Clinical trial NCT03657264
Conditions: Healthy Volunteers
Keywords: Gadolinium-based contrast agent Cardiac safety ECG Gadopiclenol
Sponsor: Guerbet
Start date: 2017-08-21; Completion date: 2018-06-07
Enrollment: 48 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The study is a Phase I, Single center, Randomized, Cross-over Double-blind Placebo-controlled and Open-label Positive-controlled (moxifloxacin) in healthy volunteers.

The primary objective is to assess the cardiac safety after administration of P03277 to 48 healthy volunteers at dose of 0.1 mmol/kg (anticipated clinical dose) and 0.3 mmol/kg (supra-clinical dose) by evaluating the QT and QTc intervals.

Detailed description:
Each subjects will be administered with 4 products (P03277 at the 2 different doses, placebo and moxifloxacin) in a 4\*4 cross over sequence balanced for first order carry over effect. Twelve subjects will be assigned to each sequence (6 males and 6 females). The volunteers will be enrolled sequentially by cohort of 8 subjects.

ECG measurements will be compared with ECG parameters collected after administration of placebo (Nacl 0.9%). The test sensitivity will be assessed using a positive control (moxifloxacin 400 mg per os) known to induce delays in QT intervals.

Arms: arm 1: The sequence of administration is: P/ScD/PC/CD

Where:

* P = Placebo (Nacl 0.9%)
* CD = P03277 tested at 0.1 mmol/kg
* ScD = P03277 tested at 0.3 mmol/kg
* PC = Positive control (moxifloxacin 400 mg - per os). arm 2: The sequence of administration is: CD/PC/ScD/P

Where:

* P = Placebo (Nacl 0.9%)
* CD = P03277 tested at 0.1 mmol/kg
* ScD = P03277 tested at 0.3 mmol/kg
* PC = Positive control (moxifloxacin 400 mg - per os). arm 3: The sequence of administration is: ScD/CD/P/PC

Where:

* P = Placebo (Nacl 0.9%)
* CD = P03277 tested at 0.1 mmol/kg
* ScD = P03277 tested at 0.3 mmol/kg
* PC = Positive control (moxifloxacin 400 mg - per os). arm 4: The sequence of administration is: PC/P/CD/ScD

Where:

* P = Placebo (Nacl 0.9%)
* CD = P03277 tested at 0.1 mmol/kg
* ScD = P03277 tested at 0.3 mmol/kg
* PC = Positive control (moxifloxacin 400 mg - per os).
Interventions: intervention 1: P03277 0.1 mmol/kg intervention 2: Moxifloxacin 400mg intervention 3: NaCl 0.9% intervention 4: P03277 0.3 mmol/kg
Intervention descriptions: intervention 1: Single intravenous bolus injection at 2 mL/sec intervention 2: One tablet per os intervention 3: Single intravenous bolus injection at 2 mL/sec intervention 4: Single intravenous bolus injection at 2 mL/sec

Protocol documents:
Prot_002.pdf: 
 
 
CONFIDENTIAL 
Protocol No. GDX-44-006 
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Date 31August 2018 
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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-44-006 
Thorough QT/QTc study to assess the electrocardiographic safety of a new gadolinium-based 
contrast agent P03277 in healthy volunteers 
Phase I Clinical Trial 
 
Design 
Phase I Clinical Trial, Single center, Randomized, Cross-over Double-blind Placebo-controlled and 
Open-label Positive-controlled (moxifloxacin) in healthy volunteers 
 
EudraCT No.: 2017-000963-34 
IND No.: 123673 
 
PRINCIPAL INVESTIGATOR 
Dr. Frédéric VANHOUTTE  
SGS Clinical Pharmacology Unit, ZNA Stuivenberg, Antwerp (BELGIUM) 
 
 
SPONSOR 
GUERBET, B.P. 57400, 95943 Roissy CdG Cedex, FRANCE  
GUERBET MEDICAL EXPERT 
 
 
PHARMACOVIGILANCE 
  
Fax : + 33 (0) 1 45 91 67 70  
E-mail: pharmacovigilance.headquarters@guerbet-group.com 
 
 


 
 
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TRIAL SYNOPSIS 
Trial Title: Thorough QT/QTc study to assess the electrocardiographic safety of a new 
gadolinium-based contrast agent P03277 in healthy volunteers 
Phase I Clinical Trial 
Trial Product(s): G03277 
Active Ingredient(s): P03277 
EudraCT No.: 2017-000963-34 
IND No.: 123673 
Participating countries (Number of sites): 
Belgium (1 site) 
Trial objectives 
Primary objective: 
To assess the cardiac safety after administration of P03277 by evaluating the QT and QTc intervals in 
healthy volunteers. 
Secondary objectives: 
To assess the cardiac, clinical, biological safety, plasma concentration, and long term elimination 
profile of P03277 following its administration in healthy volunteers. 
 
Trial design and methodology 
Phase I Clinical Trial, single center, randomized, cross-over double-blind placebo-controlled and 
open-label positive-controlled (moxifloxacin) in healthy volunteers. 
The three Investigational Medicinal Products (IMPs) will be: 
- 
P = Placebo (Nacl 0.9%) 
- 
CD = P03277 tested at anticipated clinical dose (0.1mmol/kg) 
- 
SD = P03277 tested at supra-clinical dose (0.3mmol/kg). 
The positive control, moxifloxacin, will be an Auxiliary Medicinal Product (AMP). 
- 
PC = Positive control (moxifloxacin 400 mg – per os). 
Subjects who have provided written informed consent and satisfied all eligibility requirements will be 
included in the trial and randomized to receive one of 4 sequences, according to a Williams design for 
a 4*4 cross over which is balanced for first order carry over effect. 
The sequences of administration could be for instance: 
- 
Sequence #1: P/CD/PC/SD 
- 
Sequence #2: CD/SD/P/PC 
- 
Sequence #3: SD/PC/CD/P  
- 
Sequence #4: PC/P/SD/CD 
 
12 subjects will be assigned to each sequence (6 males and 6 females). 
Sequence and IMP/AMP will be randomly assigned to subjects. 
All subjects will be monitored with a 12-lead Holter electrocardiogram (ECG) from 1 hour before any 
product administration until 24 hours post-administration. 
ECGs parameters will be measured as triplicate based on the following timepoints from the 12-lead 


 
 
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Holter ECG monitoring: 
- 
moxifloxacin: pre-dose up to 24 hours post-dose:  
[-1hour, 30min, 1 hour,1.5 hours, 2 hours, 3 hours, 4 hours, 8 hours, 24 hours] 
- 
P03277 and Placebo: pre-dose up to 24 hours post-dose:  
[-1hour, 5min, 10 min, 20 min, 30min, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 8 hours, 24 
hours]. 
Regarding ECG measurements, there will be one baseline per administration period. The baseline is 
defined as the mean of 3 triplicates ECGs timepoint measurements within one hour before each 
administration. 
Blood will be drawn for all subjects for: 
- 
Blood samples based on the same timepoints than triplicate ECGs, to implement a concentration-
response approach and to assess the effect of P03277 on QT/QTc intervals according to plasma 
concentration of the product 
- 
Blood sample to assess biochemistry and hematological parameters at screening and 2 days after 
each IMP administrations. 
All subject will undergo 12-leads ECGs to assess subject’ safety to monitor subject and trial stopping 
rules related to the QTcF values. Those ECGs will be done as triplicate within 1 hour before 
administration and 10 minutes and 3 hours post-administration. 
All subjects will be asked to come back at the phase I clinical trial unit at 1 and 3 months after last 
IMP administration. Blood sample and urine collection will be performed to assess long term 
elimination of P03277. 
Time windows allowance have been defined for each procedures as described in the relevant study 
plans listed in section 18.2 
Number of subjects: 
A total of 48 subjects will be randomized in the trial. The recruitment could be stopped before 48 
subjects, from the time the number of fully evaluable subjects for the primary criterion is 40. That is to 
say having taken part to the study, till the last scheduled ECG Holter recording. 
 
Eligibility criteria 
Inclusion criteria: 
1. Adult healthy volunteers at least 18 years old and below 60 (exclusive) 
2. Subject having read the information and provided his/her consent to participate in writing by 
dating and signing the informed consent prior to any trial-related procedure being conducted 
3. Subject assessed as healthy by a comprehensive clinical assessment (detailed medical history and 
complete physical examination) 
4. Subject with a Body Mass Index (BMI) > 19 kg/m2 and < 28 kg/m2 and a weight at least of 40 kg 
for female and 50 kg for male and at maximum of 100 kg.  
5. Subject able and willing to participate in the trial 
To be included in the trial, the subject must meet all these inclusion criteria. 
Non-inclusion criteria: 
1. Subject with any history or family history of inherited or acquired Long QT syndrome (LQTS) 
2. Subject with any history or family history of risk factors for Torsade de Pointe (TdP), unexplained 
loss of consciousness or convulsion 
3. Subject with any history of clinically significant bradycardia  


 
 
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4. Subject with any history of clinically significant cardiac impairment by decreasing of left 
ventricular ejection fraction (LVEF) 
5. Subject with any history of clinically significant arrhythmia (including Wolf-Parkinson-White 
syndrome) 
6. Subject with presence of cardiac pacemaker 
7. Subject with frequent headaches and/or migraine, recurrent nausea and/or vomiting (more than 
twice a month) 
8. Subject with abnormal 12-lead ECG: PR < 120 ms or PR > 200 ms, QRS > 100 ms, QTc > 450 
ms, flat T-waves at screening visit (results provided by the independent ECGs Core Laboratory) 
9. Subject with following abnormal vital signs after 10 minutes resting in supine position at 
screening visit: 
o systolic blood pressure < 90 mmHg or > 160 mmHg 
o diastolic blood pressure < 45 mmHg or > 90 mmHg 
o resting heart rate < 45 bpm or > 80 bpm 
10. Subject with any history or presence of relevant cardiovascular, pulmonary, gastrointestinal, 
hepatic, renal, metabolic, hematological, psychiatric, systemic, ocular, or infectious disease; any 
acute infection or signs of acute illness 
11. Subject with abnormal biological, hematological or coagulation tests considered as clinically 
significant  by the investigator  and with the following abnormal laboratory parameters (out of 
normal ranges) (results have to be available at the latest at Day 1) : 
o Low potassium blood level (K+ < 3.5 mmol/L) 
o Low magnesium blood level (Mg++ < 0.66 mmol/L) 
o Estimated creatinine clearance rate (eCCr) < 90 mL/min  (Cockcroft-Gault formula)  
o Impaired liver function and transaminases  > 2 fold ULN 
12.  Subject carrier of: HBs antigen, anti-HCV antibodies, anti-HIV1 antibodies, anti-HIV2 antibodies 
at screening 
13. Subject with any history of severe allergic or anaphylactic reactions to any allergen including 
drugs and contrast agents, or allergic disease diagnosed and treated by a physician 
14. Subject with any history of tendinopathy following a fluoroquinolone treatment 
15. Subject with any history of allergy to moxifloxacin or one of its compounds or other moxifloxacin 
contra-indications according to the SmPC description 
16. Subject with known contra-indication(s) to the use or with known sensitivity to one of the 
products under investigation or to drugs from a similar pharmaceutical class 
17. Subject treated with any concomitant medications which could induce a QT prolongation 
18. Subject with presence of narcotics or alcohol abuse (alcohol consumption > 40 grams/Day) at 
screening 
19. Subject smoking more than 10 cigarettes or equivalent /Day, unable to stop smoking during the 
confinement period 
20. Subject having an excessive consumption of beverages with xanthine bases (tea, coffee, chocolate) 
(>6 cups or glasses /Day) and not able to refrain from consuming  grapefruit (fresh fruit, juice, 
ice...) the day before inclusion and during the confinement period 
21. Subject having done a blood donation within 3 months before first trial product administration 
22. Subject having received any medication within 21 days prior to inclusion, or within 5 times the 
elimination half-life of that drug, whichever the longest, with the exception of hormonal 
contraception for female and of Hormonal Replacement Therapy (HRT) in case of menopausal 
volunteers and paracetamol 
23. Subject having received an administration of any contrast agent within 2 weeks before inclusion, 
or scheduled to receive any contrast agent within 3 months after the last IMP administration 
24. Subject having participated to a clinical trial involving an investigational drug or device within 21 
days prior to screening, or within 5 times the elimination half-life of that drug whichever the 


 
 
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longest. 
25. Subject having a planned simultaneous participation to another clinical trial involving an 
investigational drug or device 
26. Subject having an inability or unwillingness to cooperate with the requirements of this trial 
27. Subject having a planned interventions (surgery, radiotherapy, chemotherapy or others) during the 
course of the trial 
28. Subject with any condition which, based on the investigator's clinical judgment, would prevent the 
subject from participating in all trial assessments and visits (for example: mental or physical 
incapacity, language comprehension, geographical localization, etc.) 
29. Female subject being pregnant or breast-feeding (a female subject of childbearing potential or with 
amenorrhea for less than 12 months must have a negative pregnancy test at inclusion and must be 
using a medically approved contraception method) 
Subjects presenting with one or more of these non-inclusion criteria must not be included in the trial. 
 
Investigational Medicinal Products administration 
Trial product 1: P03277 (0.1 and 0.3 mmol/kg) has to be administered as an IV bolus at 2 mL/sec. 
Trial product 2: Placebo (Nacl 0.9%) has to be administered like P03277 as an IV bolus at 2 mL/sec. 
 
Auxiliary Medicinal Product administration 
Positive control (moxifloxacin 400 mg) has to be administered per os in open label. 
 
Trial duration for subjects  
Minimum trial duration for subjects: 95 days 
Maximum trial duration for subjects: 122 days (in case the subject signs the informed consent form 
within 28 days before inclusion). 
Within 4-weeks up to 1 day run-in period, subjects will be screened for the trial. Inclusion in the trial 
will occur the day the subject will be admitted to the phase I clinical trial unit for the first 
administration period of the allocated sequence (subjects may be admitted in the phase I clinical trial 
unit at Day -1 to ensure availability of all results prior to administration). Each subject will have 4 
administration periods. Period’s duration for moxifloxacin, placebo period, P03277 at clinical dose 
and P03277 at supra-clinical dose will each be 72 hours. The total duration for all periods will be 12 
days.  
During the 12 days of assessment and monitoring, the subject will have to stay in the phase I clinical 
trial unit. Healthy volunteers will be discharged on Day 12 after that all trial procedures have been 
performed and that all safety results have been reviewed by the investigator who will determine that it 
is safe to discharge the subject. 
1 month and 3 months following the last IMP administration on Day 10, subjects will be asked to 
come back at the phase I clinical trial unit to assess the P03277 long term elimination (in plasma and 
urine).  
The trial will be considered as completed once all the ECGs collected for all the subjects are reviewed 
by a core lab and all P03277 plasma concentration and elimination data are available. 
 


 
 
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Evaluation criteria 
For each subject, all ECG parameters will be extracted from the 12-lead Holter ECG in triplicates and 
read centrally by a core lab. The mean of the triplicate ECG recordings will be considered for each 
timepoint.  
P03277 plasma and urine concentrations samples will be analyzed for each subject by an analytical 
center. All other drawn samples will be kept by the analytical center for the trial duration.  
Primary criterion:  
Cardiovascular safety assessment is defined as the largest time-matched placebo-corrected, change-
from-baseline mean effect of P03277 (at 0.1 and 0.3 mmol/kg) of QT interval expressed as QTc 
according to Fridericia’s formula (∆∆QTcF) (in ms). No significant QTc Prolongation will be 
considered if the upper limit of the 90 % confidence interval of the maximum ∆∆QTcF is < 10%. 
Secondary criteria: 
Secondary criteria will consist of cardiac, clinical and biological safety evaluations as follow: 
- 
Cardiac safety: 
o Assay sensitivity assessment is defined as the largest time-matched placebo-corrected, 
change-from-baseline mean effect of moxifloxacin of QT interval expressed as QTc according 
to Fridericia’s formula (∆∆QTcF) (in ms) 
o Time-matched placebo-corrected, change-from-baseline mean effect, measured at any 
timepoints of the 12-lead Holter ECG recording : 
• 
QT (ms) 
• 
QTc(ms) according to population specific correction formula (QTcPOP) 
• 
QTc (ms) according to Bazett’s formula (QTcB) 
o Parameters measured at any timepoints: 
• 
QT 
• 
QTcF 
• 
QTcPOP 
• 
QTcB 
• 
RR (ms) 
• 
QRS (ms) 
• 
PR (ms) 
• 
Heart rate (bpm) 
o T wave morphology changes (yes/no) and U wave occurrence 
o Sinus rhythm (yes/no) 
o Bradycardia and arrhythmia  
The following assessments will be done during the subject participation: 
- 
Adverse Events: 
Adverse event will be recorded throughout the start of subject participation up to the end of 
confinement period except pregnancy (subject’s or subject’s partner) that will be recorded up 
to day 17 (7 days after the last IMP administration). During follow-up period, only related 
AEs and AESI will be recorded. 
- 
Biology: 


 
 
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o Clinical laboratory parameters at screening visit, Day 1 and 2 days after each administration 
Parameters at selection visit and two days after each administration:  
Hematology: Red Blood Cells (RBCs), White Blood Cells (WBCs), neutrophils, eosinophils, 
basophils, lymphocytes and monocytes, platelet count, hemoglobin, hematocrit, Mean red blood 
Cells Volume (MCV) 
Biochemistry: sodium, potassium, magnesium, chloride, glucose, urea, creatinine, eGFR , total 
protein, calcium, phosphorus, total bilirubin, unconjugated and conjugated bilirubin, aspartate 
amino transferase (AST), alanine amino transferase (ALT), alkaline phosphatase, lactate 
dehydrogenase (LDH). triglycerides (TG) 
- 
Vital Signs: 
Vital signs (blood pressure, pulse rate) will be assessed at screening visit, before each trial product 
administration and at the same timepoints as the ECGs. Body weight will be assessed at screening 
visit, inclusion visit and after each trial product administration. 
- 
Tolerance at the injection site: 
Tolerance at the injection site will be recorded during injection of P03277 or Placebo, up to 30 min 
and 1 Day post-injection 
- 
Safety 12-leads ECGs: 
Those ECGs will be done as triplicate within 1 hour before administration and 10 minutes and 3 hours 
post-administration. 
- 
P03277 plasma concentration and long term elimination: 
Plasma concentration of P03277 based on the same timepoints of ECGs and plasma and urine 
concentration of P03277 for long term elimination assessment analysis will be subcontracted to an 
analytical center. 
 
Statistical methods 
- 
Primary analysis: 
In order to be “negative” (successful), the trial must show that both 0.1 and 0.3 mmol/kg doses of 
P03277 do not increase the QT interval corrected by Fridericia formula (QTcF). 
The null hypothesis is that the difference between each of the two doses of P03277 and placebo for the 
largest mean change from baseline for the QTcF is greater than the non-inferiority margin set to 10 ms 
according to regulatory guidance. This test is performed at a one-sided at the 5% significance level, 
which is equivalent to compare the upper limit of the two-sided 90% confidence intervals of the 
difference with the non-inferiority margin of 10 ms. To conclude that P03277 is non-inferior to 
placebo, the null hypothesis has to be rejected for both doses simultaneously. 
The primary analysis is performed using an analysis of covariance (ANCOVA) model for crossover 
data with the baseline data and sex as covariate. 
- 
Secondary analyses:  
o In order to validate the assay sensitivity, the trial must show that the positive control increases 
the QTcF by at least 5 ms. 
The null hypothesis is that the difference between the positive control and placebo for mean 
change from baseline for the QTcF is less than 5 ms according to regulatory guidance. This 
test is performed one-sided at the 5% significance level. To conclude that positive control is 
superior to placebo, the null hypothesis has to be rejected. 


 
 
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As multiple timepoints are examined separately, the overall Type I error rate needs to be 
adjusted. To address this issue, the method described by Hochberg and Tamhane will be used. 
To minimize the correction and because the positive control effect is well known, only five 
timepoint around the peak effect (1h, 1h30, 2h, 3h and 4h) will be used. 
o Same analysis as for primary end-point will be repeated for QT, QTcPOP and QTcB 
o Descriptive statistics at any time from administration up to 24h post dose of Time-matched 
change from baseline, placebo controlled, of the QT, QTcF, QTcPOP and the QTcB will be 
provided 
o Number and percentage of subjects showing values above predefined threshold for QT, QTcB 
and QTcF (under placebo and two doses of P03277) 
o Descriptive statistics at any time of QT, QTcF, QTcPOP, QTcB, RR (ms), QRS (ms), PR (ms), 
Heart rate (bpm) 
o QT/QTc values according to plasma concentrations of P03277 
o Descriptive statistics on T wave morphology changes, U wave occurrence and sinus rhythm 
will be presented 
o Descriptive statistics on bradycardia and arrhythmia will be presented 
o Descriptive statistics will summarize safety data: 
• 
Biochemistry and hematology  
• 
Tolerance at the injection site  
• 
Adverse events  
• 
Vital signs 
• 
Safety ECGs 
o P03277 plasma concentration description and data will be presented 
o Long term (1 and 3 months post-administration) P03277 elimination (blood and urine) data 
will be descriptively presented. 
 






 
 
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TRIAL DIAGRAM 
(example of possible sequences) 
 
 
 
PC= Positive Control, P= Placebo, CD= P03277 at anticipated clinical dose, SD= P03277 at supra-clinical dose. 
Screening can be done within 28 up to 1 days before inclusion. 
Minimum trial duration for subjects: 95 days 
Maximum trial duration for subjects: 122 days (In case of ICF is signed 28 days before inclusion). 
Day -28 
to Day -1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 11
Day 12
(…)
Day 38
(…)
Day 94
P
PC
Inclusion / Randomization
CD
SD
Screening
Day 1
P
PC
P
SD
CD
P
CD
SD
Discharge
Follow-up 1
Follow-up 2
SD
PC
CD
PC


 
 
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SIGNATURE PAGE 
 
 
 
 
 
 
PRINCIPLE 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 Harmonisation (ICH) and all other laws 
and regulations in force on the use of investigational medicinal products. 


 
 
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ABBREVIATIONS 
AE 
 
Adverse Event 
AMP  
Auxiliary Medicinal Product 
AR 
 
Adverse Reaction 
BMI 
 
Body Mass Index 
CA 
 
Competent Authority 
CRA 
 
Clinical Research Associate (syn. Monitor) 
CRF/eCRF 
Case Report Form/ electronic Case Report Form 
CRO 
 
Contract Research Organization 
DMC  
Data Monitoring Committee 
ECG 
 
Electrocardiogram 
EMA  
European Medicine Agency 
FAS 
 
Full Analysis Set 
FDA 
 
Food and Drug Administration 
FSI 
 
First Subject In 
GBCA  
Gadolinium Based Contrast Agent 
GCP 
 
Good Clinical Practice 
GMP  
Good Manufacturing Practice 
IB 
 
Investigator’s Brochure 
ICH 
 
International Conference on Harmonisation 
IEC 
 
Independent Ethics Committee 
IMP 
 
Investigational Medicinal Product 
IRB 
 
Institutional Review Board 
ISF 
 
Investigator Site File 
ITT 
 
Intention To Treat 
LQTS  
Long QT Syndrome 
LSO 
 
Last Subject Out 
QTc 
 
QT corrected for heart rate 
QTcB  
QT corrected for heart rate according to Bazett's formula 
QTcF  
QT corrected for heart rate according to Fridericia's formula 
QTcPOP  
QT corrected for heart rate according a population-derived correction mode 
SAE 
 
Serious Adverse Event 
SAR 
 
Serious Adverse Reaction 
SPC/SmPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 


 
 
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ULN   
Upper 
limit 
normal


 
 
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TABLE OF CONTENTS 
TRIAL SYNOPSIS ................................................................................................................................. 2 
TRIAL FLOW CHART .......................................................................................................................... 9 
TRIAL DIAGRAM ............................................................................................................................... 11 
SIGNATURE PAGE ............................................................................................................................. 12 
ABBREVIATIONS ............................................................................................................................... 13 
TABLE OF CONTENTS ...................................................................................................................... 15 
LIST OF TABLES ................................................................................................................................ 20 
LIST OF FIGURES ............................................................................................................................... 20 
 
1 
INTRODUCTION AND TRIAL RATIONALE ....................................................................... 26 
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 ................................................................................................................. 29 
3.3 
Interim Analysis (if applicable) ...................................................................................... 30 
3.4 
Trial Committee(s) ......................................................................................................... 30 
4 
SUBJECT SELECTION ........................................................................................................... 31 
4.1 
Inclusion Criteria ............................................................................................................ 31 
4.2 
Non Inclusion Criteria .................................................................................................... 31 
4.3 
Subject Identification .................................................................................................... 33 
5 
INVESTIGATIONAL MEDICINAL PRODUCTS .................................................................. 34 
5.1 
Investigational and Auxiliary Medicinal Products Description ......................................... 34 
5.1.1 
Investigational Medicinal Product 1: P03277 ............................................................ 34 
5.1.2 
Investigational Medicinal Product 2: Placebo ........................................................... 35 
5.1.3 
Auxiliary Medicinal Product 1: Positive control: moxifloxacin ................................... 35 
5.2 
Packaging, Labeling, Storage ............................................................................................ 35 
5.2.1 
Investigational Medicinal Products ........................................................................... 35 
5.2.2 
Auxiliary Medicinal Product: moxifloxacin ................................................................ 36 
5.3 
Condition of IMP and AMP Allocation ............................................................................ 36 
5.3.1 
Investigational Product(s) Allocation / Randomization ............................................. 36 
5.3.2 
Auxiliary Product Allocation ...................................................................................... 39 


 
 
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5.3.3 
Double-Blind Conditions ............................................................................................ 39 
5.3.4 
Individual Trial Treatment Unblinding ....................................................................... 39 
5.4 
IMP and AMP Management .............................................................................................. 40 
5.5 
Trial Product(s) Compliance and Accountability .............................................................. 40 
6 
CONCOMITANT MEDICATIONS / PROCEDURES ............................................................ 41 
6.1 
Concomitant Medications .................................................................................................. 41 
6.1.1 
Concomitant Treatments of Special Attention .......................................................... 41 
6.1.2 
Prohibited Concomitant Treatments ......................................................................... 41 
6.2 
Procedures ......................................................................................................................... 41 
7 
EVALUATION CRITERIA ...................................................................................................... 42 
7.1 
Primary Criterion ............................................................................................................... 42 
7.2 
Secondary Criteria ............................................................................................................. 42 
7.2.1 
Cardiac Safety ............................................................................................................ 42 
7.2.2 
Clinical and Biological safety ..................................................................................... 43 
7.2.2.1 
Adverse Events .......................................................................................................... 43 
7.2.2.2 
Biology ....................................................................................................................... 43 
7.2.2.3 
Vital signs ................................................................................................................... 43 
7.2.2.4 
Tolerance at injection site ......................................................................................... 43 
7.2.2.5 
Safety 12-leads ECGs ................................................................................................. 44 
7.2.3 
P03277 plasma concentration and long term elimination parameters .................... 44 
7.2.3.1 
Plasma concentration parameters ............................................................................ 44 
7.2.3.2 
Long term elimination parameters............................................................................ 44 
8 
TRIAL SCHEDULE AND PROCEDURES ............................................................................. 45 
8.1 
Trial Schedule .................................................................................................................... 45 
8.1.1 
Screening Visit – (Day -28) to (Day -1) ....................................................................... 45 
8.1.2 
Inclusion visit – (Day  1 or the day before (Day-1) ..................................................... 45 
8.1.3 
(Day 1) to (Day 3), (Day 4) to (Day 6), (Day 7) to (Day 9) and (Day 10) to (Day 12) – 
Periods 1, 2, 3 and 4: ................................................................................................................. 46 
8.1.3.1 
Before IMP/AMP administration ............................................................................... 46 
8.1.3.2 
Within 1 hour before administration ........................................................................ 46 
8.1.3.3 
Administration of the allocated IMP/AMP ................................................................ 46 
8.1.3.4 
After administration .................................................................................................. 47 
8.1.3.5 
Days following administration ................................................................................... 47 


 
 
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8.1.4 
(Day 12) - Discharge .................................................................................................. 48 
8.1.5 
(Day 38) and (Day 94) – Follow-up Period ................................................................. 48 
8.1.6 
Confinement period ................................................................................................... 48 
8.2 
Imaging Protocol ............................................................................................................... 49 
8.3 
ECGs records and readings ............................................................................................... 49 
8.3.1 
On site-ECG Recording ............................................................................................... 49 
8.3.1.1 
ECGs equipment and consumables ........................................................................... 49 
8.3.1.2 
Safety 12-leads ECGs ................................................................................................. 49 
8.3.1.3 
12-leads ECG Holter ................................................................................................... 49 
8.3.2 
On site-Reading of 12-leads ECGs.............................................................................. 49 
8.3.3 
Off Site Reading of ECGs ............................................................................................ 50 
8.3.3.1 
Site Qualification ....................................................................................................... 50 
8.3.3.2 
Receipt and Tracking of ECGs .................................................................................... 50 
8.3.3.3 
ECG Processing and Quality Check ............................................................................ 50 
8.3.3.4 
Expert ECG Reader(s) Training ................................................................................... 50 
8.3.3.5 
Blinded Assessment of ECGs ..................................................................................... 51 
8.3.3.6 
Inter and Intra-Reader Variability Assessment ......................................................... 51 
8.3.3.7 
ECG Warehouse and Final Deliverables .................................................................... 51 
8.4 
Other Centralized Trial Procedures ................................................................................... 51 
8.4.1 
P03277 plasma concentration and long term elimination samples .......................... 51 
8.4.2 
Sample management ................................................................................................ 52 
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 ................................................................................... 53 
9.2 
Serious Adverse Event ...................................................................................................... 54 
9.2.1 
Definition of Serious Adverse Event ........................................................................... 54 
9.2.2 
Reporting Serious Adverse Events (SAE) .................................................................... 55 
9.3 
Special situations ............................................................................................................... 56 
9.3.1 
Cases of overdose, lack of efficacy, drug-drug interaction, medication errors or 
misuses 56 


 
 
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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 or moxifloxacin .... 57 
9.4 
Other important safety issue /New fact ............................................................................. 58 
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 Subject’s premature discontinuation ........................................................ 59 
11 
STATISTICAL ANALYSIS ................................................................................................. 61 
11.1 
Statistical Method (null and alternative hypotheses) ................................................... 61 
11.2 
Sample Size .................................................................................................................... 62 
11.3 
Planned Analysis ............................................................................................................ 62 
11.3.1 
Disposition of Subjects ............................................................................................... 62 
11.3.2 
Data Sets Analyzed .................................................................................................... 62 
11.3.3 
Protocol deviations .................................................................................................... 63 
11.3.4 
Demographic and Baseline Characteristics ............................................................... 63 
11.3.5 
P03277 plasma Concentration and long term elimination........................................ 63 
11.3.6 
Cardiac safety Data ................................................................................................... 64 
11.3.7 
Adverse events ........................................................................................................... 66 
11.3.8 
Laboratory biological data ........................................................................................ 68 
11.3.9 
Other safety observations ......................................................................................... 68 
11.4 
Statistical/Analytical issues ........................................................................................... 68 
11.4.1 
Adjustment for covariates ......................................................................................... 68 
11.4.2 
Handling of Dropouts or Missing Data ...................................................................... 69 
11.4.3 
Interim Analysis ......................................................................................................... 69 
11.4.4 
Multicentre Trials ...................................................................................................... 69 
11.4.5 
Multiple Comparisons/Multiplicity ............................................................................ 69 
11.4.6 
Use of a subset of Subjects for Cardiac Safety Analysis............................................. 69 
11.4.7 
Active control trials Intended to Show Equivalence .................................................. 69 
11.4.8 
Examination of Subgroups ......................................................................................... 69 
12 
TRIAL COMMITTEE .......................................................................................................... 70 
13 
ETHICAL AND REGULATORY CONSIDERATIONS ..................................................... 71 


 
 
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13.1 
References ..................................................................................................................... 71 
13.2 
Institutional Review Board/Independent Ethics Committee and Regulatory/Competent 
Authorities ................................................................................................................................. 72 
13.3 
Subject Informed Consent ............................................................................................. 72 
13.4 
Trial Records and Archiving ........................................................................................... 73 
14 
QUALITY CONTROL / QUALITY ASSURANCE ............................................................ 74 
14.1 
Direct Access to Source Data/Documents ......................................................................... 74 
14.2 
Clinical Monitoring ........................................................................................................... 74 
14.3 
Clinical Data Handling ...................................................................................................... 74 
14.3.1 
Data Reported in the eCRF ........................................................................................ 74 
14.3.2 
Data Reported in the eCRF according to Subject Status ............................................ 75 
14.3.3 
Data Management System ........................................................................................ 75 
14.4 
Audits and Inspections ...................................................................................................... 75 
15 
PUBLICATIONS RULES..................................................................................................... 76 
16 
REFERENCES ...................................................................................................................... 77 
17 
COMPANY LIABILITY INSURANCE .............................................................................. 78 
18 
APPENDICES ....................................................................................................................... 79 
 
 
18.2 
List of Study Plans For Time Window Allowance .......................................................... 80 
 
 


 
 
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LIST OF TABLES 
Table 1: Possible assignments of positive control, placebo, P03277 at anticipated clinical dose and 
P03277 at supra-clinical dose ..................................................................................................................... 29 
Table 2: Volume of P03277/Placebo injection by dose and body weight .................................................. 38 
Table 3: Time periods for the assessment of AEs ...................................................................................... 66 
 
LIST OF FIGURES 
 
Figure 2: Atrial depolarization (P-wave), ventricular depolarization (QRS complex) and ventricular 
repolarization (T wave, U wave) [1] ..................................................................................................... 27 
 
 
 
 


 
 
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1 
INTRODUCTION AND TRIAL RATIONALE 
Gadolinium-Based Contrast Agents (GBCAs) have been used extensively in a large range of indications 
in MRI examinations. GBCAs consist of the active substance gadolinium (Gd) and a chelating agent. 
They can be categorized by their chemical structures into linear and macrocyclic agents and further 
subdivided by their charge (ionic or non-ionic). In vitro experiments have shown that the macrocyclic 
compounds are the most stable, with an undetectable release of Gd3+ ions under physiological conditions.  
 
P03277 is a new chemical entity discovered and developed by Guerbet. It is a non-ionic macrocyclic 
gadolinium (Gd) complex having a high kinetic stability. It is intended to be used in human, by 
intravenous bolus injection, as a contrast agent for Magnetic Resonance Imaging (MRI). Potential 
applications may include but are not limited to imaging of the Central Nervous System (CNS), of “whole 
body” pathologies and magnetic resonance angiography (MRA), etc. 
 
P03277 has a molecular weight of 970.11 g/mol
 
P03277 is used as an aqueous injectable solution for injection at a concentration of 0.5 M. 
 
P03277 is a Gd chelate with a very high stability, limiting the risk of release of toxic free Gd in the body. 
The results of preclinical data indicate a good tolerance and a low toxicity profile at dose levels and 
exposure much higher than the anticipated clinical dose. This satisfactory tolerance has been confirmed in 
a phase I/IIa trial. In this trial, 36 healthy volunteers and 12 patients were administered with a single dose 
of P03277 and 18 volunteers with placebo. No serious adverse reaction occurred in any of these 
volunteers and patients at any of tested dose at 0.025, 0.5, 0.75, 0.1, 0.2, and 0.3 mmol/kg BW. No 
clinically significant changes in vital signs or laboratory findings were noted.  
No ECG findings were reported as AE during the phase I/IIa trial but limited ECG data were available in 
this first in man trial. 
Moreover, a phase IIb dose ranging trial has started in Europe, North America and South Korea where 
approximately 280 patients will undergo a brain MRI under administration of P03277. During this phase 
IIb trial ECG monitoring is also performed as 12-leads ECG evaluated at several timepoints until 1 day 
post-administration. 
According the guideline ICH E14 “The clinical evaluation of QT/QTc interval (Figure 2) prolongation 
and proarrhythmic potential for non-antiarrhythmic drugs” applicable since November 2005, it is 
recommended to assess the cardiac tolerance (ECG data) of a new product having systemic bioavailability 


 
 
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by conducting a well-controlled trial to assess the potential of a drug to delay cardiac repolarization. This 
assessment should include testing the effects of new agents on the QT/QTc interval as well as the 
collection of cardiovascular adverse events. 
 
 
Figure 2: Atrial depolarization (P-wave), ventricular depolarization (QRS complex) and ventricular 
repolarization (T wave, U wave) [1] 
 
This GDX-44-006 trial will fulfill this regulatory requirement and is part of a clinical development plan to 
be performed in order to support EMA and FDA approval of P03277. 


 
 
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2 
TRIAL OBJECTIVES 
2.1 Primary Objective 
To assess the cardiac safety after administration of P03277 by evaluating the QT and QTc intervals in 
healthy volunteers. 
 
2.2 Secondary Objectives 
To assess the cardiac, clinical and biological safety, plasma concentration, and long term elimination 
profile of P03277 following its administration in healthy volunteers. 
 
2.3 Sub-Trial / Ancillary Trial Objectives 
Not applicable 
 
 


 
 
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3 
TRIAL DESCRIPTION 
3.1 Protocol Design 
Phase I clinical trial, single center, randomized, cross-over double-blind placebo-controlled and open-
label positive-controlled (moxifloxacin) [2]  in healthy volunteers. 
This trial will be conducted as 4*4 cross-over design that is more sensitive for detecting QT changes. 
According the guideline ICH E14, a “Thorough QT/QTc trial” has to assess the anticipated therapeutic 
dose and a higher dose than the anticipated therapeutic dose. 
The anticipated therapeutic dose for P03277 is 0.1 mmol/kg, which is a standard dose for most GBCAs 
currently approved. The supra-therapeutic dose of P03277 that will be assessed is 0.3 mmol/kg. Indeed, it 
is the dose also used with some currently approved GBCAs for limited applications, and it is important in 
phase I clinical trial to ensure that there is no impact on QT/QTc at this high dose level. 
 
The three Investigational Medicinal Products (IMPs) will be: 
- 
P = Placebo (Nacl 0.9%) 
- 
CD = P03277 tested at anticipated clinical dose (0.1mmol/kg) 
- 
SD = P03277 tested at supra-clinical dose (0.3mmol/kg). 
The positive control, moxifloxacin, is an auxiliary medicinal product. 
- 
PC = Positive control (moxifloxacin 400 mg – per os) 
Subjects who have provided written informed consent and satisfied all eligibility requirements will be 
included in the trial and randomized, according to a randomization list generated by a statistician not 
operationally involved in the study, to receive one of 4 sequences according to a Williams design for a 
4*4 cross over which is balanced for first order carry over effect. 
The sequences of administration could be for instance: 
 
  
Period 1 
Period 2 
Period 3 
Period 4 
Sequence #1 
P 
CD 
PC 
SD 
Sequence #2 
CD 
SD 
P 
PC 
Sequence #3 
SD 
PC 
CD 
P 
Sequence #4 
PC 
P 
SD 
CD 
 
Table 1: Possible assignments of positive control, placebo, P03277 at anticipated clinical dose and P03277 at 
supra-clinical dose 
12 subjects will be assigned to each sequence (6 males and 6 females). 
3.2 Trial Duration 
The duration of subject’s participation could be from 95 days up to 122 days (in case the subject signs the 
informed consent form (ICF) within 28 days before inclusion). 
Within 4-weeks up to 1 day run-in period, subjects will be screened for the trial. Inclusion in the trial will 
occur the day the subject will be admitted to the phase I clinical trial unit  for the first administration 
period of the allocated sequence (subjects may be admitted in the phase I clinical trial unit at Day -1 to 


 
 
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ensure availability of all results prior to administration). Each subject will have 4 administration periods. 
Period’s duration for moxifloxacin, placebo period, P03277 at clinical dose and P03277 at supra-clinical 
dose periods will each be 72 hours. The total duration for all periods will be 12 days. 
During the 12 days of assessment and monitoring, the subject will have to stay in the phase I clinical trial 
unit. Healthy volunteers will be discharged on Day 12 after that all trial procedures have been performed 
and that all safety results have been reviewed by the investigator who will determine that it is safe to 
discharge the subject. 
One month and 3 months following the last IMP/AMP administration on Day 10, subjects will be asked 
to come back at the phase I clinical trial unit to assess the P03277 long term elimination (in plasma and 
urine).  
For each subject, all ECG parameters will be extracted from the 12-lead Holter ECG in triplicates (3 
ECGs taken in close succession according to the ECG core lab specifications) and read centrally by an 
ECG core lab. The mean of the triplicate ECGs recordings will be considered for each timepoint. 
P03277 plasma and urine concentration samples will be analyzed and data reported by an analytical 
center as described in section 8.4. All other drawn samples will be kept by the analytical center for the 
trial duration and then will be discarded. 
The trial will be considered as completed once all the ECG collected for all the subjects are reviewed by a 
core lab and all P03277 plasma concentration and elimination data are available. 
3.3 Interim Analysis (if applicable) 
Not applicable 
3.4 Trial Committee(s) 
A Data Monitoring Committee (DMC) will be set up for assessing the safety of the Investigational 
Medicinal Products (IMPs/AMP) during the trial and for monitoring the overall conduct of the clinical 
trial (see section 12) and will be responsible ensuring the subjects stopping rules for safety reasons are 
applied (see section 10.2).  
The DMC will consist of members of Guerbet team and the principal investigator. 
 
 


 
 
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4 
SUBJECT SELECTION 
4.1 Inclusion Criteria 
To be included in the trial, the subject must meet all these inclusion criteria. 
1. Adult healthy volunteers at least 18 years old and below 60 (exclusive) 
2. Subject having read the information and provided his/her consent to participate in writing by dating and 
signing the informed consent prior to any trial-related procedure being conducted 
3. Subject assessed as healthy by a comprehensive clinical assessment (detailed medical history and 
complete physical examination) 
4. Subject with a Body Mass Index (BMI) > 19 kg/m2 and < 28 kg/m2 and a weight at least of 40 kg for 
female and 50kg for male and at maximum of 100kg 
5. Subject able and willing to participate in the trial 
 
4.2 Non Inclusion Criteria 
Subjects presenting with one or more of these non-inclusion criteria must not be included in the trial. 
1. Subject with any history or family history of inherited or acquired Long QT syndrome (LQTS) 
2. Subject with any history or family history of risk factors for Torsade de Pointe (TdP), unexplained 
loss of consciousness or convulsion 
3. Subject with any history of clinically significant bradycardia 
4. Subject with any history of clinically significant cardiac impairment by decreasing of left ventricular 
ejection fraction (LVEF) 
5. Subject with any history of clinically significant arrhythmia (including Wolf-Parkinson-White 
syndrome) 
6. Subject with presence of cardiac pacemaker 
7. Subject with frequent headaches and/or migraine, recurrent nausea and/or vomiting (more than twice 
a month) 
8. Subject with abnormal 12-lead ECG: PR < 120 ms or PR > 200 ms, QRS > 100 ms, QTc > 450 ms, 
flat T-waves at screening visit (results provided by the independent ECGs Core Laboratory). 
9. Subject with following abnormal vital signs after 10 minutes resting in supine position at screening 
visit: 
o systolic blood pressure < 90 mmHg or > 160 mmHg 
o diastolic blood pressure < 45 mmHg or > 90 mmHg 
o resting heart rate < 45 bpm or > 80 bpm 
10. Subject with any history or presence of relevant cardiovascular, pulmonary, gastrointestinal, hepatic, 
renal, metabolic, haematological, psychiatric, systemic, ocular, or infectious disease; any acute 
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11. Subject with abnormal biological, hematological or coagulation tests considered as clinically 
significant  by the investigator  and  with the following abnormal laboratory parameters (out of 
normal ranges) (results have to be available at the latest at Day 1)  
o Low potassium blood level (K+ < 3.5 mmol/L) 
o Low magnesium blood level (Mg++ < 
 0.66 mmol/L) 
o Estimated creatinine clearance rate (eCCr) < 90 mL/min (Cockroft & Gault formula) 
o Impaired liver function and transaminases  > 2 fold ULN 
12. Subject carrier of: HBs antigen, anti-HCV antibodies, anti-HIV1 antibodies, anti-HIV2 antibodies at 
screening 
13. Subject with any history of severe allergic or anaphylactic reactions to any allergen including drugs 
and contrast agents, or allergic disease diagnosed and treated by a physician 
14. Subject with any history of tendinopathy following a fluoroquinolone treatment 
15. Subject with any history of allergy to moxifloxacin or one of its compounds or other moxifloxacin 
contra-indications according to the SmPC description 
16. Subject with known contra-indication(s) to the use or with known sensitivity to one of the products 
under investigation or to drugs from a similar pharmaceutical class 
17. Subject treated with any concomitant medications which could induce a QT prolongation 
18. Subject with presence of narcotics or alcohol abuse (alcohol consumption > 40 grams/Day) at 
screening 
19. Subject smoking more than 10 cigarettes or equivalent /Day, unable to stop smoking during the 
confinement period 
20. Subject having an excessive consumption of beverages with xanthines bases (tea, coffee, chocolate) 
(>6 cups or glasses /Day) and not able to refrain from consuming  grapefruit (fresh fruit, juice, ice...) 
the day before inclusion and during the confinement period  
21. Subject having done a blood donation within 3 months before first trial product administration 
22. Subject having received any medication within 21 days prior to inclusion, or within 5 times the 
elimination half-life of that drug, whichever the longest, with the exception of hormonal 
contraception for female and of Hormonal Replacement Therapy (HRT) in case of menopausal 
volunteers and paracetamol 
23. Subject having received an administration of any contrast agent within 2 weeks before inclusion, or 
scheduled to receive any contrast agent within 3 months after the last IMP administration. 
24. Subject having participated to a clinical trial involving an investigational drug or device within 21 
days prior to screening, or within 5 times the elimination half-life of that drug whichever the longest 
25. Subject having a planned simultaneous participation to another clinical trial involving an 
investigational drug or device 
26. Subject having an inability or unwillingness to cooperate with the requirements of this trial 
27. Subject having a planned interventions (surgery, radiotherapy, chemotherapy or others) during the 
course of the trial 
28. Subject with any condition which, based on the investigator's clinical judgment, would prevent the 
subject from participating in all trial assessments and visits (for example: mental or physical 
incapacity, language comprehension, geographical localization, etc…) 


 
 
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29. Female subject being pregnant or breast-feeding (a female subject of childbearing potential or with 
amenorrhea for less than 12 months must have a negative pregnancy test at inclusion and must be 
using a medically approved contraception method) 
4.3 Subject Identification 
After having obtained the written informed consent, Subjects will be included in the trial and will be 
allocated a unique Identification Number (Subject ID). 
This Subject 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 subject enrolment. The lowest 
enrolment number will correspond to the first subject enrolled at this site and the highest number to the 
last subject enrolled. 
 
 


 
 
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5 
INVESTIGATIONAL MEDICINAL PRODUCTS 
Investigational Medicinal Product(s) will be manufactured (or commercially available for placebo), 
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 (or commercially available for placebo), packaging, labeling and 
release will comply with any local applicable regulatory requirement. 
Allocation of IMP/AMP to subject will be randomized according to a randomization list generated by a 
statistician not operationally involved in the study. 
Moxifloxacin as positive control is qualified as “Auxiliary Medicinal Product”. 
 
5.1 Investigational and Auxiliary Medicinal Products Description 
5.1.1 Investigational Medicinal Product 1: P03277 
Name: P03277 
 
Pharmaceutical form: vial of 20 mL, solution for injection  
Concentration: 0.5 M 
Route and method of administration: by intravenous (IV) bolus injection at 2 mL/s rate without dilution, 
followed by a saline flush (at least 10 mL) to ensure complete injection of the contrast agent. 
Regarding P03277, the IMP will consist of an individually packaged vial in a carton box with a single use 
detachable label that will allow ensuring accuracy of IMP allocation per subject 
P03277 is an aqueous solution. Each vial contains 20 mL of solution presented as a sterile, clear, yellow, 
ready-to-use solution for injection. 
P03277 dose per administration: P03277 will be injected to a pre-specified ordering according to 
sequence allocated by randomization at 0.1 and 0.3 mmol/kg BW (corresponding to 0.2 and 0.6 mL/kg 
body weight) via a peripheral vein (the antecubital vein is preferred). The IV injection line will consist of 
a large bore indwelling catheter (at least 18 gauge).  
Sufficient IMP must be allocated to one subject by calculation according to the subject body weight (see 
section 5.3.1). 
The P03277 administration is to be performed by power injector in order to better control injection rate. 
Please refer to the ongoing version of Investigator Brochure for more information on P03277. 
 


 
 
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5.1.2 Investigational Medicinal Product 2: Placebo 
Name: NaCl solution 
Pharmaceutical form: ampoule of 10 mL, ready to use for injection 
Concentration: 0.9 % 
Route and method of administration: by intravenous (IV) bolus injection at 2 mL/s rate like P03277 and 
followed by a saline flush (at least 10 mL) to ensure the blind conditions. 
Regarding Placebo, the IMP will consist of two packaged ampoules in a carton box with a single use 
detachable label that will allow ensuring accuracy of IMP allocation per subject 
Placebo administration: NaCl solution 0.9 % will be injected like P03277. The IV injection line will 
consist of a large bore indwelling catheter (at least 18 gauge).  
Volume of placebo to inject for each patient will be equivalent to the volume of P03277 0.3 mmol/kg and 
determined by calculation according to the subject body weight (see section 5.3.1). 
The NaCl solution 0.9 % administration is to be performed by power injector in order to better control 
injection rate. 
Please refer to the ongoing version of summary of product characteristics for more information on NaCl 
solution. 
5.1.3 Auxiliary Medicinal Product 1: Positive control: moxifloxacin 
Moxifloxacin is a medicinal product given to the trial subject as a tool to assess the assay sensitivity; it is 
not being tested or used as a reference in this clinical trial. For this reason, moxifloxacin is called 
Auxiliary Medicinal Product (AMP) in this trial. 
Name: moxifloxacin  
Pharmaceutical form: 400 mg film-coated tablets 
Dose per administration: 400 mg 
Route of administration: per os 
Regarding moxifloxacin, AMP will consist in a box that contains 1 blister of 1 tablet with a single use 
detachable label that will allow ensuring accuracy of AMP allocation per subject  
All selected subjects will be randomly administered with a single dose of positive control in open 
condition, as it will be administered orally (as opposed to intravenous injection of P03277 and of 
Placebo). 
Please refer to the ongoing version of summary of product characteristics for more information on 
moxifloxacin. 
5.2 Packaging, Labeling, Storage 
Packaging and labeling will be performed in strict accordance with the local regulatory specifications and 
requirements. 
5.2.1 Investigational Medicinal Products 
The packaging and labeling of P03277 and Placebo will be performed by Guerbet (or its designee).  


 
 
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In addition to the usual and regulatory labeling for clinical studies, each IMP will have a white detachable 
sticker indicating the protocol number, IMP number and other locally required information. This label 
will be stuck on the subject file or trial documentation.  
For P03277, IMP will consist in a box that contains one 20 mL vial of P03277. 
For Placebo, IMP will consist in a box that contains two 10 mL ampoules of NaCl 0.9%. 
 
In case of damaged IMP, a new IMP will be allocated to the subject. 
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 the SmPC or Investigator’s Brochure. The IMPs should 
be stored at a temperature between 15°C and 25°C 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. 
5.2.2 Auxiliary Medicinal Product: moxifloxacin 
The positive control will be commercially purchased and used with its primary packaging. 
The secondary packaging and labeling of positive control will be performed by Guerbet (or its designee). 
In addition to the usual and regulatory labeling for clinical studies, each AMP will have a white 
detachable sticker indicating the protocol number, AMP number and other locally required information. 
This label will be stuck on the subject file or trial documentation.  
For positive control, AMP will consist in a box that contains 1 blister of 1 tablet. 
In case of damaged AMP, a new AMP will be allocated to the subject by chronological order. 
All AMPs will be stored in a secure place, under the responsibility of the Investigator or other authorized 
individual and under the conditions described in the SmPC. The AMPs should be stored at a temperature 
between 15°C and 25°C in the original package and not frozen. 
At the time of the trial completion, all used (including empty box) and unused AMPs should have been 
returned to the Sponsor or to the predefined location for storage before destruction. 
5.3 Condition of IMP and AMP Allocation 
5.3.1 Investigational Product(s) Allocation / Randomization 
Subjects who have provided written informed consent and satisfied all eligibility requirements will be 
included in the trial and randomized to receive one of 4 sequences described in section 3.1.  
IMP will be randomly assigned to subjects according to a randomization list generated by a statistician 
not operationally involved in the study.  
The volume (mL) of P03277 or placebo having to be injected to the subjects will be determined by 
calculation according to the subject body weight before each administration (see Table 2: Volume of 
P03277/Placebo injection by dose and body weight). 
The weight to be used to determine the dose to be administered will be the rounded weight below the 
subject’s measured weight. The standard volume for Placebo will correspond to the P03277 volume given 
at the high dose 0.3 mmol/kg, i.e. 0.6 mL/kg. 
 
 
 
 


 
 
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Volume of P03277/Placebo injection by dose and body weight 
 
Adults 
P03277 - CD 
P03277 - SD  
P  
Dose (mmol/kg) 
Dose (mmol/kg) 
Placebo 
0.1 
0,3 
Dose (mL/kg) 
Dose (mL/kg) 
0.2 
0,6 
Body Weight 
Volume 
Volume 
Volume 
Kilograms (kg) 
(mL) 
(mL) 
(mL) 
40 
8 
24 
24 
41 
8 
24 
24 
42 
8 
25 
25 
43 
8 
25 
25 
44 
8 
26 
26 
45 
9 
27 
27 
46 
9 
27 
27 
47 
9 
28 
28 
48 
9 
28 
28 
49 
9 
29 
29 
50 
10 
30 
30 
51 
10 
30 
30 
52 
10 
31 
31 
53 
10 
31 
31 
54 
10 
32 
32 
55 
11 
33 
33 
56 
11 
33 
33 
57 
11 
34 
34 
58 
11 
34 
34 
59 
11 
35 
35 
60 
12 
36 
36 
61 
12 
36 
36 
62 
12 
37 
37 
63 
12 
37 
37 
64 
12 
38 
38 
65 
13 
39 
39 
66 
13 
39 
39 
67 
13 
40 
40 
68 
13 
40 
40 


 
 
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69 
13 
41 
41 
70 
14 
42 
42 
71 
14 
42 
42 
72 
14 
43 
43 
73 
14 
43 
43 
74 
14 
44 
44 
75 
15 
45 
45 
76 
15 
45 
45 
77 
15 
46 
46 
78 
15 
46 
46 
79 
15 
47 
47 
80 
16 
48 
48 
81 
16 
48 
48 
82 
16 
49 
49 
83 
16 
49 
49 
84 
16 
50 
50 
85 
17 
51 
51 
86 
17 
51 
51 
87 
17 
52 
52 
88 
17 
52 
52 
89 
17 
53 
53 
90 
18 
54 
54 
91 
18 
54 
54 
92 
18 
55 
55 
93 
18 
55 
55 
94 
18 
56 
56 
95 
19 
57 
57 
96 
19 
57 
57 
97 
19 
58 
58 
98 
19 
58 
58 
99 
19 
59 
59 
100 
20 
60 
60 
 
Table 2: Volume of P03277/Placebo injection by dose and body weight 
 
The administration has to be performed by power injector in order to better control the injection rate. 
In case of problem of IMP allocation (e.g. wrong IMP administered to a subject), the site must 
immediately report the incident to Guerbet unblinded staff in order to ensure that all corrective actions are 


 
 
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taken. Corrective actions may include transferring the IMP to quarantine to prevent further IMP allocation 
by the site until the situation is under control again.  
5.3.2 Auxiliary Product Allocation 
AMP will be randomly assigned to subjects according to a randomization list generated by a statistician 
not operationally involved in the study. 
In case of problem of AMP allocation (e.g. wrong AMP administered to a subject), the site must 
immediately report the incident to Guerbet in order to ensure that all corrective actions are taken. 
Corrective actions may include transferring the AMP to quarantine to prevent further AMP allocation by 
the site until the situation is under control again. 
5.3.3 Double-Blind Conditions 
To ensure that administrations of the P03277 and placebo are carried out under double-blind conditions, 
third party (nurse, technician, pharmacist and/or physician) will be responsible for preparing and 
administrating the IMP(s) according to the randomization list prepared by the statistician. This (these) 
person(s) will ensure non-disclosure of information. He/she will stick the detachable label of the box into 
the Subject’s records or appropriate form. He/she will also write his/her name, date and signature and the 
subject number on the box, and after use, he/she will close the box with a seal.  
The phase I clinical trial unit must ensure that the subject and investigator remain blind about the 
administered product. 
Any disclosure relating to the nature of the IMP injected by the person responsible for IMP allocation will 
be considered a protocol deviation. 
12-lead Holter ECG reading of all patients will be evaluated in blinded conditions regarding subject, 
product, date and time-point identifier as described in section 8.3.3.5 
5.3.4 Individual Trial Treatment Unblinding 
The blinding system will be made of two sets of envelopes. 
One sealed envelopes set is kept at the phase I clinical trial unit, the other at the Guerbet 
pharmacovigilance Representatives (Sérénité 24/24h).  
The sets of envelopes should be kept in a safe place and accessible to any person authorised to unblind. 
In case of an adverse event occurring for a subject and which nature would require immediate knowledge 
of the allocated IMP, the individual trial treatment may be unblinded, if absolutely necessary for the 
safety of the subjects and if unblinding impacts the management of medical care (see section 9.5).  
Conditions and procedure for breaking the code will be reviewed with the investigator and his/her team 
during the initiation visit. 
The persons authorized to unblind trial product during the trial usually are: the principal investigator and 
the Sponsor Pharmacovigilance physician/officer.  
If a Guerbet representative receives an external request for unblinding (Authorities, health care 
professionals taking care of the subject, etc.), he/she must inform the Sponsor Pharmacovigilance 
Physician/Officer. 


 
 
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If the investigator and the Sponsor Pharmacovigilance physician/officer unblind the trial product, he/she 
must inform the Clinical Project Manager as soon as possible by letter, fax or e-mail but shall not reveal 
the nature of the trial product in order to protect as much as possible the double-blind design of the trial.  
Unblinding must be documented on the opened envelope by indicating the subject’s identification 
number, age and gender, the date, time and the reason for unblinding, the identity of the person who 
performed the unblinding.  
Please refer to section 9.5 for detailed information on subject safety monitoring. 
5.4 IMP and AMP Management 
The investigator, the pharmacist, or other personnel allowed to store and dispense Investigational 
Medicinal Product(s) and Auxiliary Medicinal Product(s) are responsible for ensuring that the IMP and 
AMP used in the clinical trial is securely maintained as specified by the sponsor and in accordance with 
the applicable regulatory requirements.  
The clinical unit has to ensure that an IMP/AMP storage temperature monitoring will be done 24 hours a 
day and 7 days a week. 
Any quality issue noticed with the receipt or use of an IMP or AMP (deficient IMP/AMP in condition, 
appearance, pertaining documentation, labeling, expiry date, etc.) or temperature excursion should be 
promptly notified to Guerbet, who will initiate a complaint procedure. 
Under no circumstances shall the investigator supply IMP or AMP to a third party, allow the IMP or 
AMP to be used other than as directed by this clinical trial protocol, or dispose of IMP or AMP in any 
other manner. 
If during the administration of IMP/AMP, the subject experiences a Serious Adverse Event (SAE), the 
IMP administration must be discontinued and the subject rendered emergency medical care and 
monitored until the event is resolved (see section 9.2) 
 
5.5 Trial Product(s) Compliance and Accountability 
The investigator, the pharmacist, or other allowed personnel will keep accurate records of Investigational 
Medicinal Products and Auxiliary Medicinal Products accountability at site level as well as accurate 
records of the batch numbers and quantities of the IMP/AMP given to each subject.  
The dosing information will be recorded in individual subject’s records or appropriate form. When 
protocol required IMP/AMP 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 
Subject having received any medication within 21 days  prior to inclusion or within 5 times the 
elimination half-life of that drug, whichever the longest (with the exception of hormonal contraception for 
female and of HRT in case of menopaused volunteers and paracetamol, which will be collected as 
concomitant medication) cannot take part to the trial GDX-44-006 (refer to non-inclusion criteria). 
6.1.1 Concomitant Treatments of Special Attention 
In case of a subject has to be administered with any other GBCAs between discharge and Follow-up 1 
and 2 for any unscheduled reason, this information will be recorded. 
6.1.2 Prohibited Concomitant Treatments 
Use of any prescription drugs (except for contraceptive pills, paracetamol and AE countermedication), 
herbal supplements medication, dietary supplements, and/or over the-counter (OTC) within 3 weeks prior 
to inclusion until the end  of the confinement period will be prohibited.  
6.2 Procedures 
Not applicable 


 
 
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7 
EVALUATION CRITERIA 
For each subject, all ECG parameters (except stopping rules ECG parameters) will be extracted from the 
12-lead Holter ECG in triplicates [3] and read centrally by a core lab. The mean of the triplicate ECG 
recordings will be considered for each timepoint. 
P03277 plasma and urine concentration samples will be analyzed for each subjects by an analytical center 
as described in section 8.4.  
Details about ECG reading process and samples to assess P03277 concentration handling will be 
described in separate documents. 
Hematology and biochemistry parameters will be assessed ongoing by the phase I clinical trial unit staff. 
7.1 Primary Criterion 
Primary criterion of cardiovascular safety assessment of P03277 is defined as the largest time-matched 
placebo-corrected, change-from-baseline mean effect of the two P03277 doses of QT interval expressed 
as QTc according to Fridericia’s formula (∆∆QTcF)(in ms). No significant QTc prolongation will be 
considered if the upper limit of the 90 % confidence interval of the maximum ∆∆QTcF is < 10%. 
To determine the ∆∆QTcF, the Heart Rate (RR) value and QT value (ms) will be assessed on triplicates 
12-lead Holter ECG: 
- 
moxifloxacin: pre-dose up to 24 hours post dose:  
[-1hour, 30min, 1 hour,1.5 hours, 2 hours, 3 hours, 4 hours, 8 hours, 24 hours] 
- 
P03277 and Placebo: pre-dose up to 24 hours post dose:  
[-1hour, 5min, 10 min, 20 min, 30min, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 8 hours, 24 
hours]. 
 
7.2 Secondary Criteria 
Secondary criteria will consist of cardiac, clinical and biological safety evaluations as follow: 
7.2.1 Cardiac Safety 
- 
Assay sensitivity assessment is defined as the largest time-matched placebo-corrected, change-from-
baseline mean effect of moxifloxacin of QT interval expressed as QTc according to Fridericia’s 
formula (∆∆QTcF) (in ms)  
- 
Time-matched placebo-corrected, change-from-baseline mean effect, measured at any timepoints for 
all IMPs/AMP (Cf. IMPs/AMP related to ECG timepoints listed in section 7.1: 
o QT (ms) 
o QTc(ms) according to population specific correction formula (QTcPOP) 
o QTc (ms) according to Bazett’s formula (QTcB)  
- 
Parameters measured at any timepoints assessed through a 25 hour 12-lead Holter ECG recording : 
o QT 
o QTcF 
o QTcPOP 
o QTcB 
o RR (ms) 
o QRS (ms) 


 
 
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o PR (ms) 
o Heart rate (bpm) 
- 
T wave morphology changes (yes/no) and U wave occurrence  
- 
Sinus rhythm (yes/no) 
- 
Bradycardia and arrhythmia  
7.2.2 Clinical and Biological safety 
7.2.2.1 Adverse Events 
Adverse event will be recorded throughout the subject participation up to end of confinement for all AEs  
except pregnancy (subject’s or subject’s partner) that will be recorded throughout the subject participation 
up to 7 days after the last IMP/AMP administration (day 17). During follow-up period only related AEs 
and AESI will be recorded. 
7.2.2.2 Biology 
For each subject, blood samples will be performed at screening visit, at Day 1 and 2 days after each 
administration. The blood analysis will be performed by the site laboratory (except P03277 plasma and 
urine concentration assessment which will be managed by an analytical center) 
 
The following parameters will be obtained and assessed:  
 
- 
Hematology: Red Blood Cells (RBCs), White Blood Cells (WBCs), neutrophils, eosinophils, 
basophils, lymphocytes and monocytes, platelet count, hemoglobin, hematocrit, Mean red blood Cells 
Volume (MCV). 
- 
Biochemistry: sodium, potassium, magnesium, chloride, glucose, urea, creatinine, eGFR, total 
protein, calcium, phosphorus, total bilirubin, unconjugated and conjugated bilirubin, Aspartate Amino 
Transferase (AST), Alanine Amino Transferase (ALT), alkaline phosphatase, Lactate DeHydrogenase 
(LDH). Triglycerides (TG). 
Blood Urea Nitrogen (BUN) will be calculated on the basis of serum Urea values. 
For all laboratory assessments, the site laboratory will flag laboratory values falling outside of the normal 
ranges on the site laboratory report (which the investigator should review and sign off) and the 
investigator will report any values considered clinically significant as an AE. 
7.2.2.3 Vital signs 
Vital signs (blood pressure, pulse rate) will be assessed at screening visit, before each trial product 
administration and on the same timepoints of ECG.  
Body weight will be assessed at screening visit, inclusion visit and after each trial product administration. 
7.2.2.4 Tolerance at injection site 
For all subjects, injection-site tolerance (burning, pain, eruption, extravasation, inflammation, or other) 
will be assessed over 1 day following each injection (during the injection, up to 30 min ± 5 min and the 
day after injection) and over a longer period if the investigator becomes aware of any related AE. In case 


 
 
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of injection-site pain, the subject will be asked to specify the level of pain using a visual analogic scale 
(VAS, 
) from 0 (no pain) to 10 (maximal pain).  
 
7.2.2.5 Safety 12-leads ECGs  
12-leads ECGs to assess subject’ safety and to monitor subject and trial stopping rules (see section 10.2) 
related to the QTcF values will be done as triplicate within 1 hour before administration and 10 minutes 
and 3 hours post-administration. 
In addition of the real-time on-site reading, all Safety ECGs will be independently reviewed by a ECGs 
Core Laboratory (independent reviewer).  
The data to be used for safety analyses (section 11.3.9) will be the ECGs Core Laboratory data. 
7.2.3 P03277 plasma concentration and long term elimination parameters 
P03277 plasma concentration and long term elimination analysis will be subcontracted to a analytical 
center and will be supervised by Guerbet.  
Specific analytical protocols will be established for analysis of P03277. All parameters description and 
data will be reported in a separate report. All analytical methods used in this trial will be validated prior to 
any sample analysis. 
7.2.3.1 Plasma concentration parameters 
Plasma concentration of P03277: blood samples will be drawn from period 1 to period 4, to every subject. 
Specifics timepoints are defined: 
Pre-dose up to 24 hours post dose:  
[-1hour, 5min, 10 min, 20 min, 30min, 1 hour, 1.5 hours, 2 hours, 3hours, 4 hours, 8 hours, 24 hours]. 
P03277 concentrations in plasma will be analyzed using a validated LC-MS-MS method. 
 
 
7.2.3.2 Long term elimination parameters 
To assess potential long term/delayed elimination of P03277, one blood and one urine sample will be 
collected for each subject (having received at least one dose of IMP) on Day 38 and Day 94.  
Only the presence and concentration of P03277 in those samples will be assessed by measuring P03277 
concentrations using a validated LC-MS-MS method. 


 
 
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8 
TRIAL SCHEDULE AND PROCEDURES 
8.1 Trial Schedule 
This paragraph describes in detail how the visits are carried out, in their chronological order and 
according to the flowchart. Time windows allowance have been defined for each study procedures as 
described in the relevant study plans listed in section 18.2. 
 
8.1.1 Screening Visit – (Day -28) to (Day -1) 
During this visit, the following tasks or assessments will be performed: 
- 
Written informed consent will be obtained from the subject as described in section 13.3; 
- 
The subject will be attributed an Identification Number as described in section 4.3; 
- 
Demographic data (such as sex, age, race and ethnicity) will be recorded;  
- 
Verification of all eligibility criteria will be done by the Investigator; 
- 
A physical examination will be performed and Vital Signs (systolic and diastolic Blood Pressure in 
supine position, Pulse Rate), body weight and height will be measured; 
- 
Medical history will be obtained. The Investigator will question on any possible previous contrast 
agents injection (name of contrast agent injected and tolerance will be recorded); 
- 
Medications and treatments on-going at the time of signing informed consent will be documented; 
- 
12-lead ECG assessment (Triplicate ECG); 
- 
Blood samples collection for biological assessment and serology; 
- 
Urine samples collection for drugs screening; 
All results have to be available at the latest at Day 1. 
If all selection requirements are fulfilled, an inclusion appointment will be scheduled to check biological 
and serology results and to proceed at the subject inclusion. 
If any of the selection requirements is not fulfilled (out of biological results if results not available on 
screening visit), the subject will not perform the inclusion in the phase I clinical trial unit and will be 
considered as a screening failure. 
8.1.2 Inclusion visit – (Day  1 or the day before (Day-1) 
At the Inclusion visit the following tasks or assessments will be performed at first: 
- 
Eligibility criteria, concomitant medication and prior contrast agents checked at the screening visit 
must be confirmed at the inclusion visit and updated if applicable; 
- 
Biology results, drug testings and serology results from screening visit will be checked by the 
Investigator; 
- 
Urinary collection for pregnancy test, only for female subject of childbearing potential or with 
amenorrhea for less than 12 months; 


 
 
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- 
Body weight (IMP volume to be injected at Day 1 should be based on weight measured at inclusion 
visit  
If all selection requirements are fulfilled, the subject will be considered as included; 
- 
Subject inclusion in the phase I clinical trial unit confirmation: start of confinement period; 
- 
Subject randomization and sequence allocation. 
If any of the selection requirements is not fulfilled, the subject will not perform the inclusion in the phase 
I clinical trial unit and will be considered as a screening failure. 
 
8.1.3  (Day 1) to (Day 3), (Day 4) to (Day 6), (Day 7) to (Day 9) and (Day 10) to 
(Day 12) – Periods 1, 2, 3 and 4: 
During these periods the subject has to stay at the phase I clinical trial unit and will be continuously 
monitored by the phase I clinical trial unit staff especially for adverse event and concomitant medication 
if applicable. 
8.1.3.1 Before IMP/AMP administration 
- 
Day 1: 
 
o Physical examination  
o Blood sample collection for baseline values of biological assessment 
o IMP/AMP allocation 
- 
Day 4, Day 7 and Day 10:  
o Physical examination 
o Biochemistry results has to be reviewed in order to check subject stopping rules (see section 
10.2): Creatinine results should be available before to proceed at the IMP/AMP allocation and 
administration 
o IMP/AMP allocation 
o IMP/AMP number have to be entered in the subject’s record and/or appropriate form 
8.1.3.2 Within 1 hour before administration 
- 
Day 1, Day 4, Day 7 and Day 10, T-1h: 
o Vital Signs (systolic and diastolic Blood Pressure in supine position after 10 minutes of rest, 
Pulse Rate) 
o 12-lead Holter ECG monitoring initiation for the next 25 hours and the Holter start date and time 
information have to be entered in the subject’s record and/or appropriate form 
o 12-lead ECG as triplicate for safety (within the 1 hour pre-dose in supine position and after 10 
minutes of rest)  
o Blood samples collection for P03277 plasma concentration assessments  
8.1.3.3 Administration of the allocated IMP/AMP 
- 
Day 1, Day 4, Day 7 and Day 10, T0 (for IMP it is the end time of injection):  
o Administration of the allocated IMP/AMP date and time information have to be entered in the 
subject’s record and/or appropriate form 


 
 
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o Only for IMPs administration  
• 
have to be done on Double-Blind Conditions (AMP will be administered on open label as 
the Route of administration is per os) 
• 
The appropriate volume of IMP will be administered by the unblinded site staff as IV 
bolus at the rate of 2 mL/second following a saline flush at the same rate.  
• 
The following information have to be entered in the subject’s record and/or appropriate 
form: subject weight, calculated volume to be administered, volume actually 
administered and actual rate of the injection, volume of saline flush, any reason for 
different rate than 2mL/s or different volumes of more than 10% than the calculated one  
• 
Tolerance at injection site will be followed during injection (except for AMP): burning, 
pain, eruption, extravasation, inflammation, or other. In case of injection-site pain, the 
subject will be asked to specify the level of pain using a visual analogic scale (VAS, 
 
) from 0 (no pain) to 10 (maximal pain).  
8.1.3.4 After administration 
- 
Day 1, Day 4, Day 7 and Day 10: 
o T[5min, 10 min, 20 min, 30min, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 8 hours] (5, 10 and 
20 min are not applicable for AMP) 
• 
Vital Signs (systolic and diastolic Blood Pressure in supine position after 10 minutes of 
rest, Pulse Rate).  
• 
Blood samples collection for P03277 plasma concentration assessment (always after vital 
signs) as close as possible of defined time point. Real time collection have to be entered 
in the subject’s record and appropriate form  
o T[10 min, 3 hours] 
• 
12-lead ECG as triplicate for safety (in supine position and after 10 minutes of rest) 
o T[30 min] 
• 
Tolerance at injection site will be followed (except for AMP): burning, pain, eruption, 
extravasation, inflammation, or other. In case of injection-site pain, the subject will be 
asked to specify the level of pain using a visual analogic scale (VAS, 
) 
from 0 (no pain) to 10 (maximal pain).  
In addition, the following information have to be entered in the subject’s record and appropriate form: 
o Meal start and end time during the Holter recording 
 
Safety ECGs have to be transferred to the ECG core laboratory. 
8.1.3.5 Days following administration 
- 
Day 2, Day 5, Day 7 and Day11, T[24 hours]: 
o Vital Signs (systolic and diastolic Blood Pressure in supine position after 10 minutes of rest, 
Pulse Rate).  
o Blood samples collection for P03277 plasma concentration assessment (always after vital signs) 
as close as possible of defined time point. Real time collection have to be entered in the subject’s 
record and appropriate form 


 
 
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In addition, the following information have to be entered in the subject’s record and appropriate form: 
o Meal start and end time during the Holter recording 
o Holter end date and time information 
 
Tolerance at injection site (except for AMP): burning, pain, eruption, extravasation, inflammation, or 
other. In case of injection-site pain, the subject will be asked to specify the level of pain using a visual 
analogic scale (VAS, 
) from 0 (no pain) to 10 (maximal pain).  
 
- 
Day 3, Day 6, Day 9:  
o Body weight 
o Blood sample collection for biological safety assessment. 
8.1.4 (Day 12) - Discharge  
On Day 12, the healthy subjects will be discharged after that all trial procedures had been performed and 
after an appropriate clinical examination including: 
- 
Physical examination 
- 
Body weight 
- 
Vital signs 
- 
12 lead ECG 
- 
Blood sample collection for biological safety assessment  
and based on which investigator has determined that it is safe to discharge the subject.  
In case of abnormal findings, the subject will be asked to stay at the clinical unit for appropriate follow-
up. 
8.1.5  (Day 38) and (Day 94) – Follow-up Period 
Healthy subjects will be asked to come back in the phase I clinical trial unit at Day10 + 1 month and 
Day10 + 3 months.  
- 
The Investigator will question on any possible GBCAs injection since the discharge day (name of 
contrast agent injected and tolerance will be recorded); 
- 
Only AEs related to the IMP or moxifloxacin, whether serious or not and AESI should be reported 
and documented in the medical file and the appropriate section of the CRF.  
- 
Blood samples and urine collection for long term P03277 elimination assessments. 
8.1.6 Confinement period 
The healthy subjects will be confined in the phase I clinical unit from Day 1 to Day 12 (2 day post last 
dosing) in order to perform investigational procedure and safety follow-up. 
During the confinement period, no grapefruit (and grapefruit derivated products), alcohol, tobacco and 
beverages with xanthine bases (tea, coffee, chocolate) will be permitted for healthy subjects. Correct 
hydration of the subjects should be ensured during the confinement period. The clinical staff will ensure 
that subjects drink at least 1.5 liters of water per day. The healthy subjects will be discharged on Day 12. 
All subjects will be asked to come back to perform safety follow-up visits on Day 10+ 1 month and on 
Day 10 + 3 months. 


 
 
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If newly-emergent changes in safety profile occur, further examination can be performed for as long as 
necessary, to assure that the changes have resolved, and/or that the subject is stable. 
 
8.2 Imaging Protocol 
Not applicable. 
8.3 ECGs records and readings 
8.3.1 On site-ECG Recording 
8.3.1.1 ECGs equipment and consumables 
12-lead ECG machine and 12-lead ECG Holter recorder equipment and consumables will be supplied 
(and re-supplied if applicable) by Guerbet (or its ECGs Core Laboratory).  
All materiel description, technical specification, specific requirements and user procedures will be 
provided to the site as part of the Site ECGs Manual.  
Guerbet (or its ECGs Core Laboratory) will document the ECGs tasks and obligations of the 
investigational site in the Site ECGs Manual. 
8.3.1.2 Safety 12-leads ECGs 
12-leads ECGs to assess subject’ safety and to monitor subject and trial stopping rules (see section 10.2) 
related to the QTcF values will be done as triplicate within 1 hour before administration and 10 minutes 
and 3 hours post-administration. 
The subject will be at rest for at least 10 minutes prior to any ECG recording.  
8.3.1.3 12-leads ECG Holter 
All subjects will be monitored with a 12-lead ECG Holter recorder from 1 hour before any product 
administration until 24 hours post-administration. 
8.3.2 On site-Reading of 12-leads ECGs 
12-leads ECGs to assess subject’ safety and to monitor subject and trial stopping rules (see section 10.2) 
related to the QTcF values will be read in real-time on-site. 
The investigator or a designee trained to the ECG reading would have to give an overall interpretation of 
the ECG at each timepoint on the following parameters: 
- 
heart rate (RR interval), 
- 
PR interval, 
- 
QRS duration, 
- 
QT 
- 
QTc Fridericia. 
All clinically significant abnormal changes will be recorded as AEs. Any clinically significant abnormal 
changes from baseline must be followed until the abnormality is resolved or is adequately explained.  


 
 
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8.3.3 Off Site Reading of ECGs 
In addition to the real-time on-site reading, all Safety ECGs will be independently reviewed by a ECGs 
Core Laboratory (independent reviewer) and data will be available within 48 hours.  
The data used for safety analysis (see section 10.2) will be the ECGs Core Laboratory data. 
The data to be retained for study and/or subject stopping rules (see section 10.2) application will be the 
ECGs Core Laboratory data. 
As far as the 12-lead Holter ECG monitoring is concerned ECGs parameters will be measured as 
triplicate and the mean of the triplicate will be considered for each following timepoints: 
- 
moxifloxacin: pre-dose up to 24 hours post-dose:  
[-1hour, 30min, 1 hour,1.5 hours, 2 hours, 3 hours, 4 hours, 8 hours, 24 hours] 
- 
P03277 and Placebo: pre-dose up to 24 hours post-dose:  
[-1hour, 5min, 10 min, 20 min, 30min, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 8 hours, 24 
hours]. 
The baseline is defined as the mean of 3 triplicates ECGs timepoint measurements within one hour before 
each administration. 
8.3.3.1 Site Qualification 
ECGs Core Laboratory will perform site training. These contacts will ensure that the protocol-stipulated 
ECGs can be performed by the site, might be programmed and prepared prior to enrollment of the first 
subject and that the Site ECG Manual will be accurately followed by the investigator.  
8.3.3.2 Receipt and Tracking of ECGs 
ECGs Core Laboratory will request that the investigational site submit anonymous Safety and Holter 
ECGs data to the ECGs Core Laboratory in a format that will be agreed prior to trial start and by 
electronic way. 
Safety ECGs and ECGs extracted from Holter recording will be tracked in database of the ECGs Core 
Laboratory. 
Investigational site has to keep a copy of all safety ECGs and Holter data as back-up if there is any 
problem of transmission and for archiving of the source data. 
8.3.3.3 ECG Processing and Quality Check 
Safety ECGs and Holter data received by the ECGs Core Laboratory will be translated to a readable and 
analyzable ECG format, according the ECGs Core Laboratory procedure. 
The ECGs Core Laboratory will ensure that all Site ECGs Manual requirements have been followed. In 
the event that a problem with Safety ECGs or Holter data is identified (e.g.: inappropriate length, 
inconsistency of with the ECGs protocol, inappropriate demographic identifier, poor quality data), the 
investigational site will be notified concerning the nature of the problems and the steps required for 
corrective action. The ECGs Core Laboratory will follow-up on all cases requiring remedial action by the 
investigational sites. Guerbet (or the ECGs Core Laboratory) may conduct site training for the 
investigator site in case of recurring data quality issues. 
8.3.3.4 Expert ECG Reader(s) Training 
ECGs Core Laboratory will train expert off-site readers to the trial ECG reading specifications. 


 
 
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8.3.3.5 Blinded Assessment of ECGs 
ECGs from Holter recorder database including all evaluable ECGs will be assessed by one or more expert 
reader(s), with expertise in the interpretation of ECGs for QT and arrhythmia assessment, who will not 
participate in the trial, and does not have affiliation with the institution where the trial will be conducted. 
The reading will be performed in a strictly fully blinded manner. 
ECGs Core laboratory has to ensure that all ECGs (except safety ECGs) of a given patient have to be read 
on the same day by the same reader and the reader has to be blind about subject, product, date and time-
point identifier [2]   
8.3.3.6 Inter and Intra-Reader Variability Assessment 
The assessments of inter and intra-reader variability will be done by the ECGs Core Laboratory and 
according their internal quality system. 
8.3.3.7 ECG Warehouse and Final Deliverables 
Guerbet (or its ECGs Core Laboratory) will submit all ECGs extracted from Holter data to the required 
competent authority’s warehouse as requested format. 
Safety ECGs, all Holter data and original ECGs copies extracted from Holter data will be maintained in a 
secure environment. The ECGs Core Laboratory will maintain a centralized ECGs archive that will 
contain every data received from the clinical investigators for the trial and original ECGs copies extracted 
from Holter. Measurements will also be stored so that these data may be audited if necessary. The 
resulting database will be transferred to Guerbet after database lock for archiving. 
8.4 Other Centralized Trial Procedures 
8.4.1 P03277 plasma concentration and long term elimination samples  
Details on samples handling for plasma concentration and long term elimination assessment, will be 
provided to the investigational site in a separate document. 
Blood samples 
A peripheral catheter will be placed until the 8 hour timepoint for blood collection in the forearm 
(controlateral to the injection site). 
For the collection at 24h, 1 and 3 months after the last IMP/AMP administration, blood samples will be 
collected by direct venipuncture. 
For P03277 analysis, blood will be collected into requested tubes. Plasma will be obtained after blood 
collection by centrifugation and aliquots stored at -20ºC [-18 to -36°] for analysis. Plasma will be divided 
into two different aliquots P03277 analysis. 
In case of remaining blood collected, it will be discarded. 
One aliquot for P03277 determination will be sent on frozen condition to the analytical center. One 
aliquot collected will be kept in the clinical center for the trial duration and will be sent to the analytical 
center only if necessary. At the end of the trial as described in section 3.2, non-sent aliquots will be 
discarded. 
 
Urine samples 
Urine fraction will be collected at 1 and 3 months after the last IMP administration.  




 
 
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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 during the confinement period of a trial subject and only 
IMP or moxifloxacin related adverse events or AESI (related or not) during follow-up period. Special 
situations such as treatment errors, suspicion of transmission of an infectious agent via an IMP or 
moxifloxacin, unusual failure in efficacy, overdose (symptomatic or not), misused, 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 subject 
administered a pharmaceutical product and which does not necessarily have to have a causal relationship 
with this treatment.  
An adverse event (AE) can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product (ICH E2A).  
 
9.1.2 Collection and Recording of Adverse Events 
The Investigator or his/her designee will invite the subject to report any experienced abnormality as part 
of the usual clinical follow-up. 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 screening visit 
(ICF signature) until the end of the confinement period, must be reported and followed even if no IMP or 
moxifloxacin were administered. Only related Adverse Events (serious or not) or AESI (related or not) 
will be recorded during follow-up visits.  
AE should be reported and documented in the medical file and the appropriate section of the CRF 
As reminder the subject’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. 
Reported 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 CRF 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 CRF. 
• 
Date and time of onset: date and clock time of the AE start 
• 
Intensity: 


 
 
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o Mild: the subject is aware of the sign or symptom, but it does not interfere with her/his 
usual daily activities and/or it is of no clinical consequence 
o Moderate: the AE interferes with the usual daily activities of the subject or it is of some 
clinical consequence 
o Severe: the subject is unable to work normally or to carry out his/her usual daily 
activities, and/or AE is of definite clinical consequence. 
• 
Date of the event end (or consolidation): The real date of event end will be entered if the event 
has come to its end. If the AE is still ongoing by the time of end of trial follow-up for the subject 
(i.e. last trial visit), the subject should be followed-up until AE resolution or a justification should 
be provided by the Investigator (i.e. chronic disease) in the medical file. 
• 
Causal relationship to the Investigational Medicinal Product or moxifloxacin: 
o Related: the definition of adverse reaction implies a reasonable possibility of a causal 
relationship between the event and the IMP or moxifloxacin. This means that there are 
facts (evidence) or arguments to suggest a causal relationship. 
o Not related: Applicable when no IMP or moxifloxacin have 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 subject’s underlying medical 
condition or concomitant therapy). 
• 
Causal relationship to a trial procedure: 
o Related 
o Not related 
• 
Outcome: 
o Recovered/Resolved: the AE is no longer present at any intensity or return to baseline 
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 subject. 
o Fatal: this AE caused or directly contributed to subject’s death. 
• 
Action taken with regard to administration of the IMP or moxifloxacin: 
o No Action: for AE occurring during the pre-administration/procedure or post-
administration/procedure period, or if the IMP or moxifloxacin administration remained 
the same in spite of AE being present. 
o IMP or moxifloxacin withdrawn. 
• 
Other action taken:  
o IMP unblinding 
o AE-targeted medication: the subject took a medication (either prescription or non-
prescription) specifically for this AE. The drug(s) should be reported in the appropriate 
section of the CRF (“concomitant drug” section) 
o Other AE-targeted action: therapeutic measures other than corrective drug administration 
(e.g. ice, heating pad, brace, cast…) or subject underwent a procedure (surgery, 
physiotherapy, additional laboratory test…) for this AE. The therapeutic measure(s) 
should be reported in the appropriate section of the CRF (“Action other than drug 
administered for the AE” section) 
• 
Assessment of the seriousness of the AE: see Section 9.2 for SAE definition. 
9.2 Serious Adverse Event 
9.2.1 Definition of Serious Adverse Event 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose (ICH E2A):  
- 
Results in death 


 
 
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- 
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 
 
Medical and scientific judgement should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the patient or may require intervention 
to prevent one of the other outcomes listed in the definition above. These should also usually be 
considered serious.  
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or development of 
drug dependency or drug abuse.  
Note: Life-threatening in the definition of a serious adverse event refers to an event in which the subject 
was at risk of death at the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe.  
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 subject/event 
outcome or action criteria. The event itself may be severe but of relatively minor medical significance.  
In this protocol, the following situations will not be considered as SAE, providing that they are clearly 
documented as such in the subject’s source data:  
- 
Any hospitalization that had been planned before the trial and that will take place during the trial, 
provided there is no aggravation of the disease to which it is related. 
- 
Hospitalizations, which are not associated to an adverse event (such as hospitalization for 
checkup). 
9.2.2  Reporting Serious Adverse Events (SAE) 
All SAEs occurring from ICF signature until end of confinement period of each subject must be 
reported immediately by the investigator to the sponsor. Only SAE related to IMP, moxifloxacin or 
procedure must be reported during the follow-up period. The investigator must immediately forward to 
Guerbet Pharmacovigilance department a duly completed SAE report form 
 provided by 
Guerbet with trial documents, even if it is obvious that more data will be needed in order to draw any 
conclusion: 
- 
By Fax #: + 33 (0)1 45 91 67 70 
- 
Or by e-mail to: pharmacovigilance.headquarters@guerbet-group.com 
In case of emergency, Guerbet Pharmacovigilance department may be contacted at: + 33 (0)1 45 91 50 
00. 
SAEs, as for all adverse events, have to be reported also in medical file and in the appropriate section of 
the CRF (see section 9.1.2) 
In order to allow the assessment and eventual subsequent regulatory reporting of the case, the following 
minimum information should be filled in:  


 
 
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- 
Subject’s details including age, sex and subject’s trial enrollment number  
- 
Subject’s medical history relevant to the assessment of the event 
- 
Type of event by reporting a diagnosis or if not available, symptoms  
- 
Date and time to onset of the event  
- 
End date of the event (will be reported in a follow-up report if the event is still ongoing at the 
time of first notification) 
- 
Date and time of investigational drug or moxifloxacin administration,  
- 
Causal relationship to the investigational drug, moxifloxacin or procedure (mandatory) 
- 
Outcome at the time of reporting 
If the investigator is aware of any new relevant information concerning an SAE (e.g.: outcome or any 
information that can have an impact on the assessment of the seriousness or the causal relationship 
between the SAE and the IMP or moxifloxacin), he has to send it immediately to Guerbet 
Pharmacovigilance department on a SAE report form 
 as a follow-up report. 
The initial and follow up reports shall identify the trial subject by his/her Identification Number assigned 
for the purpose of the trial. 
Additional information (e.g. autopsy results, biological values …) or clarifications may be required by the 
Sponsor in a timely fashion to ensure accurate follow-up and assessment of each case and should be 
transmitted, anonymized, with a specific form 
 as soon as they are available. 
SAEs should be followed up by the investigators until complete recovery of the subject or, if not possible, 
until stabilization of sequelae. The investigator may be requested by Guerbet to provide follow-up 
information in order to comply with current regulations as well as for comprehensive assessment 
purposes. 
SAEs associated with trial procedures are to be notified using the same reporting procedure as described 
above. 
In addition, if occurring after the end of the subject’s follow-up period defined for this trial, serious 
adverse and/or unexpected 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.  
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/AMP 
- 
Suspected drug-drug interaction with another product. 
- 
Overdose: In this protocol, the overdose is defined as more than 0.3 mmol/kg for P03277 and 
more than 400mg for moxifloxacin. Any overdose, with or without adverse event, will be 
reported as AE and, in addition, on SAE form if the associated event is serious. 


 
 
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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 subject who becomes pregnant or is aware of a pregnancy (subject’s partner) during 
trial participation should inform immediately the investigational site. The female subject should be 
immediately withdrawn from IMP or moxifloxacin administration. 
Any pregnancy (with or without an Adverse Event) of women participating in the trial or of partners of 
men participating in the trial, that is discovered after the ICF signature until Day 17, i.e. 7 days after the 
last IMP/AMP administration, must be reported to Guerbet Pharmacovigilance via the SAE Report Form 
 (see section 9.2.2).  
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 woman and any risk factor of pregnancy complication, and on the follow-up and outcome of the 
pregnancy.  
Any complication of pregnancy will be reported as an AE or SAE, as appropriate.  
9.3.3 Adverse Events of Special Interest 
An Adverse Event of Special Interest (AESI) is an AE designated by Guerbet for transmission to 
Pharmacovigilance in the same time frame as an SAE. 
The list of AESI for this protocol is the following:  
- 
Nephrogenic Systemic Fibrosis (NSF). 
- 
Torsade de pointes 
- 
Sudden death;  
- 
Ventricular tachycardia;  
- 
Ventricular fibrillation and flutter;  
- 
Syncope (excluding vasovagal reaction due to blood sampling);  
- 
Seizures 
Also, any suspicion of transmission of an infectious agent via an IMP/AMP should be considered as a 
serious and processed as an SAE. 
In addition, any adverse event resulting from an occupational exposure may be directly reported to 
Guerbet. 
 
9.3.4 Any suspicion of transmission of an infectious agent via an IMP or 
moxifloxacin 
Any suspicion of transmission of an infectious agent via an IMP or moxifloxacin should be considered as 
serious and processed as an SAE. 
 


 
 
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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 subjects 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 subject population such as lack of efficacy of an IMP used for the 
treatment of a life-threatening disease (if applicable). 
- 
A new major finding from an animal 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 DMC, if any, where relevant for the safety of subjects, 
- 
Any serious adverse reaction, expected or not, involving healthy volunteers. 
According to local requirements, Guerbet or its representatives will communicate relevant safety 
information to the appropriate agency (ies), IEC/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 amendments 
- 
Premature discontinuation of the trial  
- 
Premature discontinuation of the subject 
 
9.5 Unblinding Procedures 
The blinding system will be made of two sets of envelopes. 
One sealed envelopes set is kept at the phase I clinical trial unit, the other at Guerbet pharmacovigilance 
representatives (Sérénité 24/24h) .The sets of envelopes should be kept in a safe place and 
accessible to any person authorized to unblind. 
The investigator may, under exceptional circumstances unblind the individual trial treatment group 
(sequence) if he/she considers that this procedure is relevant to the safety of the trial subject. Individual 
trial treatment unblinding is described in section 5.3.4. Unblinding must be documented on the opened 
envelope, in the subject medical file, completed in the SAE form sent to Guerbet Pharmacovigilance 
Department, if applicable. 
Suspected Unexpected Serious Adverse Reaction (SUSARs) will be unblinded by Guerbet 
Pharmacovigilance Department for regulatory reporting purposes; however, these SUSARs will remain 
blinded to the investigator and to Guerbet personnel responsible for trial management, data analysis, and 
interpretation of results at the trial’s conclusion. 
 
 


 
 
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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 Subject’s premature discontinuation 
Screening Failure: a subject may be discontinued from trial in case of non-fulfillment of eligibility 
criteria. Subject having been screened and meeting all selection criteria but not included in the 28 days 
screening period could be re-screened. This implies that the subject will sign a new informed consent 
form before performing the screening visit and will be allocated with a new trial subject number. 
 
Criteria for premature discontinuation of subjects: 
- 
Adverse Event (according to the investigator’s judgement); 
- 
Withdrawal of subject’s consent; 
- 
Subject lost to follow-up (date of last contact will be documented in the medical file and the eCRF). 
Any effort will be undertaken to know the reason for this loss to follow-up and/or to exclude any 
adverse reaction as this reason. This will be documented in the medical file; 
- 
Discovery of an unexpected, significant, or unacceptable risk to the subjects enrolled in the trial; 
- 
At the discretion of the investigator if the subject safety or well-being is not compatible with trial 
continuation; 
Specific subjects stopping rules:  
If any of the events described below occurs, injection of IMP/AMP should not be done and the subject 
should be discontinued from the trial:  
- 
Torsade de pointes event;  
- 
Ventricular tachycardia;  
- 
Ventricular fibrillation and flutter;  
- 
Seizures; 
- 
QTc Fridericia >500 ms or an increase of > 60 ms (ECG Core laboratory data) over the baseline (the 
baseline for safety ECG is defined as the 12-leads triplicate ECGs recorded within 1 hour prior to 
each administration) measurement before each IMP/AMP administration; 
- 
Renal toxicity characterized by an increase in serum creatinine by more than 25% or 0.5 mg/dl (44 
μmol/l) compared to the baseline value;  
- 
Any events which investigator or Guerbet considers raising a significant concern.  
Specific trial stopping rules:  
If this event described below occurs, enrolment should be suspended and the trial will be on hold:  


 
 
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- 
Torsade de pointes event in 1 subject; 
- 
Sudden death in 1 subject;  
- 
Ventricular tachycardia in 2 subjects;  
- 
Ventricular fibrillation and flutter in 2 subjects;  
- 
Seizures in 2 subjects; 
- 
QTc Fridericia >500 ms or an increase of > 60 ms (ECG Core laboratory data) over the baseline (the 
baseline for safety ECG is defined as the 12-leads triplicate ECGs recorded within 1 hour prior to 
each administration) repeated in 2 subjects; 
- 
Renal toxicity characterized by an increase in serum creatinine by more than 25% or 0.5 mg/dl (44 
μmol/l) compared to the baseline value repeated in 2 subjects; 
The DMC will review the cases and will decide to stop definitely the trial or not. 
Data collected for subjects subsequently discontinuing from the trial (please refer to section 14.3.2): 
For subjects prematurely discontinuing the trial, 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, P03277 
plasma concentration data, ECG data and reason for discontinuation The investigator must make every 
effort to collect and record all follow-up safety information (i.e., adverse events, injection-site tolerance, 
as appropriate), unless the subject withdraws consent for further data collection/participation for/in the 
trial. 
 
 


 
 
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11  STATISTICAL ANALYSIS 
The following section summarizes the statistical analysis method, which is fully described in the 
Statistical Analysis Plan. 
Continuous variables (e.g., age) will be summarized using the number of observations (n), mean, standard 
deviation (SD), median, minimum, and maximum. 
Categorical variables (e.g., sex, race and ethnicity) will be summarized using the number of observations 
(n) and percentage in each category. 
11.1 Statistical Method (null and alternative hypotheses) 
Primary analysis 
Primary endpoint is defined as the largest time-matched placebo-corrected, change-from-baseline mean 
effect of the two P03277 doses of QT interval expressed as QTc according to Fridericia’s formula 
(∆∆QTcF) (in ms).  
Primary endpoint is considered as following a standard normal distribution. Normality will be checked by 
means of plots.  
Per ICH E14, a “negative” (successful) ‘thorough QT/QTc trial’ is one in which the upper bound of the 
95% one-sided confidence interval for the largest time-matched placebo-corrected, change-from-baseline 
mean effect of the drug on the QTc interval excludes 10 ms. Consequently, the trial must show that both 
0.1 and 0.3 mmol/kg doses of P03277 do not increase the QT interval corrected by Fridericia formula 
(QTcF) at all timepoints. 
The null hypothesis is that the difference between each of the two doses of P03277 and placebo for the 
largest mean change from baseline for the QTcF is greater than the non-inferiority margin set to 10 ms 
according to regulatory guidance. An Intersection-Union test is performed at a one-sided 5% significance 
level. This is equivalent to compare at each timepoint the upper limit of the two-sided 90% confidence 
intervals of the difference between each of the two doses of P03277 and placebo with the non-inferiority 
margin of 10 ms. To conclude that P03277 is non-inferior to placebo, the null hypothesis has to be 
rejected for all timepoints and both doses simultaneously hence the overall Type I error rate does not need 
to be adjusted. 
Assay sensitivity 
Assay sensitivity assessment is defined as the largest time-matched placebo-corrected, change-from-
baseline mean effect of moxifloxacin of QT interval expressed as QTc according to Fridericia’s formula 
(∆∆QTcF)(in ms). 
In order to validate the assay sensitivity of the trial, the trial must show that the positive control increase 
the QTcF by at least 5 ms for at least one timepoint.  
The null hypothesis is that the difference between the positive control and placebo for the mean change 
from baseline for the QTcF is less than 5 ms according to regulatory guidance. This test is performed one-
sided at the 5% significance level which is equivalent to compare the upper limit of the two-sided 90% 
confidence intervals of the difference with 5 ms. To conclude that positive control is superior to placebo, 
the null hypothesis has to be rejected at, at least, one timepoint. 
As multiple timepoints are examined separately, the overall Type I error rate needs to be adjusted. To 
address this issue, the method described by Hochberg and Tamhane  will be used. To minimize the 
correction and because the positive control effect is well known, only five timepoint around the peak 
effect (1h, 1h30, 2h, 3h and 4h) will be used.  


 
 
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11.2 Sample Size 
A total of 48 subjects will be included in the study trial. 
The sample size is determined using published recommendations for a thorough QT trial (Statistical 
Issues Including Design and Sample Size Calculation in Thorough QT/QTc Studies [4]). 
N can be estimated by N = 2*(tα(γ) + tβ’(γ))2 [σ/(δ − 10)] 2 
where  
• 
σ2 is the within subject variability 
• 
γ = N – 2 
• 
β’= 1-(1- β)1/L) where β is the Type II error and L the number of measurements 
• 
α is the Type I error 
• 
tα(γ) the critical values for a Student T distribution with γ degrees of freedom at an α level.  
• 
δ is the expected difference between active drug and placebo (0 if no difference excepted, >0 if 
drug is expected to slightly increase QT)  
 
Considering an expected intra-variability of the primary endpoint of σ = 9 ms and an expected difference 
of δ = 2 ms between P03277 (two doses) and placebo, 40 subjects are needed to demonstrate non-
inferiority with a non-inferiority margin of 10 ms, a power of 1- β = 85% and a Type I error of α = 5% 
one-sided on the L = 9 measurements. 
This sample size is also sufficient to detect a difference of 5 ms (with an expected difference of 12 ms for 
at least one timepoint and an expected intra-variability of the primary endpoint of σ = 9 ms) of the 
primary endpoint between moxifloxacin and placebo with a power of 85%. 
To account for potential dropouts and/or unevaluable data points, 48 subjects will be randomized in the 
trial. The recruitment could be stopped before 48 subjects from the time the number of fully evaluable 
subjects for the primary criterion is 40. That is to say having took part to the study, till the last scheduled 
ECG Holter recording. 
A dropout is a subject who is prematurely discontinuing the trial before the end of the last Holter ECG 
recording. 
11.3 Planned Analysis 
11.3.1 Disposition of Subjects 
Number of completed subjects and number of prematurely discontinued subjects breaking down by 
reason of prematurely discontinuation including screen-failures will be tabulated. 
 
11.3.2 Data Sets Analyzed 
There will be four subject sets defined for this trial: All enrolled subjects set, the Safety Set (SS), the Full 
Analysis Set (FAS) and the Per-Protocol Set (PPS). 
All enrolled Subjects Set will include all subjects having signed their inform consent form. This set will 
be used for subject disposition summaries and individual listings. 


 
 
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The Safety Set will include all subjects, receiving at least one administration of IMP/AMP, regardless of 
the quantity. This set will be used for evaluation of safety and description of demographic data and 
baseline characteristics. 
The Full Analysis Set will include all randomized subjects. This set will be used for evaluation of cardiac 
safety and description of demographic data and baseline characteristics. 
The Per Protocol Set will be a subset of the FAS and will include all subjects who have no major protocol 
deviations throughout their whole trial period. Major deviations will be defined as having an impact on 
the primary criterion. Primary analysis will be performed on this set. 
11.3.3 Protocol deviations 
Protocol deviations will be split in major and non-major deviations. A major deviation is defined as a 
deviation being an impact on the primary criteria. A first categorization will be done in the Statistical 
Analysis Plan (SAP), then final categorization will be done before the breaking the blind during the 
Statistical Data Review Meeting. 
Frequency and percentages of subjects with protocol deviations will be presented breaking down by status 
(major/non major). 
11.3.4 Demographic and Baseline Characteristics 
Demographic parameters are age, sex, race, ethnicity, childbearing potential, body weight, height, and 
body mass index (BMI). Baseline characteristics are the subject's history (including the medical history), 
prior contrast agents and concomitant medication, the physical examination and cardiac status from ECG 
exam at inclusion (QT,QTcF, QTcPOP, QTcB and T wave morphology changes and U wave occurrence). 
Summary statistics will be calculated for age, body weight, height and BMI and presented overall. 
Frequency and percentages will be calculated for gender, childbearing potential and ECGs status at 
inclusion, and presented overall. 
Subject's medical history will be coded using the MedDRA dictionary and tabulated by body system, 
preferred term and status (concomitant or not) and presented overall. 
Subject's prior contrast agents and concomitant medication will be coded using the Anatomical 
Therapeutic Chemical (ATC) Drug dictionary and tabulated by ATC codes and presented overall. 
Meal date and start and end time will be listed for each period. 
 
11.3.5 P03277 plasma Concentration and long term elimination 
Plasma concentration and long term elimination analysis will be subcontracted to an analytical center and 
will be supervised by Guerbet.  
Specific analytical protocols will be established for analysis of P03277. All parameters description and 
data will be reported in a separate report. All analytical methods used in this trial will be validated prior to 
any sample analysis. 
 
- 
Based on the individual plasma concentration versus time profiles, the plasma 
concentration will be determined for each subject having received P03277  
- 
Long term P03277 elimination data will be presented in a separate report. 


 
 
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11.3.6 Cardiac safety Data 
Cardiac safety data are coming from 12-lead Holter ECG recording read by off-site cardiologists. 
Triplicate values will be issued for each measurement and the average of the 3 replicates will be used for 
statistics analyses. Therefore there will be one measure by timepoint by subject. 
- 
Baseline value 
There will be one baseline by administration period. 
The baseline is defined as the mean of 3 triplicates ECGs timepoint measurements within one hour before 
each IMP/AMP administration. 
- 
Primary analysis 
Primary analysis will be done using the Per Protocol Set 
Primary endpoint is defined as the largest time-matched placebo-corrected, change-from-baseline mean 
effect of the two P03277 doses of QT interval expressed as QTc according to Fridericia’s formula 
(∆∆QTcF) (in ms). 
The primary analysis is performed using an analysis of covariance (ANCOVA) model for crossover data 
with baseline data as covariate, sequence, period, time, trial drug, trial drug by time and sex as fixed 
effect and subject as a random effect. 
Test 
Differences between means will be tested through the model for each timepoint and for the two doses of 
P03277 using Student’s t-test according to the following items: 
- 
µij is the expected average of QTcF for each dose of P03277 at each timepoint (where i is 
corresponding to one timepoint and j to the 2 doses) 
- 
µij0 is the expected average of QTcF for corresponding placebo 
 
Null hypothesis 
Hi: µij - µij0 ≥ 10, i = 1…9, j=1,2 
Alternative hypothesis 
Ki: µi - µi0 < 10, i = 1…9, j=1,2 
For each timepoint, the two-sided 90% confidence intervals of the difference between each of the two 
doses of P03277 and placebo is calculated for testing above hypotheses.  
The trial will be considered as successful if, no test is significant that is to say if the upper range of the 
90% CI is lower than 10 ms for all tests. 
The appropriateness of a linear model will be assured by inspecting the goodness of fit, e.g., by looking at 
normal QQ-plots for the residuals and plots of the residuals over predicted values. If there is an indication 
that a linear model is inappropriate, the nonlinearity detected will be taken into account by an appropriate 
transformation of the concentration values (e.g., log(conc/lloq)) or by the use of an appropriate nonlinear 
model. 
- 
Secondary analysis:  
Secondary analysis will be done using the Full Analysis Set except otherwise specified. 


 
 
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o Primary analysis will be repeated using the Full Analysis Set. 
o Assay sensitivity analysis: 
The assay sensitivity analysis is performed using an analysis of covariance (ANCOVA) model for 
crossover data with baseline data as covariate, time, trial drug, trial drug by time and sex as fixed 
effect and subject as a random effect. 
Test 
Differences between means will be tested through the model for each timepoint using Student’s t-
test according to the following items: 
- 
µi is the expected average of QTcF for positive control at each timepoint (where i is 
corresponding to one timepoint) 
- 
µi0 is the expected average of QTcF for corresponding placebo 
Null hypothesis 
Hi: µi - µi0 ≤ 0, i = 1…5  
Alternative hypothesis 
Ki: µi - µi0 > 0, i = 1…5 
For each timepoint, the p-value for comparing the doses of positive control with corresponding 
placebo is calculated for testing above hypotheses.  
Hochberg’s step-up procedure:  
Let p1, p2, p3, p4, p5 be the ordered p-values (from the lower to the upper value) and H1, H2, 
H3, H4, H5 be the corresponding ordered null hypothesis. The testing procedure starts with the 
less significant comparison and continues as long as tests are not significant (meaning that the 
alternative statistics is not met). The procedure stops the first time a significant comparison 
occurs and all remaining hypotheses will be not tested. 
In the first step, H5 is rejected if p5 ≤ α, in the second step (if any) H4 is rejected if p4≤ α/2, in 
the third step (if any), H3 is rejected if p3≤ α/3, in the fourth step, H2 is rejected if p2≤ α/4, and in 
the fifth and last step, H1 is rejected if p1≤ α/5 with α being the 1-sided significance level of 
0.025. 
The trial will be considered as positive in terms of assay sensitivity if, at the end of the 
Hochberg’s step-up procedure, at least one test is significant. 
o Assay sensitivity will be repeated using the Per Protocol Set. 
o Same analysis as for primary end-point will be repeated for QT, QTcPOP and QTcB 
o Descriptive statistics at any time from administration up to 24h post dose of Time-matched 
change from baseline, placebo controlled, of the QT, QTcF, QTcPOP and the QTcB will be 
provided. 
o Number and percentage of subjects showing values above predefined threshold for QT, QTcB 
and QTcF (under placebo and two doses of P03277): 
o Absolute QTc interval prolongation:  
 
QTc interval > 450 ms 
 
QTc interval > 480 ms 
 
QTc interval > 500 ms 
o Change from baseline in QTc interval:  


 
 
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 
QTc interval increases from baseline > 30 ms 
 
QTc interval increases from baseline > 60 ms 
o Descriptive statistics at any time of QT, QTcF, QTcPOP, QTcB, RR (ms), QRS (ms), PR (ms), 
Heart rate (bpm) 
o QT/QTc values according to plasma concentrations of P03277. 
o Descriptive statistics on T wave morphology changes, U wave occurrence and sinus rhythm will 
be presented: 
o Descriptive statistics on bradycardia and arrhythmia will be presented 
11.3.7 Adverse events  
All analyses of AEs will be based on the number of subjects with AEs (and not on the number of AEs) 
except otherwise specified and using the safety set. 
Adverse event will be coded with the MedDRA dictionary. 
The time period for the assessment of AEs will be divided into 5 mutually exclusive and exhaustive 
periods (see Table 3 below): 
 
Start 
End 
Before IMP/AMP   
 
Informed consent signature 
Start 
of 
the 
first  
administration  
Period 1  
Start 
of 
the 
first 
administration 
Start 
of 
the 
second 
administration 
Period 2 
Start 
of 
the 
second 
administration 
Start 
of 
the 
third 
administration 
Period 3 
Start 
of 
the 
third 
administration 
Start 
of 
the 
fourth 
administration 
Period 4 
Start 
of 
the 
fourth 
administration 
Day 12 (except pregnancy 
cf.9.39.3)  
Table 3: Time periods for the assessment of AEs 
Events will be classified by trial products according to time of onset in the corresponding cycle related to 
trial products.  
Events will be classified as treatment-emergent if they have started since the first administration.  
Partial start dates/times will be queried. If information is not available to reliably allocate to a session and 
period, the allocation will be agreed at the data review meeting before database lock. If there is any doubt 
about treatment emergence, AEs will be classified as treatment emergent. 
Overall overview  
The number (%) of subjects having at least one AE (AE) as follows will be summarized for each trial 
product and overall for: 
• 
At least one TEAE 
• 
At least one AE with each of the following classification of intensity 


 
 
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o Mild 
o Moderate 
o Severe 
• 
At least one adverse reaction (relationship to trial treatment classified as ‘Related’) 
• 
At least one AE with each of the following classifications of action taken with trial treatment: 
o Dose not changed 
o Trial product withdrawn 
• 
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 
 
The table will show the same information for serious AE, defined as AEs with serious classified as ‘yes’ 
or missing. 
The table will be repeated for all TEAEs. 
Distribution of AEs and SAEs 
A table will be presented showing the total numbers of AEs and SAEs and the distribution of AEs 
(number [%] of subjects with 0, 1, 2 etc. AEs) for each IMP/AMP and overall. The table will also show 
the same information for SAEs defined as TEAEs with serious classified as ‘yes’ or missing, unless the 
number of SAEs make this uninformative. 
Summaries by System Organ Classes (SOC) and Preferred Term (PT)  
Summaries by SOC and PT will be presented for all treatment-emergent events and all related treatment-
emergent events for each IMP/AMP and overall. 


 
 
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11.3.8 Laboratory biological data 
Laboratory data analysis will be done using the safety set. 
The baseline is defined as the last measure before the first trial product administration. 
The statistical analysis will present results (see section 7.2) in standard international units and 
conventional United States units. Original units will be only listed. Laboratory data will be analyzed 
quantitatively and qualitatively. Qualitative analyses will be done via comparison of laboratory data to 
their reference ranges and according to their clinical significance. Quantitative analyses will be done by 
tabulating raw data and change from baseline. They will be displayed qualitatively as well by means of 
shift tables. 
11.3.9 Other safety observations 
Other safety observation will be presented on the safety set. 
Extent of exposure 
Duration between IMP/AMP administrations and end of trial, volume/dose theoretically administered, 
volume/dose actually administered, actual IMP rate of administration, theoretical IMP rate of 
administration and location of injection site will be tabulated. Frequency tabulation of theoretical 
volume/dose actually administered and theoretical rate of administration/dose actually performed will be 
also displayed per trial products groups and overall. 
Vital signs 
The baseline is defined as the last measure before the first trial product administration.  
Vital signs (see section 7.2) will be analyzed quantitatively and qualitatively. 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. 
ECG data 
The baseline is defined as the last measure before each IMP/AMP administration.  
ECG data (see section 7.2) will be analyzed quantitatively and qualitatively. Qualitative analyses will be 
done via comparison of ECG data to their normal ranges and according to their clinical significant 
changes. Quantitative analyses will be done by tabulating raw data and change from baseline. 
Injection site tolerance  
Number of subjects experiencing burning, pain, eruption, extravasation and inflammation at site injection 
will be tabulated per IMPs groups and overall. Pain at injection site will be measured using the Visual 
Assessment Scale (VAS) and VAS measurements for these subjects will be tabulated. 
 
11.4 Statistical/Analytical issues 
11.4.1 Adjustment for covariates 
For the primary analysis and the assay sensitivity, covariates (baseline of the primary endpoint and sex) 
are taken into account in the models used for the analyses. 


 
 
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11.4.2 Handling of Dropouts or Missing Data 
No imputation will be performed in this trial. 
11.4.3 Interim Analysis 
Not applicable 
11.4.4 Multicentre Trials 
Not applicable 
11.4.5 Multiple Comparisons/Multiplicity 
As stated in sections 11.1 and 11.3.6, the multiplicity is handled by considering a study “negative” (that is 
to say successful) if both P03277 doses rejects simultaneously the null hypothesis for all timepoints and 
if for the assay sensitivity, the null hypothesis is rejected at, at least, one timepoint, using the method 
described by Hochberg and Tamhane to deal with multiple timepoints.  
11.4.6 Use of a subset of Subjects for Cardiac Safety Analysis 
Because the primary analysis is a non-inferiority analysis, it will be done using the Per Protocol Set and 
then the analysis will be repeated using the Full Analysis Set. The assay sensitivity analysis will be done 
using the Full Analysis Set and then repeated using the Per Protocol Set 
11.4.7 Active control trials Intended to Show Equivalence 
Not applicable 
11.4.8 Examination of Subgroups 
The trial is stratified by sex which will be taken into account for the primary analysis and the assay 
sensitivity by putting it in the model. No other examination of subgroups is planned. 


 
 
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12  TRIAL COMMITTEE 
The purpose of this phase I trial as per current ICH E14 Guidance, is to satisfy with the regulatory 
requirement for a new drug in development to conduct a thorough QT/QTc trial in order to demonstrate 
that P03277 does not prolong the QT and QTc intervals in healthy volunteers. 
P03277 is a MRI contrast agent belonging to a well-known product class (GBCA) and there is, a priori, 
no particular expected safety concerns. In addition, the P03277 has a linear pharmacokinetic profile 
similar to the other Gd chelates and the preliminary results obtained during the phase I trial with several 
doses of P03277 showed no clinical and biological alert signal. 
Regarding placebo there is no particular expected safety concerns. The positive control is a well-known 
fluoroquinolone which has been shown to prolong the QTc interval on the electrocardiogram in some 
patients. 
The trial duration per subject is maximum 122 days, P03277 are injected at two different doses in 
addition of Placebo and Positive Control. The P03277 doses selected for the current trial have been tested 
as single dose during the phase I trial for which no safety alert was identified.  
Trial stopping rules and specific subjects stopping rules have been set up in the trial protocol (see section 
10.2) and check points at patient level are done before to proceed to any injection (in order to keep the 
blind conditions).  
For all these reasons, an IDMC (Independent Data Monitoring Committee) has not been established for 
the trial.  
However, a Data Monitoring Committee (DMC) will be set up for assessing the safety of P03277 during 
the trial and for monitoring the overall conduct of the clinical trial as well as ensuring that the trial and 
subjects stopping rules for safety reasons are applied when required.  
The DMC members will be: the principal investigator and Guerbet team (drug safety physician, Medical 
Expert, clinical project manager and ad-hoc team members). All the members will remain blinded 
regarding all the trial data. The role and responsibilities of this DMC will be described in a separate 
document (Data Safety Monitoring Plan). 
 


 
 
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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: 
- 
International Conference on Harmonisation (ICH) of Technical Requirements for Registration of 
Pharmaceuticals for Human Use: The Clinical Evaluation Of QT/QTc Interval Prolongation And 
Proarrhythmic Potential For Non-Antiarrhythmic Drugs E14 Current Step 4 version dated 12 
May 2005 
- 
World Medical Association Declaration of Helsinki, Ethical Principles for Medical Research 
Involving Human Subjects, June 1964, and amended in: October 1975 (Tokyo), October 1983 
(Venice), September 1989 (Hong Kong), October 1996 (Somerset West), Scotland, October 2000 
(Edinburgh), 2002 (Washington), 2004 (Tokyo), October 2008 (Seoul), October 2013 (Fortaleza) 
- 
International Conference on Harmonisation (ICH) of Technical Requirements for Registration of 
Pharmaceuticals for Human Use: Integrated Addendum to ICH E6(R1): Guideline for Good 
Clinical Practice E6 (R2) Current Step 4 version dated 9 November 2016 
- 
International Conference on Harmonisation (ICH) of Technical Requirements for Registration of 
Pharmaceuticals for Human Use: Clinical Safety Data Management: Definitions and Standards 
for Expedited Reporting E2A Current Step 4 version dated 27 October 1994 
- 
International Conference on Harmonisation (ICH) of Technical Requirements for Registration of 
Pharmaceuticals for Human Use: General Considerations for Clinical Trials E8 Current Step 4 
version dated 17 July 1997 
- 
Directive 95/46/EC of the European Parliament and of the Council of 24 October 1995 on the 
protection of individuals with regard to the processing of personal data and on the free movement 
of such data. 
- 
Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the 
approximation of the laws, regulations and administrative provisions of the Member States 
relating to the implementation of good clinical practice in the conduct of clinical trials on 
medicinal products for human use 
- 
Commission Directive 2003/94/EC of 8 October 2003 laying down the principles and guidelines 
of good manufacturing practice in respect of medicinal products for human use and 
investigational medicinal products for human use 
- 
Commission Directive 2005/28/EC of 8 April 2005 laying down principles and detailed 
guidelines for good clinical practice as regards investigational medicinal products for human use, 
as well as the requirements for authorisation of the manufacturing or importation of such products 
- 
International Conference on Harmonisation (ICH) of Technical Requirements for Registration of 
Pharmaceuticals for Human Use: Ethnic Factors in the Acceptability of Foreign Clinical Data 
E5(R1) Current Step 4 version dated 5 February 1998 
- 
EudraLex, The Rules Governing Medicinal Products in the European Union, Volume 4, EU 
Guidelines to Good Manufacturing Practice - Medicinal Products for Human and Veterinary Use, 
Annex 13 Investigational Medicinal Products 
- 
US Food and Drug Administration, Title 21 Code of Federal Regulations Part 11 on Electronic 
Records; Electronic Signatures 


 
 
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- 
US Food and Drug Administration, Title 21 Code of Federal Regulations Part 211 on Current 
Good Manufacturing Practice for Finished Pharmaceuticals 
- 
US Food and Drug Administration, Title 21 Code of Federal Regulations Part 54 Financial 
Disclosure By Clinical Investigators 
- 
Regional / local regulations and other specific populations regulations 
 
13.2 Institutional Review Board/Independent Ethics Committee and 
Regulatory/Competent Authorities 
As per international regulation, the clinical trial may be initiated only after having received the approval 
by and Institutional Review Board/Independent Ethics Committee (IRB/IEC) and the authorization by the 
national Regulatory/Competent Authority. The final written approval and authorization must be available 
for a given investigational site when initiating the trial conduct at this particular site. Amongst all 
documents required locally, the approval and authorization must be obtained for the protocol, 
investigator’s brochure/SmPC, the subject informed consent form and any other written information or 
document to be provided to the subjects. 
In case of modifications to the trial protocol, subject informed consent form or any other written 
information provided to the subjects, 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 subjects’ safety may be at risk, Guerbet may implement 
emergency safety measures prior to obtaining IRB/IEC approval and Regulatory/Competent Authority 
opinion. In parallel to implementing these measures, Guerbet will immediately notify the concerned 
IRB/IEC and Regulatory/Competent Authorities of such implementation. 
The documentation related to the approvals and authorizations must be filed in the 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 Subject Informed Consent 
Prior to participation, all subjects must confirm their free and voluntary willingness to participate in the 
trial. This confirmation is obtained in writing after having received a full oral and written explanation on 
the trial: 
- 
Aims, methodology and duration of the trial; 
- 
Potential benefits, foreseeable risks and inconveniencies related to the trial; 
- 
Rights and responsibilities of subjects, 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/AMP and its administration; 


 
 
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- 
Contact details of persons dedicated to the trial at the investigational site. 
The language used when informing the subjects and answering their questions must be as understandable 
as possible and shall not induce any misunderstanding or feeling to be influenced to participate. Subjects 
must be given ample time to decide whether they agree to participate or not. 
Subjects may consent to participate after having received all necessary information and all satisfactory 
answers to their questions. Their consent must be confirmed in writing by dating and signing the informed 
consent form(s) approved by the corresponding IRB/IEC. 
When the consent may not be directly obtained in writing, a legal representative/impartial witness may be 
involved in the process and confirm in writing that the subject consented freely and voluntarily. 
The information of subjects may only be conducted by qualified investigational site personnel, whose 
involvement and responsibility for subject information has been fully documented and approved by the 
Principal Investigator. 
The Principal Investigator must ensure that local applicable regulations/requirements are fully observed 
by the staff under her/his responsibility. 
In case of modifications of the subject informed consent or of any other document to be provided to the 
subjects, the IRB/IEC approval must be obtained prior to implementing the new document(s). Subjects 
who already consented may be asked to confirm their willingness to continue participating in writing. In 
any case, the same information and consent process as described above must be followed. 
 
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 unauthorized access to the data. 
The investigator undertakes, in accordance with the regulation in force, to make anonymous any subject 
data before collection by Guerbet. Especially the name and address of the subjects will be deleted from 
any medium such as CRF, document for biological results or digital supports. 
- 
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 subjects 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. 
The representative will perform regular investigational site visits and report all discussions, subject and 
IMP/AMP data verification performed with particular attention to subjects’ 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 subject 
visit, and all other documents provided by Guerbet (e.g. documents relating to the IMP management…) 
and to reply to any data clarifications raised in a timely manner. 
The investigator and the appropriate person 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. 
 


 
 
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14.3.2 Data Reported in the eCRF according to Subject Status  
For screening failure/non selected subjects, only the date of visit, date of informed consent signature, 
demographic data, the adverse event, the date and reason for non-selection will be reported. 
For included subjects, withdrawn before the first administration of study product, only the selection data, 
the safety data and the date and reason for discontinuation will be reported. 
For subjects withdrawn from the trial after the first administration of study product, 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, P03277 plasma concentration data, date and reason for discontinuation …). The 
investigator must make every effort to collect and record all follow-up safety information (i.e., adverse 
events, injection-site tolerance, as appropriate), unless the subject 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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15  PUBLICATIONS RULES 
 


 
 
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16  REFERENCES 
Investigator Brochure of the P03277; Please refer to the Investigator Brochure in force. 
 
Moxifloxacin Summary of Product Characteristics; Please refer to the moxifloxacin Summary of Product 
Characteristics in force. 
 
NaCl 0.9% Summary of Product Characteristics; Please refer to the NaCl 0.9% Summary of Product 
Characteristics in force. 
 
[1] C. Almange (Rennes), X. André-Fouët (Lyon), M.-C. Aumont (Paris),P. Beaufils (Paris), G. 
Dérumeaux (Rouen), J.-M. Fauvel (Toulouse), H. Milon (Lyon), J.-C. Quiret (Amiens), G. Roul 
(Strasbourg), J.E. Wolf (Dijon), Actualisé en 2009 par :M-C. Aumont (Paris), H. Douard (Bordeaux), L. 
Fauchier (Tours), E. Ferrari (Nice),G. Grollier (Caen), G. Vanzetto (Grenoble), J.E. Wolf (Dijon) : 
Sémiologie Cardiologique – CNEC. 
[2] B. Darpo. Themed Section: QT Safety Review, The thorough QT/QTc trial 4 years after the 
implementation of the ICH E14 guidance. British Journal of Pharmacology (2010) 159, 49–57. 
 
[3] Scott D Patterson. Investigating Drug-Induced QT and QTc Prolongation in the Clinic: A Review of 
Statistical Design and Analysis Considerations: Report from the Pharmaceutical Research and 
Manufacturers of America QT Statistics Expert Team. Drug Infomation Journal. Vd. 39, pp. 243-
266,2005 0092-8615/2005 
 
 
[4] Joanne Zhang & Stella G. Machado (2008) Statistical Issues Including Design and Sample Size 
Calculation in Thorough QT/QTc Studies , Journal of Biopharmaceutical Statistics, 18:3, 451-467, DOI: 
10.1080/10543400802020938, To link to this article: http://dx.doi.org/10.1080/10543400802020938 
 
 


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


 
 
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18  APPENDICES 
 
 


 
 
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18.2 List of Study Plans For Study Procedure Time Window Allowance  
Procedures performed at Screening Visit 
Time windows for the procedures performed at screening visit at the Phase I center are specified in the 
Screening Setup Form BE-80-1606627 GDX44-006  document. 
 
Procedures performed during Confinement Period and Follow-up Visits 
Time windows for all the procedures performed during the confinement period and follow-up visits at the 
Phase I center are specified in the Study Setup Form_BE-80-1606627 GDX44-006 document. 
 
12-Lead Holter ECG Extractions 
Time windows for the 12-Lead Holter ECG extractions are defined in the GDX-44-006_ScopeOfWork 
document produced by the ECGs Core Laboratory. 
 

SAP_003.pdf: 




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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
AE 
Adverse Event 
AV 
Atrioventricular 
ATC 
Anatomical Therapeutic Chemical 
AMP 
Auxiliary Medicinal Product 
BMI 
Body Mass Index 
BPM 
Beats Per Minute 
CRF/eCRF Case Report Form/electronic Case Report Form 
CRO 
Contract Research Organization 
DRM 
Data Review Meeting 
ECG 
Electrocardiogram 
eGFR 
Estimated Glomerular Filtration Rate 
FAS 
Full Analysis Set 
ICH 
International Conference on Harmonization 
IMP 
Investigational Medicinal Product 
MedDRA 
Medical Dictionary For Regulatory Activities 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PP 
Per Protocol 
RBBB 
Right Bundle Branch Block 
SAE 
Serious Adverse event 
SD 
Standard Deviation 
TEAE 
Treatment Emergent Adverse Event 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................................................. 3 
 
SUMMARY OF THE STUDY PROTOCOL ........................................................................................................ 6 
1.1. 
STUDY OBJECTIVES ............................................................................................................................................. 6 
1.2. 
STUDY DESIGN .................................................................................................................................................... 6 
 
EVALUATION CRITERIA ................................................................................................................................... 8 
2.1. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .................................................................................. 8 
2.2. 
CARDIAC SAFETY CRITERIA ................................................................................................................................ 8 
2.2.1. 
Primary cardiac safety criterion ................................................................................................................ 8 
2.2.2. 
Secondary cardiac safety criteria .............................................................................................................. 9 
2.3. 
OTHER SAFETY CRITERIA .................................................................................................................................... 9 
2.3.1. 
Clinical and biological safety .................................................................................................................... 9 
2.3.2. 
Plasma concentration and long term elimination parameters ................................................................. 11 
 
STATISTICAL METHODS ................................................................................................................................. 12 
3.1. 
GENERAL CONSIDERATIONS ............................................................................................................................. 12 
3.2. 
NULL AND ALTERNATIVE HYPOTHESIS ............................................................................................................. 12 
3.3. 
DETERMINATION OF SAMPLE SIZE ..................................................................................................................... 14 
3.4. 
ADJUSTMENT FOR COVARIATES ........................................................................................................................ 14 
3.5. 
HANDLING OF DROPOUTS OR MISSING DATA ..................................................................................................... 14 
3.6. 
INTERIM ANALYSES AND DATA MONITORING .................................................................................................... 14 
3.7. 
MULTICENTER STUDIES .................................................................................................................................... 15 
3.8. 
MULTIPLE COMPARISONS/MULTIPLICITY .......................................................................................................... 15 
3.9. 
USE OF A SUBSET OF SUBJECTS FOR CARDIAC SAFETY ANALYSIS ...................................................................... 15 
3.10. 
ACTIVE CONTROL STUDIES INTENDED TO SHOW EQUIVALENCE .................................................................... 15 
3.11. 
EXAMINATIONS OF SUBGROUPS .................................................................................................................... 15 
 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES .......................................... 15 
 
STATISTICAL AND ANALYTICAL PLANS ................................................................................................... 16 
5.1. 
DISPOSITION OF SUBJECTS ................................................................................................................................ 16 
5.2. 
DATA SETS ANALYSED AND PROTOCOL DEVIATIONS ........................................................................................ 16 
5.3. 
MEASUREMENTS OF STUDY DRUG COMPLIANCE ............................................................................................... 24 
5.4. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ................................................................................ 24 
5.4.1. 
Demographic data ................................................................................................................................... 24 
5.4.2. 
Study disease ............................................................................................................................................ 24 
5.4.3. 
Risk factors .............................................................................................................................................. 24 
5.4.4. 
Medical history and concomitant diseases .............................................................................................. 24 
5.4.5. 
Clinical laboratory evaluation at baseline .............................................................................................. 25 
5.4.6. 
Vital signs, physical findings and other observations related to safety at baseline ................................. 25 
5.4.7. 
Prior medication and procedures ............................................................................................................ 25 
5.4.8. 
12-lead ECG assessment .......................................................................................................................... 25 
5.4.9. 
Other baseline characteristics ................................................................................................................. 25 
5.5. 
CARDIAC SAFETY EVALUATION ........................................................................................................................ 26 
5.5.1. 
Primary analysis of the primary criteria ................................................................................................. 26 
5.5.2. 
Supportive analyses of primary criterion ................................................................................................. 27 
5.5.3. 
Additional analyses of primary criterion ................................................................................................. 28 
5.5.4. 
Analysis of secondary criteria.................................................................................................................. 28 
5.6. 
SAFETY EVALUATION ....................................................................................................................................... 33 
5.6.1. 
Extent of exposure .................................................................................................................................... 33 


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5.6.2. 
Adverse events .......................................................................................................................................... 33 
5.6.3. 
Deaths, serious adverse events and other significant adverse events ...................................................... 34 
5.6.4. 
Clinical laboratory evaluation ................................................................................................................. 35 
5.6.5. 
Vital signs, physical findings and other observations related to safety ................................................... 36 
5.6.6. 
Concomitant medications and procedures ............................................................................................... 37 
5.6.7. 
PK evaluation .......................................................................................................................................... 38 
 
LIST OF TABLES, FIGURES AND LISTINGS ................................................................................................ 39 
6.1. 
CLINICAL STUDY REPORT IN-TEXT TABLES, FIGURES AND LISTINGS .................................................................. 39 
6.2. 
CONTENTS OF CLINICAL STUDY REPORT SECTION 14 ........................................................................................ 39 
6.2.1. 
Demographic data summary and figures (section 14.1 of ICH report) ................................................... 39 
6.2.2. 
Efficacy data summary figures and tables (section 14.2.1 of ICH report) ............................................... 40 
6.2.3. 
Safety data summary figures and tables (section 14.3 of ICH report) ..................................................... 42 
6.3. 
CONTENTS OF CLINICAL STUDY REPORT SECTION 16.2 ..................................................................................... 44 
6.3.1. 
Disposition of subjects (section 16.2.1 of ICH report) ............................................................................ 45 
6.3.2. 
Protocol deviations (section 16.2.2 of ICH report) ................................................................................. 45 
6.3.3. 
Patients excluded from efficacy analysis (section 16.2.3 of ICH report) ................................................. 45 
6.3.4. 
Demographics data and baseline characteristics (section 16.2.4 of ICH report) ................................... 45 
6.3.5. 
Compliance and drug concentration data (section 16.2.5 of ICH report) ............................................... 45 
6.3.6. 
Individual efficacy response data (section 16.2.6 of ICH report) ............................................................ 45 
6.3.7. 
Adverse event listings (section 16.2.7 of ICH report) .............................................................................. 46 
6.3.8. 
Listings of individual laboratory measurements (section 16.2.8 of ICH report) ..................................... 46 
6.3.9. 
Vital signs, physical findings and other observations related to safety ................................................... 46 
6.3.10. 
Follow-up observations related to safety ................................................................................................. 46 
 
SHELLS FOR TABLES, FIGURES AND LISTINGS ....................................................................................... 47 
7.1. 
CLINICAL STUDY REPORT IN-TEXT TABLES, FIGURES AND LISTINGS .................................................................. 47 
7.2. 
CONTENTS OF CLINICAL STUDY REPORT SECTION 14 ........................................................................................ 47 
7.3. 
CONTENTS OF CLINICAL STUDY REPORT SECTION 16.2 ..................................................................................... 47 
 
REFERENCES ...................................................................................................................................................... 48 
 
APPENDICES ........................................................................................................................................................ 49 
 
 
 


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 SUMMARY OF THE STUDY PROTOCOL  
This document presents the statistical analysis plan (SAP) for Guerbet, Protocol No. GDX-44-006: 
“Thorough QT/QTc study to assess the electrocardiographic safety of a new gadolinium-based 
contrast agent P03277 in healthy volunteers”. 
This analysis plan is based on the final protocol Version 4.0 including amendment n° 2 dated 27 
September 2017.  
 
1.1. Study objectives 
The primary objective is to assess the cardiac safety after administration of P03277 by evaluating the 
QT and QTc intervals in healthy volunteers. 
 
The secondary objective of the trial is to assess the cardiac, clinical and biological safety, plasma 
concentration, and long term elimination profile of P03277 following its administration in healthy 
volunteers. 
 
1.2. Study design 
GDX-44-006 is a Phase I, single center, randomized, cross-over double-blind placebo-controlled and 
open-label positive-controlled trial which aims to assess the electrocardiographic safety of a new 
gadolinium-based contrast agent P03277 in healthy volunteers. 
 
Subjects included in the trial should be administered with three Investigational Medicinal Products 
(IMPs) and one Auxiliary Medicinal Product (AMP) in a 4*4 cross over sequence according to a 
William design balanced for first order carry over effect. Twelve subjects will be assigned to each 
sequence (6 males and 6 females). The volunteers will be enrolled sequentially by cohort of 8 
subjects. Sequence and IMP/AMP will be randomly assigned to subjects. 
 
The three IMPs will be: 
- 
P = Placebo (Nacl 0.9%) 
- 
CD = P03277 tested at anticipated clinical dose (0.1mmol/kg) 
- 
SD = P03277 tested at supra-clinical dose (0.3mmol/kg). 
The AMP will be: 
- 
PC = Positive control (moxifloxacin 400 mg - per os). 
 
Period’s duration for moxifloxacin, placebo, P03277 at clinical dose and P03277 at supra-clinical 
dose will each be 72 hours. The total duration for all periods (confinement) will be 12 days. 
 
After all eligibility requirements satisfied, subject will be randomized to a sequence of IMP/AMP 
administration.  Each subject will be monitored with a 12-lead Holter electrocardiogram (ECG) from 
1 hour before any product administration until 24 hours post-administration. 
ECGs parameters will be measured as triplicate based on the following timepoints from the 12-lead 
Holter ECG monitoring: 


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- 
moxifloxacin: pre-dose up to 24 hours post-dose: [-1 hour, 30 min, 1 hour, 1.5 hours, 2 hours, 
3 hours, 4 hours, 8 hours, 24 hours] 
- 
P03277 and Placebo: pre-dose up to 24 hours post-dose: [-1 hour, 5 min, 10 min, 20 min, 30 
min, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 8 hours, 24 hours]. 
 
ECG measurements will be compared with ECG parameters collected after administration of placebo 
(Nacl 0.9%). The test sensitivity will be assessed using a positive control (moxifloxacin 400 mg per 
os) known to induce delays in QT intervals.  
 
All subjects will undergo 12-leads ECGs to assess subject’ safety and trial stopping rules related to 
the QTcF values. Those ECGs will be done as triplicate within 1 hour before administration and 10 
minutes and 3 hours post-administration.  
 
Blood samples will be taken to implement a concentration-response approach and to assess the effect 
of P03277 on QT/QTc intervals according to plasma concentration of the product. Sampling will 
match with the extracted ECGs timepoints. 
 
All subjects will be asked to come back at the phase I clinical trial unit at 1 and 3 months after last 
IMP administration. Blood sample and urine collection will be performed to assess long term 
elimination of P03277. 
 
 
 


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 EVALUATION CRITERIA 
2.1. Demographic and other baseline characteristics 
Demographic parameters are age, sex, race, ethnicity, childbearing potential, body weight, height, 
and body mass index (BMI). These parameters will be collected during the screening visit. 
Baseline characteristics are: 
- 
the medical history 
- 
prior contrast agents  
- 
prior medications 
- 
the physical examination 
- 
vital signs (systolic and diastolic blood pressure, pulse rate) 
- 
blood samples collection   
The laboratory data analysis will be performed by the site laboratory.  
The following parameters will be assessed: 
 Hematology: red blood cells (RBCs), white blood cells (WBCs), neutrophils, 
eosinophils, basophils, lymphocytes and monocytes, platelet count, hemoglobin, 
hematocrit, Mean red blood Cells Volume (MCV). 
 Biochemistry: sodium, potassium, chloride, glucose, blood urea nitrogen (BUN) / 
urea, creatinine, creatinine clearance estimated by Cockcroft-Gault, eGFR (CKD-
EPI), total protein, calcium, magnesium, phosphorus, total bilirubin, unconjugated 
and conjugated bilirubin, aspartate amino transferase (AST), alanine amino 
transferase (ALT), alkaline phosphatase, lactate dehydrogenase (LDH), triglycerides 
(TG). 
- 
cardiac status from ECG exam (QT, QTcF, QTcB, QRS, PR, RR, heart rate, sinus rhythm). 
 
2.2. Cardiac safety criteria 
For each subject, all ECG parameters extracted from the 12-lead Holter ECG in triplicates and read 
centrally by a core lab will be analysed in the section cardiac safety. The mean of the triplicate ECG 
recordings will be assessed 1 hour before each administration and up to 24 hours post-administration: 
- 
moxifloxacin: pre-dose up to 24 hours post dose: 
[-1 hour, 30 min, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 8 hours, 24 hours] 
- 
P03277 and Placebo: pre-dose up to 24 hours post dose: 
[-1 hour, 5 min, 10 min, 20 min, 30 min, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 8 hours, 
24 hours]. 
The safety 12-lead ECG assessments measured on-site will be available on real-time and used for 
monitoring (and withdrawn if needed) the subject during the course of the study. Those ECGs will 
be done as triplicate within 1 hour before administration, 10 minutes and 3 hours post-administration 
and read by a core lab. These assessments will be presented along with other safety criteria in the 
safety evaluation section.  
2.2.1. Primary cardiac safety criterion 
The primary criterion of the study is the QT interval expressed as QTc according to Fridericia’s 
formula (QTcF) change from baseline (in ms).  


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2.2.2. Secondary cardiac safety criteria 
Secondary cardiac safety criteria included to support the primary endpoint are the followings: 
- 
Parameters measured at any timepoints: 
 QT (ms) 
 QTcPOP (ms), Qtc according to population specific correction formula 
 QTcB (ms), QTc according to Bazett’s formula 
 RR (ms) 
 QRS (ms) 
 PR (ms) 
 Heart rate (bpm) 
 Interpretation 
 Sinus rhythm (yes/no) 
- 
Morphological analysis: 
 Changes in T and U wave morphologies will be described through the description of 
morphological abnormalities (Q or QS pattern, axis and voltage, hypertrophy, ST 
depression and elevation, T/U wave abnormalities, AV conduction, intraventricular 
conduction defects, rhythm, technical quality). Changes from baseline that represent 
the appearance or worsening of the morphological abnormality will be analysed.  
 
QTcPOP will be obtained using a linear mixed modelling of QT interval (ms) vs RR interval (ms) on 
all available extracted Holter ECG from placebo period data.  
 
SAS Procedure: 
proc mixed data = dataset method = REML; 
 
class subj ; 
 
model log(QT) = log(RR) / SOLUTION ddfm = kr; 
 
random subj / type = cs; 
run; 
 
The slope will determine the correction formula of QTcPOP: 𝑄𝑇/𝑅𝑅∝ where RR interval is in 
seconds. The correction derived from placebo period will be applied to all trial products data. 
2.3. Other safety criteria 
2.3.1. Clinical and biological safety 
 
2.3.1.1 
Adverse events 
Adverse events will be recorded throughout the start of subject participation up to the end of 
confinement period except pregnancy (subject’s or subject’s partner) that will be recorded up to day 
17 (7 days after the last IMP/AMP administration). During follow-up period only related AEs and 
AESI will be recorded. 
 


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2.3.1.2 
Laboratory data 
For each subject, blood samples will be collected before the first trial product administration and 2 
days after each administration. The laboratory data analysis will be performed by the site laboratory.  
The following parameters will be assessed: 
- 
Hematology: red blood cells (RBCs), white blood cells (WBCs), neutrophils, eosinophils, 
basophils, lymphocytes and monocytes, platelet count, hemoglobin, hematocrit, Mean red 
blood Cells Volume (MCV). 
- 
Biochemistry: sodium, potassium, chloride, glucose, blood urea nitrogen (BUN) / urea, 
creatinine, eGFR (CKD-EPI), total protein, calcium, phosphorus, total bilirubin, 
unconjugated and conjugated bilirubin, aspartate amino transferase (AST), alanine amino 
transferase (ALT), alkaline phosphatase, lactate dehydrogenase (LDH), triglycerides (TG). 
 
2.3.1.3 
Vital signs 
Vital signs (Systolic Blood Pressure, Diastolic Blood Pressure, Pulse Rate) will be assessed before 
each trial product administration, on the same timepoints than cardiac safety parameters and at Day 
12. 
Body weight will be assessed at inclusion visit and after each trial product administration to 
determine the volume of IMP to be administered (except at Day 12).  
 
2.3.1.4 Tolerance at injection site 
For all subjects, injection-site tolerance (burning, pain, eruption, extravasation, inflammation, or 
other) will be assessed over the day following each injection (during the injection, up to 30 min ± 5 
min and one day after injection) and over a longer period if the investigator becomes aware of any 
related AE. In case of injection-site pain, the subject will be asked to specify the level of pain using 
a visual analogic scale (VAS) from 0 (no pain) to 10 (maximal pain). 
 
2.3.1.5 Safety 12-leads ECGs 
12-leads ECGs to assess subjects’ safety and to monitor subject and trial stopping rules related to the 
QTcF values will be collected as triplicates within 1 hour before administration, 10 minutes, 3 hours 
after administration and at Day 12. 
In addition to the real-time on-site reading, all safety ECGs (QT, QTcF, QTcB, QRS, PR, RR, heart 
rate, sinus rhythm) will be independently reviewed by a ECGs Core Laboratory (independent 
reviewer). 
The safety analyses will be based on the ECGs Core Laboratory data. 
 
2.3.1.6 Concomitant medications 
Concomitant medications will be recorded at the time of informed consent form signature until end 
of the study.  
 
 


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2.3.2. Plasma concentration and long term elimination parameters 
 
2.3.2.1 Plasma concentration parameters 
Blood samples will be drawn from period 1 to period 4, for every subject, to evaluate plasma 
concentration of P03277. 
Specific timepoints are defined for pre-dose up to 24 hours post dose: [-1 hour, 5 min, 10 min, 20 
min, 30 min, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 8 hours, 24 hours]. 
 
2.3.2.2 Long-term elimination parameters 
One blood sample and one urine sample will be collected at Day 38 and Day 94 for each subject who 
received at least one dose of IMP in order to assess the potential long term/delayed elimination of 
P03277. 
Presence and concentration of P03277 in those samples will be measured. 
 
 




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An Intersection-Union test is performed at a one-sided 5% significance level. This is equivalent to 
compare at each timepoint the upper limit of the two-sided 90% confidence intervals of the difference 
between each of the two doses of P03277 and placebo with the non-inferiority margin of 10 ms: 
- 
 𝜇𝑖𝑗 is the expected average of QTcF for each dose of P03277 at each timepoint (where 𝑖 is 
corresponding to one timepoint and 𝑗 to the 2 doses) 
- 
𝜇𝑖𝑗0 is the expected average of QTcF for corresponding placebo 
 
Null hypothesis: 
𝐻𝑖: 𝜇𝑖𝑗 − 𝜇𝑖𝑗0  ≥ 10, 𝑖 =  1 … 11, 𝑗= 1,2  
Alternative hypothesis: 
𝐾𝑖: 𝜇𝑖𝑗 − 𝜇𝑖𝑗0 <  10, 𝑖 =  1 … 11, 𝑗= 1,2. 
 
To conclude that P03277 is non-inferior to placebo, the null hypothesis has to be rejected for all 
timepoints and both doses simultaneously hence the overall Type I error rate does not need to be 
adjusted. 
 
Assay sensitivity 
Assay sensitivity assessment is defined as the largest time-matched placebo-corrected, change-from-
baseline mean effect of moxifloxacin of QT interval expressed as QTc according to Fridericia’s 
formula (in ms). 
In order to validate the assay sensitivity of the trial, the positive control must increase the QTcF by 
at least 5 ms for at least one timepoint. 
 
The null hypothesis is that the difference between the positive control and placebo for the mean 
change from baseline for the QTcF is less than 5 ms according to regulatory guidance.  
This test is performed one-sided at the 5% significance level which is equivalent to compare the 
lower limit of the two-sided 90% confidence intervals of the difference with 5 ms: 
- 
𝜇𝑖 is the expected average of QTcF for positive control at each timepoint (where 𝑖 is 
corresponding to one timepoint) 
- 
𝜇𝑖0 is the expected average of QTcF for corresponding placebo 
 
Null hypothesis 
𝐻𝑖: 𝜇𝑖 − 𝜇𝑖0  <  5, 𝑖 =  1 … 5 
Alternative hypothesis 
𝐾𝑖: 𝜇𝑖 − 𝜇𝑖0  ≥ 5, 𝑖 =  1 … 5 
  
To conclude that positive control is superior to placebo, the null hypothesis has to be rejected for at 
least one timepoint. 
 
As multiple timepoints are examined separately, the overall Type I error rate needs to be adjusted. 
To address this issue, the method described by Hochberg and Tamhane [3] will be used.  
To minimize the correction and because the positive control effect is well known, only five timepoints 
around the peak effect will be used: 1h, 1h30, 2h, 3h and 4h. 
 


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3.3. Determination of sample size 
A total of 48 subjects will be included in the study trial. 
 
The sample size is determined using published recommendations for a thorough QT trial [4]. 
 
𝑁 can be estimated by 
 𝑁= 2 ∗[𝑡𝛼(𝛾) + 𝑡𝛽′(𝛾)]
2[𝜎(𝛿−10)
⁄
]2 
where 
- 
𝜎2 is the within subject variability 
- 
𝛾 =  𝑁 –  2 
- 
𝛽’ =  1 −(1 − 𝛽)1/𝐿 where 𝛽 is the Type II error and 𝐿 the number of measurements 
- 
𝛼 is the Type I error 
- 
𝑡𝛼(𝛾) the critical values for a Student T distribution with 𝛾 degrees of freedom at an 𝛼 level. 
- 
𝛿 is the expected difference between active drug and placebo (0 if no difference excepted, >0 
if drug is expected to slightly increase QT). 
 
Considering an expected intra-variability of the primary endpoint of 𝜎 = 9 ms and an expected 
difference of 𝛿 = 2 ms between P03277 (two doses) and placebo, 40 subjects are needed to 
demonstrate non-inferiority with a non-inferiority margin of 10 ms, a power of 1 - 𝛽 = 85% and a 
Type I error of 𝛼 = 5% one-sided on the 𝐿 = 9 measurements. 
This sample size is also sufficient to detect a difference of 5 ms (with an expected difference of 12 
ms for at least one timepoint and an expected intra-variability of the primary endpoint of 𝜎 = 9 ms) 
of the primary endpoint between moxifloxacin and placebo with a power of 85%. 
 
To account for potential dropouts and/or unevaluable data points, 48 subjects will be randomized in 
the trial. The recruitment could be stopped before 48 subjects from the time the number of fully 
evaluable subjects for the primary criterion is 40. That is to say having took part to the study, until 
the last scheduled ECG holter recording. 
A dropout is a subject who is prematurely discontinuing the trial before the end of the last holter ECG 
recording. 
 
3.4. Adjustment for covariates 
For the primary analysis and the assay sensitivity, QTcF at baseline and sex are considered as 
covariates taken into account in the models used for the analyses. 
3.5. Handling of dropouts or missing data 
No imputation will be performed in this trial.  
3.6. Interim analyses and data monitoring 
Safety analysis will be performed for data monitoring committee (DMC) during the trial. 


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3.7. Multicenter studies 
Not Applicable. 
3.8. Multiple comparisons/multiplicity 
The multiplicity is handled by considering a study “negative” (i.e. successful) if both P03277 doses 
reject simultaneously the null hypothesis for all timepoints and if for the assay sensitivity, the null 
hypothesis is rejected for at least one timepoint, using the method described by Hochberg and 
Tamhane to deal with multiple timepoints. 
3.9. Use of a subset of subjects for cardiac safety analysis 
The primary analysis will be done using the Per Protocol Set and will be repeated using the Full 
Analysis Set.  
The assay sensitivity analysis will be done using the Full Analysis Set and repeated using the Per 
Protocol Set. 
3.10. 
Active control studies intended to show equivalence 
Not Applicable. 
3.11. 
Examinations of subgroups 
The trial is stratified by sex which will be taken into account for the primary analysis and the assay 
sensitivity by putting it in the model. No other examination of subgroups is planned. 
 
 
 
 CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES 
Primary analysis will test each timepoint: 11 instead of 9 mentioned in the protocol. 
A model will be performed for each timepoint, the time will no more be included in the model. There 
is no change on the statistical analysis as Intersection-Union test was planned. 
 
In secondary analysis, same analysis as for primary endpoint will be repeated for HR in addition of 
QT, QTcPOP and QTcB.  
Descriptive analysis on number and percentage of subjects showing values above predefined 
threshold will be presented for PR and QRS. 
  
 


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 STATISTICAL AND ANALYTICAL PLANS 
5.1. Disposition of subjects 
Subject disposition will be based on all subjects who have signed their informed consent form and 
tabulated by sequence and overall for the following categories: 
 
 Total number of subjects included; 
 Total number of subjects exposed to each trial product; 
 Number (percentage) of subjects completing the study; 
 Number (percentage) of subjects prematurely discontinuing from study. 
 
Reason of screen-failure and premature discontinuation will be presented. 
5.2. Data sets analysed and protocol deviations 
Data sets analysed 
There will be four subject sets defined for this study: All enrolled subjects set, the Safety Set (SS), 
the Full Analysis Set (FAS) and the Per-Protocol Set (PPS). 
 
All enrolled Subjects Set will include all subjects who signed their informed consent form. This set 
will be used for subject disposition summaries and individual listings. 
All subjects who failed the screening visit (not selected) or withdrawn from the study before the 
randomization are screen-failed subjects and will be presented in the all enrolled data set. Those 
subjects have different data collected depending on the selection status i.e. complete screening visit 
and inclusion visit data collected for volunteers who have been selected at screening visit while only 
screening visit data were collected for subjects who did not comply with the eligibility criteria.  
 
The Safety Set will include all subjects receiving at least one administration of IMP, regardless of 
the quantity. This set will be used for evaluation of safety and description of demographic data and 
baseline characteristics. 
 
The Full Analysis Set will include all randomized subjects. This set will be used for evaluation of 
cardiac safety and description of demographic data and baseline characteristics. 
 
The Per Protocol Set will be a subset of the FAS and will include all subjects who have no major 
protocol deviations throughout their whole trial period. Major deviations will be defined as having 
an impact on the primary criterion. Primary analysis will be performed on this set. 
 
The number of subjects by analysis set will be tabulated by sequence group and overall. 
 
The following table describes how the above defined subjects sets will be used in the different 
analyses conducted.  
 
 


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Analyses Sets 
Safety Set 
Full 
Analysis 
Set (FAS) 
Per 
protocol 
(PP) Set 
Demographic 
data 
and 
baseline 
characteristics 
 
  
 * 
Exposure 
 
 
 
Cardiac safety assessment  
 
 
 
Safety assessment  
 
 
 
*: If the difference between FAS and PP set is greater than 10% 
 
Protocol deviations 
 
As per ICH E3 guideline, a protocol deviation is any change, divergence, or departure from the study 
design or procedures defined in the protocol, with or without impact to the patient safety or the 
efficacy assessments. Protocol deviations are displayed in the Clinical Study Report (CSR) as a 
metric of the feasibility and reliability of the study. The list of protocol deviations are presented in 
the table below and can be updated if necessary before breaking the blind. Protocol deviations will 
be gathered from monitoring files, clinical database and external vendors of off-site data (Laboratory 
data, ECG…)  
Protocol deviations will be split in major and non major deviations. A major deviation is defined as 
a deviation being an impact on the primary criteria. A first categorisation is done in this document, 
then categorisation will be done before breaking the blind during the statistical data review meeting. 
The decision will be duly described in the meeting minutes.  
 
The deviations are listed in the table below: 
 
Category 
Description 
Source 
Status 
Inclusion 
criteria not met 
Adult healthy volunteers not aged at least 
18 years old 
Clinical 
database 
(prior amendment 2) 
Non 
major 
 
Adult healthy volunteers not aged at least 
18 years old and below 60 (exclusive) 
Clinical 
database 
(after amendment 2) 
Non 
major 
 
Subject not having read the information and 
not provided his/her consent to participate 
in writing by dating and signing the 
informed consent prior to any trial-related 
procedure being conducted 
Monitoring 
Major 
 
Subject not assessed as healthy by a 
comprehensive 
clinical 
assessment 
(detailed medical history and complete 
physical examination) 
Clinical database 
Non 
major 
 
Subject without a Body Mass Index (BMI) 
> 19 kg/m² and < 28 kg/m² or a weight at 
least of 40 kg for female and 50 kg for male 
and at maximum of 100 kg 
Clinical database 
Non 
major 


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Subject not able or not willing to participate 
in the trial 
Clinical database 
Non 
major 
Non-Inclusion 
criteria met 
Subject with any history or family history 
of inherited or acquired Long QT syndrome 
(LQTS) 
Clinical database 
Major 
 
Subject with any history or family history 
of risk factors for Torsade de Pointe (TdP), 
unexplained loss of consciousness or 
convulsion 
Clinical database 
Major 
 
Subject with any history of clinically 
significant bradycardia 
Clinical database 
Major 
 
Subject with any history of clinically 
significant 
cardiac 
impairment 
by 
decreasing of left ventricular ejection 
fraction (LVEF) 
Clinical database 
Major 
 
Subject with any history of clinically 
significant arrhythmia (including Wolf-
Parkinson-White syndrome) 
Clinical database 
Major 
 
Subject 
with 
presence 
of 
cardiac 
pacemaker 
Clinical database 
Major 
 
Subject with frequent headaches and/or 
migraine, recurrent nausea and/or vomiting 
(more than twice a month) 
Clinical database 
Non 
major 
 
Subject with abnormal 12-lead ECG: PR < 
120 ms or PR > 200 ms, QRS > 100 ms, 
QTc > 450 ms, flat T-waves at screening 
visit (results provided by the independent 
ECGs Core Laboratory) 
Clinical database 
Major 
 
Subject with following abnormal vital signs 
after 10 minutes resting in supine position 
at screening visit: <90 SBP >160mmHg, 
<45 DBP >90mmHg, <50 HR >80bpm  
Clinical 
database 
(prior amendment 2) 
Non 
major 
 
Subject with following abnormal vital signs 
after 10 minutes resting in supine position 
at screening visit: <90 SBP >160mmHg, 
<45 DBP >90mmHg, <45 HR >80bpm  
Clinical 
database 
(after amendment 2) 
Non 
major 
 
Subject with any history or presence of 
relevant cardiovascular, pulmonary, 
gastrointestinal, hepatic, renal, metabolic, 
hematological, psychiatric, systemic, 
ocular, or infectious disease; any acute 
infection or signs of acute illness 
Clinical database 
Non 
major 
 
At Day-1: K+ < 3.6 mmol/L, Mg++ < 0.8 
mmol/L, eCCr < 90 mL/min, impaired liver 
f./ALT-AST > 2xULN 
Clinical database / 
Monitoring 
(prior 
amendment 2)   
Non 
major 


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At Day-1: K+ < 3.5 mmol/L, Mg++ < 0.66 
mmol/L, eCCr < 90 mL/min, impaired liver 
f./ALT-AST > 2xULN 
Clinical 
database 
(after amendment 2) 
Non 
major 
 
Subject carrier of: HBs antigen, anti-HCV 
antibodies, anti-HIV1 antibodies, anti-
HIV2 antibodies at screening 
Clinical database 
Non 
major 
 
Subject with any history of severe allergic 
or anaphylactic reactions to any allergen 
including drugs and contrast agents, or 
allergic disease diagnosed and treated by a 
physician 
Clinical database 
Non 
major 
 
Subject with any history of tendinopathy 
following a fluoroquinolone treatment 
Clinical database 
Non 
major 
 
Subject with any history of allergy to 
moxifloxacin or one of its compounds or 
other 
moxifloxacin 
contra-indications 
according to the SmPC description 
Clinical database 
Non 
major 
 
Subject with known contra-indication(s) to 
the use or with known sensitivity to one of 
the products under investigation or to drugs 
from a similar pharmaceutical class 
Clinical database 
Non 
major 
 
Subject treated with any concomitant 
medications which could induce a QT 
prolongation 
Clinical database 
Major 
 
Subject with presence of narcotics or 
alcohol abuse (alcohol consumption > 40 
grams/Day) at screening 
Clinical database 
Non 
major 
 
Subject smoking more than 10 cigarettes or 
equivalent /Day, unable to stop smoking 
during the confinement period 
Clinical database 
Non 
major 
 
Subject having an excessive consumption 
of beverages with xanthine bases (tea, 
coffee, chocolate) (>6 cups or glasses /Day) 
and not able to refrain from consuming 
grapefruit (fresh fruit, juice, ice...) the day 
before 
inclusion 
and 
during 
the 
confinement period 
Clinical database 
Non 
major 
 
Subject having done a blood donation 
within 3 months before first trial product 
administration 
Clinical database 
Non 
major 
 
Subject having received any medication 
within 21 days prior to inclusion, or within 
5 times the elimination half-life of that 
drug, whichever the longest, with the 
exception of hormonal contraception for 
Clinical database 
Non 
major 


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female and of Hormonal Replacement 
Therapy (HRT) in case of menopausal 
volunteers and paracetamol 
 
Subject having received an administration 
of any contrast agent within 2 weeks before 
inclusion, or scheduled to receive any 
contrast agent within 3 months after the last 
IMP administration 
Clinical database 
Non 
major 
 
Subject having participated to a clinical 
trial involving an investigational drug or 
device within 21 days prior to screening, or 
within 5 times the elimination half-life of 
that drug whichever the longest 
Clinical database 
Non 
major 
 
Subject having a planned simultaneous 
participation to another clinical trial 
involving an investigational drug or device 
Clinical database 
Non 
major 
 
Subject 
having 
an 
inability 
or 
unwillingness to cooperate with the 
requirements of this trial 
Clinical database 
Non 
major 
 
Subject having a planned interventions 
(surgery, radiotherapy, chemotherapy or 
others) during the course of the trial 
Clinical database 
Non 
major 
 
Subject with any condition which, based on 
the investigator's clinical judgment, would 
prevent the subject from participating in all 
trial assessments and visits (for example: 
mental or physical incapacity, language 
comprehension, geographical localization, 
etc.) 
Clinical database 
Non 
major 
 
Pregnant or breast-feeding (a childbearing 
potential woman or amenorrhea less than 
12 months must have a negative pregnancy 
test at inclusion and be using a medically 
approved contraception method) 
Clinical database / 
Monitoring 
 
Non 
major 
Subject 
not 
withdrawal 
as 
per protocol 
Stopping rules detected on laboratory 
measurements and subject not withdrawn: 
increase in serum creatinine by more than 
25% or 0.5 mg/dL (44 umol/L) compared 
to the baseline value  
Laboratory database 
Non 
major 
 
Stopping 
rules 
detected 
on 
ECG 
measurements and subject not withdrawn: 
QTc Friderica > 500 ms or an increase of > 
60 ms over the baseline  
ECG database 
Non 
major 


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Stopping 
rules 
detected 
on 
ECG 
measurements and subject not withdrawn: 
Torsade de pointes event / Ventricular 
tachycardia / Ventricular fibrillation flutter 
/ Seizures 
ECG database 
Non 
major 
 
Subject received a contrast agent within 
two weeks before the inclusion up to the 
end of confinement period and subject not 
withdrawn 
Clinical database 
Major 
 
Any exam performed after a withdrawal of 
consent 
Clinical 
database, 
Laboratoty database, 
ECG database 
Non 
major 
Unblinding 
The blind was not maintained on-site 
Monitoring 
Non 
major 
 
The blind was not maintained off-site 
Monitoring 
Major 
 
The code was broken 
Clinical database 
Major 
Forbidden 
concomitant 
medication  
Concomitant medication taken during the 
confinement period having an impact on 
the primary criteria 
Monitoring 
Major 
Trial 
product 
deviation 
Subject randomisation not followed the 
sequential list of sequences 
Clinical database 
Non 
major 
 
IMP/AMP 
administered 
is 
not 
the 
IMP/AMP allocated by randomisation 
Randomisation 
database 
Major 
 
The volume actually administered is 
different from 10% to 20% than the 
calculated one 
Clinical database 
Non 
major 
 
The volume actually administered is 
different of more than 20% than the 
calculated one 
Clinical database 
Major 
 
Power injector not used 
Clinical database 
Non 
major 
 
The actual injection rate is different than 
2mL/s  
Clinical database 
Non 
major 
 
Saline flush volume administered not at 
minimum of 10 mL 
Clinical database 
Non 
major 
 
Location of injection site is not adequate 
Clinical database 
Non 
major 
 
The dose of AMP actually administered is 
different from 400 mg  
Clinical database 
Non 
major 
 
Temperature excursion for trial product 
Monitoring 
Non 
major 
 
Extravasation 
Clinical database 
Major 


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Missing data 
Age is missing 
Clinical database 
Non 
major 
 
Sex is missing 
Clinical database 
Non 
major 
 
Weight is missing at screening visit 
Clinical database 
Non 
major 
 
Height is missing 
Clinical database 
Non 
major 
 
Race is missing 
Clinical database 
Non 
major 
 
Physical examination not performed 
Clinical database 
Non 
major 
 
Vital signs not measured 
Clinical database 
Non 
major 
 
Other contrast agent administration not 
completed 
Clinical database 
Non 
major 
 
Urine sample not done or missing at 
screening visit 
Clinical database 
Non 
major 
 
Pregnancy test is missing 
Clinical database 
Non 
major 
 
12-lead safety ECG not performed in 
triplicates  
Clinical database  
Non 
major 
 
12-lead safety ECG results missing 
ECG database 
Non 
major 
 
12-lead safety ECG from paper instead of 
digital analysis 
ECG database 
Non 
major 
 
12-lead Holter ECG not performed 
Clinical database  
Major 
 
12-lead extracted QTCF from Holter ECG 
with more than 3 measurements of 
triplicates at baseline missing 
ECG database 
Major 
 
12-lead 
extracted 
Holter 
ECG 
not 
performed in triplicates 
ECG database 
Non 
major 
 
Blood sample for central laboratory 
assessment not performed 
Clinical database 
Non 
major 
 
Laboratory biochemistry results missing 
Laboratory database 
Non 
major 
 
Laboratory hematology results missing 
Laboratory database 
Non 
major 
 
Urine sample for long term elimination not 
performed 
Clinical database 
Non 
major 
 
Urinary result for long term elimination 
missing 
PK database 
Non 
major 
 
Blood sample for long term elimination not 
performed 
Clinical database 
Non 
major 


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Blood sample results for long term 
elimination missing 
PK database 
Non 
major 
 
Blood sample for plasma concentration not 
performed 
Clinical database 
Non 
major 
 
Results for plasma concentration missing 
PK database 
Non 
major 
 
Tolerance at injection site not performed 
Clinical database 
Non 
major 
 
VAS questionnaire not completed while 
subject reported pain 
Clinical database 
Non 
major 
 
Visit not done 
Clinical database 
Non 
major 
Non respect of 
study’s schedule 
and procedures 
Urine sample for drug screening not 
performed at latest the day before first 
administration 
Clinical database 
Non 
major 
 
Blood samples collection for P03277 
plasma 
concentration 
assessment 
not 
performed after vital signs  
Clinical database 
Non 
major 
 
Blood samples collection for laboratory 
data not performed before IMP /AMP 
administration of first period  
Clinical database 
Non 
major 
 
Vitals signs not performed at scheduled 
time  
Clinical database 
Non 
major 
 
Blood samples collection for P03277 
plasma concentration not performed at 
scheduled timepoint 
Clinical database 
Non 
major 
 
12-lead Holter ECG not performed at 
scheduled time 
ECG database 
Non 
major 
 
12-lead safety ECG not performed at 
scheduled time 
ECG database 
Non 
major 
 
Initiation of Holter not performed 1 hour 
before administration 
Clinical database 
Non 
major 
 
12-lead 
Holter 
ECG 
not 
performed 
according to procedures 
Monitoring 
Non 
major 
 
12-lead 
safety 
ECG 
not 
performed 
according to procedures 
Monitoring 
Non 
major 
 
Blood sample collection not performed at 
scheduled time 
Clinical database 
Non 
major 
 
Not allowed retest 
Monitoring 
Non 
major 
 
VAS questionnaire not correctly printed 
Monitoring 
Non 
major 
 
Subjects presenting at least one major protocol deviation will be excluded from the Per Protocol Set. 
 


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Frequency and percentages of subjects with protocol deviations will be presented by sequence group 
and overall breaking down by status (major/non major). A listing of all protocol deviations will also 
be provided in CSR appendix 16.2.2 and major protocol deviations will be flagged. 
 
5.3. Measurements of study drug compliance 
Study drug in this study refers to the injection of the contrast media. Number of subjects with 
theoretical volume to be administered not equal to the one actually administered will be presented 
and the difference for those subjects will be tabulated in mL and percentage:  
 
𝐶𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒= (1 −𝑡ℎ𝑒𝑜𝑟𝑒𝑡𝑖𝑐𝑎𝑙 𝑣𝑜𝑙𝑢𝑚𝑒− 𝑎𝑐𝑡𝑢𝑎𝑙 𝑣𝑜𝑙𝑢𝑚𝑒 
𝑡ℎ𝑒𝑜𝑟𝑒𝑡𝑖𝑐𝑎𝑙 𝑣𝑜𝑙𝑢𝑚𝑒
) ×  100 
5.4. Demographic and other baseline characteristics 
5.4.1. Demographic data 
Demographic parameters are age, sex, childbearing potential, body weight in kilograms (kg), height 
in centimetres (cm), BMI (kg/m²) and ethnic origin (self-reported race/ethnicity).  
Summary statistics (number [n], mean, standard deviation [SD], median, minimum, and maximum) 
will be calculated for age, body weight, height and BMI. Frequency and percentages will be 
calculated for sex.  
 
BMI will be derived for each collection of body weight using the formula:  
 
𝐵𝑀𝐼= 𝐵𝑜𝑑𝑦 𝑊𝑒𝑖𝑔ℎ𝑡 (𝑘𝑔)
𝐻𝑒𝑖𝑔ℎ𝑡 (𝑚)2
 
 
5.4.2. Study disease 
Not Applicable. 
5.4.3. Risk factors 
Not Applicable. 
5.4.4. Medical history and concomitant diseases 
Medical history and concomitant diseases will be coded in System Organ Classes (SOC) and 
preferred terms (PT) using the Medical Dictionary for Regulatory Activities (MedDRA) version 21.0 
or the latest version available at the date of data base lock. Medical histories are the ones flagged as 
"Not Ongoing" and concomitant diseases are those flagged as "Ongoing" at the screening visit. 
Summary tables (number and % of subjects) grouped by SOC and PT will be presented by sequence 
group and overall for Medical history firstly then for concomitant diseases.  
Listing of demographics, study disease characteristics and all diseases will be presented in CSR 
Appendix 16.2.4 with a flag for ongoing diseases. 


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5.4.5. Clinical laboratory evaluation at baseline 
Laboratory data analysis will be done using the safety set by sequence group and overall. Blood 
samples will be performed during screening visit. Urinalysis data will be listed only. 
 
Results will be presented in standard international (SI) units and conventional United States units 
(See Table 1 and    Table 2 respectively). Original units will only be listed. Laboratory data will be 
analyzed quantitatively and qualitatively. Qualitative analyses will be done via comparison of 
laboratory data to their reference ranges. Quantitative analyses will be done by tabulating raw data. 
5.4.6. Vital signs, physical findings and other observations related to safety at baseline 
Abnormality detected during physical examination will be listed in section 16.2.9., it will be 
described in the Adverse Events section.  
Summary statistics (number [n], mean, standard deviation [SD], median, minimum, and maximum) 
will be calculated for vital signs (systolic blood pressure, diastolic blood pressure and pulse rate) at 
screening visit and presented by sequence group and overall. Qualitative analyses of 
Systolic/Diastolic Blood Pressure (mmHg) and Pulse Rate (beats/min) will be done via comparison 
of vital signs data to their normal ranges.  
5.4.7. Prior medication and procedures 
Prior therapies are defined as therapies ended before the first administration. 
Prior medications will be coded using the WHODRUG dictionary version September 2016. Prior 
procedures are therapies not coded as per WHODRUG dictionary. 
The number and percent of subjects taking prior medications and procedures will be presented by 
sequence group and overall.  
Summary tables (number and % of subjects) grouped by the first and the fourth level of ATC code 
will be presented by sequence group and overall for prior medication. 
Listing of all prior therapies will be presented in CSR appendix 16.2.4. 
5.4.8. 12-lead ECG assessment 
Summary statistics (number [n], mean, standard deviation [SD], median, minimum, and maximum) 
will be calculated for cardiac status from the mean of the ECG triplicate examination at screening 
visit by sequence group and overall (QT, QTcF, QTcB, QRS, PR, RR, heart rate). Frequency and 
percentages will be calculated for sinus rhythm (yes/no). The number (%) of subjects having at least 
one “No” for sinus rhythm or having all “Yes” will be summarized.  
 
5.4.9. Other baseline characteristics 
Data concerning contrast agent history at screening and inclusion and pregnancy test will be only 
listed in section 16.2.4.  
 
Meal date and start and end time will be listed for each period. 
 
 


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5.5. Cardiac safety evaluation 
All cardiac safety analysis will be conducted using the FAS except otherwise specified. 
Listing of all cardiac safety data will be presented in CSR appendix 16.2.6. Listing of drug 
concentration data will be presented in CSR appendix 16.2.5. 
 
5.5.1. Primary analysis of the primary criteria 
Cardiac safety data are coming from 12-lead Holter ECG recording read by off-site cardiologists. 
Triplicate values will be issued for each measurement and the average of the 3 replicates will be used 
for statistics analyses. Therefore there will be one measure by timepoint by subject. 
 
5.5.1.1 Baseline value 
There will be one baseline by administration period. 
The baseline is defined as the mean of the 3 triplicates ECGs measured within one hour before each 
IMP/AMP administration (i.e., first the mean of the 3 triplicates ECGs is done for each timepoint 
prior IMP/AMP administration: 45, 30 and 15 minutes before administration, then the 3 means are 
averaged). 
 
5.5.1.2 Primary analysis 
The primary analysis is performed using an analysis of covariance (ANCOVA) model for crossover 
data with baseline data as covariate, sequence, period, trial drug and sex as fixed effect and subject 
as a random effect. 
 
Test 
Differences between means will be tested through the model for each timepoint and for the two doses 
of P03277 using Student’s t-test. 
 
For each timepoint, the two-sided 90% confidence intervals of the difference between each of the 
two doses of P03277 and placebo is calculated for testing the hypotheses. 
The trial will be considered as successful if no test is significant that is to say if the upper range of 
the 90% CI is lower than 10 ms for all tests. 
 
The appropriateness of a linear model will be assured by inspecting the goodness of fit by looking at 
normal QQ plots for the residuals and plots of the residuals over predicted values.  
 
The primary analysis will be performed using the Per Protocol Set. 
 
 
SAS procedure: 
proc mixed data = dataset method = REML plots=all; 
  class Seq Per Trt subj gender; 
  model ΔQTcF = Baseline Seq Per Trt gender / ddfm = kr residual outp=ipred outpm=pred; 
  random  subj / type = cs; 


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  lsmeans Trt; 
  Estimate "P03277 0.1 mmol/kg - Placebo 5min after administration" Trt 1 0 0 -1 / alpha = 0.1 
cl; 
run; 
 
 
5.5.2. Supportive analyses of primary criterion 
Primary analysis will be repeated using the Full Analysis Set. 
 
Assay sensitivity analysis 
The assay sensitivity analysis is performed using an analysis of covariance (ANCOVA) model for 
crossover data with baseline data as covariate, sequence, period, trial drug and sex as fixed effect and 
subject as a random effect. 
 
Test: 
Differences between means will be tested through the model for each timepoint using Student’s t-
test. Only the five following timepoints will be used: 1h, 1h30, 2h, 3h and 4h. 
 
For each timepoint, the p-value for comparing the doses of positive control with corresponding 
placebo is calculated for testing above hypotheses. 
 
Hochberg’s step-up procedure: 
Let 𝑝1, 𝑝2, 𝑝3, 𝑝4, 𝑝5 be the ordered p-values (from the lower to the upper value) and 
𝐻1, 𝐻2, 𝐻3, 𝐻4, 𝐻5 be the corresponding ordered null hypothesis. The testing procedure starts with 
the less significant comparison and continues as long as tests are not significant (meaning that the 
alternative hypothesis is not met). The procedure stops the first time a significant comparison occurs 
and all remaining hypotheses will be not tested. 
- 
In the first step, 𝐻5 is rejected if 𝑝5 ≤ 𝛼,  
- 
in the second step (if any) 𝐻4 is rejected if 𝑝4 ≤ 𝛼/2,  
- 
in the third step (if any), 𝐻3 is rejected if 𝑝3 ≤ 𝛼/3, 
- 
in the fourth step, 𝐻2 is rejected if 𝑝2 ≤ 𝛼/4,  
- 
and in the fifth and last step, 𝐻1 is rejected if 𝑝1 ≤ 𝛼/5 with 𝛼 being the 1-sided significance 
level of 0.05. 
The trial will be considered as positive in terms of assay sensitivity if, at the end of the Hochberg’s 
step-up procedure, at least one test is significant. CI will be adjusted according to the procedure.  
 
Assay sensitivity will be repeated using the Per Protocol Set. 
 
SAS procedure: 
proc mixed data = dataset method = REML plots=all; 
  class Seq Per Trt subj gender; 
  model ΔQTcF = Baseline Seq Per Trt gender / ddfm = kr residual outp=ipred outpm=pred; 
  random  subj / type = cs; 
  lsmeans Trt; 
  Estimate "Positive control - Placebo 1hour after administration" Trt 0 0 1 -1 / alpha = 0.1 cl; 


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run; 
 
5.5.3. Additional analyses of primary criterion 
Not Applicable. 
 
5.5.4. Analysis of secondary criteria 
 
Analysis of secondary criteria will be done using the Full Analysis Set except otherwise specified. 
 
5.5.4.1 
Primary endpoint 
 
Same analysis as for primary end-point will be repeated for QT, QTcPOP, QTcB and HR. 
 
5.5.4.2 
Descriptive analysis  
 
 Descriptive statistics (number [n], mean, standard deviation [SD], median, minimum, and 
maximum) at any time from administration up to 24h post dose of time-matched change from 
baseline, placebo controlled, of the QT, QTcF, QTcPOP and the QTcB will be provided by 
trial product group. 
 
 Number and percentage of subjects showing values above predefined threshold for PR, QRS, 
QT, QTcB, QTcPOP and QTcF: 
o PR interval 
 Value > 220 ms 
 Relative change > 25% 
o QRS interval  
 Value > 120 ms 
 Relative change > 25% 
o Absolute QTc interval prolongation: 
 QTc interval > 450 ms 
 QTc interval > 480 ms 
 QTc interval > 500 ms 
o Change from baseline in QTc interval: 
 QTc interval increases from baseline > 30 ms 
 QTc interval increases from baseline > 60 ms 
 
 
 Descriptive statistics (number [n], mean, standard deviation [SD], median, minimum, and 
maximum) at any time of QT, QTcF, QTcPOP, QTcB, RR (ms), QRS (ms), PR (ms), Heart 
rate (bpm) will be presented by trial product group. Frequency and percentages will be 
calculated for interpretation. The worst case of interpretation by triplicates (Abnormal 
clinically significant > Abnormal non clinically significant > Unable to evaluate/unable to 
evaluate but measurements provided are correct > Normal ECG) will be presented.  


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 Frequency and percentages will be calculated for sinus rhythm (yes/no) globally by trial 
product group. The number (%) of subjects having at least one “No” for sinus rhythm or 
having all “Yes” after baseline will be summarized.  
 
5.5.4.3 
QT/QTc values according to plasma concentrations of P03277 
 
Concentration-response relationship will be investigated between QTc and P03277 
concentrations using a mixed model approach. 
This analysis will be performed on the Per Protocol Set including all time points for which a 
pair of QTc and P03277 concentrations is available. 
Graphical exploration: 
In order to assess quality of QTcF correction before and after dosing the following figures 
will be provided: 
 Scatter plot of QTcF (y-axis) versus RR (x-axis) for baseline and placebo data with a 
regression line 
 Scatter plot of ΔQTcF (y-axis) versus ΔRR (x-axis) for values collected during 
P03277 treatment periods with a regression line. 
In both cases, the regression lines should tend toward an horizontal line, otherwise, a 
dependency still exist between QTcF and RR and QTcPOP may be considered as preferred 
dependent variable. 
The following exploratory plots will also be performed before starting the modelling: 
 Scatter plot of individual QTc values vs. time-matched concentrations including a 
nonparametric trend curve will be provided to assess the pattern of the relationship 
 Scatter plot of individual HR values vs. time-matched concentrations including a 
nonparametric trend curve will be provided to detect impact of the treatment on HR 
 Time course of ΔΔQTc by dose level as calculated during the primary criteria analysis 
 Time course of ΔΔHR (or ΔΔRR) by dose level as calculated during the secondary 
criteria analysis 
The SAS syntax corresponding to the scatter plot of change in QTc vs. concentrations 
including a trend curve is:  
proc sgplot data = dataset ; 
scatter x=Concentrations y=CHG/  transparency=0.6 group=TRT name="p1" 
legendlabel="Individual Delta QTc-Concentration pairs"; 


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loess x= Concentrations y=CHG/ nomarkers  smooth=0.3 name="p2" 
legendlabel="Trend line" lineattrs=(color=green); 
refline 0/axis=y; 
label TRT="Actual treatment"; 
xaxis grid label="Concentration Unit"; 
yaxis grid label="ms"; 
keylegend "p1" "p2"; 
run; 
 
 
Model development: 
The model development will start with the pre-specified mixed linear model as detailed in 
Garnett et al. [1] considering QTcF as dependent variable. In case of the graphical 
exploration suggests that Fridericia correction does not account for all RR variation, 
QTcPOP will be used instead.  
Placebo data will be considered for the analysis with concentration values set to 0. Moreover, 
concentrations below the limit of quantification will also be set to 0. 
The fixed effect parameters of the pre-specified model will be intercept, slope for P03277 
concentrations, influence of baseline (centered on mean) on intercept, treatment specific 
intercept (0=P03277, 1=Placebo), and theoretical timepoints post-administration. Subject 
specific random effects will be added on intercept and slope parameters with an unstructured 
covariance matrix. In case of the unstructured covariance matrix is not supported by the data, 
other simplified or reduced structures will be investigated (ex. variance components). 
∆𝑄𝑇𝑐𝑖𝑗𝑘= (𝜃0 + 𝜂0,𝑖) + 𝑇𝑅𝑇𝑗+ (𝜃1 + 𝜂1,𝑖)𝐶𝑖𝑗𝑘+ 𝑇𝐼𝑀𝐸𝑘+ 𝜃2(𝑄𝑇𝑐𝑖𝑗𝑘=0 −𝑄𝑇𝑐0
̅̅̅̅̅̅̅) + 𝜀𝑖𝑗𝑘 
(1) 
 
Where i is the subject, j the treatment and k the time. 
The QTc and their 2-sided 90% confidence intervals will be calculated at P03277 0.1 
mmol/kg and 0.3 mmol/kg Cmax geometric means as follows: 
QTci = (TRT0-TRT1) + θ1Cmaxi 
The SAS syntax corresponding to Equation 1 and QTc estimation is:  
proc mixed data = dataset method = REML plots=all; 
ods output estimates=EST solutions=SOL CovParms=COV; 
  class Trt Time subj; 
  model QTc = Baseline Trt Concentration Time / ddfm = kr solution alphap=.05  
  residual outp=ipred outpm=pred; 
  random  INT Concentration/ subject = subj  type = un; 


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  Estimate "ΔΔQTc P03277 0.1 mmol/kg" Trt 1 -1 Concentration Cmax1 / alpha = 0.1 
cl; 
  Estimate "ΔΔQTc P03277 0.3 mmol/kg" Trt 1 -1 Concentration Cmax2 / alpha = 0.1 
cl; 
run; 
No additional covariate investigation will be performed and in order to avoid unnecessary 
model-building steps, non-significant fixed parameters will not be removed from the model, 
unless they cause problem of convergence or estimability issues. Random effects not 
supported by the model will be remove as they may result in non-convergence problems. 
 
Model evaluation: 
Goodness of fit plots will be provided, consisting on: 
 QQ plot of residuals 
 Concentrations versus residuals 
 Time, baseline and treatment versus residuals 
Any marked bias in residual plots may suggest model misspecification. Moreover, a large and 
significant treatment specific intercept (TRT term in the model) may also indicate model 
misspecification (i.e. lack of linearity). 
In addition, structural model hypothesis will be checked from graphical exploratory plots: 
 The absence of effect on HR will be investigated from time course of ΔΔQTc by dose 
level 
 The hypothesis of direct relationship will be evaluated from the time course of ΔΔQTc 
by dose level. If the primary analysis allow to reject the hypothesis of QT/QTc 
prolongation, hysteresis phenomenon will not be considered, otherwise, hysteresis 
will be investigated by visual inspection comparing time of peaks in QT response and 
concentrations 
 The hypothesis of linear relationship between ΔQTc and concentrations will be 
evaluated from exploratory scatter plot and the goodness of fit plots. 
In case of the linear relationship between ΔQTc and P03277 concentrations cannot be 
accepted, an alternative model such as saturable model will be considered. 
∆𝑄𝑇𝑐𝑖𝑗𝑘= (𝜃0 + 𝜂0,𝑖) + 𝑇𝑅𝑇𝑗+
(𝜃1+𝜂1,𝑖)𝐶𝑖𝑗𝑘
𝛾
(𝜃2+𝜂2,𝑖)
𝛾+𝐶𝑖𝑗𝑘
𝛾+ 𝑇𝐼𝑀𝐸𝑘+ 𝜃3(𝑄𝑇𝑐𝑖𝑗𝑘=0 −𝑄𝑇𝑐0
̅̅̅̅̅̅̅) + 𝜀𝑖𝑗𝑘 
(2) 


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In Equation 2, the parameter 1 is the maximum asymptotic effect due to treatment, and the 
parameter 2 is the concentration at which the effect is half 1. 
In case of a hysteresis phenomenon cannot be discarded, an effect compartment model 
combining a population PK model on P03277 and a PKPD model will be envisaged.  
Display of results 
Parameters estimated from the selected model will be presented with their standard error and 
95% confidence interval. 
QTc predicted for each dose level will be presented with their 2-sided 90% confidence 
interval and a graphical display of predicted QTc over the concentration range collected 
during the study will also be provided. 
Decision rule 
The impact of P03277 on QT/QTc prolongation will be considered as below the threshold of 
regulatory concern if the upper bound of the 90% confidence interval of QTc predicted at 
supra-clinical dose Cmax is below 10 ms. 
 
5.5.4.4 
Morphological analysis 
 
Analysis of morphology will be based on the number of subjects with at least one emergent 
abnormality. The number (%) of subjects having changes from baseline will be summarized 
by the finding’s conclusion (see Appendices) for each trial product. Localization will be taken 
into account. The table will exclude reported statement associated to a normal ECG if 
necessary: 
 
 
 
Category 
Term includes: 
Q or QS pattern 
Small Q waves in inferior leads, consider normal variant 
Axis and Voltage 
Poor Precordial R wave progression, consider normal variant 
Axis and Voltage 
Abnormal P wave axis, consider normal variant 
Hypertrophy 
Left ventricular hypertrophy by QRS voltage consider normal variant 
ST depression and elevation 
ST elevation, consider normal variant 
ST depression and elevation 
Early repolarization, consider normal variant 
T/U wave abnormalities 
Normal repolarization pattern 
T/U wave abnormalities 
U wave, consider normal variant 
AV conduction 
First degree AV block, consider normal variant 
AV conduction 
Short PR interval, consider normal variant 
Intraventricular conduction defects 
Incomplete RBBB, consider normal variant (QRS<=120msec) 
Rhythm 
Normal sinus rhythm, rate 50-100 bpm 
Rhythm 
Possible normal sinus rhythm, rate 50-100 bpm 
Rhythm 
Dominant sinus rhythm 
Rhythm 
Uncertain supraventricular rhythm, consider normal variant 
Rhythm 
Respiratory sinus arrhythmia 
Rhythm 
Respiratory sinus arhythmia, consider normal variant 
Rhythm 
Sinus tachycardia, rate 100-130 bpm, consider normal variant 
Rhythm 
Sinus bradycardia, rate 40-49 bpm, consider normal variant 
Rhythm 
Wandering atrial pacemaker, consider normal variant, unsinusal rhythm 
Rhythm 
Atrial electronic pacemaker 


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Rhythm 
Atrial electronic pacemaker, intermittent 
Rhythm 
Ventricular electronic pacemaker, unsinusal rhythm 
Rhythm 
Ventricular electronic pacemaker, intermittent, unsinusal rhythm 
Rhythm 
Dual chamber electronic pace maker 
Rhythm 
Dual chamber electronic pace maker, intermittent 
 
 
 
5.6. Safety evaluation 
5.6.1. Extent of exposure 
Duration between trial products administration and end of period, summary of durations during the 
study, volume theoretically administered, volume actually administered, dose actually administered, 
actual rate of administration, volume of saline flush, location of injection site, mode of injection and 
occurrence of an overdose will be tabulated.  Frequency tabulation of actual injection rate will be 
also displayed per trial product group and overall. 
Body weight measured at inclusion visit and after each trial product administration (i.e. before the 
next administration) will be presented by each trial product group and overall. 
 
The extent of exposure summary will be presented using the Safety Set. 
 
Listing of exposure will be presented in CSR appendix 16.2.5. 
 
5.6.2. Adverse events 
All analyses of AEs will be based on the number of subjects with AEs (and not on the number of 
AEs) except otherwise specified and using the safety set. 
Adverse events (AEs) will be coded using MedDRA version 21.0. 
 
The time period for the assessment of AEs will be divided into 5 mutually exclusive and exhaustive 
periods: 
- 
Before IMP/AMP: between informed consent signature and start of the first administration 
- 
Period 1: between start of the first administration and start of the second administration 
- 
Period 2: between start of the second administration and start of the third administration 
- 
Period 3: between start of the third administration and start of the fourth administration 
- 
Period 4: between start of the fourth administration and Day 12 included (date of Day 12 
corresponds to date of Day 10 + 2 days not taking into account the time) 
- 
After confinement period: during follow-up periods (> Day 12).  
 
Events will be classified by trial products according to time of onset in the corresponding cycle 
related to trial products. 
Events will be classified as treatment-emergent if they have started since the first administration. 
 
Partial start dates/times will be queried. If information is not available to reliably allocate to a session 
and period, the allocation will be agreed at the data review meeting before database lock. If there is 
any doubt about treatment emergence, AEs will be classified as treatment emergent. 


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The number (%) of subjects having at least one AE as follows will be summarized for each trial 
product and overall for: 
- 
At least one TEAE 
- 
At least one AE with each of the following classification of intensity 
 Mild 
 Moderate 
 Severe 
- 
At least one adverse reaction (relationship to trial treatment classified as ‘Related’) 
- 
At least one AE with each of the following classifications of action taken with trial treatment: 
 Dose not changed 
 Trial product withdrawn 
- 
At least one AE with each of the following classifications of outcome: 
 Recovered/resolved 
 Recovered/resolved with sequelae 
 Not recovered/Not resolved 
 Fatal 
 
The table will show the same information for serious AE, defined as AEs with serious classified as 
‘yes’ or missing. The table will be repeated for all TEAEs. 
 
A table will be presented showing the total numbers of AEs and SAEs and the distribution of AEs 
(number [%] of subjects with number of AEs) for each IMP/AMP and overall. The table will also 
show the same information for SAEs defined as TEAEs with serious classified as ‘yes’ or missing, 
unless the number of SAEs make this uninformative. 
Summaries by SOC and PT will be presented for all treatment-emergent events and all related 
treatment-emergent events for each IMP/AMP and overall.  
Adverse events during follow-up period will be presented overall by SOC and PT. 
 
Data listings will present all AEs reported, including non-TEAEs. Adverse event listings will be 
sorted by subject number and will display also the study procedure, body system, and preferred term, 
time of onset, duration, intensity, seriousness, outcome, relationship to the IMP/AMP, relationship 
to a study procedure, action taken with IMP/AMP, IMP unblinding, AE-targeted medication, other 
AE-targeted action, date and time of IMP/AMP administration (presented in CSR appendix 16.2.7).  
 
AE Duration will be computed in days as Date of End of AE - Date of Onset of AE + 1. Date and 
time of administration displayed will be those of trial product administration preceding the date and 
time of onset of the AE. If the AE started before Day 1 or after the follow-up period, no date and 
time of administration will be displayed. 
 
5.6.3. Deaths, serious adverse events and other significant adverse events 
All deaths, all serious adverse events and all adverse events of special interest experienced during 
the treatment period related to the study drug will be separately listed per subject number, presenting: 
first/last application, treatment phase (Initial or Follow-up), emergence, description, SOC, preferred 


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term, start and end date, duration, the relationship to study drug, the action taken and the seriousness 
criteria. 
 
The list of preferred terms of adverse events of special interest is the following: 
 
MedDRA Code 
MedDRA Term 
10076948 
Acute encephalitis with refractory, repetitive partial seizures 
10003628 
Atonic seizures 
10049612 
Autonomic seizure 
10075606 
Change in seizure presentation 
10053398 
Clonic convulsion 
10010920 
Convulsions local 
10010927 
Convulsive threshold lowered 
10079424 
Focal dyscognitive seizures 
10018100 
Generalised tonic-clonic seizure 
10067467 
Nephrogenic systemic fibrosis 
10061334 
Partial seizures 
10056209 
Partial seizures with secondary generalisation 
10076981 
Post stroke seizure 
10039906 
Seizure 
10071350 
Seizure cluster 
10040703 
Simple partial seizures 
10042772 
Syncope 
10043994 
Tonic convulsion 
 
5.6.4. Clinical laboratory evaluation 
All laboratory values recorded during the study will be individually listed and flagged for values 
outside reference ranges and clinically significant (presented in CSR appendix 16.2.8).  
Laboratory data analysis will be done using the safety set and displayed by trial product group. 
 
The baseline is defined as the last measure before the first trial product administration. 
The statistical analysis will present results in standard international (SI) units and conventional 
United States units (See Table 1 and    Table 2 respectively). Original units will be only listed. 
Laboratory data will be analyzed quantitatively and qualitatively. Qualitative analyses will be done 
via comparison of laboratory data to their reference ranges. Quantitative analyses will be done by 
tabulating raw data and change from baseline. They will be displayed qualitatively as well by means 
of shift tables. 
 


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Table 1 Hematology parameters 
Hematology parameters 
 
SI Units 
US Units 
Basophils 
BASO 
109/L 
103/μL 
Basophils/Leukocytes 
BASOLE 
% 
% 
Eosinophils 
EOS 
109/L 
103/μL 
Eosinophils/Leukocytes 
EOSLE 
% 
% 
Hematocrit 
HCT 
v/v 
% 
Hemoglobin 
HGB 
g/L 
g/dL 
Lymphocytes 
LYM 
109/L 
103/μL 
Lymphocytes/Leukocytes 
LYMLE 
% 
% 
Mean red blood cells volume 
MCV 
fL 
µm3 
Monocytes 
MONO 
109/L 
103/μL 
Monocytes/Leukocytes 
MONOLE 
% 
% 
Neutrophils 
NEUT 
109/L 
103/μL 
Neutrophils/Leukocytes 
NEUTLE 
% 
% 
Platelet count 
PLAT 
109/L 
103/μL 
Red blood cells = Erythrocytes 
RBC 
1012/L 
106/µL 
White blood cells = Leukocytes 
WBC 
109/L 
103/µL 
 
   Table 2 Biochemistry parameters 
Biochemestry parameters 
 
SI Units 
US Units 
Magnesium* 
MG 
mmol/L 
mg/dL 
Sodium 
SODIUM 
mmol/L 
mEq/L 
Potassium 
K 
mmol/L 
mEq/L 
Chloride 
CL 
mmol/L 
mEq/L 
Glucose Random 
GLUC 
mmol/L 
mg/dL 
Urea Nitrogen  
UREAN 
mmol/L 
mg/dL 
Urea 
UREA 
mmol/L 
mg/dL 
Creatinine 
CREAT 
µmol/L 
mg/dL 
Protein 
PROT 
g/L 
g/dL 
Calcium 
CA 
mmol/L 
mg/dL 
Phosphorus 
PHOS 
mmol/L 
mg/dL 
Total bilirubin 
BILI 
µmol/L 
mg/dL 
Indirect Bilirubin 
BILIND 
µmol/L 
mg/dL 
Conjugated/Direct bilirubin 
BILDIR 
µmol/L 
mg/dL 
Aspartate amino transferase  
AST 
U/L 
U/L 
Alanine amino transferase  
ALT 
U/L 
U/L 
Alkaline phosphatase 
ALP 
U/L 
U/L 
Lactate dehydrogenase 
LDH 
U/L 
U/L 
Triglycerides 
TRIG 
mmol/L 
mg/dL 
eGFR* 
GFRE 
mL/min/1.73m² 
mL/min/1.73m² 
 
 
 
 
 
 
 
 
 
 
 
* Magnesium and creatinine clearance from Cockcroft-Gault method measured only at screening visit. 
5.6.5. Vital signs, physical findings and other observations related to safety 
The baseline is defined as the last measure before the first trial product administration. 
Vital signs will be analyzed quantitatively and qualitatively by trial product group. Qualitative 
analyses of Systolic/Diastolic Blood Pressure (mmHg) and Pulse Rate (beats/min) will be done via 
comparison of vital signs data to their normal ranges. Normal ranges for the shift tables are [90; 160] 


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mmHg for SBP, [45; 90] mmHg for DBP and [45; 80] for pulse rate. Quantitative analyses of the 
same parameters will be done by tabulating raw data and change from baseline. 
Listings of weight and vital signs will be provided in CSR appendix 16.2.9, including all other 
parameters recorded in the database [BMI (kg/m2), Systolic/Diastolic Blood Pressure (mmHg), Pulse 
Rate (beats/min)] and flag for clinically significant. 
 
Holter ECG parameters will only be listed. 
 
The baseline is defined as the mean of the ECGs triplicates measured before each IMP/AMP 
administration. 
12-lead safety ECG will be analyzed quantitatively and qualitatively by trial products group.  
Triplicate values will be issued for each measurement and the average of the 3 replicates will be used 
for statistics analyses. Qualitative analyses will be done via comparison of ECG data to their normal 
ranges. Quantitative analyses will be done by tabulating raw data and change from baseline. Listings 
of 12-lead safety ECG with interpretation, morphology analysis and flag for clinically significant 
will be provided. 
 
Number of subjects experiencing burning, pain, eruption, extravasation and inflammation at site 
injection will be tabulated per IMPs groups and overall. Pain at injection site will be measured using 
the Visual Assessment Scale (VAS) and VAS measurements for these subjects will be tabulated. 
 
Physical examination will only be listed in CSR appendix 16.2.9. 
 
5.6.6. Concomitant medications and procedures 
Concomitant medications are those ongoing at or started after the first treatment application.  
Concomitant medications will be coded using the WHODRUG dictionary version September 2016. 
Concomitant procedures are therapies not coded as per WHODRUG dictionary. 
 
Incidence of concomitant medications and procedures will be tabulated. The number and percent of 
subjects taking concomitant medications and concomitant procedures will be presented by trial 
product group. The denominator will be the number of subjects in the safety set. 
 
Concomitant medications and procedures will be associated to trial product group according to the 
following rules: 
 
 
 
 
 
 
 
 
 
End Period 




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 SHELLS FOR TABLES, FIGURES AND LISTINGS  
All outputs will be produced using SAS version 9.2 or a later version. 
All data recorded in the Case Report Form (CRF) will be listed. In addition, all derived data used in 
the analyses will be listed. The listings will include all subjects and will be ordered by subject. 
Unless otherwise indicated, in case of continuous or ordinal variables summary statistics are the n, 
mean, SD, median, minimum and maximum. The mean and median and SD will be reported to 1 
decimal more than the data and minimum and maximum to the same number of decimals as the data. 
In case of nominal variables, summary statistics are the n and the frequency in terms of percentage. 
7.1. Clinical study report in-text tables, figures and listings 
7.2. Contents of clinical study report section 14 
7.3. Contents of clinical study report section 16.2 
 
 


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 REFERENCES  
1. Garnett C & al. Scientific white paper on concentration-QTc modelling. Journal of 
Pharmacokinetics and Pharmacodynamics 5 Dec 2017 
2. ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential 
for Non-Antiarrhythmic Drugs 
3. Hochberg Y, Tamhane AC Multiple comparison procedures. John Wiley & Sons, Inc. New 
York, NY, USA ©1987  
4. Zhang J, Machado SG Statistical Issues Including Design and Sample Size Calculation in 
Thorough QT/QTc Studies. Journal of Biopharmaceutical Statistics 2008; 18(3): 451-467 
 
 


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