination for NSF not performed 
Clinical data base 
Non major 
 
Time of injection is missing 
Clinical data base 
Major 
 
Time of all PK sampling are missing 
Clinical data base 
Major 
 
Urine pregnancy test not performed 
Clinical data base 
Non major 
 
MRI examination not performed 
Clinical data base 
Non major 
 
MRI Machine brand name is missing 
Clinical data base 
Non major 
 
MRI machine field strength is missing 
Clinical data base 
Non major 
 
Adequate MRI sequence not performed 
Clinical data base 
Non major 
 
Follow-up one-week visit not performed 
Clinical data base 
Non major 
 
Follow-up one-week visit not performed due to COVID Clinical data base 
Non major 
 
Follow-up 3-month visit not performed 
Clinical data base 
Non major 
 
Follow-up 3-month visit not performed due to COVID 
Clinical data base 
Non major 
Gadopiclenol Administration 
 
 
The volume of gadopiclenol actually administered is 
different from the theoretical one by ≤20 % 
Clinical data base 
Non major 
 
The volume of gadopiclenol actually administered is 
different from the theoretical one by more than 20 % 
Clinical data base 
Major 
 
Actual gadopiclenol injection rate not adequate 
Clinical data base 
Non major 
 
Extravasation 
Clinical data base 
Major 
 
Gadopiclenol storage conditions not respected 
Monitoring 
Non major 
 
Patient not administered with gadopiclenol  
Clinical data base 
Major 
Non respect of study’s schedule and procedures 
 
 
PK blood sample storage conditions not respected 
Monitoring 
Non major 
 
PK blood sample assessed out of stability period 
Monitoring 
Major 
 
Urine sample storage conditions no respected 
Monitoring 
Non major 
 
Urine sample assessed out of stability period 
Monitoring 
Non major 
 
Blood samples for PK collected out of the scheduled 
time windows  
Clinical data base 
Non major 
 
Blood samples for PK collected with no sufficient bio-
analytical assessments to calculate reliable estimates of 
the PK parameters 
PK expert 
Major 
 
Urine samples for PK collected out of the scheduled 
time windows  
Clinical data base 
Non major 
 
Total urine collection more than 8 hours 
Clinical data base 
Non major 


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Urine samples for PK collection date different from the 
day of visit 
Clinical data base 
Non major 
 
Urine samples for PK collected with no sufficient bio-
analytical assessments to calculate reliable estimates of 
the PK parameters 
PK expert 
Non major 
 
Vital signs performed out of the scheduled time 
windows  
Clinical data base 
Non major 
 
Blood pressure and pulse rate not performed in supine 
position after a rest for at least 5 minutes 
Monitoring 
Non major 
 
Blood pressure measured on the arm used for the 
injection 
Monitoring 
Non major 
 
Standard 12-lead ECG not performed in supine position 
after a rest for at least 5 minutes 
Monitoring 
Non major 
 
ECG measured out of the scheduled time windows 
Clinical data base 
Non major 
 
Blood samples for safety storage conditions not 
respected 
Monitoring 
Non major 
 
Blood samples for safety collected out of scheduled 
time windows 
Clinical data base 
Non major 
 
Time between screening visit and gadopiclenol 
administration is greater than 14 days 
Clinical data base 
Non major 
 
One week safety follow-up performed out of the 
scheduled time windows 
Clinical data base 
Non major 
 
 
 
 
 
3 month safety follow-up performed out of the 
scheduled time windows 
Clinical data base 
Non major 
 
 
 
 
 
End of Study visit not performed at visit 4  
Clinical data base 
Non major 
 
IWRS recording not appropriate 
Monitoring 
Non major 
 
PK profile unexpected 
PK expert 
Non major 
Forbidden concomitant medication 
 
 
Patient having concomitant procedure that may altered 
gadopiclenol PK parameters 
Monitoring/ 
PK 
expert 
Major 
 
Patient having received concomitant treatment that may 
altered gadopiclenol PK parameters 
Monitoring/ 
PK 
expert 
Major 
 
Patient having received contrast agent one week before 
or after the gadopiclenol administration 
Clinical data base 
Non major 
Good Clinical Practice (GCP) deviation 
 
 
ICF management not appropriate 
Monitoring 
Non major 


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Source document management not appropriate 
Monitoring 
Non major 
 
SAE management not appropriate 
Monitoring 
Non major 
 
 
Frequency and percentages of patients with protocol deviations will be presented breaking down by status 
(major/non major).  
 
A listing of all protocol deviations will also be provided in CSR appendix 16.2.3. 
 
5.3. Measurements of compliance with gadopiclenol 
Volume theoretically administered, volume actually administered, and difference between theoretical and actual 
volumes will be described by descriptive statistics using the SS per age group, cohort, and overall. The difference 
in mL and in % will be presented for the patients with a difference between the 2 volumes. The reasons of the 
differences will be only listed. 
 
5.4. Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics will be presented on the Safety Set (and possibly the PPS). 
5.4.1. Demographic data 
 
Demographic parameters and baseline characteristics will be described per age group, cohort and overall with 
descriptive statistics. 
 
5.4.2. Study disease 
 
Not applicable 
 
5.4.3. Risk factors  
 
Not applicable 
 
5.4.4. Medical history and concomitant diseases 
 
Summary tables (number and % of patients) will be presented first for medical history then for concomitant diseases 
per age group, cohort and overall, and tabulated by System Organ Class (SOC), Preferred Term (PT) and 
concomitant status. Tables will be sorted by descending frequency of SOC and, within each SOC, by descending 
frequency of PT according overall group. 
 
5.4.5. Prior medications and procedures 
 
The number and percentage of patients who took concomitant medications ended before the gadopiclenol 
administration will be summarized according to Anatomical Therapeutic Chemical (ATC) system main group 
(ATC1, ATC first level corresponds to the first letter of the ATC code) for each age group, cohort and overall. 


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The table will be sorted according to the percentage of patients reporting at least one previous medication from the 
most to the least frequent globally. 
 
Patient’s prior procedures will be tabulated by SOC and PT, and sorted by decreasing frequency of SOC, and 
decreasing frequency of PT within SOC according overall group. 
 
5.5. PK Evaluation 
All PK analyses (population PK analysis and analytical PK analysis) are detailed in dedicated reports and will be 
presented on the PPS. 
 
5.6. Safety Evaluation 
 
All safety parameters will be presented using the SS per age group (CNS and Body mixed), cohort and overall, 
unless otherwise specified.  
 
5.6.1. Extent of Exposure 
 
All durations will be described as quantitative variables. 
 
The modalities of the contrast agent administration will be presented as qualitative or quantitative variables. The 
following parameters will only be listed: administered treatment number and reason why the volume administered 
is different from the theoretical calculated volume. 
 
5.6.2. Adverse Events 
 
An overall summary of AEs in term of number of patients and number of AEs will be presented overall using the 
All Enrolled patients Set: 
- 
At least one AE 
- 
Distribution of AEs per patient (only the number and the percentage of patients with 1, 2, etc. … AEs) 
- 
At least one AE with each of the following classification of intensity 
o Mild 
o Moderate 
o Severe 
- 
At least one AE with each of the following classifications of outcome: 
o Recovered/resolved 
o Recovered/resolved with sequelae 
o Not recovered/Not resolved 
o Fatal 
- 
At least one AE leading to AE-targeted medication 
- 
At least one AE leading to other AE-targeted action 
- 
At least one serious AE 
- 
At least one Adverse Event of Special Interest (AESI) 
 
An overall summary of AEs before gadopiclenol administration will be also presented using the SS. 
 


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TEAE will be presented using the SS and by age group, cohort and overall as follows: 
- 
At least one TEAE 
- 
Distribution of TEAEs per patient (only the number and the percentage of patients with 1, 2, etc. … TEAEs) 
- 
At least one TEAE with each of the following classification of intensity 
o Mild 
o Moderate 
o Severe 
- 
At least one TEAE with causal relationship to gadopiclenol 
- 
At least one TEAE with causal relationship to the trial procedure 
- 
At least one TEAE with each of the following classifications of outcome: 
o Recovered/resolved 
o Recovered/resolved with sequelae 
o Not recovered/Not resolved 
o Fatal 
- 
At least one TEAE with each of the following classification of action taken with regard to gadopiclenol 
administration 
o No action 
o Gadopiclenol withdrawn 
- 
At least one TEAE leading to TEAE-targeted medication 
- 
At least one TEAE leading to other TEAE-targeted action 
- 
At least one serious TEAE 
- 
At least one AESI during the one-week safety follow-up period, and during the 3-month safety follow-up 
period 
 
Summaries by SOC and PT will be presented for all TEAEs and all related TEAEs (related to IMP and related to 
study procedure respectively separately) using the SS. These analyses will be based on the number of patients with 
at least one TEAEs and the number of TEAEs. 
 
5.6.3. Deaths, serious adverse events and other significant adverse events 
 
All deaths, all other serious adverse events (SAE) and AESI occurred on SS will be listed per patient number, age 
group, cohort, with indication of date/time of onset, date of event end, Primary SOC, PT, description (investigator’s 
wording), duration, outcome (recovered / resolved, recovered / resolved with sequelae, not recovered / not resolved, 
fatal),  intensity (mild, moderate, severe), seriousness criteria, causal relationship to gadopiclenol (related, not 
related), causal relationship to a study procedure (related / not related), the action taken with regard to gadopiclenol 
administration (No action, gadopiclenol withdrawn), other action taken (Yes, No) and the study phase  defined 
according to the start date of the event and the study visit: screening visit, inclusion visit before injection, inclusion 
visit after injection, 1-week safety follow-up, 3-months safety follow-up. 
 
5.6.4. Clinical laboratory evaluation 
 
Hematology, biochemistry and coagulation parameters will be described as quantitative variables and qualitative 
variables in both SI and US units. Original units will be only listed. 
 
Quantitative analyses will be done by tabulating raw data and change from baseline. 
 
Qualitative analyses will be done via: 
- 
Comparison of laboratory data to their reference ranges 


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- 
Shift tables presenting relative change from baseline in eGFR, creatinine and blood urea nitrogen in classes 
(≤ -50%, > -50% and ≤ -25%, > -25% and ≤ -15%, > -15% and < 0%, ≥ 0% and < 15%, ≥ 15% and < -
25%, ≥ 25% and < 50% and ≥ 50 %) will be displayed. 
 
5.6.5. Vital signs, physical findings and other observations related to safety 
 
5.6.5.1 
Vital signs 
 
Vital signs parameters will be presented at each time point as quantitative variables and qualitative variables. 
 
Quantitative analyses will be done by tabulating raw data and changes in vital signs parameter from baseline. 
 
Qualitative analyses will be provided according to the following classes: 
 
<90, [90; 160], >160 mmHg for SBP 
 
<10, [10; 120], >120 mmHg for DBP 
 
<10, [10; 200], >200 bpm for pulse rate 
 
5.6.5.2 
ECG 
 
ECG parameters will be presented at each time point as quantitative variables and qualitative variables 
 
If applicable, quantitative analyses will be done by tabulating raw data and changes in ECG parameter from 
baseline, else qualitative analyses will be presented. For QTc change, both quantitative and qualitative (>450 ms 
and increase > 30 ms from baseline) analyses will be provided. 
 
 
5.6.5.3 
Injection Site Tolerance 
 
The number of patients experiencing eruption, extravasation, inflammation or other will be tabulated at each time 
point. Other events will be listed. 
 
 
5.6.5.4 
Physical examination 
 
Physical examination data will be presented at each time point. 
 
5.6.6. Concomitant medications and procedures 
 
The number and percentage of patients who took concomitant medications started before and after gadopiclenol 
injection will be presented according to ATC code. 
 
The table will be sorted according to the percentage of patients reporting at least one medication from the most to 
the least frequent globally. 
 
Patient’s concomitant procedures will be tabulated by body system, and PT and sorted by decreasing frequency of 
the SOC, and decreasing frequency of the PT within the SOC of overall group. 
 
 
 


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5.7. Efficacy Evaluation 
All efficacy analyses will be done using the FAS per CNS age group, cohort and overall. When relevant, the 
denominator will be the number of lesion (instead of number of patients). 
 
Gadopiclenol-enhanced MRI efficacy evaluation will be evaluated by on-site radiologist based on following 
parameters: 
 
- 
Images adequacy (pre and post) 
o Technical adequacy for diagnosis 
 
Patient score will be tabulated qualitatively for pre and post contrast images  
 
Shift tables between pre and post scores will be provided. 
o Characteristics of assessment of images (assessability and reasons for non-assessability) will be 
tabulated qualitatively for pre and post contrast images.  
o Total number of detected lesions per subject will be presented quantitatively and qualitatively for 
pre and post contrast images. 
 
- 
Evaluation of lesions (3 most representatives lesions) will be tabulated qualitatively (location of lesion) and 
quantitatively for pre (largest diameter, SI) and post (largest diameter, SI, SIb) contrast images. 
 
- 
Assessment of contrast quality will be tabulated for all parameters (E% and LBR) quantitatively. 
 
- 
Lesion visualization 
o For each parameter (lesion border delineation, internal morphology and contrast enhancement), 
lesion score will be tabulated qualitatively for pre and post contrast images 
o A shift table between pre and post scores will be provided. 
o The sum of lesion score (patient score) and its variation (post minus pre) will be described 
quantitatively. 
 
- 
Change in diagnostic confidence and main diagnosis will be tabulated qualitatively for post contrast images 
 
 
 
 


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 LIST OF TABLES, FIGURES AND LISTINGS 
6.1. Contents of clinical study report section 14 
This section lists all Tables and Figures in the order in which they are expected to appear in Section 14 of the CSR. 
6.1.1. Demographic data 
 
6.1.1.1 
Disposition of Patients 
 
Table 14.1.1.1  
Patient Overall Disposition – All Enrolled Patients Set – CNS Cohort 
Table 14.1.1.2  
Patient Overall Disposition – All Enrolled Patients Set – Body Cohort 
Table 14.1.1.3  
Patient Overall Disposition – All Enrolled Patients Set  
Table 14.1.1.4  
Disposition by Visit – All Enrolled Patients Set 
Table 14.1.1.5   
Number of Patients by Center – All Enrolled Patients Set 
 
Table 14.1.1.6  
Reasons for Screening Failure– All Enrolled Patients Set 
Table 14.1.1.7 
 Reasons for Premature Discontinuation – Safety Set 
 
6.1.1.2 
Protocol Deviations 
 
Table 14.1.2.1  
Major Protocol Deviations – All Enrolled Patients Set 
Table 14.1.2.2  
Non Major Protocol Deviations – All Enrolled Patients Set 
 
6.1.1.3 
Data Sets Analysed 
 
Table 14.1.3.1  
Number of Patients in Safety Set – Safety Set 
Table 14.1.3.2  
Number of Patients in Full Analysis Set And Per Protocol Set – Safety Set 
 
 
6.1.1.4 
Demographics and Baseline Characteristics 
 
Demographics characteristics 
 
Table 14.1.4.1 Demographic Characteristics – Safety Set 
 
If PPS are presented, the number of tables will be incremented by one. 
 
Baseline characteristics 
 
Table 14.1.4.2 Physical Examination at Screening Visit – Safety Set 
Table 14.1.4.3 Medical/Surgical History at Screening Visit - Safety Set 
Table 14.1.4.4 Urine Collection Data - Safety Set 
Table 14.1.4.5 Pregnancy Test at Inclusion Visit - Safety Set 
Table 14.1.4.6 Prior Medications According to ATC System Main Group - Safety Set 
Table 14.1.4.7 Prior Procedures - Safety Set 
Table 14.1.4.8 Previous Experience With Contrast Agent Administration - Safety Set 
 
Table 14.1.5.1 MRI Examination – Full Analysis Set – CNS Cohort 
Table 14.1.5.2 MRI Examination – Full Analysis Set – Body Cohort 
 
 


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If PPS are presented, the number of tables will be incremented by one. 
 
 
6.1.1.5 
Compliance with gadopiclenol administration 
 
Table 14.1.5.3  
Compliance With Gadopiclenol Administration – Safety Set 
 
6.1.2. PK data 
 
Not detailed in this SAP 
 
6.1.3. Safety data 
 
6.1.3.1 
Extent of exposure 
 
Table 14.3.1.1  
Summary of Durations in the Study – Safety Set 
Table 14.3.1.2  
Study Contrast Agent Administration Modalities – Safety Set 
 
6.1.3.2 
Adverse events 
 
Table 14.3.2.1  
Adverse Events – Overall Overview – All Patients Set 
Table 14.3.2.2  
Adverse Events Before Gadopiclenol Administration – Overall Overview – Safety Set 
 
Table 14.3.2.3  
Treatment Emergent Adverse Events – Overall Overview – Safety Set 
Table 14.3.2.4 
 Treatment Emergent Adverse Events by Primary System Organ Class and Preferred Term 
– Safety Set 
Table 14.3.2.5 
 Treatment Emergent Adverse Events With Causal Relationship to Gadopiclenol by Primary 
System Organ Class and Preferred Term – Safety Set 
Table 14.3.2.6 
 Treatment Emergent Adverse Events With Causal Relationship to a Study Procedure by 
Primary System Organ Class and Preferred Term – Safety Set 
 
6.1.3.3 
Deaths, serious adverse events and other significant adverse events 
 
Table 14.3.2.7  
Listing of Death – Safety Set 
Table 14.3.2.8  
Listing of Serious Adverse Events – Safety Set 
Table 14.3.2.9  
Listing of Adverse Events of Special Interest – Safety Set 
 
6.1.3.4 
Laboratory data 
 
Table 14.3.3.1 
Hematology Data – SI Units – Safety Set 
Table 14.3.3.2 
 Biochemistry Data – SI Units – Safety Set 
Table 14.3.3.3 
 Coagulation Data – SI Units – Safety Set 
Table 14.3.3.4 
Hematology Data – Conventional US Units – Safety Set 
Table 14.3.3.5 
 Biochemistry Data - Conventional US Units – Safety Set 
Table 14.3.3.6 
 Coagulation Data - Conventional US Units – Safety Set 
 
Table 14.3.3.7 
 Shift Table of Serum Creatinine, eGFR, and BUN - SI Units – Safety Set 
Table 14.3.3.8 
 Shift Table of Serum Creatinine, eGFR, and BUN – Conventional US Units – Safety Set 
 


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6.1.3.5 
Vital Signs, physical findings and other observations related to safety 
 
6.1.3.5.1 Vital signs 
 
Table 14.3.4.1  
Vital Signs Data – Safety Set 
 
6.1.3.5.2 ECG 
 
Table 14.3.4.2  
ECG Data – Safety Set 
 
6.1.3.5.3 Other observations 
 
Table 14.3.4.3  
Physical Examination – Safety Set 
Table 14.3.4.4  
Injection Site Tolerance – Safety Set 
 
6.1.3.6 
Concomitant medications / Procedures 
 
Table 14.3.4.5  
Concomitant Medications Started Before Gadopiclenol Administration According to ATC 
Drug Dictionary – Safety Set 
Table 14.3.4.6  
Concomitant Medications Started After Gadopiclenol Administration According to ATC 
Drug Dictionary – Safety Set 
Table 14.3.4.7  
Concomitant Procedures – Safety Set 
6.1.4. Efficacy data 
 
Table 14.2.1 
 Images Adequacy And Number of Lesions Detected – Unenhanced MRI – Full Analysis 
Set 
Table 14.2.2 
 Images Adequacy And Number of Lesions Detected – Contrast-Enhanced MRI – Full 
Analysis Set 
Table 14.2.3 
 Technical Adequacy For Diagnosis Between Unenhanced And Contrast-Enhanced MRI – 
Full Analysis Set 
 
Table 14.2.4 
 
Evaluation of Lesions – Unenhanced MRI – Full Analysis Set 
Table 14.2.5 
 
Evaluation of Lesions – Contrast-Enhanced MRI – Full Analysis Set 
 
Table 14.2.6 
 
Assessment of Contrast Quality – Full Analysis Set 
 
Table 14.2.7 
 
Lesion visualization – Unenhanced MRI – Full Analysis Set 
Table 14.2.8 
 
Lesion visualization – Contrast-Enhanced MRI – Full Analysis Set 
Table 14.2.9 
 Lesion Border Delineation Between Unenhanced And Contrast-Enhanced MRI – Full 
Analysis Set 
Table 14.2.10 
 Internal Morphology Between Unenhanced And Contrast-Enhanced MRI – Full Analysis 
Set 
Table 14.2.11 
 Degree of Contrast Enhancement Between Unenhanced And Contrast-Enhanced MRI – 
Full Analysis Set 
Table 14.2.12  
Sum of Lesions Scores and Variation – Age Group 1 in CNS Cohort– Full Analysis Set  
Table 14.2.13  
Sum of Lesions Scores and Variation – Age Group 2 in CNS Cohort – Full Analysis Set 
Table 14.2.14   
Sum of Lesions Scores and Variation – Age Group 3 in CNS Cohort – Full Analysis Set 
Table 14.2.15   
Sum of Lesions Scores and Variation – CNS Cohort – Full Analysis Set 
Table 14.2.16  
Sum of Lesions Scores and Variation – Body Cohort – Full Analysis Set 
Table 14.2.17  
Sum of Lesions Scores and Variation – All Cohorts – Full Analysis Set 
Table 14.2.18  
Change in Diagnosis Confidence – Full Analysis Set 


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6.2. Contents of clinical study report section 16.2 
This section lists all Listings in the order in which they are expected to appear in the CSR. 
 
6.2.1. Demographic Data 
 
6.2.1.1 
Disposition of Patients 
 
Listing 16.2.1.1 
Patient Disposition – All Enrolled Patients Set 
Listing 16.2.1.2 
Patient Status – All Enrolled Patients Set 
Listing 16.2.1.3 
Inclusion Criteria Not Met – All Enrolled Patients Set 
Listing 16.2.1.4 
Non-Inclusion Criteria Met – All Enrolled Patients Set 
 
 
6.2.1.2 
Protocol Deviations 
 
Listing 16.2.1.5 
Major Protocol Deviations – All Enrolled Patients Set 
Listing 16.2.1.6 
Non Major Protocol Deviations – All Enrolled Patients Set 
 
6.2.1.3 
Data Sets Analysed 
 
Listing 16.2.1.7 
Analysis Data Sets – All Enrolled Patients Set 
 
6.2.1.4 
Demographics and Baseline Characteristics 
 
Listing 16.2.1.8 
Demographics – All Enrolled Patients Set 
Listing 16.2.1.9 
Physical Examination – All Enrolled Patients Set 
Listing 16.2.1.10 
Medical/Surgical History – All Enrolled Patients Set 
Listing 16.2.1.11 
Total Urine Collection – All Enrolled Patients Set 
Listing 16.2.1.12 
Urine Pregnancy Test– All Enrolled Patients Set 
Listing 16.2.1.13 
Concomitant Medications – All Enrolled Patients Set 
Listing 16.2.1.14 
Prior Procedures – All Enrolled Patients Set 
Listing 16.2.1.15 
Previous Experience With Contrast Agent Administration – All Enrolled Patients Set 
 
6.2.2. PK Data 
 
Not applicable 
 
6.2.3. Safety Data 
 
6.2.3.1 
Extent of exposure 
 
Listing 16.2.3.1 
Summary of Durations in the study – All Enrolled Patients Set 
Listing 16.2.3.2 
Study Contrast Agent Administration Modalities – All Enrolled Patients Set 
 
 


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6.2.3.2 
Adverse Events 
 
Listing 16.2.3.3 
Adverse Events – All Enrolled Patients Set 
 
6.2.3.3 
Death 
 
All listings are including with tables in the last section. 
 
6.2.3.4 
Laboratory Data 
 
Listing 16.2.3.4 
Hematology Data – SI Units – All Enrolled Patients Set 
Listing 16.2.3.5 
Biochemistry Data – SI Units – All Enrolled Patients Set 
Listing 16.2.3.6 
Coagulation Data – SI Units – All Enrolled Patients Set 
Listing 16.2.3.7 
Hematology Data – Conventional US Units – All Enrolled Patients Set 
Listing 16.2.3.8 
Biochemistry Data – Conventional US Units – All Enrolled Patients Set 
Listing 16.2.3.9 
Coagulation Data – Conventional US Units – All Enrolled Patients Set 
 
 
6.2.3.5 
Vital Signs, physical findings and other observations 
 
Listing 16.2.3.8 
Vital Signs – All Enrolled Patients Set 
Listing 16.2.3.9 
ECG Parameters – All Enrolled Patients Set 
Listing 16.2.3.10 
Injection Site Tolerance – All Enrolled Patients Set 
 
6.2.4. Efficacy Data 
 
Listing 16.2.4.1 
 
MRI Examination – All Enrolled Patients Set 
Listing 16.2.4.2 
 
MRI Sequence – All Enrolled Patients Set 
Listing 16.2.4.3 
 
MRI Evaluation – All Enrolled Patients Set 
Listing 16.2.4.4 
 
Lesions Evaluation – Unenhanced MRI – All Enrolled Patients Set 
Listing 16.2.4.5 
 
Lesions Evaluation – Contrast-Enhanced MRI – All Enrolled Patients Set 
Listing 16.2.4.6 
 
Contrast Quality – All Enrolled Patients Set 
 
 
 
 


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