Clinical trial NCT04653766
Conditions: Healthy
Keywords: Antithrombotic Intrinsic coagulation pathway
Sponsor: Bioxodes S.A.
Start date: 2019-09-12; Completion date: 2023-01-04
Enrollment: 32 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this First-in-Human study is to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of Ir-CPI, a novel dual inhibitor of FXIIa and FXIa, following IV administration of single ascending doses in healthy male volunteers.

Detailed description:

Arms: arm 1: Participants received a single intravenous dose of 1.5 mg/kg of Ir-CPI during 6 hours arm 2: Participants received a single intravenous dose of 3.0 mg/kg of Ir-CPI during 6 hours arm 3: Participants received a single intravenous dose of 6.0 mg/kg of Ir-CPI during 6 hours arm 4: Participants received a single intravenous dose of 9.0 mg/kg of Ir-CPI during 6 hours arm 5: Participants received a single intravenous dose of placebo during 6 hours
Interventions: intervention 1: Ir-CPI - Dose 1 intervention 2: Ir-CPI - Dose 2 intervention 3: Ir-CPI - Dose 3 intervention 4: Ir-CPI - Dose 4 intervention 5: Placebo
Intervention descriptions: intervention 1: 6 participants received a single intravenous dose of 1.5 mg/kg of Ir-CPI during 6 hours intervention 2: 6 participants received a single intravenous dose of 3.0 mg/kg of Ir-CPI during 6 hours intervention 3: 6 participants received a single intravenous dose of 6.0 mg/kg of Ir-CPI during 6 hours intervention 4: 6 participants received a single intravenous dose of 9.0 mg/kg of Ir-CPI during 6 hours intervention 5: For each dose group, 2 additional participants received a single intravenous dose of placebo during 6 hours (8 in total).

Protocol documents:
Prot_000.pdf: 
BIOXODES SA 
Parc d’activités économiques du Wex 
Rue de la Plaine, 11 
6900 Marche-en-Famenne 
BELGIUM 
EudraCT N°: 2019-002305-22 
Clinical Study Protocol N° Clin_IrCPI_101 
Biotrial Code: 2BIOXO1 
ATC study code: M2154 
A Phase I, Double Blind, Placebo Controlled, Single Ascending Dose Study of 
Intravenously Administered Ir-CPI to Evaluate Pharmacokinetics, Pharmacodynamics, 
Safety and Tolerability in Healthy Male Volunteers. 
 
 
Investigational Medicinal Product Code:  
Ixodes ricinus-Contact Phase Inhibitor 
(Ir-CPI) 
Development Phase:  
I 
Principal investigator: 
Sponsor: 
Bernard JANDRAIN, MD  
ATC SA, 
Clinical Pharmacology Unit,  
CHU of Liège, B35, Route 124,  
4000 Liège 
BELGIUM 
Edmond GODFROID 
BIOXODES SA, 
Parc d’activités économiques du Wex, 
Rue de la Plaine, 11 
6900 Marche-en-Famenne 
BELGIUM  
 
 
Version: V5.0 
Date: 15 OCT 2020 
 
 
This information may not be used, published or otherwise disclosed without prior written 
authorisation from the Sponsor 
 
 




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TABLE OF CONTENTS 
1. 
SYNOPSIS ......................................................................................................................... 7 
2. 
SCHEDULE OF ACTIVITIES (SOA) ......................................................................... 18 
2.1. 
Part 1 SOA: single 6-hour infusion ...................................................................................................... 18 
2.1.1. 
Part 1 SOA: single 6-hour infusion for Cohorts A, B and C ..................................................... 18 
2.1.2. 
Part 1 SOA: single 6-hour infusion for Cohorts D and E .......................................................... 22 
2.2. 
Part 2 SOA: loading dose infusion of 30 minutes followed by fixed dose continuous infusion over 
5.5 hours .............................................................................................................................................................. 26 
3. 
INTRODUCTION .......................................................................................................... 33 
3.1. 
Study Rationale ...................................................................................................................................... 33 
3.2. 
Background ............................................................................................................................................ 34 
3.3. 
Benefit/Risk Assessment........................................................................................................................ 37 
4. 
OBJECTIVES AND ENDPOINTS ............................................................................... 39 
5. 
STUDY DESIGN ............................................................................................................ 41 
5.1. 
Overall Design ........................................................................................................................................ 41 
5.1.1. 
Part 1 ............................................................................................................................................... 41 
Table 1: Suggested Doses of Ir-CPI for Dose Escalation in Part 1 .......................................................... 42 
5.1.2. 
Part 2 ............................................................................................................................................... 42 
Table 2: Suggested Doses of Ir-CPI for Dose Escalation in Part 2 .......................................................... 44 
5.2. 
Number of Participants ......................................................................................................................... 44 
5.2.1. 
Part 1 ............................................................................................................................................... 44 
5.2.2. 
Part 2 ............................................................................................................................................... 45 
5.3. 
Number of Study Centres ..................................................................................................................... 45 
5.4. 
End of Study Definition and Duration of Participation ..................................................................... 45 
5.5. 
Scientific Rationale for Study Design .................................................................................................. 45 
5.6. 
Justification for Dose ............................................................................................................................. 46 
Figure 1: Simulation of evolution of plasma Ir-CPI concentration upon single infusion (6 hours) of 
ascending doses of Ir-CPI ........................................................................................................................ 46 
5.7. 
Identification of Source Data ................................................................................................................ 48 
6. 
STUDY POPULATION ................................................................................................. 49 
6.1. 
Inclusion criteria .................................................................................................................................... 49 
6.2. 
Exclusion criteria ................................................................................................................................... 50 
6.3. 
Lifestyle restrictions .............................................................................................................................. 51 


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6.4. 
Screen Failures....................................................................................................................................... 53 
7. 
IMP .................................................................................................................................. 53 
7.1. 
Investigational Medicinal Products Administered ............................................................................. 53 
Table 3: IMPs .......................................................................................................................................... 53 
7.2. 
Method of Treatment Assignment ....................................................................................................... 54 
Table 4: Randomisation ........................................................................................................................... 55 
7.2.1. 
Blinding .......................................................................................................................................... 55 
7.3. 
Dose administration ............................................................................................................................... 56 
7.3.1. 
IMP preparation .............................................................................................................................. 56 
7.3.2. 
Doses administered in Part 1........................................................................................................... 56 
Table 5: Part 1 Suggested Doses of Ir-CPI for Dose Escalation .............................................................. 57 
7.3.3. 
Doses administered in Part 2........................................................................................................... 57 
In the end, part 2 was not performed. ............................................................................................................... 57 
Table 6: Part 2 Suggested Doses of Ir-CPI for Dose Escalation .............................................................. 57 
7.3.4. 
Dosing and meals ............................................................................................................................ 57 
7.4. 
Dose Escalation Rules and Dose Staggering Approach ...................................................................... 57 
7.5. 
Stopping Rules ....................................................................................................................................... 58 
7.6. 
Supply, Packaging and labelling of the investigational products ...................................................... 60 
Table 7: IMP packaging labels ................................................................................................................ 60 
7.7. 
Storage of the investigational products ................................................................................................ 60 
7.8. 
Accountability, reconciliation and return of the investigational products ....................................... 61 
7.9. 
Treatment compliance ........................................................................................................................... 61 
7.10. 
Prior Treatments ................................................................................................................................... 61 
7.11. 
Concomitant Treatments ...................................................................................................................... 62 
8. 
DISCONTINUATION CRITERIA AND RELATED PROCEDURES .................... 63 
8.1. 
Withdrawal criteria ............................................................................................................................... 63 
8.2. 
Discontinuation of Study Treatment (Infusion) .................................................................................. 63 
8.3. 
Discontinuation of Study ....................................................................................................................... 63 
8.4. 
Unscheduled Visit .................................................................................................................................. 63 
8.5. 
Lost to Follow Up................................................................................................................................... 63 
8.6. 
Withdrawn participant data collection ................................................................................................ 64 
8.7. 
Replacement of participants ................................................................................................................. 64 
9. 
PROCEDURES ............................................................................................................... 65 
9.1. 
Investigational schedule ........................................................................................................................ 65 


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9.2. 
Total volume of blood collected ............................................................................................................ 65 
Table 8: Time windows for sampling collection ..................................................................................... 65 
9.3. 
Pharmacokinetic Evaluation ................................................................................................................ 66 
9.3.1. 
Pharmacokinetic Assessment Methods and Timing ....................................................................... 66 
9.3.2. 
PK Sample handling and labelling .................................................................................................. 66 
9.3.3. 
PK Sample shipment and storage ................................................................................................... 66 
9.3.4. 
PK Bioanalytical method ................................................................................................................ 66 
9.3.5. 
Pharmacokinetic Criteria ................................................................................................................ 66 
9.4. 
Pharmacodynamic Evaluation ............................................................................................................. 67 
9.4.1. 
Pharmacodynamic outcome measurements .................................................................................... 67 
9.4.2. 
Pharmacodynamic Assessment Methods and Timing ..................................................................... 67 
9.4.3. 
PD Sample handling and labelling .................................................................................................. 67 
9.4.4. 
PD Sample shipment and storage ................................................................................................... 67 
9.4.5. 
PD Bioanalytical method ................................................................................................................ 67 
9.5. 
Exploratory Biomarkers Evaluation .................................................................................................... 67 
9.5.1. 
Exploratory outcome measurements ............................................................................................... 68 
9.5.2. 
Exploratory Assessment Methods and Timing ............................................................................... 68 
9.5.3. 
Exploratory Biomarkers Sample handling and labelling ................................................................ 68 
9.5.4. 
Exploratory Biomarkers Sample shipment and storage .................................................................. 68 
9.5.5. 
Exploratory Biomarkers Bioanalytical method ............................................................................... 69 
9.6. 
Adverse events and treatment emergence ........................................................................................... 69 
9.6.1. 
Documentation and Treatment of Adverse Events by the Investigator ........................................... 69 
9.6.2. 
Method of Detecting AEs, AESIs and SAEs .................................................................................. 70 
9.6.3. 
Follow-up of AE, AESI and SAE ................................................................................................... 70 
9.6.4. 
Regulatory Reporting of Serious Adverse Events .......................................................................... 70 
9.6.5. 
Treatment of Overdose ................................................................................................................... 71 
9.7. 
Safety Assessment .................................................................................................................................. 71 
9.7.1. 
Physical Examination ..................................................................................................................... 71 
9.7.2. 
Weight, height and BMI ................................................................................................................. 71 
9.7.3. 
Vital Signs ...................................................................................................................................... 72 
9.7.3.1. Parameters ....................................................................................................................................... 72 
9.7.3.2. Method of assessment ..................................................................................................................... 72 
Table 9: normal ranges for vital signs ..................................................................................................... 72 
9.7.4. 
Telemetry monitoring ..................................................................................................................... 72 
9.7.4.1. 
Parameters .................................................................................................................................. 72 
9.7.4.2. 
Method of assessment ................................................................................................................ 72 
9.7.5. 
Standard 12-lead ECG .................................................................................................................... 72 
9.7.5.1. 
Parameters .................................................................................................................................. 72 
9.7.5.2. 
Method of assessment ................................................................................................................ 73 
Table 10: normal ranges for ECG parameters ......................................................................................... 73 
9.7.6. 
Laboratory safety parameters .......................................................................................................... 73 
9.7.6.1. 
Serology, drug screen and alcohol breath test ............................................................................ 73 
9.7.6.2. 
Laboratory Safety ....................................................................................................................... 73 
9.7.6.2.1. 
Blood safety analysis ............................................................................................................ 73 
9.7.6.2.2. 
Urinalysis parameters ........................................................................................................... 74 
9.7.6.2.3. 
Method of assessment .......................................................................................................... 74 
9.7.6.2.4. 
Laboratory safety determinations ......................................................................................... 74 
9.7.7. 
Occult Blood in Faeces ................................................................................................................... 74 
9.7.7.1. 
Parameters .................................................................................................................................. 74 
9.7.7.2. 
Method of assessment ................................................................................................................ 74 
9.7.8. 
Tick bite exposure monitoring ........................................................................................................ 74 
9.7.8.1. 
Parameters .................................................................................................................................. 74 
9.7.8.2. 
Method of assessment ................................................................................................................ 74 


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10. 
DATA MANAGEMENT AND STATISTICS .......................................................... 75 
10.1. 
Data entry and management ................................................................................................................ 75 
10.1.1. 
Data collection ................................................................................................................................ 75 
10.1.2. 
Data coding ..................................................................................................................................... 75 
10.1.3. 
Data validation ................................................................................................................................ 75 
10.2. 
Statistical considerations ....................................................................................................................... 75 
10.2.1. 
Sample size ..................................................................................................................................... 75 
10.2.2. 
Statistical methods .......................................................................................................................... 76 
10.2.3. 
Description of data sets ................................................................................................................... 76 
10.2.3.1. 
Definition of data sets ............................................................................................................ 76 
10.2.3.2. 
Description of the sets ............................................................................................................ 76 
10.2.4. 
Demographic and baseline characteristics ...................................................................................... 77 
10.2.5. 
Protocol deviations ......................................................................................................................... 77 
10.2.6. 
Pharmacokinetic analysis ................................................................................................................ 77 
10.2.6.1. 
Plasma concentration and PK parameters .............................................................................. 77 
10.2.7. 
Pharmacodynamic analysis ............................................................................................................. 77 
10.2.7.1. 
Criteria ................................................................................................................................... 77 
10.2.7.2. 
Statistical methodology .......................................................................................................... 78 
10.2.8. 
Exploratory Pharmacokinetic / Pharmacodynamic analysis ........................................................... 78 
10.2.9. 
Exploratory biomarkers’ analysis ................................................................................................... 78 
10.2.9.1. 
Criteria ................................................................................................................................... 78 
10.2.9.2. 
Statistical methodology .......................................................................................................... 78 
10.2.10. 
Safety analysis ................................................................................................................................ 78 
10.2.10.1. 
Criteria ................................................................................................................................... 78 
10.2.10.2. 
Statistical methodology .......................................................................................................... 79 
11. 
REFERENCES ............................................................................................................ 80 
12. 
APPENDICES ............................................................................................................. 81 
Appendix 1: Regulatory and legal considerations ................................................................................... 81 
Appendix 2: Adverse event and serious adverse event definitions .......................................................... 90 
 
LIST OF TABLES 
Table 1: Suggested Doses of Ir-CPI for Dose Escalation in Part 1 ......................................... 42 
Table 2: Suggested Doses of Ir-CPI for Dose Escalation in Part 2 ......................................... 44 
Table 3: IMPs ........................................................................................................................... 53 
Table 4: Randomisation ........................................................................................................... 55 
Table 5: Part 1 Suggested Doses of Ir-CPI for Dose Escalation.............................................. 57 
Table 6: Part 2 Suggested Doses of Ir-CPI for Dose Escalation.............................................. 57 
Table 7: IMP packaging labels ................................................................................................ 60 
Table 8: Time windows for sampling collection ..................................................................... 65 
Table 9: normal ranges for vital signs...................................................................................... 72 
Table 10: normal ranges for ECG parameters ......................................................................... 73 
 


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1. SYNOPSIS 
Name of Company: 
BIOXODES SA 
Parc d’activités économiques du Wex ; Rue de la Plaine, 11; 6900 Marche-en-Famenne; BELGIUM 
Name of Finished Product: NA 
Name of active ingredient: Ixodes ricinus-Contact Phase Inhibitor (Ir-CPI) 
Title of Study:  
A Phase I, Double Blind, Placebo Controlled, Single Ascending Dose Study of Intravenously Administered 
Ir-CPI to Evaluate Pharmacokinetics, Pharmacodynamics, Safety and Tolerability in Healthy Male 
Volunteers. 
Principal Investigator: 
Bernard Jandrain, MD 
 
Study centre: 
ATC SA, Clinical Pharmacology Unit, CHU of Liège, B35, Route 124, 4000 Liège, BELGIUM 
Publication (reference):  
NA 
Clinical Phase: 
Phase I 
 
Rationale: 
Ixodes ricinus-Contact Phase Inhibitor (Ir-CPI) is under development for the prevention of thrombosis in 
hospital procedures in which blood is exposed to non-biological surfaces known to activate the intrinsic 
pathway of the coagulation cascade (e.g. percutaneous endovascular interventions, cardiopulmonary bypass), 
especially under clinical circumstances where the use of classical anticoagulation is not adequate due to 
heparin intolerability and/or high risk of bleeding. As Ir-CPI has to be administered by intravenous (IV) 
infusion and as it has a half-life of a few hours, it is intended for specialised use in a hospital setting.  
This study will be the first-in-human study of Ir-CPI. This study will provide an initial assessment of the 
safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of Ir-CPI after a single 
administration of a 6-hour infusion at ascending doses without (Part 1) and with a loading dose (Part 2) to 
healthy adult participants. 
The doses to be evaluated are based on the results obtained in pharmacology studies. Once PK results are 
obtained in Part 1 of the study (increasing single doses of Ir-CPI in healthy participants upon 6-hour infusion), 
a combination of rapid (30 minutes) and slow (5.5 hours) infusions will be administered to healthy 
participants in Part 2 of the study. These results will be used thereafter in Proof of Concept (POC) efficacy 
studies in human where there is a need for reliable anticoagulation, such as – but not limited to – 
coronarography procedures and arterio-venous shunting. In the end, part 2 of the study was not performed. 
This design will be used to define the experimental condition(s) of administration allowing to rapidly reach 
and maintain steady state Ir-CPI concentration for up to 6 hours. 
Objective(s) and associated endpoints: 
 
Objectives 
Endpoints 
Primary 
Part 1: Assess the safety and tolerability of 
Ir-CPI following a single ascending 6-hour 
intravenous infusion in healthy male 
participants. 
Safety parameters [adverse events (AEs), 
physical examinations, vital signs, telemetry 
including SpO2, weight, Hemoccult® test, 
supine 12-lead ECG, serum chemistry, 
haematology, standard coagulation aPTT, 
urinalysis, and monitoring for concomitant 
medications]. 
Part 2*: Assess the safety and tolerability 
of Ir-CPI following a combination of rapid 
(30 minutes) and slow (5.5 hours) 
intravenous infusions over a total of 6 
hours in healthy male participants. 


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Name of Company: 
BIOXODES SA 
Parc d’activités économiques du Wex ; Rue de la Plaine, 11; 6900 Marche-en-Famenne; BELGIUM 
Name of Finished Product: NA 
Name of active ingredient: Ixodes ricinus-Contact Phase Inhibitor (Ir-CPI) 
Secondary  
Part 1: Assess the pharmacokinetics (PK) 
of Ir-CPI following single ascending 6-
hour intravenous infusion in healthy male 
participants. 
Maximum plasma concentration (Cmax), time 
to reach maximum plasma concentration 
(tmax), Area under the plasma concentration-
time curve from time zero to 6h (AUC0-6), 
Area under the plasma concentration-time 
curve from time zero to time of infinity 
(AUCinf), apparent terminal elimination rate 
constant (λz), terminal elimination half-life 
(t1/2),  volume of distribution (Vd), total 
body clearance (CL). 
Part 2*: Assess the PK of Ir-CPI following 
a combination of rapid (30 minutes) and 
slow (5.5 hours) intravenous infusions over 
a total of 6 hours in healthy male 
participants. 
Investigate 
the 
preliminary 
Pharmacodynamics (PD) of Ir-CPI in 
healthy male participants using a GCLP 
validated method according to FDA 
guidelines 2018 for activated Partial 
Thromboplastin Time (aPTT). Inhibition 
of Factor XI (FXI) and Factor XII (FXII) 
procoagulant 
activities 
will 
also 
be 
assessed to support the aPTT dynamics. 
Change from baseline in aPTT and residual 
FXI and FXII activities. 
Exploratory 
Investigate the potential of Ir-CPI to 
induce 
the 
formation 
of 
anti-drug 
antibodies 
(ADA), 
including 
their 
capability to neutralize drug activity.  
Immunogenicity assessed by ADA plasma 
levels. 
Investigate the effect of Ir-CPI on markers 
related to the coagulation system 
D-dimers, fibrinogen and prothrombin time 
(PT) levels in whole blood. 
Investigate the effect of Ir-CPI on 
biomarkers for renal injury. 
Blood assay: serum cystatin C (CysC). 
Urinary assay: urinary microalbumin, 
Kidney Injury Molecule-1 (KIM-1), urinary 
neutrophil gelatinase-associated lipocalin 
(NGAL). 
Investigate the effect of Ir-CPI on 
inflammatory markers. 
tumor necrosis factor alpha (TNFα), high 
sensitivity C-reactive protein (hsCRP) levels 
in serum. 
Assess the PK of Ir-CPI in urine. 
Total amount excreted in urine (Ae), Ae%, 
volume of urine excreted (Vol_UR), 
Maximal excretion rate (Cmax rate), Time to 
reach maximum excretion (Tmax) rate and 
Renal Clearance (CLR). 
 
PK-PD relationship. 
No new endpoint: only graphical 
investigation of PK and PD parameters. 
*: because part 2 was not performed, these objectives are not applicable. 
 
Design:  
This is a Phase 1, double-blind, placebo controlled, single dose escalation study of Ir-CPI in healthy male 
participants. The terms panel and cohort can be used interchangeably. The study will consist of two parts: 
Part 1: an Ir-CPI or matching placebo single ascending dose administration in healthy male participants using 
a continuous 6-hour intravenous infusion. 
Part 2: an Ir-CPI or matching placebo single ascending dose administration in healthy male participants using 
a single ascending 30-minute loading dose infusion followed by a fixed dose of continuous 5.5-hour 


Study Protocol Clin_IrCPI_101 
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Name of Company: 
BIOXODES SA 
Parc d’activités économiques du Wex ; Rue de la Plaine, 11; 6900 Marche-en-Famenne; BELGIUM 
Name of Finished Product: NA 
Name of active ingredient: Ixodes ricinus-Contact Phase Inhibitor (Ir-CPI) 
intravenous infusion (maintenance infusion). In the end, part 2 was not performed. 
In both parts, a screening visit will take place from Day (D)-28 to D-2.  
In Cohorts A, B and C, participants will then remain in-house between D-1 and D2. Consecutively, 
ambulatory visits will be planned every day until 96h postdose (D5, postdose refers to the beginning of 
infusion). 
In Cohort D and subsequent cohorts, participants will then remain in-house from D-1 and will remain 
hospitalised until the investigator is able to review the 24h aPTT assay results. If, for each participant, the 
results are less than or equal to 2X aPTT level at baseline (i.e. D1 predose), then the participants may leave 
the clinic. They will return for the ambulatory visits on D3 (48h post infusion start), D4 (72h), D5 (96h) and 
D7 (144h). If the 24h safety aPTT assay of one participant is above 2X the participant’s baseline aPTT, then 
all participants will remain hospitalised until the completion of the D3 (48h) assessments and an additional 
aPTT sample will be drawn at 36h. If the 36h aPTT assay result of a participant is more than 2X baseline 
aPTT of this participant, the investigator will decide the most appropriate procedures for the follow-up of this 
participant. Participants will return for the ambulatory visits on D4 (72h), D5 (96h) and D7 (144h). 
The dosing period will be followed by a discharge visit held on D10 ± 2 days. An extra ambulatory visit will 
be planned approximately on D30 (1 month ± 3 days) and on D90 (3 months ± 7 days) after dosing for 
immunogenicity testing. AEs occurring between the discharge visit and the 2 extra ambulatory visits will be 
recorded during the 2 extra ambulatory visits. Concomitant treatment after the discharge visit (D10 ± 2 days) 
will be recorded only if an AE is recorded between the discharge visit and the extra ambulatory visits. At the 
extra ambulatory visits, laboratory samples will be taken to look for immunogenicity (presence of ADAs and 
neutralizing antibodies if applicable). If ADAs are detected at the D90 extra ambulatory visit, a supplemental 
ambulatory visit will be planned on D180 (6 months ± 7 days) after dosing.  
Supplemental ADA samplings (“long-term follow-up of ADAs”): 
If ADAs are detected at the D180 ambulatory visit, supplemental samplings will be performed every 3 months 
(±14 days) for the first year after the D180 visit and then every 6 months (±30 days) for the following 4 years 
(i.e. follow-up of immunogenicity testing for a maximum of 5 years after D180). The samplings will be 
performed until the participants reach a negative status, until they show the same ADA titre result for 3 
samplings in a row, or up to a maximum of 5 years after D180, whichever comes first. 
Details of timing of each clinical visit, and the assessments to be performed at each visit are summarised in 
the schedule of activities (SOA). 
Number of participants: 
Part 1: Approximately forty (40) healthy male participants will be enrolled in 5 sequential panels. Each panel 
will have 8 participants (6 active: 2 placebo). The fifth group will be optional depending on the PK and PD 
data obtained in the previous groups.  
Part 2: Approximately twenty-four (24) healthy male participants will be enrolled in 3 sequential panels. Each 
panel will have 8 participants (6 active: 2 placebo). 
In the end, the optional fifth group in part 1, and part 2 were not performed. 
Rationale for Number of Participants: 
The number of participants is not based on statistical power considerations. A sample size of 8 participants per 
cohort (i.e., 6 active and 2 placebo) was chosen based on the design of similar studies and is considered 
adequate to provide an initial assessment of the safety and tolerability profile of Ir-CPI. 
Number of study centres:  
1 
Duration of treatment: 
The study duration for each participant for the main study part (from the screening visit until the discharge 
visit) will be approximately 6 weeks. Participants will be followed up until D90 (or D180) for 
immunogenicity testing. The total study duration will be approximately 18 weeks in total for a given 


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Name of Company: 
BIOXODES SA 
Parc d’activités économiques du Wex ; Rue de la Plaine, 11; 6900 Marche-en-Famenne; BELGIUM 
Name of Finished Product: NA 
Name of active ingredient: Ixodes ricinus-Contact Phase Inhibitor (Ir-CPI) 
participant, and up to 31 weeks in case of D180 visits.  
Supplemental ADA samplings (“long-term follow-up of ADAs”): 
Additional samplings for immunogenicity testing may be performed until the participants reach a negative 
status, until they show the same ADA titre for 3 samplings in a row, or up to 5 years after the end of the study 
in participants with positive ADA results at D180 whichever comes first. 
Study products, dose and mode of administration: 
Ir-CPI will be supplied frozen, as 5 mL PBS solution containing 25 mg/mL Ir-CPI in glass vials (10 mL). The 
vials will be thawed at room temperature under gentle agitation. The matching placebo will consist of NaCl 
0.9 % solution for intravenous administration. All doses are expressed in mg/kg, and the body weight of each 
participant at the screening visit will be used to calculate the exact amount of study drug needed to prepare the 
allocated total dose for each participant. 
In Part 1, single doses of Ir-CPI or its matching placebo will be administered to the participants using a 
continuous 6-hour intravenous infusion. 
In Part 2, single doses of Ir-CPI or its matching placebo will be administered to the participants using a single 
ascending 30-minute loading dose infusion followed by a fixed dose of continuous 5.5-hour intravenous 
infusion. In the end, part 2 was not performed. 
Fasting conditions are required for the blood sample collection at the selection visit, on D3 (ambulatory or 
inpatient), for the ambulatory visits [D4/D5/D7 (D7 for Cohort D and subsequent cohorts only)/Discharge 
visit] and for the D1 predose blood sample.  
Water intake is allowed during the infusion. Meals will be standardised across the different panels during the 
in-patient period of the study. Following the D1 predose blood sample collection, a light breakfast (2 slices of 
bread with ham or cheese and jam, glass of water) / snack can be given between 2h and 1h before the start of 
the infusion. Lunch will be served after completion of the study drug infusion.  
A light breakfast / snack will also be given after the D1H24 (D2) blood sample collection and after the blood 
sample collections performed on D3 (ambulatory or inpatient), at the ambulatory visits on D4, D5 and D7 (D7 
for Cohort D and subsequent cohorts only) and at the Discharge visit. 
Participants must not be in fasting condition for the safety aPTT 36h sample and the extra ambulatory visits. 
Details of the infusion rates, doses and suggested total dose administered are provided below: 
Study Part 
Group 
Infusion rate (mg/kg/h)** 
Infusion Duration (h) 
Total dose (mg/kg) 
1 
A 
0.25 
6 
1.5 
1 
B 
0.75 
6 
4.5 
1 
C 
1.50 
6 
9 
1 
D 
3.00 
6 
18 
1 
E# 
4.5 
6 
27 
2## 
F 
Rapid infusion*: 6 
0.5 
11.25* 
Slow infusion*: 1.5 
5.5 
2## 
G 
Rapid infusion*:7 
0.5 
11.75* 
Slow infusion*: 1.5 
5.5 
2## 
H 
Rapid infusion*: 8 
0.5 
12.25* 
Slow infusion*: 1.5 
5.5 
*The rapid and the slow infusion rates will be calculated based on Part 1 emerging safety, PD and PK data. The total 
dose administered by rapid and by slow infusion will not exceed the highest total dose tested in Part 1. The infusion rate 
(in mg/kg/h) for the slow infusion will not exceed the maximum infusion rate used in Part 1. The dose may also be 
adjusted.  
**Weight of the participant at the screening visit will be used to calculate the dose of study drug. 
#: Cohort E was not performed according to a recommendation from the Ethics Committee. 
##: Part 2 was not performed because the targeted plasmatic PK concentration was planned in the unperformed group E. 
Escalation to the next higher dose will only take place after review of the Investigator Safety Report from the 
previous dose levels by the PI, in consultation with the Sponsor’s representative [called hereafter the Safety 


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Name of Company: 
BIOXODES SA 
Parc d’activités économiques du Wex ; Rue de la Plaine, 11; 6900 Marche-en-Famenne; BELGIUM 
Name of Finished Product: NA 
Name of active ingredient: Ixodes ricinus-Contact Phase Inhibitor (Ir-CPI) 
Review Committee (SRC)]. Dose escalation will be based on any relevant information on participants’ 
demographics/characteristics, medical history, physical examination, concomitant medications, AEs, 
clinically significant out of ranges safety clinical laboratory tests results (as assessed by the PI), physical 
examination results (including basic neurological testing for isocoria, light reflexes, gait and balance) 
including clinical significance for abnormal findings, ECG and vital sign results including clinical 
significance for abnormal value, and the statement of the PI’s recommendation regarding dose decision. Other 
parameters of interest will be considered as per SRC charter (blinded PK, PD). 
Within the planned dose range, a dose lower than the next planned dose may be tested, depending on 
emerging safety, tolerability and/or other relevant data, such as blinded PK or PD. The final dose to be used 
for each cohort will be decided based on the results of the previous panel and can be adjusted downward if 
deemed necessary. If the highest planned dose level is found to be safe and tolerable, also considering the PK 
and PD data, additional higher doses may be added by amendment. 
Within each panel, the first 2 study participants will be designated as sentinel study participants. The sentinel 
study participants will be randomized 1:1 to receive either placebo or Ir-CPI (1 study participant each). 
Between the first participants of 2 consecutive panels, a period of at least 7 days will be respected between the 
administrations of treatment. 
The PI and Sponsor medical monitor will review at least 24hrs of post-dose safety data (vital signs, labs, 
electrocardiograms [ECGs], telemetry and physical examination) for the sentinel study participants. If no 
safety concerns are identified, the remainder of the cohort will be randomized in a 5:1 ratio and dosed. 
The SRC will meet for deciding on the continuation of dosing after intake in at least 6 participants (i.e. a 
minimum of 4 on active treatment). However, stopping rules will be applicable from dosing of the first 
sentinel participant. 
Diagnosis and main criteria for inclusion / exclusion: 
Inclusion: 
Participants must satisfy all of the following inclusion criteria before being allowed to enter the study: 
1. Have given written informed consent approved by the relevant Ethics Committee (EC) governing the site, 
indicating that they understand the purpose of and procedures required for the study and are willing to 
participate in the study.  
2. Male participants between 18 and 55 years of age, inclusive at screening. 
3. Otherwise healthy with no clinically significant abnormalities as determined by medical history, physical 
examination, blood chemistry assessments, haematological assessments, coagulation and urinalysis, 
measurement of vital signs, and ECG. Isolated out-of-range values judged by the PI (or designated 
physician) to be of no clinical significance can be allowed. This determination must be recorded in the 
participant’s source documents. 
4. Have a body weight in the range of 50 to 90 kg inclusive at screening. Have a body mass index (BMI) of 19 
to 28 kg/m2 inclusive at screening. 
5. Agree to abstain from alcohol intake 24 hours before administration of study drug, during the in-patient 
period of the study and 24 hours prior to all other ambulatory visits, up until and including the discharge 
visit. 
6. Agree not to use prescription medications within 14 days prior to study drug administration and through the 
duration of the study, unless approved by the PI and Sponsor medical monitor. 
7. Non-smokers or abstinence from tobacco or nicotine-containing products for at least 3 months prior to 
screening. 
8. Agree not to use over-the-counter (OTC) medications [including decongestants, antihistamines, and herbal 
medication (including herbal tea and St. John’s Wort], within 14 days prior to study drug administration 
through the discharge visit, unless approved by the PI and Sponsor medical monitor. Occasional use of 
paracetamol at recommended doses is allowed. Special rules apply for aspirin, corticosteroids and 
nonsteroidal anti-inflammatory drugs (NSAIDS (see exclusion criteria 6-7-8-9) 
9. Venous access (both arms) sufficient to allow blood sampling and study drug administration as per 


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Name of Company: 
BIOXODES SA 
Parc d’activités économiques du Wex ; Rue de la Plaine, 11; 6900 Marche-en-Famenne; BELGIUM 
Name of Finished Product: NA 
Name of active ingredient: Ixodes ricinus-Contact Phase Inhibitor (Ir-CPI) 
protocol. 
Inclusion (continued): 
10. Participants and their partners of childbearing potential [meaning who are not surgically sterile (tubal 
ligation/obstruction or removal of ovaries or uterus) or post-menopausal (absence of menstrual periods for 
at least 12 consecutive months)] must be willing to use 2 methods of contraception:  
 
- a highly effective method of birth control starting at screening. Highly effective methods of birth control 
are defined as those that result in a low failure rate (i.e. Pearl Index less than 1% per year) when used 
consistently and correctly, such as implants, rings, patches, injectable or combined oral contraceptives, 
intrauterine devices (IUDs), or sexual abstinence (periodic abstinence e.g. calendar, ovulation, 
symptothermal, postovulation methods, declaration of abstinence for the duration of the trial, and 
withdrawal are not acceptable methods of contraception) . 
- and a local barrier form of contraception. Acceptable barrier methods are either the participant’s use of a 
condom or the partner’s use of an occlusive cap or diaphragm, or spermicides. 
 
Participants will not donate sperm from the selection visit and up to 90 days after the infusion. In case of 
sterile or vasectomised participants, no contraception will be required for their partners of childbearing 
potential. 
11. Willing/able to adhere to the study visit schedule and other requirements, prohibitions and restrictions 
specified in this protocol. 
Exclusion: 
If any of the following exclusion criteria apply, the participant must not enter the study: 
1. Currently have or have a history of any clinically significant medical illness or medical disorders the PI 
considers should exclude the participant, including (but not limited to) cardiovascular disease, 
neuromuscular, haematological disease, immune deficiency state, respiratory disease, hepatic or 
gastrointestinal disease, neurological or psychiatric disease, ophthalmological disorders, neoplastic disease, 
renal or urinary tract diseases, or dermatological disease. 
2. History of personal or familial bleeding disorders; including prolonged or unusual bleeding.  
3. History of deficiency in factor XII (FXII) or haemophilia type A (FVII) or type B (FIX) or type C (FXI). 
4. History of cerebral bleeding (e.g. after a car accident), stroke and cerebrovascular accident (CVA). 
5. Anamnestic history of Lyme disease or tick-borne encephalitis. 
6. Use of Acetylsalicylic-Acid (ASA)-containing OTC medications within 1 month prior to screening. 
7. Chronic administration of NSAIDs, chronic use of corticosteroids within 1 month prior to screening. 
8. Chronic administration of clopidogrel, ticlopidin, dipyridamole, Coumadin-like anticoagulants, new oral 
anticoagulant dabigatran, rivaroxaban, apixaban or edoxaban within 3 months prior to screening. 
9. Administration of unfractionated heparin, low molecular weight heparin, fibrinolytic agents and anti-FXa 
within 3 months prior to screening. 
10. Have an active acute or chronic infection or diagnosed latent infection. 
11. Systolic blood pressure (SBP) greater than 150 or less than 90 mmHg, diastolic blood pressure (DBP) 
greater than 90 or less than 50 mmHg, and heart rate (HR) greater than 100 or less than 40 bpm. 
12. Acute clinically relevant illness within 7 days prior to study drug administration or have had a major illness 
or hospitalisation within 1 month prior to study drug administration. 
13. Major or traumatic surgery within 12 weeks of screening. 
14. Any participant who plans to undergo elective surgery within 4 weeks prior to study drug administration 
and through the discharge visit. 
15. Positive serology test for HIV antibodies, hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) 
antibodies at screening. 
Exclusion (continued): 
16. Recent history (within previous 6 months) of alcohol or drug abuse. 


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Name of Company: 
BIOXODES SA 
Parc d’activités économiques du Wex ; Rue de la Plaine, 11; 6900 Marche-en-Famenne; BELGIUM 
Name of Finished Product: NA 
Name of active ingredient: Ixodes ricinus-Contact Phase Inhibitor (Ir-CPI) 
17. Have positive urine toxicology screen at screening or D −1 for substances of abuse including 
amphetamines, benzodiazepine, cocaine, opiates, barbiturate and cannabinoids. 
18. Have a positive alcohol breath test at screening or D-1. 
19. Consumes, on average, more than approximately 500 mg/day of caffeine (as contained in 5 cups of tea or 
coffee or 8 cans of caffeine-containing soda or other caffeinated products per day). 
20. Donated blood (i.e. 500 mL) within 3 months before D1.  
21. Have a history of active drug and/or food allergy or other active allergic disease requiring the constant use 
of medications, or a history of severe allergic reaction, angioedema or anaphylaxis. 
22. Received any other experimental therapy or new investigational drug within 30 days or 5 half-lives 
(whichever is longer) of study drug administration. 
Concomitant medications and lifestyle restrictions: 
Water intake is allowed during the infusion. 
Any medication the participant takes during the study, and until the discharge visit, other than the study drugs, 
including any prescription or OTC drug (including vitamins, herbal and mineral supplements), is considered a 
concomitant medication. At the extra visits scheduled for ADA assessment (i.e. up to D180), only the 
medications that are administered in treatment of AEs will be considered concomitant medication.  
Participants will be requested to comply with the following restrictions during the study and abstain from: 
- 
Strenuous exercise, as judged by the Investigator, from the selection visit until after the discharge visit. 
- 
Use of prescriptions or OTC medications [including decongestants, antihistamines], and herbal 
medication (including herbal tea and St. John’s Wort), within 14 days prior to study drug administration 
through the discharge visit, unless approved by the PI and Sponsor medical monitor. Occasional use of 
paracetamol at recommended doses is allowed. Specific rules apply for aspirin, corticosteroids and 
NSAIDS (see exclusion criteria 6, 7, 8 and 9). 
- 
Consumption of grapefruit, grapefruit juice, Seville oranges, Seville orange marmalade or other 
products containing grapefruit or Seville oranges from selection visit until after the discharge visit. 
- 
Consumption of any alcoholic beverages 24 hours before administration of study drug, during the in-
patient period of the study and 24 hours prior to all other ambulatory visits, up until and including the 
discharge visit. 
- 
Smoking and using nicotine-containing products excluded for at least 3 months prior to the screening 
visit, and until after the discharge visit. 
- 
Use of Acetylsalicylic-Acid (ASA)-containing over-the-counter medications within 1 month prior to 
screening and until the discharge visit. 
- 
Consumption of any caffeine-containing products (e.g. coffee, tea, chocolate, or Coca-Cola like/ energy 
drinks): excluded from 24 hours prior to D1 until the end of the in-patient period. Limited to less than 
500 mg/day of caffeine (as contained in 5 cups of tea or coffee or 8 cans of caffeine-containing soda or 
other caffeinated products per day) until the discharge visit.  
- 
Donation of blood (i.e. 500 mL) within 3 months before D1, throughout the study and for 3 months after 
the end of the study (D90 or D180). 
The compliance of the participant to these lifestyle restrictions will be checked at each visit. 
Participants and their partners of childbearing potential must be willing to use 2 methods of contraception, one 
of which must be a barrier method, and participants will not donate sperm, from the selection visit and up to 
90 days after the infusion. 
Supplemental ADA samplings (“long-term follow-up of ADAs”): 
At the additional samplings scheduled for ADA assessment after D180, only treatments given for Serious 
Adverse Drug Reactions (SADRs) will be considered concomitant medications, and they will be collected 
only in the Pharmacovigilance (PV) database. 


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Name of Company: 
BIOXODES SA 
Parc d’activités économiques du Wex ; Rue de la Plaine, 11; 6900 Marche-en-Famenne; BELGIUM 
Name of Finished Product: NA 
Name of active ingredient: Ixodes ricinus-Contact Phase Inhibitor (Ir-CPI) 
Study Schedule: 
Screening: 
Participants will be screened for eligibility within 28 days of admission to D-2. 
Written informed consent will be obtained before any study procedure is performed. The screening will 
consist of: demography, medical and medication history, physical examination, vital signs, weight, height and 
BMI, supine 12-lead ECG, haematology, safety aPTT, serum chemistry and urinalysis tests, HIV, hepatitis B 
and hepatitis C serology, urine drug screen, presence of blood in faeces and alcohol breath test, and review of 
the inclusion / exclusion criteria and prior/concomitant treatments. 
The results of screening must be known to the Investigator prior to the participant’s admission to the treatment 
period. 
Treatment period (D-1 to D5 for cohorts A-C and D-1 to D7 for cohort D and subsequent cohorts): 
In both parts of the study, eligible participants will be admitted to the research facilities on D-1 in the evening, 
to assess eligibility based on urine drug screen, breath alcohol test, and adherence to the study restrictions. 
Inclusion and exclusion criteria will be reviewed, and a physical examination will be performed. Participants 
will be randomised to active treatment or placebo on D1, and study drug administration will be performed on 
D1. The participants will be hospitalised at the clinical unit until at least 24h after the start of study drug 
administration (D2). Participants included in Cohort D and subsequent cohorts may remain hospitalised up to 
48h after the start of study drug administration (D3), if deemed necessary by the investigator. 
Ambulatory visits will be planned on D3* (48h post infusion start), D4 (72h), D5 (96h) and D7 (144h) (D7 for 
Cohort D and subsequent cohorts only), for safety, PD and PK assessments.  
The dosing period will be followed by a study discharge visit on D10 ± 2 days after infusion. 
*Note: for Cohort D and subsequent cohorts, D3 may be inpatient. 
Discharge visit (D10 ± 2 days after infusion or early discontinuation): 
A discharge visit will take place between D10 ± 2 days after infusion or early discontinuation, and will 
involve physical examinations, vital signs, weight, supine 12-lead ECG, serum chemistry, haematology, 
urinalysis, AE monitoring, concomitant medication monitoring, last PD samples for cluster A and cluster B, 
immunogenicity testing (ADA) and exposure to tick bites. 
Following the discharge visit procedures, the participants will be discharged and will return for 2 or 3 extra-
ambulatory visits. 
Extra ambulatory visits: 
An extra ambulatory visit will be planned approximately at D30 (1 month ± 3 days) and at D90 (3 months ± 
7 days) after dosing for immunogenicity testing. AEs will be recorded during this visit. A laboratory sample 
will be taken to look for immunogenicity (presence of anti-drug antibodies, neutralizing antibodies). If ADAs 
are detected at D90, a supplemental ambulatory visit will be planned on D180 (6 months ±7 days).  
 
Supplemental ADA samplings (“long-term follow-up of ADAs”): 
If ADAs are still detected at the D180 ambulatory visit, supplemental samplings will be planned every 3 
months (±14 days) for the first year and every 6 months (±30 days) until the participants reach a negative 
status, until they show the same ADA titre for 3 samplings in a row, or for a maximum of 5 years after the 
D180 visit whichever comes first. With regards to safety, only SADRs and related information will be 
reported in the PV database at these sampling time points. 
Criteria for evaluation: 
Pharmacokinetic 
Assessments 
Blood samples (4.5 mL) will be drawn, for the assay measuring plasma Ir-CPI  
concentration, at the following time-points:  
In Part 1: D1, pre-dose and at 30min, 60min, 90min, 2h, 4h, 6h, 6h30, 7h, 
7h30, 8h, 10h, 12h, 16h, then D2 (24h), D3 (48h), D4 (72h), D5 (96h) and D7 
(144h, Cohort D and subsequent cohorts only) post-dose (after start of 


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Name of Company: 
BIOXODES SA 
Parc d’activités économiques du Wex ; Rue de la Plaine, 11; 6900 Marche-en-Famenne; BELGIUM 
Name of Finished Product: NA 
Name of active ingredient: Ixodes ricinus-Contact Phase Inhibitor (Ir-CPI) 
infusion)**. 
 
In Part 2: D1 pre-dose and at 15min, 30min, 45min, 60min, 90min, 2h, 4h, 6h, 
6h30, 7h, 7h30, 8h, 10h, 12h, 16h, then D2 (24h), D3 (48h), D4 (72h), D5 (96h) 
and D7 (144h) post-dose**. In the end, part 2 was not performed. 
** In case of infusion less than 6 hours, blood sample for Ir-CPI pharmacokinetics will 
be done at the end of infusion then 30min, 60min, 90min, 2h, 4h, 6h, 10h, 18h, 42h, 66h, 
90h and 138h (138h for Cohort D and subsequent cohorts only) after end of infusion. 
Urine samples will be collected at the following intervals: 
In Part 1: predose, [0-6h[, [6-12h[ and [12-24h] after start of infusion. 
In Part 2: predose, [0-6h[, [6-12h[ and [12-24h] after start of infusion. 
The following parameters will be derived by compartmental or non-
compartmental analysis, as appropriate, from the plasma Ir-CPI concentration-
time profiles: Cmax, tmax, AUC0-6, AUCinf, λz, t1/2,  Vd, CL. 
Pharmacodynamic 
Assessments 
Blood samples (4.5 mL) will be drawn for the assay of PD aPTT, Factor XI and 
Factor XII activities at the following time-points: 
In Part 1:  
The effect of Ir-CPI on aPTT and on FXI/FXII activities (Cluster A sampling 
times) will be measured on D1: pre-dose, then at 30min, 60min, 90min, 2h, 4h, 
6h, 6h30, 7h, 7h30, 8h, 10h, 12h, 16h post-dose, then on D2 (24h), D3 (48h), 
D4 (72h), D5 (96h), D7 (144h, Cohort D and subsequent cohorts only) and 
discharge visit**. 
** In case of infusion less than 6 hours, blood sample for aPTT and FXI/FXII activities 
will be done at the end of infusion then 30 min, 60 min, 90 min, 2h, 4h, 6h, 10h, 18h, 
42h, 66h, 90h and 138h (138h for Cohort D and subsequent cohorts only) after end of 
infusion. 
Note: The effect of Ir-CPI on the following exploratory biomarkers (BM) 
(Cluster B sampling times) will be measured on D1 predose and at 2h, 4h, 6h, 
8h, 12h and 24h after start of infusion (D2), then then 48h (D3), and 72h (D4) 
after start of infusion and at the discharge visit: PT (sec and INR), D-dimers, 
fibrinogen, hsCRP, TNFα). In case of infusion less than 6 hours, blood sample 
for PD cluster B parameters will be done at the end of infusion then 2h, 6h, 
18h, 42h, 66h after end of infusion and at the discharge visit. 
In Part 2:  
The effect of Ir-CPI on aPTT and on FXI/FXII activities (Cluster A sampling 
times) will be measured on D1 pre-dose and at 15min, 30min, 45min, 60min, 
90min, 2h, 4h, 6h, 6h30, 7h, 7h30, 8h, 10h, 12h, 16h, then D2 (24h), D3 (48h), 
D4 (72h), D5 (96h), and D7 (144h) and discharge visit**. 
** In case of infusion less than 6 hours, blood sample for aPTT and FXI/FXII activities 
will be done at the end of infusion then 30 min, 60 min, 90min, 2h, 4h, 6h, 10h, 18h, 42h, 
66h, 90h and 138h after end of infusion. 
Note: The effect of Ir-CPI (Cluster B sampling times) on the following 
exploratory BM will be measured on D1 predose and at 2h, 4h, 6h, 8h, 12h and 
24h postdose (D2), then 48h (D3), 72h (D4) after the start of infusion and at the 
discharge visit: PT (sec and INR), D-dimers, fibrinogen, hsCRP, TNFα). In 
case of infusion less than 6 hours, blood sample for PD cluster B parameters 
will be done at the end of infusion then 2h, 6h, 18h, 42h, 66h after end of 
infusion and at the discharge visit. 
In the end, part 2 was not performed. 


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Name of Company: 
BIOXODES SA 
Parc d’activités économiques du Wex ; Rue de la Plaine, 11; 6900 Marche-en-Famenne; BELGIUM 
Name of Finished Product: NA 
Name of active ingredient: Ixodes ricinus-Contact Phase Inhibitor (Ir-CPI) 
Exploratory Biomarkers 
(BM) Assessments 
Blood: 
The following blood sample volumes will be drawn for the assay of exploratory 
BM (one sample per group of BM as described below): 
- 
For PT, D-dimers and fibrinogen assay: 4.5 mL; 
- 
For CysC and inflammatory BM assay (hsCRP and TNFα): 8 mL; 
The effect of Ir-CPI on exploratory BM will be measured at Cluster B sampling 
times: 
In Part 1: CysC samples will be drawn at the same timepoints as the safety 
blood chemistry and haematology samples. The other biomarkers samples will 
be drawn at D1, predose then at 2h, 4h, 6h, 8h, 12h post-dose, on D2 (24h post-
dose), on D3, D4 and at the discharge visit. 
In Part 2: CysC samples will be drawn at the same timepoints as the safety 
blood chemistry and haematology samples. The other biomarkers samples will 
be drawn at D1, predose then at 2h, 4h, 6h, 8h, 12h post-dose, on D2 (24h post-
dose), D3 and D4 and at the discharge visit. 
Blood samples will be drawn for immunogenicity testing, i.e. for the detection 
of anti-drug antibodies (ADA). 
In both parts, immunogenicity samples will be drawn on D1 (predose), at the 
discharge visit (D10 ± 2 days) and at the 2 to 3 extra ambulatory visits.  
Supplemental ADA samplings (“long-term follow-up of ADAs”): 
A maximum of 12 additional samplings for immunogenicity may be performed 
for long-term follow-up of ADAs. 
Urine: 
In both parts, urine biomarkers for renal injury (Urinary microalbumin, KIM-1, 
NGAL) will be assessed using the urine PK collection. 
In the end, part 2 was not performed. 
Demographic and Safety 
Assessments 
Screening and demography assessment will cover demography (including race 
and ethnicity), inclusion / exclusion criteria, medical and medication history, 
drug / alcohol screen and serology. 
Safety will be evaluated from: reported AEs, physical examinations (the 
complete examination includes basic neurological testing for isocoria, light 
reflexes, gait and balance), vital signs, telemetry including SpO2, weight, 
presence of occult blood in faeces (Hemoccult® test), supine 12-lead ECG, 
serum chemistry, haematology, coagulation aPTT (safety aPTT), laboratory 
safety urinalysis, and monitoring for concomitant medications. Exposure to 
potential tick bites will be monitored (extra serology sample for archiving at 
baseline for anti-Borrelia IgG and IgM assays, and question asked to 
participants on D1, at the discharge visit, and at the extra-ambulatory visits 
performed for ADA analysis).  
AEs related to bleeding (e.g. positive Hemoccult® testing, gingival bleeding, 
bruising/haematoma, conjunctival bleeding, prolonged bleeding after trauma) 
will be considered as adverse events of special interest (AESI). Also considered 
as AESI are all infusion site reactions, including hypersensitivity reactions that 
would occur during or after study drug administration.  
AEs will be monitored from the screening visit until the last extra-ambulatory 
visit. 
Statistical methods: 
Statistical analysis of clinical parameters will be performed under the 
responsibility of Biotrial. 


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Name of Company: 
BIOXODES SA 
Parc d’activités économiques du Wex ; Rue de la Plaine, 11; 6900 Marche-en-Famenne; BELGIUM 
Name of Finished Product: NA 
Name of active ingredient: Ixodes ricinus-Contact Phase Inhibitor (Ir-CPI) 
PK analysis: 
Ir-CPI individual and mean plasma concentrations at each sampling time point 
will be presented by listings and descriptive summary statistics including 
means, geometric means, medians, ranges, standard deviations and coefficients 
of variation. Individual and mean plasma concentrations versus time will be 
plotted on linear and log-linear scales. Descriptive statistics and graphs will be 
also performed for the plasma PK parameters.  
Relevant plasma PK parameters will be derived for the parent by 
compartmental methods for plasma and tabulated along with descriptive 
statistics.  
The linear dose-proportionality of Cmax, AUC0-6 and AUCinf (if applicable) will 
be assessed using an exponential regression model ("power model") in part 1 
and part 2.  
PD analysis: 
Descriptive statistics will be provided on values and changes from baseline for 
each time-point. 
Exploratory PK-PD analysis: 
As an exploratory analysis, evaluation of the relationship between doses and 
concentrations of Ir-CPI and the change from baseline in coagulation 
parameters will be investigated. 
Exploratory Biomarkers Analysis 
Descriptive statistics will be provided on values and changes from baseline for 
each time-point. 
Presence of ADA will be described by time-point until D180.  
Safety Analysis 
All AEs and treatment-emergent AEs will be described overall and by preferred 
term and system organ class until D180. Summary descriptive statistics will be 
provided for the other safety parameters. 
Supplemental ADA samplings (“long-term follow-up of ADAs”): 
ADA results from the additional samplings after D180 will only be listed and 
appended to the final Clinical Study Report (CSR). SADRs and related 
information after D180 will only be collected in the PV database. 


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2. SCHEDULE OF ACTIVITIES (SOA) 
2.1. 
Part 1 SOA: single 6-hour infusion 
2.1.1. Part 1 SOA: single 6-hour infusion for Cohorts A, B and C 
Assessments 
Screening visit 
[1] 
Treatment Period 
Discharge Visit  
Extra ambulatory 
visits for ADA 
analysis 
Additional ADA 
sampling in case of 
ADAs detected at 
D180 
Visit 1 (V1) 
D-28 to D-2 
V2 
D-1 
V3 
D1 
[2] 
V4 
D2 
V5 
D3 
V6 
D4 
V7 
D5 
V8 
D10 ± 2d 
V9: D30 (±3d), 
V10: D90 (±7d) 
V11: D180 (±7d) 
[22] 
From D270 (±14d), 
and up to every 3 
months (±14d) for 
the first year and 
every 6 months 
(±30d) for the 
following 4 years 
[24] 
Screening / Administrative / Other Assessments 
 
Informed consent 
X 
 
Demography [3] 
X 
 
Inclusion / exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
Medical and medication 
history 
X 
 
 
 
 
 
 
 
 
 
Life restriction monitoring 
 
X 
 
 
X 
X 
X 
X 
 
 
Drug / alcohol screen[4] 
X 
X 
 
Serology[5] 
X 
 
Randomisation to 
treatment 
 
 
X 
 
 
 
 
 
 
 
In-patient period 
 
 
 
 
 
 
 
 
Safety Assessments 
 
Physical exam [6] 
X 
X 
X 
X 
 
Brief physical exam [7] 
X 
 
Vital signs [8] 
X 
X 
X 
X 
X 
X 
 
Telemetry (including 
SpO2)[9] 
 
 
 
 
 
 
 
 
 
 
Height and BMI 
X 
 
Weight  
X 
X 
 
Faeces collection 
(Hemoccult® test) 
X 
 
 
 
 
 
 
 


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Assessments 
Screening visit 
[1] 
Treatment Period 
Discharge Visit  
Extra ambulatory 
visits for ADA 
analysis 
Additional ADA 
sampling in case of 
ADAs detected at 
D180 
Visit 1 (V1) 
D-28 to D-2 
V2 
D-1 
V3 
D1 
[2] 
V4 
D2 
V5 
D3 
V6 
D4 
V7 
D5 
V8 
D10 ± 2d 
V9: D30 (±3d), 
V10: D90 (±7d) 
V11: D180 (±7d) 
[22] 
From D270 (±14d), 
and up to every 3 
months (±14d) for 
the first year and 
every 6 months 
(±30d) for the 
following 4 years 
[24] 
Supine 12-lead ECG [10] 
X 
X 
X 
X 
X 
X 
 
Serum chemistry[11] 
X 
X 
X 
X 
X 
 
Haematology [11] 
X 
X 
X 
X 
X 
 
Exposure to tick bites [12] 
 
 
X 
 
 
 
 
X 
X 
 
Anti-Borrelia immunity 
(IgG/IgM) [13] 
 
 
X 
 
 
 
 
 
 
 
Safety aPTT [14] 
X 
X 
X 
X 
X 
X 
 
Urinalysis [15] 
X 
X 
X 
X 
X 
 
Adverse event monitoring 
 
Only SADRs  
Concomitant medication 
monitoring 
 
 
 
 
Only if related to the 
reported AE 
Only if related to 
SADRs 
Study drug Administration / Pharmacokinetic / Pharmacodynamic Assessments 
 
Study drug administration 
[16] 
 
 
X 
 
 
 
 
 
 
 
PD samples cluster A: PD 
aPTT (central lab) and 
FXI/FXII activities [17] 
 
 
X 
X 
X 
X 
X 
X 
 
 
PD samples cluster B [18] 
X 
X 
X 
X 
X 
 
CysC samples [19] 
X 
 
X 
X 
 
X 
 
X 
 
 
Blood PK samples [20] 
X 
X 
X 
X 
X 
 
Immunogenicity Testing 
(ADA) [21] 
 
 
X 
 
 
 
 
X 
X [22] 
X[24] 
Urine collection [23] 
 
 
NOTE: postdose is defined as « after start of infusion” 
1. 
Screening procedures must occur within 28 days up to 2 days before study drug administration. 
2. 
The results of the analysis of the D1 predose samples are collected to establish baseline references and are not needed before administration. 
3. 
Demography includes: year of birth, age, sex, ethnicity and race. 


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4. 
See laboratory safety parameter assessments (section 9.7.6) for list of tests to be run. 
5. 
See laboratory safety parameter assessments (section 9.7.6) for list of tests to be run. 
6. 
Physical Examination (including basic neurological testing for isocoria, light reflexes, gait and balance) should be performed at screening, on D-1, then 24h postdose (D2) and at the 
discharge visit. 
7. 
An abbreviated physical exam should be performed at 8h postdose on D1. 
8. 
Supine vital signs should be measured after 5 minutes of rest in a supine position and include body temperature, resting pulse rate, and blood pressure: at screening, then from D1 to D4, 
vital signs should be done predose, 60min, 2h, 4h, 6h, 8h, 10h, 12h, 24h, 48h, 72h postdose, and then at the discharge visit (D10+/-2d). 
9. 
Cardiac monitoring using telemetry (3-lead minimum and including SpO2) is to be performed from 1h predose up to 12h postdose. 
10. ECG should be done at screening, then on D1 (predose, 2h, 4h, 6h, 8h, 12h), 24h (D2), 48h (D3), 72h (D4) postdose and at the discharge visit. Timing can be adjusted based on emerging 
PK data. 
11. See laboratory safety parameter assessments for list of tests to be run (section 9.7.6): screening, then from D1 to D4: Predose (D1), 24h (D2), 72h postdose (D4), and then at the discharge 
visit. 
12. Participants will be asked at baseline if they have been previously exposed to tick bites. At the discharge and extra-ambulatory visits performed for ADA analysis, the participants will be 
asked if they have been exposed to tick bite since the previous visit (response recorded as yes/no/unknown). If the answer is yes, then the participant will be asked to provide information on 
treatment (e.g. antibiotics) and on presence of erythema migrans and other signs or symptoms. 
13. The baseline chemistry (predose sample) will also contain an extra archive serum sample for anti-Borrelia serology testing (IgG and IgM) as backup to test for anti-Borrelia antibodies due 
to previous exposure via potential tick bites. 
14. Safety aPTT (local lab) at screening, then on D1, predose, then 2h, 4h, 6h, 8h, 12h, D2 (24h), D3 (48h) and D4 (72h) postdose and at the discharge visit. 
15. Urinalysis at screening, then predose (D1), 24h (D2), 72h postdose (D4) and at the discharge visit. See laboratory safety parameter assessments for list of tests to be run (section 9.7.6). 
16. All participants will receive a single intravenous dose of Ir-CPI/Placebo given as a 6-hour infusion. Post dose is measured after the beginning of infusion. A light breakfast (2 slices of bread 
with ham or cheese and jam, glass of water) can be given between 2h and 1h before start of infusion. Lunch will be served after completion of the infusion.  
17. Cluster A (central lab): the effect of Ir-CPI on PD aPTT (central lab) (not to be confused with safety aPTT) and on FXI/FXII activities will be measured on D1: pre-dose, then at 30min, 
60min, 90min, 2h, 4h, 6h, 6h30, 7h, 7h30, 8h, 10h, 12h, 16h post-dose, then on D2 (24h), D3 (48h), D4 (72h), D5 (96h) and discharge visit. In case of infusion less than 6 hours and besides 
assessment at predose, 30 min, 60 min, 90 min, 2h and 4h after start of infusion, Cluster A (central lab) parameters should be measured at the end of infusion, then 30 min, 60 min, 90 min, 
2h, 4h, 6h, 10h, then 18h, 42h, 66h and 90h after the end of infusion and then at the discharge visit. 
18. Cluster B (local lab) the effect of Ir-CPI on PT (sec and INR), D-dimers, fibrinogen, hsCRP and TNFα will be measured on D1, predose then at 2h, 4h, 6h, 8h, 12h post-dose, on D2 (24h 
post-dose), D3 (48h) and D4 (72h) and discharge visit. In case of infusion less than 6 hours and besides assessment on D1 at predose and at 2h and 4h after start of infusion, Cluster B (local 
lab) parameters will be measured at the end of infusion, then 2h, 6h, 18h, 42h and 66h after the end of infusion and then at the discharge visit. 
19. CysC (central lab) will be collected at screening, then from D1 to D4: Predose (D1), 24h (D2), 72h postdose (D4), and then at the discharge visit. 
20. Blood samples for Ir-CPI PK will be done on D1, pre-dose and at 30min, 60min, 90min, 2h, 4h, 6h, 6h30, 7h, 7h30, 8h, 10h, 12h, 16h, then D2 (24h), D3 (48h), D4 (72h) and D5 (96h) 
post-dose (after start of infusion). In case of infusion less than 6 hours, blood sample for Ir-CPI pharmacokinetics will be done at the end of infusion then 30min, 60min, 90min, 2h, 4h, 6h, 
10h, 18h, 42h, 66h and 90h after end of infusion. 
21. ADA analysis sample: pre-dose on the day of infusion, at the discharge visit, on D30 and on D90. 


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22. D180 only if ADAs are detected in the D90 samples. 
23. Urine collections for PK assay are to be done at these intervals predose, [0-6h[, [6-12h[ and [12-24h] after start of infusion. Urinary NGAL, microalbuminuria and KIM-1 will be assessed. 
24. Samplings will be performed until the participants reach a negative status, until they show the same ADA titre result for 3 samplings in a row, or up to a maximum of 5 years after D180, 
whichever comes first. Otherwise, samplings will be performed every 3 months for the first year then every 6 months up to a maximum of 5 years after the D180 ambulatory visit. As the 
D180 visit was performed on the same day for all participants (and not according to D1 of a given cohort), these additional samplings will be performed in the same time-frame for all 
concerned participants. If a planned sampling is missed, the subsequent samplings can still be performed. 
 


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2.1.2. Part 1 SOA: single 6-hour infusion for Cohorts D and E 
Note: Cohort E was not performed according to a recommendation from the Ethics Committee 
Assessments 
Screening 
visit [1] 
Treatment Period 
Discharge Visit  
Extra ambulatory 
visits for ADA 
analysis 
Additional ADA 
sampling in case of 
ADAs detected at 
D180 
Visit 1 (V1) 
D-28 to D-2 
V2 
D-1 
V3 
D1 
[2] 
V4 
D2 [6] 
V5 
D3 [6] 
V6 
D4 
V7 
D5 
V8 
D7 
V9 
D10 ± 2d 
V10: D30 (±3d), 
V11: D90 (±7d) 
V12: D180 (±7d) [23] 
From D270 (±14d) 
and up to every 3 
months (±14d) for 
the first year and 
every 6 months 
(±30d) for the 
following 4 years [25] 
Screening / Administrative / Other Assessments 
 
Informed consent 
X 
 
 
Demography [3] 
X 
 
 
Inclusion / exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Medical and medication 
history 
X 
 
 
 
 
 
 
 
 
 
 
Life restriction monitoring 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
Drug / alcohol screen[4] 
X 
X 
 
 
Serology[5] 
X 
 
 
Randomisation to treatment 
X 
 
 
In-patient period [6] 
 
 
 
 
 
 
 
 
 
Safety Assessments 
 
Physical exam[7] 
X 
X 
X[7] 
X[7] 
 
X 
 
Brief physical exam[8] 
X 
 
 
Vital signs[9] 
X 
X 
X 
X 
X 
 
X 
 
Telemetry (including 
SpO2)[10] 
 
 
 
 
 
 
 
 
 
 
 
Height and BMI 
X 
 
 
Weight  
X 
 
X 
 
Faeces collection 
(Hemoccult® test) 
X 
 
 
 
 
 
 
 
 
Supine 12-lead ECG[11] 
X 
X 
X 
X 
X 
 
X 
 
Serum chemistry[12] 
X 
X 
X 
X 
 
X 
 
Haematology [12] 
X 
X 
X 
X 
 
X 
 
Exposure to tick bites [13] 
 
 
X 
 
 
 
 
 
X 
X 
 


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Assessments 
Screening 
visit [1] 
Treatment Period 
Discharge Visit  
Extra ambulatory 
visits for ADA 
analysis 
Additional ADA 
sampling in case of 
ADAs detected at 
D180 
Visit 1 (V1) 
D-28 to D-2 
V2 
D-1 
V3 
D1 
[2] 
V4 
D2 [6] 
V5 
D3 [6] 
V6 
D4 
V7 
D5 
V8 
D7 
V9 
D10 ± 2d 
V10: D30 (±3d), 
V11: D90 (±7d) 
V12: D180 (±7d) [23] 
From D270 (±14d) 
and up to every 3 
months (±14d) for 
the first year and 
every 6 months 
(±30d) for the 
following 4 years [25] 
Anti-Borrelia immunity 
(IgG/IgM) [14] 
 
 
X 
 
 
 
 
 
 
 
 
Safety aPTT[15] 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis[16] 
X 
X 
X 
X 
 
X 
 
Adverse event monitoring 
 
Only SADRs 
Concomitant medication 
monitoring 
 
Only if related to the 
reported AE 
Only if related to 
SADRs 
Study Drug Administration / Pharmacokinetic / Pharmacodynamic Assessments 
 
Study drug 
administration[17] 
 
 
X 
 
 
 
 
 
 
 
 
PD samples cluster A: PD 
aPTT (central lab) and 
FXI/FXII activities [18] 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
PD samples cluster B[19] 
X 
X 
X 
X 
 
X 
 
CysC samples [20] 
X 
 
X 
X 
 
X 
 
 
X 
 
 
Blood PK samples[21] 
X 
X 
X 
X 
X 
X 
 
Immunogenicity Testing 
(ADA) [22] 
 
 
X 
 
 
 
 
 
X 
X[23] 
X [25] 
Urine collection [24] 
 
 
 
 
 
 
 
 
 
 
NOTE: postdose is defined as « after start of infusion” 
1. 
Screening procedures must occur within 28 days up to 2 days before study drug administration. 
2. 
The results of the analysis of the D1 predose samples are collected to establish baseline references and are not needed before administration. 
3. 
Demography includes: year of birth, age, sex, ethnicity and race. 
4. 
See laboratory safety parameter assessments (section 9.7.6) for list of tests to be run. 
5. 
See laboratory safety parameter assessments (section 9.7.6) for list of tests to be run. 
6. 
A safety aPTT sample is drawn on D2, 24h after D1 administration. All participants will remain hospitalised until the investigator is able to review the 24h aPTT assay results. If, for each 
participant, the results are less than or equal to 2X aPTT level at baseline (i.e. D1 predose), then the participants may leave the clinic. They will return for the ambulatory visits on D3 (48h 
post infusion start), D4 (72h), D5 (96h) and D7 (144h). If the 24h safety aPTT assay of one participant is above 2X the participant’s baseline aPTT, then all participants will remain 


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hospitalised until the completion of the D3 (48h) assessments and an additional aPTT sample will be drawn at 36h. If the 36h aPTT assay result of a participant is more than 2X baseline 
aPTT of this participant, the investigator will decide the most appropriate procedures for the follow-up of this participant. Participants will return for the ambulatory visits on D4 (72h), D5 
(96h) and D7 (144h). 
7. 
A full physical examination (including basic neurological testing for isocoria, light reflexes, gait and balance) should be performed at screening, on D-1, then, at 24h postdose (D2), also at 
48h (D3) if hospitalisation is extended (see footnote 6), and at the discharge visit.  
8. 
An abbreviated physical examination will be performed at 8h postdose on D1.  
9. 
Supine vital signs should be measured after 5 minutes of rest in a supine position and include body temperature, resting pulse rate, and blood pressure: at screening, then from D1 to D4, 
vital signs should be done predose, 60min, 2h, 4h, 6h, 8h, 10h, 12h, 24h, 48h, 72h postdose, and then at the discharge visit (D10+/-2d). 
10. Cardiac monitoring using telemetry (3-lead minimum and including SpO2) is to be performed from 1h predose up to 12h postdose. 
11. ECG should be done at screening, then on D1 (predose, 2h, 4h, 6h, 8h, 12h), 24h (D2), 48h (D3), 72h (D4) postdose and at the discharge visit. Timing can be adjusted based on emerging 
PK data. 
12. See laboratory safety parameter assessments for list of tests to be run (section 9.7.6): screening, then from D1 to D4: Predose (D1), 24h (D2), 72h postdose (D4), and then at the discharge 
visit. 
13. Participants will be asked at baseline if they have been previously exposed to tick bites. At the discharge and extra-ambulatory visits performed for ADA analysis, the participants will be 
asked if they have been exposed to tick bite since the previous visit (response recorded as yes/no/unknown). If the answer is yes, then the participant will be asked to provide information on 
treatment (e.g. antibiotics) and on presence of erythema migrans and other signs or symptoms. 
14. The baseline chemistry (predose sample) will also contain an extra archive serum sample for anti-Borrelia serology testing (IgG and IgM) as backup to test for anti-Borrelia antibodies due 
to previous exposure via potential tick bites. 
15. Safety aPTT (local lab) at screening, then on D1, predose, then 2h, 4h, 6h, 8h, 12h, 24h (D2), 36h (D2, optional sample only drawn if hospitalisation is extended at least until 36h postdose, 
see footnote 6), D3 (48h), D4 (72h), D5 (96h), D7 (144h) postdose and at the discharge visit.  
16. Urinalysis at screening, then predose (D1), 24h (D2), 72h postdose (D4) and at the discharge visit. See laboratory safety parameter assessments for list of tests to be run (section 9.7.6). 
17. All participants will receive a single intravenous dose of Ir-CPI/Placebo given as a 6-hour infusion. Post dose is measured after the beginning of infusion. A light breakfast (2 slices of bread 
with ham or cheese and jam, glass of water) can be given between 2h and 1h before start of infusion.  Lunch will be served after completion of the infusion.  
18. Cluster A (central lab): the effect of Ir-CPI on PD aPTT (central lab) (not to be confused with safety aPTT) and on FXI/FXII activities will be measured on D1: pre-dose, then at 30min, 
60min, 90min, 2h, 4h, 6h, 6h30, 7h, 7h30, 8h, 10h, 12h, 16h post-dose, then on D2 (24h), D3 (48h), D4 (72h), D5 (96h), D7 (144h) and discharge visit. In case of infusion less than 6 hours 
and besides assessment at predose, 30 min, 60 min, 90 min, 2h and 4h after start of infusion, Cluster A (central lab) parameters should be measured at the end of infusion, then 30 min, 
60 min, 90 min, 2h, 4h, 6h, 10h, then 18h, 42h, 66h, 90h and 138h after the end of infusion and then at the discharge visit. 
19. Cluster B (local lab) the effect of Ir-CPI on PT (sec and INR), D-dimers, fibrinogen, hsCRP and TNFα will be measured on D1, predose then at 2h, 4h, 6h, 8h, 12h post-dose, on D2 (24h 
post-dose), D3 (48h) and D4 (72h) and discharge visit. In case of infusion less than 6 hours and besides assessment on D1 at predose and at 2h and 4h after start of infusion, Cluster B (local 
lab) parameters will be measured at the end of infusion, then 2h, 6h, 18h, 42h and 66h after the end of infusion and then at the discharge visit. 
20. CysC (central lab) will be collected at screening, then from D1 to D4: Predose (D1), 24h (D2), 72h postdose (D4), and then at the discharge visit. 
21. Blood samples for Ir-CPI PK will be done on D1, pre-dose and at 30min, 60min, 90min, 2h, 4h, 6h, 6h30, 7h, 7h30, 8h, 10h, 12h, 16h, then D2 (24h), D3 (48h), D4 (72h), D5 (96h) and D7 
(144h) post-dose (after start of infusion). In case of infusion less than 6 hours, blood sample for Ir-CPI pharmacokinetics will be done at the end of infusion then 30min, 60min, 90min, 2h, 
4h, 6h, 10h, 18h, 42h, 66h, 90h and 138h after end of infusion. 


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22. ADA analysis sample: pre-dose on the day of infusion, at the discharge visit, on D30 and on D90. 
23. D180 only if ADAs are detected in the D90 samples. 
24. Urine collections for PK assay are to be done at these intervals predose, [0-6h[, [6-12h[ and [12-24h] after start of infusion. Urinary NGAL, microalbuminuria and KIM-1 will be assessed. 
25. Samplings will be performed until the participants reach a negative status, until they show the same ADA titre result for 3 samplings in a row, or up to a maximum of 5 years after D180, 
whichever comes first. Otherwise, samplings will be performed every 3 months for the first year then every 6 months up to a maximum of 5 years after the D180 ambulatory visit. As the 
D180 visit was performed on the same day for all participants (and not according to D1 of a given cohort), these additional samplings will be performed in the same time-frame for all 
concerned participants. If a planned sampling is missed, the subsequent samplings can still be performed. 


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2.2. 
Part 2 SOA: loading dose infusion of 30 minutes followed by fixed dose continuous infusion over 5.5 hours 
Note: Part 2 was not performed because the targeted plasmatic PK concentration was planned in the unperformed group E. 
Assessments 
Screening visit [1] 
Treatment Period 
 
Discharge Visit  
Extra ambulatory visits for ADA analysis 
V1 
D-28 to -2 
V2 
D-1 
V3 
D1 
[2] 
V4 
D2 [6] 
V5 
D3 [6] 
V6 
D4 
V7 
D5 
V8 
D7 
V9 
D10 (±2d) 
V10: D30 (±3d),  
V11: D90 (±7d)  
V12: D180 (±7d) [23] 
Screening / Administrative / Other Assessments 
Informed consent 
X 
 
Demography [3] 
X 
 
Inclusion / exclusion criteria 
X 
X 
 
Medical and medication history 
X 
 
Lifestyle restriction monitoring 
 
X 
 
 
X 
X 
X 
X 
X 
 
Drug / alcohol screen[4] 
X 
X 
 
Serology[5] 
X 
 
Randomization to treatment 
X 
 
In-patient stay [6] 
 
 
 
 
 
 
 
 
Safety Assessments 
Physical exam[7] 
X 
X 
 
X[7] 
X[7] 
 
X 
Brief physical exam[8] 
X 
 
Vital signs[9] 
X 
X 
X 
X 
X 
 
X 
Telemetry (including SpO2)[10] 
 
 
Height and BMI 
X 
 
Weight  
X 
 
X 
Faeces collection (Hemoccult® 
test) 
X 
 
 
 
 
 
 
 
Supine 12-lead ECG[11] 
X 
X 
X 
X 
X 
 
X 
Serum chemistry[12] 
X 
X 
X 
X 
 
X 
Haematology[12] 
X 
X 
X 
X 
 
X 
Exposure to tick bites [13] 
 
 
X 
 
 
 
 
 
X 
X 
Anti-Borrelia immunity (IgG/IgM) 
[14] 
 
 
X 
 
 
 
 
 
 
 
Safety aPTT[15] 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis[16] 
X 
X 
X 
X 
 
X 
Adverse event monitoring 
 
Concomitant medication 
monitoring 
 
Only if related to the reported AE 


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Assessments 
Screening visit [1] 
Treatment Period 
 
Discharge Visit  
Extra ambulatory visits for ADA analysis 
V1 
D-28 to -2 
V2 
D-1 
V3 
D1 
[2] 
V4 
D2 [6] 
V5 
D3 [6] 
V6 
D4 
V7 
D5 
V8 
D7 
V9 
D10 (±2d) 
V10: D30 (±3d),  
V11: D90 (±7d)  
V12: D180 (±7d) [23] 
Study Drug Administration / Pharmacokinetic / Pharmacodynamic Assessments 
Study Drug administration[17] 
X 
 
PD samples cluster A: PD aPTT 
(central lab) and FXI/FXII 
activities [18] 
 
 
X 
X 
X 
X 
X 
X 
X 
 
PD samples cluster B [19] 
X 
X 
X 
X 
 
X 
CysC sample [20] 
X 
 
X 
X 
 
X 
 
 
X 
 
PK samples [21] 
X 
X 
X 
X 
X 
X 
Immunogenicity Testing (ADA) 
[22] 
 
 
X 
 
 
 
 
 
X 
X[23] 
Urine collection [24] 
 
 
 
 
 
 
 
 
 
NOTE: postdose is defined as « after start of infusion” 
1. 
Screening procedures must occur within 28 days up to 2 days before study drug administration. 
2. 
The results of the analysis of the D1 predose samples are collected to establish baseline references and are not needed before administration. 
3. 
Demography includes: years of birth, age at screening, sex, ethnicity and race. 
4. 
See laboratory safety parameter assessments (section 9.7.6) for list of tests to be run. 
5. 
See laboratory safety parameter assessments (section 9.7.6) for list of tests to be run. 
6. 
A safety aPTT sample is drawn on D2, 24h after D1 administration. All participants will remain hospitalized until the investigator is able to review the 24h aPTT assay results. If, for each 
participant, the results are less than or equal to 2X aPTT level at baseline (i.e. D1 predose), then the participants may leave the clinic. They will return for the ambulatory visits on D3 (48h 
post infusion start), D4 (72h), D5 (96h) and D7 (144h). If the 24h safety aPTT assay of one participant is above 2X the participant’s baseline aPTT, then all participants remain hospitalized 
until the completion of the D3 (48h) assessments and an additional aPTT sample will be drawn at 36h. If the 36h aPTT assay result of a participant is more than 2X baseline aPTT of this 
participant, the investigator will decide the most appropriate procedures for the follow-up of this participant. The participant will return for the ambulatory visits on D4 (72h), D5 (96h) and 
D7 (144h). 
7. 
A full physical examination (including basic neurological testing for isocoria, light reflexes, gait and balance) should be performed at screening, on D-1, then, at 24h postdose (D2), also at 
48h (D3) if hospitalization is extended (see footnote 6), and at the discharge visit.  
8. 
An abbreviated physical examination will be performed at 8h postdose on D1. 
9. 
Supine vital signs should be measured after 5 minutes of rest in a supine position and include body temperature, resting pulse rate, and blood pressure: at screening, then from D1 to D4, 
vital signs should be done predose, 60min, 2h, 4h, 6h, 8h, 10h, 12h, 24h, 48h, 72h postdose, and then at the discharge visit (D10+/-2d). 
10. Cardiac monitoring using telemetry (3-lead minimum and including SpO2) is to be performed as of 1h predose up to 12h postdose. 
11. ECG should be done at screening, then at D1 (predose, 2h, 4h, 6h, 8h, 12h), 24h (D2), 48h (D3), 72h (D4) postdose and discharge visit. Timing can be adjusted based on emerging PK data. 
12. See laboratory safety parameter assessments (section 9.7.6) for list of tests to be run:  at screening, then D1 predose, D2 (24h), D4 (72h postdose), and discharge visit. 


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13. Participants will be asked at predose visit if they have been previously exposed to tick bites. At the discharge and extra-ambulatory visits performed for ADA analysis, the participants will 
be asked if they have been exposed to tick bite since the previous visit (response recorded as yes/no/unknown). If the answer is yes, then the participant will be asked to provide information 
on treatment (e.g. antibiotics) and on presence of erythema migrans and other signs or symptoms. 
14. The baseline chemistry (predose sample) will also contain an extra archive serum sample for anti-Borrelia serology testing (IgG and IgM) as backup to test for anti-Borrelia antibodies due 
to previous exposure via potential tick bites. 
15. Safety aPTT (local lab) at screening, then on D1, predose, then 2h, 4h, 6h, 8h, 12h, 24h (D2), 36h (D2, optional sample only drawn if hospitalisation is extended at least until 36h postdose, 
see footnote 6), D3 (48h), D4 (72h), D5 (96h), D7 (144h) postdose and at the discharge visit. 
16. Urinalysis at screening, then D1 predose, D2 (24h) and D4 (72h postdose), and discharge visit. See laboratory safety parameter assessments for list of tests to be run (section 9.7.6). 
17. All participants will receive a single intravenous loading dose of Ir-CPI/Placebo given as a 30-minute infusion. A light breakfast (2 slices of bread with ham or cheese and jam, glass of 
water) can be given between 2h and 1h before start of infusion. Upon completion of the loading dose infusion, all participants will receive a single intravenous dose of Ir-CPI/Placebo given 
as a 5.5-hour infusion. Postdose is measured after the beginning of infusion. 
18. Cluster A (central lab): the effect of Ir-CPI on PD aPTT (not to be confused with safety aPTT) and on FXI/FXII activities will be measured at D1 pre-dose and at D1 15min, 30min, 45min, 
60min, 90min, 2h, 4h, 6h, 6h30, 7h, 7h30, 8h, 10h, 12h, 16h, then D2 (24h), D3 (48h), D4 (72h), D5 (96h), D7 (144h) and discharge visit. In case of infusion less than 6 hours and besides 
assessment at predose, 15 min, 30 min, 45 min, 60 min, 90 min, 2h and 4h after start of infusion, Cluster A (central lab) parameters should be measured at the end of infusion, then 30 min, 
60 min, 90 min, 2h, 4h, 6h, 10h, then 18h, 42h, 66h, 90h and 138h after the end of infusion and then at the discharge visit. 
19. Cluster B (local lab) the effect of Ir-CPI on PT (sec and INR), D-dimers, fibrinogen, hsCRP and TNFα will be measured on D1, predose then at 2h, 4h, 6h, 8h, 12h post-dose, on D2 (24h 
post-dose), D3 (48h) and D4 (72h) and at the discharge visit. In case of infusion less than 6 hours and besides assessment on D1 at predose and at 2h and 4h after start of infusion, Cluster B 
(local lab) parameters will be measured at the end of infusion, then 2h, 6h, 18h, 42h and 66h after the end of infusion and then at the discharge visit. 
20. CysC (central lab) will be collected at screening, then from D1 to D4: Predose (D1), 24h (D2), 72h postdose (D4), and then at the discharge visit. 
21. Blood samples for Ir-CPI pharmacokinetics will be done D1 pre-dose and at 15min, 30min, 45min, 60min, 90min, 2h, 4h, 6h, 6h30, 7h, 7h30, 8h, 10h, 12h, 16h, then D2 (24h), D3 (48h), 
D4 (72h), D5 (96h) and D7 (144h) post-dose (after start of infusion). In case of infusion less than 6 hours, blood sample for Ir-CPI pharmacokinetics will be done at the end of infusion then 
30min, 60min, 90min, 2h, 4h, 6h, 10h, 18h, 42h, 66h, 90h and 138h after end of infusion. 
22. ADA analysis sample: pre-dose on the day of infusion, at the discharge visit, on D30 and on D90. 
23. D180 only if ADAs are detected in the D90 samples. As this study part was not performed in the end, no additional samplings after D180 are applicable. 
24. Urine collections for PK assay are to be done at the following intervals: predose, [0-6h[, [6-12h[ and [12-24h]. Urinary NGAL, microalbuminuria and KIM-1 will be assessed. 


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LIST OF ABBREVIATIONS 
 
ADA 
Anti-Drug Antibodies 
ADME 
Absorption, distribution, metabolism and excretion 
AE 
Adverse Event 
Ae 
Total amount excreted in urine 
AESI 
Adverse Event of Specific Interest 
Ag 
Antigen 
ALT 
Alanine Amino Transferase 
AMM 
Autorisation de Mise sur le Marché (French Drug Marketing Licence) 
ANOVA 
Analysis of Variance 
API 
Active Pharmaceutical Ingredient 
aPTT 
activated Partial Thromboplastin Time 
AST 
Aspartate Amino Transferase 
AUC 
Area Under the Curve  
AUCinf 
Area under the plasma concentration time curve from time 0 to the infinity 
BMI 
Body Mass Index 
CA 
Competent Authorities 
CL 
Clearance 
CLR 
Renal Clearance 
Cmax rate 
Maximal excretion rate 
CONSORT 
Consolidated Standards of Reporting Trials 
CPB 
CardioPulmonary Bypass 
CPK 
Creatinine Phospho Kinase 
CRO 
Contract Research Organization 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CTA 
Clinical Trial Application 
CTD 
Clinical Trial Document 
CV 
Coefficient of variation 
CysC 
Cystatin C 
DBP 
Diastolic Blood Pressure 
DRD 
Daily Recommended Dose 
ECG 
Electrocardiogram 
ECMO 
Extracorporeal membrane oxygenation 


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EMEA 
European Medical Agency 
EudraCT 
European Clinical Trials Database  
EU-GMP 
European Union-Good Manufacturing Practice 
FAMHP 
Federal Agency for Medicines and Health Products (Belgium’s CA) 
FIH 
First-In-Human 
FXI 
Factor XI 
FXIa 
Activated FXI 
FXII 
Factor XII 
FXIIa 
Activated FXII 
FU 
Follow-up visit 
GGT 
Gamma Glutamyl Transferase 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HBc 
Hepatitis B core 
HBs 
Hepatitis B surface Antigen 
HCV 
Hepatitis C Virus 
HED 
Human Equivalent Dose 
HIT 
Heparin-induced Thrombocytopenia 
HIV 
Human Immunodeficiency Virus 
HR 
Heart Rate 
hsCRP 
High sensitivity C-reactive protein 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonization 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 
IgE 
Immunoglobulin E 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
Ir-CPI 
Ixodes ricinus-Contact Phase Inhibitor 
KIM-1 
Kidney Injury Molecule 1 
LC-MS/MS 
Liquid chromatography coupled to tandem Mass Spectrometry 


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LPLV 
last patient last visit 
MABEL 
minimum anticipated biological effect level 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRSD 
Maximum Recommended Starting Dose 
MTD 
Maximum Tolerated Dose 
NCS 
Non Clinically Significant 
NGAL 
neutrophil gelatinase-associated lipocalin 
NOAEL 
No Observed Adverse Effect Level 
NOEL 
No Observed Effect Level 
OTC 
Over the Counter 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
POC 
Proof of Concept 
pp 
Per protocol 
PV 
Pharmacovigilance 
QA 
Quality Assurance 
SADR 
Serious Adverse Drug Reaction 
SAE 
Serious Adverse Event 
SBP 
Systolic Blood Pressure 
SOP 
Standard Operating Procedure 
SpO2 
Peripheral Capillary Oxygen Saturation 
SRC 
Safety Review Committee 
SUSARs 
Suspected Unexpected Serious Adverse Reactions 
SVT 
Supraventricular Tachycardia 
t1/2 
Half-life 
Tmax rate 
Time to reach maximum excretion rate 
TEAE 
Treatment Emergent Adverse Event 
TNFα 
tumor necrosis factor alpha 
UFH 
Unfractionated Heparin 
ULN 
Upper Limit of Normal 
Vol_UR 
Volume of urine excreted 
WHODDRUG World Health Organization Drug Dictionary 
VT 
Ventricular Tachycardia 
WMA 
World Medical Association 
 


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3. INTRODUCTION 
3.1. 
Study Rationale 
Ixodes ricinus-Contact Phase Inhibitor (Ir-CPI) is under development for the prevention of 
thrombosis in hospital procedures in which blood is exposed to non-biological surfaces 
known to activate the intrinsic pathway of the coagulation cascade (e.g. percutaneous 
endovascular interventions, cardiopulmonary bypass).  
Inhibitors specific to factor XI and factor XII (FXI/FXII) of the intrinsic pathway are 
expected to have preventive antithrombotic effects with lower risk of bleeding compared to 
the currently available anticoagulants. They would particularly be indicated for preventing 
clotting on blood-contacting medical devices or extracorporeal circuits. Indeed, exposure of 
blood to polyanionic artificial surfaces induces a highly procoagulant condition through the 
activation of the intrinsic pathway of the coagulation.  
Potential indications for Ir-CPI will be the prevention of thrombotic events associated to the 
use of contact phase activating devices, e.g. percutaneous endovascular interventions, 
extracorporeal circulation during cardiac surgical interventions (CPB), especially under 
clinical circumstances where the use of classical anticoagulation is not adequate due to 
heparin intolerability (HIT, Heparin-induced Thrombocytopenia) and/or high risk of 
bleeding.  
As Ir-CPI has to be administered by intravenous (IV) infusion and as it has a half-life of a 
few hours, it is intended for specialised use in a hospital setting. The infusion of Ir-CPI would 
have to be initiated prior to and last until the end of the procedure. In the context of a CPB, 
the infusion would last for 4-6 hours, depending on the duration of the intervention. In the 
context of an endovascular intervention, the infusion would last around 2 hours. Due to the 
possible anti-drug antibody (ADA) generation, intended indications will be medical 
prevention in acute situation, with no repeated or chronic use of Ir-CPI. 
This study will be the first-in-human study of Ir-CPI. This study will provide an initial 
assessment of the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of 
Ir-CPI after intravenous administration as 6 hour-infusion at different doses without [single 
ascending dose (SAD) part 1] or with a loading dose [single ascending dose (SAD) part 2] to 
healthy adult male participants. 
A pivotal good laboratory practice (GLP) toxicity study in monkey was designed to support 
the First-In-Human (FIH) clinical trial design, by mimicking as much as possible the route 
and type of administration foreseen, by testing an appropriate safety margin (3, 10 and 30-
fold) in regards to the first human clinical dose and by choosing a continuous infusion 
duration largely exceeding the one foreseen in the FIH clinical trial (i.e. 6 hours). This 
toxicity study was performed with Ir-CPI administered by continuous IV infusion during 24h 
at 3 dose levels (mid, high, super high) with systemic exposure to Ir-CPI up to at least 30-fold 
the expected therapeutic concentration in humans. The 24h infusion was followed by a 
recovery period (24h or 14 days) at high and super high doses. No clinical sign or 
macroscopic findings was observed, except an increase in kidney weight in males at the super 
high dose (2/3 animals). Microscopic examination showed adverse toxicity (kidneys) in both 
females and males only at the super high dose in the early scheduled euthanasia animals (24h 
after ending infusion). Immuno-histochemical staining suggested that there was no formation 
of immune complexes (high and super high doses tested), either for the early or late 
scheduled euthanasia animals, suggesting a direct effect of Ir-CPI at the highest dose in the 
renal tissue. No effect related to ADAs was observed, even though ADAs were detected 9 


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(one animal) or 11 (all animals) days after ending infusion in the high and super high dose 
groups. A loss of proportionality in Ir-CPI plasma concentration was observed between the 
high and the super high dose. During post-infusion, a decrease of Ir-CPI clearance was only 
observed at the super high dose with a possible link to renal toxicity. Considering these 
results, the no-observed-adverse-effect-level (NOAEL) was set at 201.6 mg/kg/day. This 
NOAEL was used to define the Maximal Recommended Starting Dose (MRSD) for this FIH 
clinical study.  
The doses to be evaluated in this study are based on the results obtained in the GLP toxicity 
studies (2-week infusion study in rats and monkeys; 24-hour infusion study in monkeys), the 
2-hour safety pharmacology study in monkeys and additional non-GLP pharmacology studies 
performed. 
Once PK results are obtained at increasing doses of Ir-CPI in healthy participants upon 6-
hour infusion, a combination of rapid (30 minutes) and slow (5.5 hours) infusions will be 
administered to healthy participants as it will be used thereafter in Proof of Concept (POC) 
efficacy studies in human such as coronarography and later in patients undergoing a 
Cardiopulmonary Bypass (CPB) intervention.  
This design will be used to define the experimental condition(s) of administration allowing to 
rapidly reach and to maintain steady state Ir-CPI concentration for up to 6 hours. 
The participants participating in the study will be followed up during a 24h hospitalisation 
combined with daily ambulatory visits thereafter (up to 96h after dosing). The proposed 
24 hours is deemed sufficient because this is a single intravenous infusion where it is 
expected that the most severe and acute reactions will occur during or very short after the 
infusion. Based on animal data, the pharmacodynamics effect and potential side effects are 
expected to be related to plasma levels that will decline rapidly after ending the IV infusion. 
The discharge from the research facility at 24h will be at the discretion of the Investigator and 
will be based on the available safety parameters [including – but not limited to – activated 
Partial Thromboplastin Time (aPTT)]. Although the combination of the presence of a 
relevant biomarker measuring study drug activity, daily visits to the research facility and the 
proposed safety testing is considered to be sufficient safety coverage to allow a discharge of 
participants at 24h after drug administration, the investigator may extend the hospitalisation 
period up to 48h if deemed necessary (Cohort D and subsequent cohorts only). 
3.2. 
Background 
Ir-CPI, a non-glycosylated recombinant protein of 67 amino acids, is a first-class candidate 
targeting the intrinsic pathway of the coagulation cascade. It is to be administered 
intravenously for the prevention of thrombosis in procedures in which blood is exposed to 
polyanionic artificial surfaces known to activate the intrinsic pathway of the coagulation 
cascade (e.g. percutaneous endovascular interventions, extracorporeal circulation during 
cardiac surgical interventions [CPB]).  
Ir-CPI is a serine protease inhibitor, originally isolated from the saliva of the tick Ixodes 
ricinus. Ticks are well known to produce salivary substances capable of counteracting the 
haemostatic system of the host. Initially produced by chemical synthesis (synth Ir-CPI), Ir-
CPI is now produced in the yeast Pichia (Komagataella) pastoris under GMP conditions (rec 
Ir-CPI).  
Ir-CPI is able to inhibit the intrinsic coagulation pathway (contact phase) through inhibition 
of the activation of FXI into FXIa by FXIIa and FXII into FXIIa by FXIa. 


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This results in an increase of the clotting time in the in vitro assay aPTT, which is specific to 
the intrinsic coagulation pathway. However, Ir-CPI has no effect on both prothrombin and 
thrombin time, assays which measure the effect of the molecule on the extrinsic or common 
pathway.  
Mechanistic data accumulated so far indicate that Ir-CPI reduces the generation of FXIa by 
interfering with upstream activation of FXI by FXIIa and reciprocal activation of FXII by 
FXIa while it has no effect on activation of FIX by FXIa. Ir-CPI was proven to be 
antithrombotic in two experimental models involving blood contact with non-biological 
surfaces (arteriovenous shunt in rabbits; CPB with open-heart surgery in sheep). In the CPB 
model, Ir-CPI was as efficient as unfractionated heparin (UFH). Ir-CPI was shown to be 
markedly safer than UFH in an experimental model of bleeding induced by liver punch 
biopsies in pigs. 
Pharmacokinetic data available in mouse, rat, rabbit, dog and monkey fit with a bi-
compartmental model. This is characterized by a high volume of distribution (Vd: 1.98-8.55 
L/Kg), a rapid half-life of distribution (t1/2α: 14-72 min), a slower terminal elimination half-
life (t1/2β: 3.9-13.7 h), giving a rapid clearance (CL: 0.17-1.51 L/kg/h) with Vd and CL 
respectively increasing and decreasing with the size of the animal species. Ir-CPI plasma 
concentrations increase proportionally to the administered dose (bolus or infusion) as was 
verified in monkeys and rats. A rapid decline in the plasma concentration was observed after 
the arrest of continuous IV infusion performed on course of toxicokinetic studies (rat and 
monkey). Absorption, distribution, metabolism and excretion (ADME) studies conducted in 
rats indicate that Ir-CPI is rapidly cleared by metabolism/catabolism in the liver and the 
kidneys. Ir-CPI is excreted in the urine as a degraded product. 
GLP toxicity studies in rats and cynomolgus monkeys were first performed with Ir-CPI 
administered by continuous IV infusion (24h/24h) during 14 days at 3 dose levels (low, mid, 
high) with systemic exposure to Ir-CPI up to at least 10-fold the expected therapeutic 
concentration in humans. This 2-week infusion was followed by a 2-week recovery period 
(high dose). In these two-week IV infusion studies, toxicity was only observed at high dose in 
rats (kidneys) and monkeys (vascular and inflammatory changes in various organs, with the 
highest severity observed at high dose). Clinical signs were observed for monkeys but not in 
rats. In rats, Ir-CPI plasma concentrations were stable during 14 days. In monkeys, Ir-CPI 
plasma concentrations were stable during the first 7 days of infusion and approximately 
proportional to the administered doses, but an abnormal increase was documented at Days 
14-15. Anti-drug antibodies (ADAs) were detected in plasmas from monkeys but not from 
rats. Immune complexes were detected by immunohistochemistry (co-localization of Ir-CPI, 
IgM and complement [C3/C3b]), in kidneys, at high dose in all tested monkeys. All findings 
were considered to be most likely related to ADA-mediated immune complex formation, 
deposition, and systemic activation of complement. Abnormal increase in Ir-CPI plasma 
concentration was also considered as most likely related to the presence of ADAs. The 
NOAEL was defined at 60 mg/kg/day in monkeys and 192 mg/kg/day in rats. 
A pivotal GLP toxicity study in monkey was then designed to support the FIH clinical trial 
design, by mimicking as much as possible the route and type of administration foreseen, by 
testing an appropriate safety margin (3, 10 and 30-fold) in regards to the first human clinical 
dose and by choosing a continuous infusion duration largely exceeding the one foreseen in 
the FIH clinical trial (i.e. 6 hours). This toxicity study was performed with Ir-CPI 
administered by continuous IV infusion during 24 h at 3 dose levels (mid, high, super high) 
with systemic exposure to Ir-CPI up to at least 30-fold the expected therapeutic concentration 
in humans. The 24 h infusion was followed by a recovery period (24 h or 14 days) at high and 


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super high doses. No clinical signs or macroscopic findings were observed, except an 
increase in kidney weight in males at the super high dose (2/3 animals). Microscopic 
examination showed adverse toxicity (kidneys) in both females and males only at the super 
high dose in the early scheduled euthanasia animals (24h after ending infusion). 
Immunohistochemical staining suggested that there was no formation of immune complexes 
(high or super high doses tested), either for the early or late scheduled euthanasia, suggesting 
a direct effect of Ir-CPI at the highest dose in the renal tissue. No effect related to ADAs was 
observed, even though ADAs were detected 9 (one animal) or 11 (all animals) days after 
ending infusion in the high and super high dose groups. A loss of proportionality in Ir-CPI 
plasma concentration was observed between the high and the super high dose. During 
post-infusion, a decrease of Ir-CPI clearance was only observed at the super high dose with a 
possible link to renal toxicity. Considering these results, the NOAEL was set at 
201.6 mg/kg/day. This NOAEL was used to define the MRSD for the FIH clinical study. 
Note that in all toxicity studies, a dose-related moderate (rats, monkeys) to marked 
(monkeys) and reversible prolongation in aPTT was observed in all animals and at all dose 
levels, showing that Ir-CPI was present and under an active form.  
In order to investigate ADA appearance and effect on product efficacy and safety, an in vivo 
study was conducted in 3 cynomolgus monkeys receiving 3 repeated administrations (Day 1, 
15, 36) of 6-h continuous IV infusion (duration of infusion corresponding to the clinical 
development of Ir-CPI). ADAs (IgM, IgG but no IgE) developed in monkeys from Day 14 
with a rather classical immune memory response profile in terms of Ig sub-class switch and 
antibody titre evolution, although interindividual variation is observed. In vitro, ADAs 
showed neutralizing effects on aPTT, but unexpectedly not in vivo as aPTT remained similar 
upon the 3 repeated administrations. Noteworthy, although ADAs were present in animal 
body from the second infusion, the repeated administrations of Ir-CPI were well tolerated and 
did not induce any macroscopic or microscopic changes in organs and no formation of 
immune complexes in tissues. 
In silico and in vitro cellular experiments suggest that the risk of immunogenicity of Ir-CPI is 
moderate in humans. 
An ex vivo human immunogenicity study was performed by analysing the presence of ADAs 
in human blood samples collected from healthy volunteers or Lyme disease patients (Belgium 
+ US). In the Belgian population, 2/50 healthy volunteers and 1/50 Lyme disease patients 
were ADA positive (with an optical density close to the cut-point). All positive samples were 
collected from donors having been bitten by ticks. None of US donors (15 Lyme and 50 
healthy) were ADA positive. Data are considered as informative due to the limited size of 
samples. 
Safety Pharmacology studies indicate that Ir-CPI did not affect cardiovascular and respiratory 
functions in cynomolgus monkeys (telemetry) (at low and mid doses through a combined 
rapid and low infusion, during 0.5h and 2h, respectively) and neurobehavioral parameters 
(FOB) in the rat (single IV administration at 10, 30 or 60 mg/kg). 
The estimation of the MRSD was performed based on safety data provided from toxicity 
studies in animals (NOAEL) (see Section 5.6). 
Further detailed information can be found in the Investigator’s Brochure [1]. 


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3.3. 
Benefit/Risk Assessment 
No evidence available at the time of the completion of this study protocol indicated that 
special warnings or precautions were appropriate, other than those noted in the Investigator’s 
Brochure. 
As this study involves volunteers who are not suffering from any disease, no therapeutic 
benefit is expected for the healthy participants taking part in this study. 
Given the new mechanism of action, the nature of the compound and the intended route of 
administration, dose staggering will be applied in this FIH trial for all panels. This dose 
staggering will be as such that 2 participants will be dosed at least 24 hours before the 
remainder of the panel. These 2 sentinel participants will be randomised as such that there 
will be one placebo and one verum. After the review of AEs, vital signs and ECGs collected 
over 24 hours postdose (up to D2), the remaining participants of the panel will receive the 
same dose level. Following completion of the initial 24-hour safety period for the sentinel 
participants, the decision to proceed with the remaining participants in that panel will be 
mutually discussed/agreed upon between Investigator (or his designee) and the Sponsor and 
the decision to dose will be formally confirmed by the Sponsor. The proposed minimal 24 
hours between the sentinel and the remainder of the cohort is deemed sufficient because this 
is a single intravenous infusion where it is expected that the most severe and acute reactions 
will occur during or very short after the infusion. Based on animal data, the 
pharmacodynamics effect and potential side effects are expected to be related to plasma 
levels that will decline rapidly after ending the IV infusion. In addition to this, aPTT, which 
is a reliable biomarker available for drug activity, will be followed up at specific time-points. 
The results of this biomarker will be available for dose escalation decisions.  
At each dose level, after completion of study drug administration in at least 6 participants (i.e. 
a minimum of 4 on active treatment), the Investigator will provide a comprehensive 
Investigator Safety Report which will include (but not limited to) the following content: 
• 
Relevant information on participants’ demographics/characteristics, medical history, 
physical examination, concomitant medications; 
• 
List of all AEs, including severity, time of onset related to study drug administration, 
duration, clearly highlighting adverse events of special interest (AESIs) and Serious 
Advert Events (SAEs) and relatedness/causality of AEs; 
• 
Any clinically significant out of ranges safety clinical laboratory tests results (as assessed 
by the Investigator); 
• 
Physical Examination (including basic neurological testing for isocoria, light reflexes, 
gait and balance) results including clinical significance for abnormal findings; 
• 
ECG and Vital Sign results including clinical significance for abnormal values; 
• 
Statement of the Principal Investigator’s recommendation regarding dose decision. 
Escalation to the next higher dose or a modification to the dose will only take place after 
review of the Investigator Safety Report from the previous dose levels by the Investigator, in 
consultation with the Sponsor’s representative [called hereafter the Safety Review Committee 
(SRC)].  
Dose escalation will be based on any relevant information on participants’ 
demographics/characteristics, 
medical 
history, 
physical 
examination, 
concomitant 
medications, AEs, clinically significant out of ranges safety clinical laboratory tests results 
(as assessed by the PI), physical examination results (including basic neurological testing for 


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isocoria, light reflexes, gait and balance) including clinical significance for abnormal 
findings, ECG and vital sign results including clinical significance for abnormal value, and 
the statement of the PI’s recommendation regarding dose decision. Other parameters of 
interest will be considered as per SRC charter (blinded PK, PD). 
Within the planned dose range, a dose lower than the next planned dose may also be tested, 
depending on emerging safety, tolerability and/or other relevant data, such as blinded PK or 
PD. If the highest planned dose level is found to be safe and tolerable, also considering the 
PK and PD data, additional higher doses may be added by amendment. 
Between the first participants of 2 consecutive panels, a period of at least 7 days will be 
respected between the administrations of treatment. 
The SRC will meet for deciding on the continuation of dosing after drug administration in at 
least 6 participants (i.e. a minimum of 4 on active treatment). However, stopping rules (see 
Section 7.5) will be applicable from dosing of the first sentinel participant on.  
The risks for the individual participant due to treatment with Ir-CPI or study related 
procedures are considered minimal because of the choice of the doses, of careful monitoring 
of all critical safety and tolerability parameters. Therefore, the risks are outweighed by the 
gain of additional knowledge on Ir-CPI and the possibility to develop a potent new treatment 
for the prevention of thrombosis. 
 


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4. OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
 
Part 1: Assess the safety and tolerability of Ir-
CPI following a single ascending 6-hour 
intravenous infusion in healthy male 
participants. 
Safety parameters [adverse events 
(AEs), physical examinations, vital 
signs, telemetry including SpO2, weight, 
Hemoccult® test, supine 12-lead ECG, 
serum chemistry, haematology, 
coagulation aPTT, urinalysis, and 
monitoring for concomitant 
medications]. 
Part 2*: Assess the safety and tolerability of Ir-
CPI following a combination of rapid (30 
minutes) and slow (5.5 hours) intravenous 
infusion over a total of 6 hours in healthy male 
participants. 
Secondary 
 
Part 1: Assess the PK of Ir-CPI following single 
ascending 6-hour intravenous infusion in 
healthy male participants. 
Maximum plasma concentration (Cmax), 
time to reach maximum plasma 
concentration (tmax), Area under the 
plasma concentration-time curve from 
time zero to 6h (AUC0-6), Area under 
the plasma concentration-time curve 
from time zero to time of infinity 
(AUCinf), apparent terminal elimination 
rate constant (λz), terminal elimination 
half-life (t1/2), volume of distribution 
(Vd), total body clearance (CL). 
Part 2*: Assess the pharmacokinetics (PK) of Ir-
CPI following a combination of rapid (30 
minutes) and slow (5.5 hours) intravenous 
infusion over a total of 6 hours in healthy male 
participants. 
Investigate the preliminary PD of Ir-CPI in 
healthy male participants using a GCLP 
validated method according to FDA guidelines 
2018 for activated Partial Thromboplastin Time 
(aPTT). Inhibition of Factor XI (FXI) and 
Factor XII (FXII) procoagulant activities will 
also be assessed to support the aPTT dynamics. 
Change from baseline in aPTT and 
residual FXI and FXII activities. 
Exploratory 
 
Investigate the potential of Ir-CPI to induce the 
formation of anti-drug antibodies (ADA), 
including their capability to neutralize drug 
activity.  
Immunogenicity assessed by ADA 
plasma levels. 
Investigate the effect of Ir-CPI on markers 
related to the coagulation system. 
D-dimers, fibrinogen and prothrombin 
time (PT) levels in whole blood. 
Investigate the effect of Ir-CPI on biomarkers for 
renal injury. 
Blood assay: serum cystatin C (CysC). 
Urinary assay: urinary microalbumin, 
Kidney Injury Molecule (KIM-1), 
urinary neutrophil gelatinase-associated 
lipocalin (NGAL). 


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Objectives 
Endpoints 
Investigate the effect of Ir-CPI on inflammatory 
markers 
tumor necrosis factor alpha (TNFα), 
high sensitivity C-reactive protein 
(hsCRP) levels in serum. 
Assess the PK of Ir-CPI in urine 
Total amount excreted in urine (Ae), 
Ae%, volume of urine excreted 
(Vol_UR), Maximal excretion rate 
(Cmax rate), Time to reach maximum 
excretion (Tmax) rate and Renal 
Clearance (CLR). 
PK PD relationship 
No new endpoint: only graphical 
investigation of PK and PD parameters. 
*: because part 2 was not performed, these objectives are not applicable. 
 


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5. STUDY DESIGN 
5.1. 
Overall Design 
This study is a First-In-Human (FIH) Phase 1, double-blind, placebo controlled, single dose 
escalation study of Ir-CPI in healthy male participants. 
The study will consist of two parts: 
• Part 1: an Ir-CPI or matching placebo single ascending dose administration in healthy 
male participants using a continuous 6-hour intravenous infusion. 
• Part 2: an Ir-CPI or matching placebo single ascending dose administration in healthy 
male participants using a single ascending 30-minute loading dose infusion followed 
by a fixed dose of continuous 5.5-hour intravenous infusion (maintenance infusion). 
In all the following descriptions, the term postdose is defined as « after start of infusion ». 
The terms panel and cohort can be used interchangeably. 
In the end, part 2 was not performed. 
5.1.1. Part 1 
Five (5) panels (A to E), each consisting of eight (8) healthy male participants will be 
randomised to receive either Ir-CPI or matching placebo: first, 2 sentinel participants (1:1 
active / placebo) then for the rest of the panel, a 5:1 ratio (active / placebo). The first four 
panels will be administered Ir-CPI/Placebo in a sequential group design. Depending of the 
PK and PD results obtained for the first 4 panels, a fifth panel (E) may be performed 
thereafter. 
Participants will be recruited on the basis of their medical history and health status as judged 
by the Investigator. Participants will be admitted in the evening of the day before dosing 
(D-1) to assess eligibility based on urine drug screen, breath alcohol test, adherence to the 
study restrictions, review of inclusion and exclusion criteria and physical examination. The 
participants will be hospitalised at the clinical unit until at least 24h after the start of study 
drug administration (D2) (Cohorts A, B and C).  
Participants included in Cohort D and subsequent cohorts will remain hospitalised until the 
investigator is able to review the 24h aPTT assay results. If, for each participant, the results 
are less than or equal to 2X aPTT level at baseline (i.e. D1 predose), then the participants 
may leave the clinic. They will return for the ambulatory visits on D3 (48h post infusion 
start), D4 (72h), D5 (96h) and D7 (144h). If the 24h safety aPTT assay of one participant is 
above 2X the participant’s baseline aPTT, then all participants will remain hospitalised until 
the completion of the D3 (48h) assessments and an additional aPTT sample will be drawn at 
36h. If the 36h aPTT assay result of a participant is more than 2X baseline aPTT of this 
participant, the investigator will decide the most appropriate procedures for the follow-up of 
this participant. Participants will return for the ambulatory visits on D4 (72h), D5 (96h) and 
D7 (144h). 
Ambulatory visits will be planned on D3 (48h postdose, may also be inpatient in the case of 
Cohort D and subsequent cohorts), D4 (72h), D5 (96h) and D7 (144h, Cohort D and 
subsequent cohorts only), for safety, PD and PK assessments. The treatment period (from D-1 
to D5 for Cohorts A to C, and from D-1 to D7 for Cohort D and subsequent cohorts) will be 
followed by a discharge visit corresponding to a post study safety evaluation on D10 ± 2 
days, after infusion. Extra ambulatory visits will be planned D30 ± 3 days and D90 ± 7 days 


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after dosing for immunogenicity testing (ADA). Any new AE will be recorded during these 
visits, and when applicable, the concomitant medications prescribed. A laboratory sample 
will be taken to look for immunogenicity (presence of anti-drug antibodies, neutralizing 
antibodies). If ADAs are detected at D90 a supplemental ambulatory visit will be planned 
D180 ± 7 days after analysis. Participants will also be asked at the ADA analysis visits if they 
are aware of an exposure to tick bites since the previous visit. 
The suggested doses of Ir-CPI for dose escalation in Part 1 are provided in Table 1.  
The final dose to be used for each cohort will be decided based on the results of the previous 
panel and can be adjusted downward if deemed necessary.  
Fasting conditions are required for the blood sample collection at the selection visit, on D3 
(ambulatory visit or inpatient), for the ambulatory visits [D4/D5/D7 (D7 for Cohort D and 
subsequent cohorts only) /Discharge visit] and for the D1 predose blood sample.  
Water intake is allowed during the infusion. 
Meals will be standardized across the different panels during the in-patient period of the 
study (D-1 evening to D2). Following the D1 predose sample collections, a light breakfast 
(2 slices of bread with ham or cheese and jam, glass of water) / snack can be given between 
2h and 1h before the start of the infusion. Lunch will be served after completion of the study 
drug infusion. A light breakfast / snack will also be given after the D1H24 (D2) blood sample 
collection and after the collections performed on D3 (may be inpatient in the case of Cohort 
D and subsequent cohorts) and at the ambulatory visits on D4, D5, D7 (D7 for Cohort D and 
subsequent cohorts only) and Discharge visit. 
Participant must not be in fasting condition for the safety aPTT 36h sample and the extra 
ambulatory visits for ADA blood sample collection. 
Table 1: Suggested Doses of Ir-CPI for Dose Escalation in Part 1 
Group 
Infusion rate* 
(mg/kg/h) 
Infusion 
Duration (h) 
Ir-CPI target plasma 
concentration (µg/mL) at 
6 hours 
Total dose 
(mg/kg) 
A 
0.25 
6 
1.4 
1.5 
B 
0.75 
6 
4.1 
4.5 
C 
1.50 
6 
8.3 
9 
D 
3.00 
6 
16.6 
18 
E** 
4.5 
6 
24.8 
27 
*Weight of the participant at the screening visit will be used to calculate the dose of study drug. 
**: Cohort E was not performed according to a recommendation from the Ethics Committee. 
 
Supplemental ADA samplings (“long-term follow-up of ADAs”): 
If ADAs are still detected at the D180 ambulatory visit, supplemental samplings will be 
performed every 3 months (± 14 days) for the first year and then every 6 months (± 30 days) 
up to a maximum of 5 years after the D180 visit. The samplings will be performed until the 
participants reach a negative status, until they show the same ADA titre for 3 samplings in a 
row, or up to a maximum of 5 years after the D180 visit, whichever comes first. 
5.1.2. Part 2 
Part 2 was not performed because the targeted plasmatic PK concentration was planned in the 
unperformed group E. 


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Three (3) panels F-G-H, each consisting of eight (8) healthy male participants will be 
randomized to receive either Ir-CPI or matching placebo. First, 2 sentinel participants (1:1 
active / placebo) then for the rest of the group, a 5:1 ratio (active / placebo). The three panels 
will be administered Ir-CPI/Placebo in a sequential group design. 
Participants will be recruited on the basis of their medical history and health status as judged 
by the Investigator. During each period, participants will be admitted on the evening of the 
day before dosing (D-1) to assess eligibility based on urine drug screen, breath alcohol test, 
adherence to the study restrictions, review of inclusion and exclusion criteria and physical 
examination. The participants will be hospitalised at the clinical unit until the investigator is 
able to review the 24h aPTT assay results. If, for each participant, the results are less than or 
equal to 2X aPTT level at baseline (i.e. D1 predose), then the participants may leave the 
clinic. They will return for the ambulatory visits on D3 (48h post infusion start), D4 (72h), 
D5 (96h) and D7 (144h). If the 24h safety aPTT assay of one participant is above 2X the 
participant’s baseline aPTT, then all participants will remain hospitalised until the completion 
of the D3 (48h) assessments and an additional aPTT sample will be drawn at 36h. If the 36h 
aPTT assay result of a participant is more than 2X baseline aPTT of this participant, the 
investigator will decide the most appropriate procedures for the follow-up of this participant. 
Ambulatory visits will be planned on D3 (48h postdose, D3 may also be inpatient), D4 (72h), 
D5 (96h) and D7 (144h) for safety, PD and PK assessments. The treatment period (from D-1 
to D7) will be followed by a discharge visit corresponding to a post study safety evaluation 
on D10 ± 2 days, after infusion. 
An extra ambulatory visit will be planned D30 ± 3 days and D90 ± 7 days after dosing for 
immunogenicity testing. Any new AE will be recorded during these visits, and when 
applicable, the concomitant medications prescribed. A laboratory sample will be taken to 
look for immunogenicity (presence of anti-drug antibodies, neutralizing antibodies). If ADAs 
are detected at D90 a supplemental ambulatory visit will be planned D180 ± 7 days (month 6) 
after dosing. Participants will also be asked at the ADA analysis visits if they are aware of an 
exposure to tick bites since the previous visit. 
The suggested doses of Ir-CPI for dose escalation in Part 2 are provided in Table 2.  
Fasting conditions are required for the blood sample collection at the selection visit, on D3 
(inpatient or ambulatory), at the ambulatory visits (D4/D5/D7/Discharge visit) and for the D1 
predose blood sample.  
Water intake is allowed during the infusion. 
Meals will be standardized across the different panels during the in-patient period of the 
study (D-1 evening to D2). Following the D1 predose sample collections, a light breakfast (2 
slices of bread with ham or cheese and jam, glass of water) / snack can be given between 2h 
and 1h before start of infusion. Lunch will be served after completion of the study drug 
infusion. A light breakfast / snack is also given after the D1H24 (D2) blood sample collection 
and after the collections performed on D3 (inpatient or ambulatory), and at the ambulatory 
visits on D4, D5, D7 and Discharge visit. 
Participants must not be in fasting condition for the safety aPTT 36h sample and the ADA 
blood sample collection visits. 
 


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Table 2: Suggested Doses of Ir-CPI for Dose Escalation in Part 2 
Group 
Infusion rate** 
(mg/kg/h) 
Time (h) 
Ir-CPI target plasma 
concentration (µg/mL) 
between 30 min and 6 
hours 
Total dose 
(mg/kg) 
F 
Rapid infusion*: 6 
0.5 
8 
11.25* 
Slow infusion*:1.5 
5.5 
G 
Rapid infusion*:7 
0.5 
8 
11.75* 
Slow infusion*:1.5 
5.5 
H 
Rapid infusion*8 
0.5 
8 
12.25* 
Slow infusion*:1.5 
5.5 
* The rapid and the slow infusion rates will be calculated based on Part 1 emerging safety, PD and 
PK data. The total dose administered by rapid and by slow infusion will not exceed the highest total 
dose tested in Part 1. The infusion rate (in mg/kg/h) for the slow infusion will not exceed the maximum 
infusion rate used in Part 1. The dose may also be adjusted. 
**Weight of the participant at the screening visit will be used to calculate the dose of study drug 
In groups F, G and H, dose levels for rapid infusion and slow infusion could be adjusted 
upward / downward based on emerging safety / tolerability and pharmacokinetic / 
pharmacodynamic data. The total dose administered by rapid and by slow infusion will not 
exceed the highest total dose tested in Part 1. The infusion rate (in mg/kg/h) for the slow 
infusion will not exceed the maximum infusion rate tested in Part 1. In Part 2, the aim is to 
reach a plasma concentration of about 8 µg/mL at the end of the rapid infusion and to 
maintain, with the slow infusion, this plasma concentration until the end of the infusion. As 
predicted with PK modelling (Figure 1), an infusion rate of 1.5 mg/kg/h is expected in the 
slow infusion part to reach a plasma concentration of 8 µg/mL. The total doses and infusion 
duration to be used will be decided on the results of the previous panels and can be adjusted 
upward/downward if needed to reach a plasma concentration of 8 µg/mL between 30 min and 
6 hours. 
5.2. 
Number of Participants 
In any part of this trial, if it is decided that additional data are needed to better define the 
safety and tolerability or PK/PD of Ir-CPI, additional panels of healthy male participants may 
be enrolled per amendment. For example, a given dose level may be repeated in newly 
enrolled participants, or a lower or intermediate dose may be administered based on emerging 
data. 
Participants who drop out for safety and tolerability reasons will not be replaced; participants 
withdrawing for other reasons might be replaced. Replacement participants will be assigned 
to the same treatment group as the participants they are replacing (as shown in Table 4). 
Randomised participants who discontinue after having been exposed to the study drug may 
be replaced, if this discontinuation is not related to safety issues. The decision to replace 
participants will be made on a case-by-case basis. 
The data collected on the withdrawn participant prior to withdrawal will be included in the 
statistical analyses. 
5.2.1. Part 1 
Approximately forty (40) healthy male participants will be enrolled in five (5) sequential 
panels (A-E). Each panel will have eight (8) participants (6 active: 2 placebo). The fifth 
group will be optional depending on the PK and PD data obtained in the previous groups. In 
the end, this group was not performed. 


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5.2.2. Part 2 
Approximately twenty-four (24) healthy male participants will be enrolled in three (3) 
sequential panels (F-H). Each panel will have eight (8) participants (6 active: 2 placebo). In 
the end, this part was not performed. 
5.3. 
Number of Study Centres 
The study will be performed at 1 investigational site in Belgium. 
5.4. 
End of Study Definition and Duration of Participation 
The end of the study is defined as the date of the last visit of the last participant in the study.  
Therefore, the end of the study is defined as either the date on which the last study participant 
completes the Month 3 visit (D90) for immunogenicity testing or, if for a given participant 
ADAs are detected, the date on which the last study participant completes the supplementary 
Month 6 visit (D180), whichever is later.  
The study duration for each participant for the main study part (from the screening visit until 
the discharge visit) will be approximately 6 weeks. Participants will be followed up until D90 
(or D180) for immunogenicity testing. The total study duration will be approximately 
18 weeks in total for a given participant, and up to 31 weeks in case of D180 visits. 
 
Following the completion of the study, a 3-month exclusion period will apply to the 
participant before they are allowed to take part in another clinical study.  
 
Supplemental ADA samplings (“long-term follow-up of ADAs”): 
Extra ambulatory samplings that will be performed after D180 in participants positive for 
ADAs at D180 will be considered as occurring after the end of the study: these samplings are 
required for long term follow-up of the potential impact of ADAs, but based on the clinical 
data accumulated in this study, no SAE or AE or AESI has been reported as associated with 
the occurrence of ADAs. The results of these additional samplings will be not collected in the 
eCRF but in source documents only, and will be added to the final Clinical Study Report 
(CSR) as an appended additional listing. 
Participants followed up after D180 for ADA analysis will be authorised to participate in 
other clinical trial studies except for clinical trials with biologicals (e.g. antithrombotic 
molecule acting on FXI and FXII). 
5.5. 
Scientific Rationale for Study Design 
The study design and data analysis follow the recommendations issued from the following 
guidance for industry: 
• EMA Guideline on strategies to identify and mitigate risks for first-in-human and early 
clinical trials with investigational medicinal products, Jul. 2017 [3] 
• FDA Guideline for Estimating the Maximum Safe Starting Dose in Initial Clinical Trials 
for Therapeutics in Adult Healthy Volunteers, Jul. 2005. [4]. 
• FDA Guideline for Immunogenicity Testing of Therapeutic Protein Products — 
Developing and Validating Assays for Anti-Drug Antibody Detection, JAN 2019. 
The participants’ race will be collected, as it constitutes a source of variability in drug 
metabolism and drug activity; for example, Caucasians from southern Europe and from 


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Middle Eastern countries display a more frequent Sickle cell trait than other Caucasians, 
which can be associated with different reactions to anticoagulants. 
 
5.6. 
Justification for Dose  
The estimation of the MRSD was performed either based on safety data provided from 
toxicity studies in animals (NOAEL) or based on pharmacological data provided from in 
vitro functional assay on human plasma [the minimum anticipated biological effect level 
(MABEL)].  
PK modelling 
Simulated Ir-CPI dose levels and plasma concentrations in human, based on allometric 
method are illustrated in Figure 1. 
Kinetics constants (K12, K21, K10, α, β, A, B) and distribution volume (V1) in human were 
extrapolated from linear regression of the Log (K10), Log (K21), Log (K12), Log (V1) as 
function of the Log (Body weight) of 5 animal species for which pharmacokinetic data are 
available (mice, rat, dog, rabbit and monkey). 
Figure 1: Simulation of evolution of plasma Ir-CPI concentration upon single infusion 
(6 hours) of ascending doses of Ir-CPI 
 
Note: Plasma concentrations were predicted in human using allometric method from 5 
species. The inter-individual variability observed in monkey was assumed to be similar in 
human and three different human bodyweights (50, 80 and 100 kg) were used for prediction. 
The lowest Cmax values at the NOAEL (53.7 µg/mL) and the minimal human active 
concentration (0.5 µg/mL) were added as reference lines. 
MRSD calculation based on NOAEL (Toxicology data) 
To determine the safe starting dose in human, the No Observed Adverse Effect Level 
(NOAEL) obtained in the most sensitive model (monkey species, 24h-infusion acute study) is 
used as the reference. In the acute 24-hour monkey toxicity study, the NOAEL is defined as 
the High-dose (i.e. 201.6 mg/kg/day or 8.4 mg/kg/h). 


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By using allometric scaling relating body weight to body surface, the Human Equivalent 
Dose (HED) corresponding to the NOAEL is calculated as a 1/3rd of the NOAEL in monkeys. 
The HED will hence be 65 mg/kg/day or 2.7 mg/kg/h.  
By using PK modelling deduced from analysis of the clearance in 5 different species, 
extrapolated human clearance is estimated as 80 mL/h/kg. The HED would be 88 mg/kg/day 
or 3.7 mg/kg/h (Dose = AUC x CL; using the AUC at the NOAEL in the 24h toxicity study 
in monkey).  
The HED calculated using allometric scaling (2.7 mg/kg/h) is lower than what is calculated 
by modelling (3.7 mg/kg/h) and therefore is used to define the MRSD. Applying a safety 
factor of 10 leads to a starting dose of 0.27 mg/kg/h. 
MRSD calculation based on MABEL: pharmacological data 
• 
In vitro increase of aPTT in human plasma of 25 % at ± 0.5 µg/mL. 
• 
In vitro inhibition of FXII procoagulant activity on human plasma in vitro of 15 % 
inhibition at ± 0.5 µg/mL. 
• 
In vivo thrombosis model of arteriovenous shunt in rabbits (most sensitive): thrombus 
inhibition of ± 30 % at the dose of 1 mg/kg = 45 min post-administration, corresponding 
to Ir-CPI plasma concentration of 1.0 µg/mL. Considering that the in vitro response to Ir-
CPI is more sensitive (± 2.5-fold) in human plasma than the response in rabbit plasma, a 
concentration of 1.0 µg/mL would correspond to ± 0.4 µg/mL (human equivalent active 
concentration). 
Therefore, using these different approaches, minimal human active concentration is estimated 
at ± 0.5 µg/mL. Based on the modelling analysis (PK parameters in humans calculated from 
the knowledge of PK in animals), the human dose required to reach a plasma concentration of 
0.5 µg/mL (0-6 hrs of infusion) would be 0.1 mg/kg/h. 
When using the MABEL approach, the HED of 0.1 mg/kg/h, would yield a plasma 
concentration of 0.5 µg/mL, compatible with an increase in aPTT of 25 %. This increase will 
not be detectible in real-life due to the variability in the assay results within the normal 
physiological range. In order to induce detectable changes in aPTT in humans, the starting 
dose according to the MABEL approach should be at least 0.2 mg/kg/h, enabling a big 
enough effect to measure with the day-to-day clinical testing of aPTT. 
In conclusion 
The starting dose, as calculated from the HED corresponding to the NOAEL of the 24-hour 
toxicity study in monkeys and applying a safety factor of 1/10, is 0.25 mg/kg/h, with an 
expected Ir-CPI plasma concentration of 1.4 µg/mL. 
Based on our preclinical work (in vitro and in vivo), it is estimated that the proposed MRSD 
(1/10th of the NOAEL in monkeys) will yield an estimated maximal plasma concentration of 
1.4 µg/mL after 6 hours of infusion.  This concentration would induce at maximum an 
increase of aPTT between 25 % and 50 % from baseline, resulting in aPTT values at or 
slightly above the Upper Limit of Normal. Such elevations in aPTT are not known to be 
associated with adverse events. Therapeutic ranges for aPTT are generally accepted to be 
150 % - 250 % of the Upper Limit of Normal, which can be equivalent to a 350 % increase 
from baseline values.  
A relevant GCLP validated according to FDA guidelines 2018 pharmacodynamic biomarker 
(aPTT) is available to follow-up this anticoagulant activity and will be assessed alongside 


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pharmacokinetics at various time-points during the study. In addition – for safety – the aPTT 
will be followed up “bedside” via regular sampling at predefined time-points. These clinical 
aPTT results will be readily available to the Principal Investigator for safety follow-up during 
and after the study drug administration.  
Based on the presence of a relevant clinical biomarker for study drug activity, a biomarker 
that can be measured “bedside”, the preclinical data – including the elaborated assays in 
human plasma (effector compartment), the mode of administration (slow intravenous 
infusion) and the preclinical toxicology results, the sponsor proposes to use 0.25 mg/kg/h as 
the MRSD – a safety factor of 10x compared with the NOAEL in the most sensitive species 
(monkey) and only slightly above the starting dose that would be used when considering 
MABEL. 
5.7. 
Identification of Source Data 
All source documents must be accurate, clear, unambiguous, permanent, and capable of being 
audited. They should be made using some permanent form of recording (ink, typing, printing, 
optical disc). They should not be obscured by correction fluid or have temporary attachments 
(such as removable self-stick notes). All data reported on the eCRF should be supported by 
source documents, unless otherwise specified. 
Electronic Data Capture (EDC) via eCRFs will be used for this study, as described in Section 
10.1.1. The source data will not be directly collected in the eCRF but will be captured in 
supportive documentation: laboratory parameters and clinical interpretation of the values on 
the analytical laboratory print outs, ECG records and clinical significance of observations 
(when applicable) on the ECG print-outs. The other investigated parameters are collected in 
the Investigator's source data book. 
The data collected on source documents will be entered by the study personnel into the 
eCRFs in a timely manner. 
Supplemental ADA samplings (“long-term follow-up of ADAs”): 
Data collected after D180 (extra ambulatory samplings for ADA analysis) will not be 
collected in the eCRF but only in source documents, and will be added to the final CSR as an 
appended additional listing. With regards to safety, only Serious Adverse Drug Reactions 
(SADRs) and any associated information will be reported after D180, and they will only be 
reported in the Pharmacovigilance (PV) database and not the study database. 


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6. STUDY POPULATION 
Each participant must participate in the informed consent process and read, sign and date the 
informed consent form (ICF) before any procedures specified in this protocol are performed. 
If necessary and after agreement of the sponsor, in order to minimize the constraints on the 
participants, screening results for a participant could be obtained from the results of any 
examinations identical to those planned for screening in this protocol and already undergone 
by the participant within the timelines given for the screening examination. In such a case, 
the participant must also sign an IEC-approved generic ICF before any such procedure is 
performed. 
6.1. 
Inclusion criteria 
Participants will be required to fulfil all of the following inclusion criteria: 
 
1. Have given written informed consent approved by the relevant Ethics Committee (EC) 
governing the site, indicating that they understand the purpose of and procedures required 
for the study and are willing to participate in the study.  
2. Male participants between 18 and 55 years of age, inclusive at screening. 
3. Otherwise healthy with no clinically significant abnormalities as determined by medical 
history, physical examination, blood chemistry assessments, haematological assessments, 
coagulation and urinalysis, measurement of vital signs, and ECG. Isolated out-of-range 
values judged by the PI (or designated physician) to be of no clinical significance can be 
allowed. This determination must be recorded in the participant’s source documents. 
4. Have a body weight in the range of 50 to 90 kg inclusive at screening. Have a body mass 
index (BMI) of 19 to 28 kg/m2 inclusive at screening. 
5. Agree to abstain from alcohol intake 24 hours before administration of study drug, during 
the in-patient period of the study and 24 hours prior to all other ambulatory visits, up until 
and including the discharge visit. 
6. Agree not to use prescription medications within 14 days prior to study drug 
administration and through the duration of the study, unless approved by the PI and 
Sponsor medical monitor. 
7. Non-smokers or abstinence from tobacco or nicotine-containing products for at least 3 
months prior to screening. 
8. Agree not to use over-the-counter (OTC) medications [including decongestants, 
antihistamines, and herbal medication (including herbal tea and St. John’s Wort], within 
14 days prior to study drug administration through the discharge visit, unless approved by 
the PI and Sponsor medical monitor. Occasional use of paracetamol at recommended 
doses is allowed. Special rules apply for aspirin, corticosteroids and nonsteroidal anti-
inflammatory drugs (NSAIDS (see exclusion criteria 6, 7, 8 and 9) 
9. Venous access (both arms) sufficient to allow blood sampling and study drug 
administration as per protocol. 
10. Participants and their partners of childbearing potential [meaning who are not surgically 
sterile (tubal ligation/obstruction or removal of ovaries or uterus) or post-menopausal 
(absence of menstrual periods for at least 12 consecutive months)] must be willing to use 
2 methods of contraception:  
 
- a highly effective method of birth control starting at screening. Highly effective methods 


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of birth control are defined as those that result in a low failure rate (i.e. Pearl Index less 
than 1% per year) when used consistently and correctly, such as implants, rings, patches, 
injectable or combined oral contraceptives, intrauterine devices (IUDs), or sexual 
abstinence (periodic abstinence e.g. calendar, ovulation, symptothermal, postovulation 
methods, declaration of abstinence for the duration of the trial, and withdrawal are not 
acceptable methods of contraception) 
. 
- and a local barrier form of contraception. Acceptable barrier methods are either the 
participant’s use of a condom or the partner’s use of an occlusive cap or diaphragm, or 
spermicides.  
 
Participants will not donate sperm from the selection visit and up to 90 days after the 
infusion. In case of sterile or vasectomised participants, no contraception will be required 
for their partners of childbearing potential. 
11. Willing/able to adhere to the study visit schedule and other requirements, prohibitions and 
restrictions specified in this protocol.  
 
6.2. 
Exclusion criteria 
If any of the following exclusion criteria apply, the participant must not enter the study: 
 
1. Currently have or have a history of any clinically significant medical illness or medical 
disorders the PI considers should exclude the participant, including (but not limited to) 
cardiovascular disease, neuromuscular, haematological disease, immune deficiency state, 
respiratory disease, hepatic or gastrointestinal disease, neurological or psychiatric disease, 
ophthalmological disorders, neoplastic disease, renal or urinary tract diseases, or 
dermatological disease. 
2. History of personal or familial bleeding disorders; including prolonged or unusual 
bleeding.  
3. History of deficiency in factor XII (FXII) or haemophilia type A (FVII) or type B (FIX) 
or type C (FXI). 
4. History of cerebral bleeding (e.g. after a car accident), stroke and cerebrovascular 
accident (CVA). 
5. Anamnestic history of Lyme disease or tick-borne encephalitis. 
6. Use of Acetylsalicylic-Acid (ASA)-containing OTC medications within 1 month prior to 
screening. 
7. Chronic administration of NSAIDs, chronic use of corticosteroids within 1 month prior to 
screening. 
8. Chronic administration of clopidogrel, ticlopidin, dipyridamole, Coumadin-like 
anticoagulants, new oral anticoagulant dabigatran, rivaroxaban, apixaban or edoxaban 
within 3 months prior to screening. 
9. Administration of unfractionated heparin, low molecular weight heparin, fibrinolytic 
agents and anti-FXa within 3 months prior to screening. 
10. Have an active acute or chronic infection or diagnosed latent infection. 
11. Systolic blood pressure (SBP) greater than 150 or less than 90 mmHg, diastolic blood 
pressure (DBP) greater than 90 or less than 50 mmHg, and heart rate (HR) greater than 
100 or less than 40 bpm. 


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12. Acute clinically relevant illness within 7 days prior to study drug administration or have 
had a major illness or hospitalisation within 1 month prior to study drug administration. 
13. Major or traumatic surgery within 12 weeks of screening. 
14. Any participant who plans to undergo elective surgery within 4 weeks prior to study drug 
administration and through the discharge visit. 
15. Positive serology test for HIV antibodies, hepatitis B surface antigen (HBsAg), or 
hepatitis C virus (HCV) antibodies at screening. 
16. Recent history (within previous 6 months) of alcohol or drug abuse. 
17. Have positive urine toxicology screen at screening or D −1 for substances of abuse 
including amphetamines, benzodiazepine, cocaine, opiates, barbiturate and cannabinoids. 
18. Have a positive alcohol breath test at screening or D-1. 
19. Consumes, on average, more than approximately 500 mg/day of caffeine (as contained in 
5 cups of tea or coffee or 8 cans of caffeine-containing soda or other caffeinated products 
per day). 
20. Donated blood (i.e. 500 mL) within 3 months before D1.  
21. Have a history of active drug and/or food allergy or other active allergic disease requiring 
the constant use of medications, or a history of severe allergic reaction, angioedema or 
anaphylaxis. 
22. Received any other experimental therapy or new investigational drug within 30 days or 5 
half-lives (whichever is longer) of study drug administration.   
During the time window authorised for the screening visit (i.e. between 28 and 2 days before 
admission to the first treatment period), the Investigator may order a re-test of any parameter 
evaluated during the initial screening visit if they need to evaluate the evolution of said 
parameter(s) or to confirm the value observed. 
6.3. 
Lifestyle restrictions 
Any medication the participant takes during the study, and until the discharge visit, other than 
the study drugs, including any prescription or OTC drug (including vitamins, herbal and 
mineral supplements), is considered a concomitant medication. At the extra visits scheduled 
for ADA assessment (i.e. up to D180), only the medications that are administered in 
treatment of AEs will be considered concomitant medication. Participants will be requested 
to comply the following restrictions during the study and abstain from: 
- 
Strenuous exercise, as judged by the Investigator, from the selection visit until after 
the discharge visit. 
- 
Use of prescriptions or OTC medications [including decongestants, antihistamines], 
and herbal medication (including herbal tea and St. John’s Wort), within 14 days prior 
to study drug administration through the discharge visit, unless approved by the PI 
and Sponsor medical monitor. Occasional use of paracetamol at recommended doses 
is allowed. Specific rules apply for aspirin, corticosteroids and NSAIDS (see 
exclusion criteria 6, 7, 8 and 9). 
- 
Consumption of grapefruit, grapefruit juice, Seville oranges, Seville orange 
marmalade or other products containing grapefruit or Seville oranges from selection 
visit until after the discharge visit. 


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- 
Consumption of any alcoholic beverages 24 hours before administration of study 
drug, during the in-patient period of the study and 24 hours prior to all other 
ambulatory visits, up until and including the discharge visit. 
- 
Smoking and using nicotine-containing products excluded for at least 3 months prior 
to the screening visit, and until after the discharge visit. 
- 
Use of Acetylsalicylic-Acid (ASA)-containing over-the-counter medications within 1 
month prior to screening and until the discharge visit. 
- 
Consumption of any caffeine-containing products (e.g. coffee, tea, chocolate, or Coca-
Cola like/ energy drinks): excluded from 24 hours prior to D1 until the end of the in-
patient period. Limited to less than 500 mg/day of caffeine (as contained in 5 cups of 
tea or coffee or 8 cans of caffeine-containing soda or other caffeinated products per 
day) until the discharge visit.  
- 
Donation of blood (i.e. 500 mL) within 3 months before D1, throughout the study and 
for 3 months after the end of the study (D90 or D180). 
The compliance of the participant to these lifestyle restrictions will be checked at each visit. 
Participants and their partners of childbearing potential must be willing to use 2 methods of 
contraception, one of which must be a barrier method, and participants will not donate sperm, 
from the selection visit and up to 90 days after the infusion. 
Water intake is allowed during the infusion. 
Meals will be standardized across the different panels. A light breakfast (2 slices of bread 
with ham or cheese and jam, glass of water) can be given between 2h and 1h before start of 
infusion. Lunch will be served after completion of the study drug infusion. 
Fasting conditions are required for the blood sample collection at the selection visit, on D3 
(may be inpatient in the case of Cohort D and subsequent cohorts), at the ambulatory visits 
[D4/D5/ D7 (D7 for Cohort D and subsequent cohorts only) /Discharge visit] and for the D1 
predose blood sample.  
On D1, lunch will be served after completion of the study drug infusion. A light breakfast / 
snack is also given after the D1H24 (D2) blood sample collection and after the collections 
performed on D3 (may be inpatient in the case of Cohort D and subsequent cohorts), at the 
ambulatory visits on D4, D5, D7 (D7 for Cohort D and subsequent cohorts only) and 
Discharge visit. 
Participants must not be in fasting condition for the safety aPTT 36h sample and the ADA 
blood sample collection visits. 
Supplemental ADA samplings (“long-term follow-up of ADAs”): 
All randomised participants will be asked to participate in an additional informed consent 
process and read, sign and date an additional ICF to authorise the use of already collected 
plasma samples for method development in the framework of Ir-CPI development and 
follow-up of ADA. For participants with positive ADA results at D180, this ICF will also 
authorise the collection of additional ADA samples for up to 5 years after D180. At the 
additional samplings scheduled for ADA assessment after D180, only treatments given for 
SADRs will be considered concomitant medications, and they will be collected only in the 
PV database. 


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6.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomised/included. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities: date of ICF signature by participant, 
demographics and reason for screen failure will be entered in the eCRF.  
Individuals who do not meet the criteria for participation in a given panel (screen failure) 
may be rescreened for a consecutive panel. Reserve participants may be rescreened (if outside 
of the protocol window) for a consecutive panel. Rescreened participants will be assigned a 
new screening number. For the new screening visit, the participant must undergo all 
screening evaluations planned in the protocol. 
7. IMP 
7.1. 
Investigational Medicinal Products Administered 
Table 3 provides an overall summary of the investigational medicinal product (IMPs) 
administered during the study, further information is provided in the Investigator’s Brochure 
[1] and in the IMPD [2]. 
Table 3: IMPs 
Study Treatment Name: 
Ir-CPI 
Placebo 
Active ingredients 
Ixodes ricinus-Contact Phase Inhibitor as a non-
glycosylated recombinant protein produced in 
the yeast Pichia Pastoris 
NA 
Excipients 
Phosphate Buffered Saline (PBS) 
NA 
Dosage formulation: 
10 mL vials: 25 mg/mL non-glycosylated 
recombinant protein produced in the yeast 
Pichia Pastoris, in 5 mL extractable PBS 
solution. 
To be stored at -20°C ± 5°C. 
NaCl 0.9% for IV 
infusion 
Unit dose strength(s)/Dosage 
level(s): 
Part I: 1.5 mg/kg, 4.5 mg/kg, 9 mg/kg, 
18 mg/kg and 27 mg/kg. 
Part II: three doses will be investigated in Part 
II, the total daily dose of Ir-CPI will be 
determined based on the emerging safety, 
tolerability and pharmacokinetic data from Part 
1. 
NA 
Route of Administration  
IV infusion 
IV infusion 
Dosing instructions: 
Refer to Section 7.3 
Refer to Section 7.3 
Packaging and Labelling 
Study Treatment will be provided in boxes 
containing 30 x 10 R glass vials. Each box and 
vial will be labelled as required per country 
 


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Study Treatment Name: 
Ir-CPI 
Placebo 
requirement. 
Details of labelling are provided in Section 7.6.  
Manufacturer 
Halix B.V.  
Commercially 
available source 
 
7.2. 
Method of Treatment Assignment 
The randomisation list will be generated by an independent statistician, who will be different 
from the study statistician, using SAS® software. This list will be transmitted to the 
unblinded pharmacist of the clinical site in a secure way in order to maintain the blinding for 
the other staff members involved in this trial. 
Two sets of individual sealed decoding envelopes will be also generated by the independent 
statistician: one set of the sealed decoding envelopes will be provided to the investigational 
site and one set will be provided to the pharmacovigilance contact for the trial. 
For this double blind, placebo controlled, ascending dose trial of single dose infusions of Ir-
CPI/Placebo, the participants will be randomised taking into account the specific 
requirements for the sentinel groups: 
In Part 1:  
Five (5) panels (A to E), each consisting of eight (8) healthy male participants will be 
randomised to receive either Ir-CPI or matching placebo: first, 2 sentinel participants (1:1 
active / placebo) then for the rest of the group, a 5:1 ratio (active / placebo). The first four (4) 
panels will be administered Ir-CPI/Placebo in a sequential group design. Depending of the 
PK and PD results obtained for the first 4 panels, a fifth panel might be performed thereafter. 
In the end, this fifth panel was not performed. 
In Part 2: 
Three (3) panels F-G-H, each consisting of eight (8) healthy male participants will be 
randomized to receive either Ir-CPI or matching placebo: there will be 2 sentinel participants 
per group (one active treatment and one placebo), the rest of the group follows a 5:1 
randomization ratio. The three (3) panels will be administered Ir-CPI/Placebo in a sequential 
group design. In the end, part 2 was not performed. 


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Table 4: Randomisation 
Study 
Part 
Group 
Randomisation 
number 
Replacement 
randomisation number 
Randomisation ratio 
Active/Placebo 
1 
A 
1101 to 1108 
5101 to 5108 
2 sentinels (1 active, 1 
placebo) then for the rest of 
the group, 5:1 ratio 
1 
B 
1201 to 1208 
5201 to 5208 
2 sentinels (1 active, 1 placebo) 
then for the rest of the group, 
5:1 ratio 
1 
C 
1301 to 1308 
5301 to 5308 
2 sentinels (1 active, 1 placebo) 
then for the rest of the group, 
5:1 ratio 
1 
D 
1401 to 1408 
5401 to 5408 
2 sentinels (1 active, 1 placebo) 
then for the rest of the group, 
5:1 ratio 
1 
E 
1501 to 1508 
5501 to 5508 
2 sentinels (1 active, 1 placebo) 
then for the rest of the group, 
5:1 ratio 
2 
F 
2101 to 2108 
6101 to 6108 
2 sentinels (1 active, 1 placebo) 
then for the rest of the group, 
5:1 ratio 
2 
G 
2201 to 2208 
6201 to 6208 
2 sentinels (1 active, 1 placebo) 
then for the rest of the group, 
5:1 ratio 
2 
H 
2301 to 2308 
6301 to 6308 
2 sentinels (1 active, 1 placebo) 
then for the rest of the group, 
5:1 ratio 
 
Participants withdrawn from the study retain their randomisation number, if already given. 
New participants must always be allotted a new randomisation number/treatment number 
(replacement treatment number): once assigned, randomisation numbers are never reused 
within the study site. Note that participants will be identified by their randomisation numbers, 
throughout the entire course of the study. 
7.2.1. Blinding 
The pharmacist and his/her attendant, the unblinded monitor who reviews the IMP-related 
documentation, and the bioanalytical staff (external lab) will be the only personnel to have 
access to the randomisation list in order to prepare the drug for administration. All Sponsor 
and Investigator site staff involved in the study will be blinded to the IMP assignment. 
In order to maintain blinding, preparation of the dosing solution will be completed by the 
Good Distribution Practice (GDP) Pharmacy. All documents related to the Pharmacy should 
be kept in a locked and secure area in order to prevent any unblinding of the staff involved in 
the trial. 
For participants who are randomised to active treatment, the solution of Ir-CPI supplied in 
vials at 25 mg/mL may be diluted in 0.9 % w/v sodium chloride to a final concentration 
calculated to achieve the correct dose according the participants weight and according dose 
assigned to the cohort. 
Placebo treatment (0.9 % w/v sodium chloride) will be prepared. The GDP Pharmacy will 
prepare the IV infusions according to the randomization list and label them with a subject-
specific label. Intravenous infusion of the IMP solution will be administered by the blinded 
study staff according to local SOPs. If needed, additional precautions (suitable ancillaries 


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such as coloured syringes and infusion lines) will be taken to ensure the blinding of the 
participant and Investigator. 
 
Emergency code break procedure 
In case of an emergency, when knowledge of the investigational product assignment is 
required for the medical management of an individual participant, the treatment for that 
participant may be unblinded. The Investigator must notify the Sponsor and study monitor 
within 24 hours after determining that it is necessary to unblind the treatment assignment for 
that participant only.  
The Sponsor Medical Monitor should be consulted before unblinding, whenever possible. 
This documentation must include the name of the individual breaking the blind, the date on 
which the blind was broken, and a description of the event that led to the unblinding. The 
Investigator must also indicate in source documents and in the eCRF that the blind was 
broken and provide the date, time, and reason for breaking the blind. Any adverse event (AE) 
or serious adverse event (SAE) associated with breaking the blind must be recorded and 
reported as specified in this protocol. 
Unblinded monitors will routinely check the integrity of the envelopes that are stored at the 
site. All code envelopes (opened or not opened) will be collected from the site prior to study 
close-out and will be returned to the Sponsor. 
7.3. 
Dose administration 
The investigational products will be administered only to participants randomized in this 
study following the procedures set out in the present clinical study protocol. 
The start and the stop time as well as the total volume of drug administered for each 
participant will be recorded. 
7.3.1. IMP preparation 
Ir-CPI will be supplied frozen, as a 5 mL PBS solution containing 25 mg/mL Ir-CPI in glass 
vials (10 mL) to be stored between -15°C and – 25°C. 
The total doses administered to the participants are presented in Table 5 and Table 6 for 
Part 1 and Part 2 respectively. 
All doses are expressed in mg/kg, and the body weight of each participant at screening will 
be used to calculate the exact amount of study drug needed to prepare the allocated total dose 
for each participant. 
The detailed instructions for preparing and calculating the doses of the IMP for 
administration are provided in the Pharmacy Manual. 
7.3.2. Doses administered in Part 1 
In Part 1, single doses of Ir-CPI or its matching placebo will be administered to the 
participants using a continuous 6-hour intravenous infusion. 


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Table 5: Part 1 Suggested Doses of Ir-CPI for Dose Escalation 
Group 
Infusion rate* 
(mg/kg/h) 
Infusion 
Duration (h) 
Ir-CPI target plasma 
concentration (µg/mL) at 
6 hours 
Total dose 
(mg/kg) 
A 
0.25 
6 
1.4 
1.5 
B 
0.75 
6 
4.1 
4.5 
C 
1.50 
6 
8.3 
9 
D 
3.00 
6 
16.6 
18 
E** 
4.5 
6 
24.8 
27 
*Weight of the participant at the screening visit will be used to calculate the dose of study drug. 
**: in the end, group E was not performed. 
7.3.3. Doses administered in Part 2 
In the end, part 2 was not performed. 
In Part 2, single doses of Ir-CPI or its matching placebo will be administered to the 
participants using a single ascending 30-minute loading dose infusion followed by a fixed 
dose of continuous 5.5-hour intravenous infusion  
Table 6: Part 2 Suggested Doses of Ir-CPI for Dose Escalation 
Group 
Infusion rate** 
(mg/kg/h) 
Time (h) 
Ir-CPI target plasma 
concentration (µg/mL) 
between 30 min and 6 
hours 
Total dose 
(mg/kg) 
F 
Rapid infusion*: 6 
0.5 
8 
11.25* 
Slow infusion*:1.5 
5.5 
G 
Rapid infusion*:7 
0.5 
8 
11.75* 
Slow infusion*:1.5 
5.5 
H 
Rapid infusion*8 
0.5 
8 
12.25* 
Slow infusion*:1.5 
5.5 
* The rapid and the slow infusion rates will be calculated based on Part 1 emerging safety, PD and 
PK data. The total dose administered by rapid and by slow infusion will not exceed the highest total 
dose tested in Part 1. The infusion rate (in mg/kg/h) for the slow infusion will not exceed the maximum 
infusion rate used in Part 1. The dose may also be adjusted. 
**Weight of the participant at the screening visit will be used to calculate the dose of study drug 
7.3.4. Dosing and meals 
Dosing is described in Section 5.1. Meals and food intake are described in Section 6.3. 
7.4. 
Dose Escalation Rules and Dose Staggering Approach 
Given the new mechanism of action, the nature of the compound (peptide) and the intended 
route of administration, dose staggering will be applied in this FIH trial for all panels. This 
dose staggering will be as such that 2 participants will be dosed at least 24 hours before the 
remainder of the cohort. These 2 sentinel participants will be randomised as such that there 
will be one placebo and one verum, as shown in Table 4. After the review of adverse events, 
vital signs, safety labs and ECGs collected over 24 hours postdose (D2), the remaining 
participants of the cohort will receive the same dose level. Following completion of the initial 
24-hour safety period for the sentinel participants, the decision to proceed with the remaining 
participants in that cohort will be mutually discussed/agreed upon between Investigator (or 
his designee) and the Sponsor and the decision to dose will be formally confirmed by the 


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Sponsor. The proposed minimal 24 hours between the sentinel and the remainder of the 
cohort is deemed sufficient because this is a single intravenous infusion where it is expected 
that the most severe and acute reactions will occur during or very short after the infusion. 
Based on animal data, the pharmacodynamic effect and potential side effects are expected to 
be related to plasma levels that will decline rapidly after ending the IV infusion. 
At each dose level, after completion of Investigational Medicinal Product (IMP) 
administration in at least 6 participants (i.e. a minimum of 4 on active treatment), the 
Investigator will provide a comprehensive Investigator Safety Report which will include (but 
not limited to) the following content: 
• 
Relevant information on participants’ demographics/characteristics, medical history, 
physical examination, concomitant medications; 
• 
List of all AEs, including severity, time of onset related to study drug administration, 
duration, clearly highlighting AESI and Serious Advert Events (SAEs) and 
relatedness/causality of AEs; 
• 
Any clinically significant out of ranges safety clinical laboratory tests results (as assessed 
by the PI); 
• 
Physical Examination (including basic neurological testing for isocoria, light reflexes, 
gait and balance) results including clinical significance for abnormal findings; 
• 
ECG and Vital Sign results including clinical significance for abnormal values; 
• 
Statement of the Principal Investigator’s recommendation regarding dose decision. 
Escalation to the next higher dose will only take place after review of the Investigator Safety 
Report from the previous dose levels by the Investigator, in consultation with the Sponsor’s 
representative [called hereafter the Safety Review Committee (SRC)]. Dose escalation will be 
based on emerging safety and tolerability data as defined by adverse events, laboratory 
results, ECGs, vital signs, and telemetry assessments. Other parameters of interest will be 
assessed (blinded pharmacokinetics, blinded pharmacodynamics) per SRC charter and section 
7.5 criterion n°5, before dosing in the next cohort can start. 
Within the planned dose range, a dose lower than the next planned dose may be tested, 
depending on emerging safety, tolerability and/or other relevant data, such as blinded 
pharmacokinetics or pharmacodynamics. The final dose to be used for each cohort will be 
decided based on the results of the previous panel and can be adjusted downward if deemed 
necessary. 
If the highest planned dose level is found to be safe and tolerable, also considering the PK 
and PD data, additional higher doses may be added by amendment. 
Between the first patients (sentinels) of two consecutive panels, a period of at least 7 days 
will be respected. 
7.5. 
Stopping Rules 
The SRC will meet for deciding on the continuation of dosing after drug administration in at 
least 6 participants [i.e. a minimum of four (4) on active treatment]. However, stopping rules 
will be applicable from dosing of the first sentinel participant on. These decisions will be 
based on the following: 
1. If a Serious AE, which is considered drug-related, occurred in one (1) participant or if a 
Severe AE, which is considered drug-related, occurred in two (2) participants in the same 
cohort, the dosing in the trial should be temporarily stopped in order to review additional 


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safety data. If after review of the additional data and unblinding of the randomisation for 
that participant the drug-relatedness assessment changes, the study can resume without 
substantial amendment.  
2. If 1 sentinel participant (out of 2) or at least two (2) out of eight (8) participants in a 
cohort experience a Dose Limiting Toxicity (DLT) that is related to Ir-CPI 
administration, the dosing in the trial should be temporarily stopped in order to review 
additional safety data. If after review of the additional data and the unblinding of the 
randomisation for that participant, the drug-relatedness assessment changes, the study can 
resume without substantial amendment; 
3. If at least one (1) DLT is reported, the SRC recommendation will depend on the DLT 
profile (i.e. identical DLTs in different participants) or the frequency and severity of 
DLTs in the same participant and on the recommendation made by the Investigator; 
4. If no DLT is reported, the planned dose escalation may proceed with the next cohort or 
part, unless the Investigator has any other safety concern;  
5. In any case, administered dose of Ir-CPI will be limited to a dose predicted to generate 
upper 95 % confidence interval (CI) Cmax value being not higher than the lowest Cmax 
values at the NOAEL (53.7 µg/mL) in the most sensitive species [24h-infusion acute 
study in monkeys at NOAEL 201.6 mg/kg/day]. PK data will be monitored, so that 
preliminary PK parameters of the 1.5 mg/kg panel (A) should be available before dosing 
the 4.5 mg/kg panel (B), 4.5 mg/kg panel (B) PK parameters before administration of 
9 mg/kg panel (C) etc. 
All decisions will be documented in writing and communicated to the study team in a timely 
manner, before dosing in the next cohort can start. 
Definition of the DLT: 
• 
Serious AE drug-related in one (1) participant (in the study);  
• 
Severe AE drug-related in two (2) participants in one cohort;  
• 
ECG: prolongation of QTcF to >500 ms or of >60 ms over baseline drug-related in two 
(2) participants in one cohort; 
• 
Safety laboratory tests: Increase in ALT/AST ≥ 5 x ULN in 2 participants in the study; 
• 
Safety laboratory tests: Increase in ALT/AST ≥ 3 x ULN and TBIL ≥ 2x ULN in one (1) 
participant in the study; 
• 
Other clinically significant changes in safety clinical laboratory tests, ECG, VS or other 
safety parameters deemed as a significant safety concern by the Investigator; 
• 
aPTT increase > 5x ULN at the 24h postdose time point in two (2) participants in one 
cohort; 
• 
Hypersensitivity reaction occurring during study drug administration or within 6h after 
end of study drug administration accompanied by symptomatic bronchospasm, with or 
without urticaria; allergy-related oedema/angioedema; hypotension in one participant. 
If no further dosing is planned due to the stopping criteria as described above, previous 
randomised and dosed participants will continue the study as planned. Safety assessments 
will be performed as planned. Pharmacokinetic assessments will be performed if deemed to 
be relevant and agreed by the Investigator and Sponsor without compromising the safety of a 
participant. 


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7.6. 
Supply, Packaging and labelling of the investigational products 
A sufficient quantity, to be defined by the Sponsor, of IMPs will be supplied under proper 
storage condition (temperature record) as well as an acknowledgement of receipt form. The 
Sponsor’s representative will provide a certificate of analysis and a batch release certificate 
for those batches of IMP used in the study. 
The investigational products will be bearing the following information on the primary 
packaging labels: 
Table 7: IMP packaging labels 
 
Secondary packaging 
(boxes of 30 vials) 
Primary packaging 
(10 R glass vials) 
Sponsor’s name, address and 
telephone number 
X 
X 
Pharmaceutical dosage form, route 
of administration, name of the 
product and dosage, quantity of 
dosage units 
X 
X 
Batch and/or code number (kit or 
vial’s number) 
X 
X 
Study code 
X 
X 
Participant number 
 
X 
Investigator’s name 
X 
 
Investigator’s site 
X 
 
Instructions for use 
X 
 
Statement “For clinical trial use 
only” 
X 
 
Storage conditions 
X 
X 
Expiry date 
X 
X 
The Investigator, or designee, will only dispense IMPs to eligible participants who are 
included in the study. Each participant will only be given the IMP carrying his number. The 
dispensing for each participant will be documented in the source documents and in the 
participant’s case report form (eCRF). 
7.7. 
Storage of the investigational products 
Prior to the preparation of individual doses, all IMPs will be stored frozen between -15oC / 
-25oC in a secure and locked storage area of limited access, with continuous temperature 
control and monitoring. 
The pharmacist at ATC pharma will be responsible for the correct storage and handling of the 
IMPs. 
Once an individual dose has been prepared it will be stored prior to administration as detailed 
in the Pharmacy Manual. 
Deviations from the storage requirements, reporting and any actions taken, must be 
documented. 


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7.8. 
Accountability, reconciliation and return of the investigational products 
The Investigator or his designee must maintain a complete and current dispensing and 
inventory record. The Investigator or his designee is accountable for all test articles supplied 
by the Sponsor. The dispenser uses this information to maintain an accurate and complete 
dispensing and inventory record. The designated copies of the completed dispensing and 
inventory record will be returned to the Sponsor. 
Regulatory agencies require accounting for the disposition of all investigational drugs 
received by the clinical site. Information on drug disposition required by law consists of the 
date received, date administered, quantity administered, and the participant to whom the drug 
was administered. 
Supplies are shipped to the investigational site as needed. Drug accounting will be reviewed 
by the unblinded monitor during routine pharmacy monitoring visits. Each time a dose is 
prepared for a participant, the following information should be recorded: the participant’s 
randomisation number, the total dose prepared, the volume of IMP used, the number of the 
batch from which the dose was prepared, the date (and time) of preparation/administration 
and the initials of the persons preparing and checking the dose.  
At defined timepoints during the study, a drug accountability review and reconciliation will 
be performed, and at the completion or termination of the study, a final drug accountability 
review and reconciliation must be completed. Any discrepancies must be investigated and 
their resolution documented. After each round of drug accountability review and 
reconciliation, partially full and full containers of IMP can be returned to the Sponsor. The 
Sponsor will review the accountability form before authorising the destruction of empty 
containers on site. For this purpose, the site will provide a destruction certificate.  
 
7.9. 
Treatment compliance 
All doses will be administered in the clinical unit under direct supervision of the Investigator 
or designee.  
The detailed definitions of overdoses, medication errors, abuse and misuse are provided in 
Appendix 2: overdoses, medication errors, abuse or misuse will be collected as part of IMP 
dosing information and/or as a protocol deviation, as required.  
 
7.10. Prior Treatments 
In addition to the compliance with the inclusion and exclusion criteria, reasonable efforts will 
be made to determine all relevant treatments received by the participant within 2 weeks 
before IMP administration. All relevant information must be recorded on the participant's 
medical records and eCRF. 
As listed in sections 6.1 and 6.2, the following treatments are banned: 
• Within three (3) months prior to screening:  
o chronic administration of clopidogrel or ticlopidin or dipyridamole, 
Coumadin-like anticoagulants, new oral anticoagulant dabigatran or 
rivaroxaban or apixaban or edoxaban; 
o unfractionated heparin, low molecular weight heparin, fibrinolytic agents and 
anti-FXa. 


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• Within one (1) month prior to screening:  
o Acetylsalicylic-Acid (ASA)-containing over-the-counter medications;  
o chronic administration of nonsteroidal anti-inflammatory Drugs (NSAIDs) 
(COX-2 inhibitors excluded); 
o chronic use of corticosteroids, defined as > 5 consecutive days (including 
topical application). 
• Within 30 days prior or 5 half-lives (whichever is longer) prior to study drug 
administrations 
o Any other experimental therapy or new investigational agent  
 
• Within 14 days prior to study drug administrations:  
o Prescription medications or OTC medications (including decongestants and 
antihistamines),  
o Herbal medication (including herbal tea, St. John’s Wort),  
o Occasional use of paracetamol at recommended doses is allowed. 
 
7.11. Concomitant Treatments 
Any medication the participant takes during the study and until the discharge visit, other than 
the study drugs, including any prescription or over-the counter drug (including vitamins, 
herbal and mineral supplements), is considered a concomitant medication. At the additional 
visits scheduled for ADA assessment, only the medications that are administered in treatment 
of AEs will be considered concomitant medications. As listed in sections 6.1, 6.2, and 6.3, 
concomitant treatment is not permitted throughout the study. No medication other than the 
study products is allowed during the study unless absolutely required for treatment of adverse 
events. Occasional use of paracetamol at recommended doses is allowed. 
For any participant, if the use of any concomitant treatment becomes necessary (e.g. the 
treatment of an adverse event), the treatment must be recorded in the source documents and 
in the eCRF, including the reason for treatment, the generic name of the drug, the dosage, the 
route, and the date of administration. If a treatment is administered, the Sponsor’s medical 
monitor must be promptly notified in order to assess the participant’s eligibility for 
continuing study participation. 
Supplemental ADA samplings (“long-term follow-up of ADAs”): 
At the additional samplings scheduled for ADA assessment after D180, only treatments given 
for SADRs will be considered concomitant medications, and they will be collected only in 
the PV database. 
 


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8. DISCONTINUATION CRITERIA AND RELATED PROCEDURES 
8.1. 
Withdrawal criteria 
Any participant may be withdrawn from the study at the discretion of the Investigator. The 
participant is also free to terminate his participation at any time. However, if the participant 
has been dosed with study medication, it is recommended to ask the participant to remain in 
contact with the centre, and the investigational site should make every effort to convince the 
participant to return for a safety visit (corresponding to the discharge visit) and a laboratory 
sample taken to look for immunogenicity (presence of anti-drug antibodies and neutralizing 
antibodies if applicable). 
The Investigator will also undertake to obtain more detailed information about any participant 
who is lost to follow-up.  
Participants who are withdrawn from the study must not be re-included. 
The eCRF must document the primary reason for withdrawal. 
Investigators should contact the Medical Monitor, whenever possible, to discuss the 
withdrawal of a participant in advance. 
Supplemental ADA samplings (“long-term follow-up of ADAs”): 
These procedures do not apply for the additional samplings performed after D180. 
8.2. 
Discontinuation of Study Treatment (Infusion) 
In case of discontinuation or interruption of the study drug regardless the reason (AE, 
technical problem …), every effort should be made to perform PK/PD sampling as per SoA. 
Any safety assessments will be performed as originally planned. 
In case of interruption of the infusion: 
- 
Infusion should never be restarted in case of paravenous infusion or other catheter site 
problems 
- 
Infusion can be restarted only in case of equipment failure and if this failure can be 
resolved within 10 minutes of the failure occurring. 
8.3. 
Discontinuation of Study 
In case of premature discontinuation, please refer to the Schedule of Assessments (SoA) for 
data to be collected at the discontinuation visit (corresponding to the discharge visit and to a 
laboratory sample taken to look for immunogenicity, i.e., presence of anti-drug antibodies, 
and neutralizing antibodies if applicable). 
8.4. 
Unscheduled Visit 
At the Investigator’s discretion, an unscheduled Visit may be completed at any time during 
the study, but before the Discharge Visit, if deemed necessary for the subject’s safety and 
well-being. 
8.5. 
Lost to Follow Up 
A participant will be considered lost to follow-up if he fails to return for scheduled visits and 
does not respond to the study site’s attempts to contact them.  
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 


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• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• In cases in which the participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 3 telephone 
calls and 1 written letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts and a copy of the written letter should be 
documented in the participant’s medical record. 
• Should the participant continue to be unreachable, they will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
Supplemental ADA samplings (“long-term follow-up of ADAs”): 
These procedures do not apply for the additional samplings performed after D180. However, 
if a sampling is missed, the next sampling can still take place and the participant will be 
encouraged to come back for this next sampling. 
8.6. 
Withdrawn participant data collection 
The principal Investigator and/or other Investigator involved in the study will document on 
the termination page of the eCRF and in the participant’s medical records the primary reason 
for the participant’s withdrawal as follows:  
- 
AE: an AE form must be completed; 
- 
Protocol deviation; 
- 
Withdrawal by participant; 
- 
Lost to follow-up; 
- 
Study terminated by the Sponsor; 
- 
Death; 
- 
Other: if none of the above-mentioned reasons are applicable, then the reason will be 
specified. 
All withdrawals will be reported to the Sponsor. 
For all withdrawals, the end-of-study visit will be arranged scheduled within 10 days after the 
day of withdrawal, and will document the progress of their condition. In every case, the eCRF 
must be filled out up to the last visit performed. 
Supplemental ADA samplings (“long-term follow-up of ADAs”): 
These procedures do not apply for the additional samplings performed after D180. 
8.7. 
Replacement of participants 
The Investigator and the Sponsor will decide whether participants who withdraw from the 
study for any reason other than safety will be replaced. 
If replacement of participants is necessary, the replacement participants will be assigned to 
the same treatment as the participants they are replacing. 
In case of moderate or severe adverse event causing the participant to withdraw, then the 
participant will not be replaced. 


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9. PROCEDURES 
9.1. 
Investigational schedule 
The schedule of assessments is described in Section 2, Schedule of Activities (SoA).  
When several procedures are scheduled at the same theoretical time, the 12-lead ECG will be 
obtained first and within 15 minutes of the scheduled time, followed by vital signs. 
The PK and PD blood samples will be collected at the scheduled time within the windows 
noted in Section 9.2. 
The Investigator cannot perform any other biological assay but those described in the 
protocol, except when investigating an AE or suspected AE requires additional samples for 
the participant’s safety. 
 
9.2. 
Total volume of blood collected 
Less than 550 mL of blood will be collected from selection visit until extra ambulatory visits 
for ADA analysis on D30. Less than 20 mL of blood will be collected for extra ambulatory 
visits for ADA analysis on D90 and D180. Such a blood sample is safe provided it is not 
followed or preceded by other important blood samples [(blood donations within 3 months 
before D1, throughout the study and for 3 months after the end of the study (D90 or D180)]. 
Blood samples for PK and PD analysis should be collected at the requested times but a 
window for sample collection will be allowed as outlined in Table 8. The exact actual time of 
collection should be noted on the source data and in the eCRFs and used for the calculations. 
All collected samples will be stored for up to 5 years [starting from the last patient last visit 
(LPLV)], unless local rules, regulations or guidelines require different timeframes or different 
procedures. 
Table 8: Time windows for sampling collection 
Time point 
Window for taking sample (min) 
Pre-dose 
anytime within 60' predose except otherwise specified (e.g. 
samples in fasted conditions taken before breakfast) 
15 min 
± 3 minutes 
30 min 
± 5 minutes 
45 min 
± 5 minutes 
1 h 
± 5 minutes 
90 min 
± 10 minutes 
2 h 
± 10 minutes 
3 h 
± 10 minutes 
4 h 
± 15 minutes 
6 h 
± 30 minutes 
8 h 
± 30 minutes 
12 h 
± 30 minutes 
24 h 
± 60 minutes 
32 h 
± 60 minutes 
36 h 
± 60 minutes 
48 h 
± 120 minutes 
72 h 
± 120 minutes 
96 h 
± 120 minutes 


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Time point 
Window for taking sample (min) 
144 h 
± 120 minutes 
 
Supplemental ADA samplings (“long-term follow-up of ADAs”): 
Less than 30 mL of blood will be collected at each additional sampling performed after D180 
for ADA analysis. 
9.3. 
Pharmacokinetic Evaluation 
Samples will not be labelled with information that directly identifies the patients but will be 
coded with the identification number for the participant.  
9.3.1. Pharmacokinetic Assessment Methods and Timing 
Plasma PK Samples 
• 
Blood samples will be collected in 4.5 mL sodium 3.2 % citrate (0.109M) tubes with 
citrate volume/blood volume equal to 1/9. These samples will be collected at the 
approximate times indicated in the study schedule 
• 
The detailed process for handling and preparing plasma PK samples is provided in the 
laboratory manual.  
Urine PK Samples (exploratory) 
• 
Participants should be instructed to void at the beginning and end of each collection 
period and to collect all urine that is passed between the start and end of the urine 
collection intervals. Urine samples (all urine voided between the time-points) will be 
collected in polypropylene jugs and should be stored refrigerated (between 2 and 8°C) 
until each collection period is completed.  
• 
The detailed process for handling and preparing urine PK samples is provided in the 
laboratory manual 
9.3.2. PK Sample handling and labelling 
Refer to laboratory manual.  
9.3.3. PK Sample shipment and storage 
The samples will be shipped in a container filled with enough dry ice to ensure that the 
samples are kept frozen. 
Study samples will be shipped to Eurofins | ADME Bioanalyses. 
9.3.4. PK Bioanalytical method 
A validated sandwich ELISA method will be used for the quantification of Ir-CPI in human 
citrate sodium plasma.  The lower limit of quantification is 5 ng/L. 
9.3.5. Pharmacokinetic Criteria 
The pharmacokinetic parameters will be determined using Phoenix® WinNonlin® version 
8.1 or higher (Certara USA, Inc., Princeton, NJ). 


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The following plasma pharmacokinetic parameters will be calculated for Ir-CPI, by 
compartmental or non-compartmental methods, as appropriate for those participants with 
sufficient plasma concentration data: 
- 
Cmax: Maximum plasma concentration, 
- 
tmax: time to reach maximum plasma concentration, 
- 
AUC0-6: Area under the plasma concentration-time curve from time zero to 6h, 
- 
AUCinf: Area under the plasma concentration-time curve from time zero to time of 
infinity, 
- 
λz: apparent terminal elimination rate constant, 
- 
t1/2: terminal elimination half-life, 
- 
Vd: volume of distribution, 
- 
CL: total body clearance. 
The list of PK parameters could be adjusted if needed during the analyses. 
9.4. 
Pharmacodynamic Evaluation 
9.4.1. Pharmacodynamic outcome measurements 
- 
PD aPTT – Factor XI and Factor XII inhibition: measured by the change from baseline 
in PD aPTT and residual FXI and FXII activities (central lab). 
9.4.2. Pharmacodynamic Assessment Methods and Timing 
For PD variables (PD aPTT, Factor XI and Factor XII), blood sampling and preparation of 
human plasma for PD analyses (avoiding activation of the contact phase of the coagulation) 
will be collected in 4.5 mL sodium citrate 3.2 % (0.109M) tubes with citrate volume/blood 
volume equal to 1/9. The detailed process for collection, preparation, handling and 
transportation of the samples is provided in the laboratory manual. 
9.4.3. PD Sample handling and labelling 
Refer to laboratory manual.  
9.4.4. PD Sample shipment and storage 
The samples will be shipped in a container filled with enough dry ice to ensure that the 
samples are kept frozen. 
Study samples will be shipped to Eurofins | Biomnis Clinical Trials. 
9.4.5. PD Bioanalytical method 
Qualified methods were used to measure the activity of Ir-CPI in human citrated plasma in 
PD aPTT, an assay measuring the intrinsic pathway of coagulation and in an aPTT-based 
method using FXI or FXII deficient plasma to measure the residual activities of FXIa or 
FXIIa, respectively. 
9.5. 
Exploratory Biomarkers Evaluation 
Collection of samples for other biomarker research is also part of this study. Blood samples 
and urine samples will be collected at visits as specified in the SoA (Section 2).  


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If the data permit, biomarker samples will be tested to evaluate their association with the 
observed clinical responses to Ir-CPI.  
9.5.1. Exploratory outcome measurements 
In Blood: 
• D-dimers, fibrinogen, prothrombin time PT (expressed in seconds and as INR),  
• TNFα, 
• hsCRP, 
• cystatin C (CysC), 
• ADA. 
In Urine: 
• Urinary microalbumin,  
• Kidney Injury Molecule (KIM-1),  
• Urinary Neutrophil Gelatinase-Associated Lipocalin (NGAL). 
9.5.2. Exploratory Assessment Methods and Timing 
The detailed process for collection, preparation, handling and transportation of each type of 
sample is provided in the laboratory manual. 
• 
For PT, D-dimers and fibrinogen, blood sample will be collected in 3 mL sodium citrate 
3.2 % (0.109M) tubes. After blood collection, store / transport the tubes upright, at room 
temperature and transport the tubes to the local lab. 
• 
For TNFα, blood samples will be collected in 8 mL SST tubes and transport the tubes to 
the local lab.  
• 
For hsCRP, 3.5 mL tube without anticoagulant will be taken. After blood collection, store 
the tubes in 2-8°C and transport it to the local lab. 
• 
For serum Cystatin assay, blood samples will be collected in 8 mL SST tubes. 
• 
For Anti-Drug Antibodies (ADA), blood samples will be collected in 4.5 mL sodium 
3.2 % citrate (0.109M) tubes with citrate volume/blood volume equal to 1/9. 
Urine samples for exploratory biomarkers, 10 mL tubes will be collected pre-dose and after 
each collection period, centrifuged and stored at -20°C.  
Supplemental ADA samplings (“long-term follow-up of ADAs”): 
Less than 30 mL of blood will be collected at the additional samplings performed after D180 
in order to analyse ADAs and develop a sensitive ADA neutralizing assay, using different 
concentrations of plasma and different concentrations of Ir-CPI. 
9.5.3. Exploratory Biomarkers Sample handling and labelling 
The labelling used to identify each aliquot of whole blood / plasma / serum / urine is provided 
in the Laboratory Manual. 
9.5.4. Exploratory Biomarkers Sample shipment and storage 
Study samples will be stored in frozen conditions until they are shipped in a container filled 
with enough dry ice to ensure that the samples are kept frozen. 


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9.5.5. Exploratory Biomarkers Bioanalytical method 
The concentrations of the exploratory biomarkers will be evaluated using the methods 
applicable in each of the analytical laboratories in charge of each assay. 
9.6. 
Adverse events and treatment emergence 
The definitions of an AE, adverse events of special interest (AESI) or SAE can be found in 
Appendix 2: Adverse event and serious adverse event definitions. 
AE will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorised representative).  
AESIs: for the purpose of this study, AEs related to bleeding (e.g. positive Hemoccult® 
testing, gingival bleeding, bruising/haematoma, conjunctival bleeding, prolonged bleeding 
after trauma) will be considered as AESIs. 
In case of extreme bleeding or emergencies, Fresh Frozen Plasma can be tried to mitigate the 
bleeding. Dialysis will eliminate the protein from the body. 
Also considered as AESI are all infusion site reactions, including hypersensitivity reactions 
that would occur during or after study drug administration. 
The Investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE, AESI or SAE and remain responsible for following 
up AEs that are serious, considered related to the study treatment or the study, or that caused 
the participant to discontinue the study (see Section 8). 
Supplemental ADA samplings (“long-term follow-up of ADAs”): 
Detection, documentation, follow-up and reporting described below do not apply for 
samplings performed after D180, where only SADRs (either expected or unexpected [i.e. 
Suspected Unexpected Serious Adverse Reactions (SUSARs)]) and related information will 
be collected and followed-up if applicable in the PV database only, and not in the eCRF. 
9.6.1. Documentation and Treatment of Adverse Events by the Investigator 
All AEs, including AESIs and SAEs, occurring within the period of observation for the 
clinical study must be recorded. 
The period of observation for the collection of AEs extends from the time when the 
participant gives informed consent until the last study visit. For all participants, this period 
will be extended to follow-up on all on-going AEs after the end of the treatment period, until 
all AEs are finally resolved or it is medically justifiable to stop further follow-up (e.g., a 
chronic condition has been reached, i.e. stabilization of symptoms). 
There is no time limit on the collection of SAEs that are considered related to IMP. If the 
investigator detects an SAE in a study participant after the end of the period of observation, 
and considers the event possibly related to prior study treatment or procedures, he or she must 
contact the Pharmacovigilance (PV) contact of the Sponsor to determine how the SAE should 
be documented and reported. 
The description of the AEs (including date and time of onset and resolution when applicable) 
must be documented as soon and as completely as possible on the “Adverse Events” pages in 
the eCRF. Follow-up information must be entered as soon as available. 


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The following will also be specified: 
• Seriousness including criteria for seriousness; 
• Severity 
• Action taken; 
• Relationship to treatment; 
• Additional therapy; 
• If it was the cause of study discontinuation; 
• Outcome. 
 
AEs that occur during the study should be treated by established standards of care that will 
protect the life and health of the participants. If such treatment constitutes a deviation from 
the protocol, the participants should be withdrawn from the study and the reason must be 
documented in the eCRF. 
9.6.2. Method of Detecting AEs, AESIs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or AESIs and/or SAEs. 
Open-ended and non-leading verbal questioning of the participant is the preferred method to 
inquire about AE occurrence. 
9.6.3. Follow-up of AE, AESI and SAE 
After the initial AE/AESI/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and non-serious AESIs (as defined in 
Appendix 2: Adverse event and serious adverse event definitions) will be followed until 
resolution, stabilization, until the event is otherwise explained, or the participant is lost to 
follow-up. Further information on follow-up procedures is given in Appendix 2. 
9.6.4. Regulatory Reporting of Serious Adverse Events  
Procedure for SAE declaration by Investigator to Sponsor: 
The Sponsor’s PV contact for the study is: 
BIOTRIAL 
Email: PV.BIOTRIAL@biotrial.com  
The Principal Investigator (PI), or designee, is responsible for providing notification to the 
Sponsor’s PV contact of any SAE, whether deemed IMP-related or not, that a participant 
experiences during his participation in the study within 24 hours of becoming aware of the 
event. For all SAE Report Forms faxed or emailed, the PI must sign and date the form. 
In addition, within one business day of receipt by Sponsor’s PV contact any other requests for 
clarification of reported SAE data, and as appropriate, a list of any source documentation to 
be requested from the site (e.g. admission/discharge summaries, relevant to the events 
reported, lab/radiology/procedure reports, death certificate, autopsy report, etc.) are sent to 
the Sponsor. 
Follow up information must be reported to the Sponsor’s PV contact and within 24 hours of 
the study site staff becoming aware of new information. 


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The Sponsor’s PV contact will be responsible for reporting all expedited reports like SAEs, 
expected SADRs and SUSARs occurring in this study to competent authorities, FAMHP 
(Federal Agency for Medicines and Health Products), Ethics Committee and European 
Medicines Agency (EMA) according to applicable guidelines. 
If an AESI occurs, the PI (or designee) will not be required to fill out a form, but must record 
the AE in the eCRF. The Sponsor will assess the AEs on a case-by-case basis to determine 
whether an AE is considered an AESI and, if necessary, will request that the PI (or designee) 
fill out a PV report form to document the event. The BIOTRIAL PV contact will then 
perform any further actions that may be required. 
9.6.5. Treatment of Overdose 
There is no known antidote in case of excessive dosing (beyond that prescribed in the 
protocol and including overdose). A symptomatic/supportive treatment will be provided. 
Excessive dosing will be recorded in the eCRF. Any SAE or AE associated with excessive 
dosing must be followed as any other SAE or AE. These events are only considered AEs or 
SAEs if there are associated clinical signs and symptoms or if the act of taking the excess 
medicine itself is an AE or SAE. 
 
9.7. 
Safety Assessment 
9.7.1. Physical Examination 
The timing of the complete physical examinations is provided in Section 2, SoA. 
The physical examinations will be performed by the Investigator or his representatives. A 
complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, dermatological, neurological (including basic 
neurological testing for isocoria, light reflexes, gait and balance), musculoskeletal and 
lymphatic systems, in addition to head, eyes, ears, nose, throat, and neck. The physical 
examination will not include rectal examinations. 
Further examination of other body systems may be performed in case of evocative symptoms 
at the Investigator’s discretion. 
Any abnormality identified at baseline should be recorded as medical history. 
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed (abbreviated physical examination). Changes from 
baseline abnormalities should be recorded in participant’s notes. New or worsened clinically 
significant abnormalities should be recorded as adverse events on the eCRF. 
9.7.2. Weight, height and BMI 
The timing of the body weight and height measurements is provided in Section 2, SoA. 
Height will only be measured at screening, and used for calculating BMI at that visit.  


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9.7.3. Vital Signs  
9.7.3.1. Parameters 
Measured parameters: Supine systolic blood pressure (SBP), diastolic blood pressure (DBP) 
and heart rate (HR), body temperature. 
9.7.3.2. Method of assessment 
Qualified staff members will perform blood pressure (BP) measurements. If possible, BP 
measurements will be taken from the arm used for the infusion (opposite of the arm that is 
used for blood sample collection) by an automated BP monitor using the oscillometric 
method (e.g., Dinamap®). If there is a clinically important change in BP from the previous 
recording, measurements will be repeated immediately to confirm the change.  
BP and HR will be measured using an automatic device for each participant, after at least 
5 minutes at rest in the supine position. 
The timing of the assessments is summarised in Section 2, SoA.  
The following normal ranges will apply: 
Table 9: normal ranges for vital signs 
Systolic blood 
pressure (mmHg) 
Diastolic blood 
pressure (mmHg) 
Heart rate (bpm) 
Tympanic 
temperature (°C) 
90 ≤ SBP ≤ 150 
50 ≤ DBP ≤ 90 
40 ≤ HR ≤ 100 
36.0 ≤ t° ≤ 37.5 
 
9.7.4. Telemetry monitoring 
9.7.4.1. 
Parameters 
SpO2, non-artifact events [arrhythmias, bradycardia, tachycardia, pause, ventricular 
tachycardia (VT), supraventricular tachycardia (SVT)]. 
9.7.4.2. 
Method of assessment 
A centralised, continuous and automatic evaluation of the ECG signal is carried out. The 
telemetry traces will be monitored in real time. Alerts are triggered as soon as an abnormal 
event occurs. Alerts are reviewed by the investigator and considered for safety management 
of the participants. In the treatment period, cardiac telemetry monitoring will begin 1 hour 
prior to study drug administration and continue until 12 hours postdose. 
9.7.5. Standard 12-lead ECG  
9.7.5.1. 
Parameters 
- 
Measured parameters: HR, PR interval, QRS duration, QRS axis, QT interval; 
- 
Derived parameters: two corrections of the QT interval will be investigated: Fridericia’s 
correction (QTcF) and Bazett's correction (QTcB).  
- 
Observations and comments on the quality of the trace (if needed), on normality or 
abnormality.  


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9.7.5.2. 
Method of assessment 
The timing of the assessments is summarised in Section 2, SoA. 
The measurements will consist of 12-lead digital ECGs. Participants must rest in the supine 
position for at least 5 minutes before the ECG recording is started. The ECG may be recorded 
during the period of rest required before the measurements of supine blood pressure and 
pulse. A qualified physician will review the ECGs promptly and any clinically important 
finding will be recorded on the appropriate CRF. The Investigator is responsible for 
providing the interpretation of all ECGs. 
Table 10: normal ranges for ECG parameters 
PR (ms) 
QRS (ms) 
QTcF(ms) 
Heart rate(bpm) 
110 ≤ PR ≤ 220 
QRS ≤ 120 
QTc ≤ 450 ms 
40 ≤ HR ≤ 100 
9.7.6. Laboratory safety parameters 
9.7.6.1. 
Serology, drug screen and alcohol breath test 
Blood tests will be carried out to test for the presence of HIV antibodies, hepatitis B surface 
antigen (HBsAg), and hepatitis C virus (HCV) antibodies. 
Urinary screening will be carried out to test for amphetamines, benzodiazepine, cocaine, 
opiates, barbiturate and cannabinoids. 
An alcohol breath test will be performed. 
The timing of the assessments is summarised in Section 2, SoA. 
9.7.6.2. 
Laboratory Safety 
9.7.6.2.1. 
Blood safety analysis 
The following parameters will be determined: 
- 
Haematology:  
- 
Haematocrit, haemoglobin, red blood cell count, WBC count, WBC differential count, 
platelets counts. 
- 
Safety coagulation: 
- 
activated Partial Thromboplastin Time (aPTT). 
- 
Blood chemistry:  
- 
fasting glucose, creatinine, urea, sodium, potassium, calcium, chloride, phosphorus, 
bicarbonate. 
- 
AST, ALT, GGT, alkaline phosphatase. 
- 
total bilirubin (fraction of direct bilirubin in case > 1.25 x ULN). 
- 
albumin, total protein. 
- 
LDH, CK (and fraction of CK-MB if > 1.5 x ULN). 
NB: The baseline chemistry sample (predose sample) will also contain an extra archive 
serum sample for anti-Borrelia serology testing as backup to test for anti-Borrelia antibodies 
suggestive of previous exposure to tick bites in case of outlying results for PK/PD. 


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9.7.6.2.2. 
Urinalysis parameters 
The following parameters will be investigated by microscopic examination of the sediment: 
cylinders, erythrocytes, leucocytes. 
9.7.6.2.3. 
Method of assessment 
Samples of blood will be collected in fasted conditions at the visits summarised in Section 2, 
SoA. 
For all clinically significant abnormal laboratory test values identified after investigational 
product administration, testing will be repeated until the values return to normal or baseline. 
If laboratory values do not return to normal or baseline within a reasonable period, the 
aetiology should be identified and the Sponsor notified. 
Samples of urine will be collected at the visits summarised in Section 2, SoA. 
9.7.6.2.4. 
Laboratory safety determinations 
Laboratory tests will be performed by Clinical Biology Department of CHU of Liège, 
Avenue Hippocrate, 15, B35, Route 52, 4000 Liège, Belgium. 
All clinical laboratory analyses will be performed at the local laboratory. Alcohol test, urine 
drug screen, will be performed at the clinical site by study personnel. 
Serology (HIV and Hepatitis B and C testing) will be performed only at the Screening Visit; 
Urine drug screen and alcohol breath test will be performed at the Screening Visit and D-1. 
9.7.7. Occult Blood in Faeces 
9.7.7.1. 
Parameters 
Absence/presence of occult blood in faeces. 
9.7.7.2. 
Method of assessment 
Faeces samples will be collected at the timepoints listed in the SOA, section 2, Hemoccult® 
testing will be performed to investigate any presence of occult blood in faeces. 
Positive findings will be recorded as AEs, and also analysed as AESIs. 
9.7.8. Tick bite exposure monitoring 
9.7.8.1. 
Parameters 
Absence/presence of exposure to tick bites. 
9.7.8.2. 
Method of assessment 
As highlighted in Section 9.7.6.2.1, an extra sample for serology testing as backup to test for 
anti-Borrelia antibodies (IgG and IgM) suggestive of previous exposure to tick bites is drawn 
at baseline. 
At the extra-ambulatory visits and samplings performed for ADA analysis, the participants 
will be asked if they have been exposed to tick bite since the previous visit (response 
recorded as yes/no/unknown). If the answer is yes, then the participant will be asked to 


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provide information on treatment (e.g. antibiotics) and on presence of erythema migrans and 
other signs or symptoms. 
10. DATA MANAGEMENT AND STATISTICS 
10.1. Data entry and management 
10.1.1. Data collection 
Electronic Data Capture (EDC) via eCRFs will be used for this study. For each participant 
who was exposed to study drug, an eCRF must be completed and signed electronically by the 
investigator or co-investigator. This also applies to those participants who fail to complete the 
study. If a participant withdraws from the study, the reason must be noted on the eCRF. 
eCRFs are to be completed on an ongoing basis. 
Study data will be collected by the investigator or dedicated study personnel. Data will be 
collected on source documents and entered by the study personnel into the eCRFs in a timely 
manner. 
All the documents must be archived for a minimum of 25 years or according to the Sponsor’s 
procedures, whichever is longer. 
Supplemental ADA samplings (“long-term follow-up of ADAs”): 
ADA analysis data (including tick bite information if applicable) collected at the additional 
samplings after D180 will be collected in source documents and not in the eCRF. The results 
will be forwarded to the Sponsor after each time-point, and at the end of the follow-up period, 
individual ADA data will be forwarded to Biotrial. 
10.1.2. Data coding 
Biotrial will ensure coding for adverse events, prior and concomitants medications and 
medical history up to D180 in compliance with the Medical Dictionary for regulatory 
activities (MedDRA) and the World Health Organization Drug Dictionary (WHODDRUG), 
using the most recent versions of MedDRA and WHODDRUG. 
10.1.3. Data validation 
Biotrial will prepare the data validation document. 
For each part, Biotrial will organise a Blind Review of the data before database locking.  
Supplemental ADA samplings (“long-term follow-up of ADAs”): 
The data lock-point date will be the D180 visit and the database will not be unlocked to add 
ADA data after this date. All data are unblinded from that point onwards. No influence of 
breaking the blind is anticipated on the dynamics of ADA. 
10.2. Statistical considerations 
10.2.1. Sample size 
The number of participants is not based on statistical power considerations. A sample size of 
8 participants per panel (i.e., 6 active and 2 placebo) was chosen based on the design of 
similar SAD studies and is considered adequate to provide an initial assessment of the safety 
and tolerability profile. 


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10.2.2. Statistical methods 
The statistical analyses will be performed by the Biostatistics Unit of Biotrial Biometrics 
using SAS software version 9.4 or higher release (SAS Institute Inc., Cary, NC, USA). 
Pharmacokinetic data will be analyzed by Biotrial using Phoenix® WinNonlin® version 8.1 
or higher (Certara USA, Inc., Princeton, NJ) and SAS software Version 9.4 or higher 
release (SAS Institute Inc., Cary, NC, USA). 
Descriptive statistics will be supplied according to the nature of the criteria: 
- 
Quantitative variable: sample size, arithmetic mean, standard deviation (SD), standard 
error of the mean (SEM), minimum, median and maximum, and quartiles if necessary 
(with geometric mean, arithmetic and geometric coefficients of variation (CV), and 
quartiles for PK parameters).  
- 
Qualitative variable: sample size, absolute and relative frequencies per class 
The statistical analysis will be performed separately for each part of the study. 
In each part of the study, all listings will be presented by treatment group and participant. 
All listings will be presented by treatment group and participant. 
No interim analysis is planned. 
Further details on statistical analysis will be described in the Statistical Analysis Plan, agreed 
by the Sponsor. 
10.2.3. Description of data sets 
10.2.3.1. Definition of data sets 
In each part of the study, the following data sets will be defined: 
The Included set will be defined as all included participants who have signed an ICF. 
The Randomised set will be defined as all randomised participants. 
The Safety set will be defined as all included participants who have received at least a partial 
dose of IMP (Ir-CPI or placebo). 
The Pharmacodynamic set will be defined as all the included participants who have 
completed the study without any protocol deviation affecting PD evaluation and with at least 
one available post-baseline PD data.  
The Pharmacokinetic set will be defined as all the included participants who have been 
administered a complete infusion of IMP without major protocol deviation affecting PK 
evaluation. The inclusion of the subjects with incomplete PK profile(s) or incomplete 
infusion will be discussed before the PK concentration dataset is locked.  
The analysis sets will be validated during the blind-review meeting. 
10.2.3.2. Description of the sets 
A summary table with the description of the number of included participants, the number of 
randomised participants, the number of participants who completed the study, the number of 
participants who discontinued classified by reason of withdrawal, the number of participants 
in each analysis set will be performed by treatment group and overall. Corresponding 
individual listings will be prepared. 


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Listings with analysis sets, end of study status and visit dates will also be carried out. A 
specific listing with discontinued participants will be also prepared as well as a listing of 
participants excluded from analysis sets.  
10.2.4. Demographic and baseline characteristics 
The following analysis will be performed on the Randomised set. 
The participants’ demographic characteristics and baseline characteristics will be summarised 
by treatment group and overall and listed.  
Tables by treatment group and overall with the number of participants having at least one 
medical or surgical history and a corresponding listing will be prepared. 
Tables by treatment group and overall with number of participants having at least one 
previous treatment will be prepared. The same table will be prepared for concomitant 
treatments. 
Details of drug dosing and meals will be listed. 
10.2.5. Protocol deviations 
A summary table by treatment group and overall of protocol deviations and the 
corresponding listing will be prepared. 
10.2.6. Pharmacokinetic analysis 
The analysis will be performed on the Pharmacokinetic Set. 
Relevant PK parameters will be calculated for Ir-CPI by non-compartmental or 
compartmental methods, as appropriate for those participants with sufficient plasma and urine 
concentration data (as described in Section 9.3). 
10.2.6.1. Plasma concentration and PK parameters 
Plasma concentrations of Ir-CPI will be summarised over time by treatment group and 
corresponding listings will be prepared.  
Time profile plots will be prepared on linear and log-linear coordinates for each participant, 
as well as arithmetic mean (±SEM) by treatment group. 
PK parameters will be summarised by treatment group and corresponding listings will be 
prepared. 
Scatter plots and/or box whisker plots will be generated for the comparison of Cmax, AUC0-6 
and AUCinf. 
For each part, the linear dose-proportionality of Cmax, AUC0-6 and AUCinf (if applicable) will 
be assessed for parent (and metabolites if appropriate) using an exponential regression model 
("power model"). The log-transformed PK parameter will be compared among the dose 
groups by using a 1-factor analysis of variance (ANOVA), with log-transformed dose as a 
fixed effect and participant as random effect. 
 
10.2.7. Pharmacodynamic analysis 
10.2.7.1. Criteria 
- 
PD aPTT 


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- 
Factor XI and Factor XII inhibition 
10.2.7.2. Statistical methodology 
Analysis of pharmacodynamic parameters will be performed on the Pharmacodynamic set. 
For each parameter, descriptive statistics will be provided by treatment group on values and 
changes from baseline for each timepoint.  
All pharmacodynamic parameters will be listed. 
10.2.8. Exploratory Pharmacokinetic / Pharmacodynamic analysis 
As an exploratory analysis, evaluation of the relationship between doses and concentrations 
of Ir-CPI and the change from baseline in coagulation parameters defined above will be 
graphically investigated and displayed. 
10.2.9. Exploratory biomarkers’ analysis 
10.2.9.1. Criteria 
- 
Serum cystatin C (CysC), 
- 
TNFα, 
- 
hsCRP, 
- 
D-dimers,  
- 
Fibrinogen,  
- 
PT, 
- 
ADA, 
- 
Urinary microalbumin, Kidney Injury Molecule (KIM-1), urinary neutrophil gelatinase-
associated lipocalin (NGAL). 
10.2.9.2. Statistical methodology 
Analysis of exploratory parameters will be performed on the Pharmacodynamic set. 
For each parameter, descriptive statistics will be provided by treatment group on values and 
changes from baseline for each timepoint.  Graphs over time by treatment group will be also 
produced. 
Presence of ADAs will be described by treatment group and timepoint until D180. 
All exploratory parameters will be listed. 
Supplemental ADA samplings (“long-term follow-up of ADAs”): 
Results after D180 will be listed when applicable and the listing will be appended to the final 
CSR. 
10.2.10. Safety analysis 
10.2.10.1. Criteria 
- 
Physical examination, brief physical examination,  
- 
Vital signs and temperature 
- 
Weight, 
- 
Telemetry (including SpO2), 
- 
Occult blood in faeces (Hemoccult® test), 
- 
Supine 12-lead ECG, 


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- 
Serum chemistry, safety coagulation, haematology, urinalysis, 
- 
AE (including AESI), 
- 
Exposure to tick bites. 
10.2.10.2. Statistical methodology 
Analysis of safety parameters will be performed on the Safety set. 
AEs (including AESIs) will be considered treatment-emergent according to the rule set out in 
Appendix 2: Adverse event and serious adverse event definitions. 
AEs (including AESIs) will be summarised by system organ class and preferred term in 
tables with: 
- 
The number of participants with at least one AE and the number of adverse events by 
treatment group and overall, 
- 
The number of participants with at least one treatment-emergent AE and the number of 
treatment-emergent AEs for each treatment group. 
Analyses taking into account intensity and drug relationship to treatment will be also carried 
out. All AEs will be listed and coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®) and characterized as either pre-treatment or treatment-emergent, according to 
the intake of the IMP. 
For other parameters, the description will be performed by treatment group and measurement 
time. 
For laboratory data, vital signs, temperature and ECG parameters, potentially clinically 
significant abnormalities (PCSA) will be specified in the Statistical Analysis Plan and 
participants with PSCA values will be summarised. The presence of orthostatic hypotension 
and abnormal HR increase will be derived and the number and percentage of participants 
with at least one orthostatic hypotension/ abnormal HR increase will be presented by 
treatment group and measurement time as well as a corresponding listing. 
All safety parameters will be listed. 
Supplemental ADA samplings (“long-term follow-up of ADAs”): 
SADRs and their related information, if applicable, after D180 will only be collected in the 
PV database and will not be analysed. 
 


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11. REFERENCES 
1. Investigator’s Brochure, current version. 
2. IMPD, current version. 
3. EMEA Guideline on strategies to identify and mitigate risks for first-in-human and early 
clinical trials with investigational medicinal products; EMEA/CHMP/SWP/28367/07 
Rev. 1; Jul 2017. 
4. Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in 
Adult Healthy Volunteers, July 2005, accessed from 
http://www.fda.gov/downloads/Drugs/Guidances/UCM078932.pdf, on 14th May 2019  
 


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12. APPENDICES 
Appendix 1: Regulatory and legal considerations 
RIGHT OF ACCESS TO DATA AND SOURCE DOCUMENTS 
Monitoring 
The Investigator will allow the representative of the Sponsor and the study Monitor: 
- 
To inspect the site, the facilities and the material used for the study, 
- 
To meet all members of the team involved in the study, 
- 
To consult all the documents relevant to the study, 
- 
To check that the eCRFs have been correctly completed, 
- 
To have direct access to source documents for comparison of data therein with 
the data in the eCRFs, 
- 
To check that AE have been documented, 
- 
To verify that the study is carried out in compliance with the protocol 
- 
This study will be monitored at regular intervals, by mutual agreement of the investigator 
and Monitor. All or part of the data will be monitored at periodic visit to the study site, 
according to a monitoring plan. All entries in the e-CRFs, corrections and alterations are to 
be made by the responsible Investigator or his/her designee. 
- 
Once monitored and cleaned, the paper-based data (either source or transcribed data) that 
have been selected for populating the database will follow a single entry process.  
Electronic data will be directly entered in the database. 
- 
Details of all data management procedures, from the initial planning to the archiving of 
final datasets / documents following database freeze/lock will be documented in 
appropriate data management and validation plan(s).  Among others, these procedures will 
also describe quality control checks, data handling process for any missing, unused or 
spurious data, as well as coding procedures for AE’s, medical history, physical 
examination and medications. 
All information dealt with during these visits will be treated as strictly confidential. 
The Investigator will provide the Sponsor with the following: 
- 
Screen logs and AE logs at regular intervals, 
- 
Adequately completed eCRFs 
 
Audit- Inspection 
The Investigator will be informed that an audit will be carried out, at the request of the 
Sponsor, before, during or after the study. 
The Investigator will be informed that the Regulatory Authorities may also carry out an 
inspection. In this case, the Investigator must inform the Sponsor the CRO as soon as he 
receives the notification of inspection. 


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The Investigator must allow the representatives of the Regulatory Authorities and persons 
responsible for the audit to: 
- 
Inspect the site, facilities and material used for the study, 
- 
Meet all members of his team involved in the study, 
- 
Have direct access to study data and source documents, 
- 
Consult all the documents relevant to the study. 
 
QUALITY CONTROL AND QUALITY ASSURANCE 
Written procedures describing data flow, data entry or electronic capture, data cleaning and 
processing, and required quality control must be utilized. 
Trained site personnel must enter data manually into the EDC system. 
The Investigator is responsible for prompt reporting of accurate, complete, and legible data in 
the eCRFs and in all required reports. 
Any change or correction to the eCRF after saving must be accompanied by a reason for the 
change. 
Corrections made after the Investigator’s review and approval (by means of a 
password/electronic signature) will be reapproved by the Investigator. 
 
The Investigator should maintain a list of personnel authorised to enter data into the eCRF. 
To ensure accurate, complete, and reliable data, the Sponsor or its representative will provide 
instructional material to the study site(s), as appropriate. Training session will be given 
during a start-up/initiation meeting for instructions on the completion/data entry of any 
source data. 
The entered data will be systematically checked by CRO (Biotrial) staff, either by using error 
messages printed from validation programs or by manual checks carried out based on 
database listings. Data checks for data consistency and plausibility must be defined and 
implemented in the EDC system. Queries are raised and resolved electronically within the 
EDC system. The Investigator or his/her designee must verify that all data entries in the e-
CRFs are accurate and correct.  If certain information is Not Done, Not Applicable, the 
Investigator must enter: ND or NA, respectively, in the appropriate field. 
Every effort should be made to ensure that all safety evaluations are completed by the same 
individual who made the initial baseline determination. 
After the completion of the data cleaning and data review process and full resolution of the 
data queries, the database will be locked. Any changes to the database after that time may 
only be made by joint written agreement between the Clinical Pharmacologist and the 
Investigator. 
 
The Investigator must guarantee the safety of the study data in the medical files by 
implementing security measures to prevent unauthorised access to the data and to the 
computer system. 
 
The Investigator should not deviate from the protocol. However, the Investigator should take 
any measure necessary in deviation from or not defined by the protocol in order to protect 


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study participants from any immediate hazard to their health and safety. In this case, this 
action should be taken immediately, without prior notification of the regulatory authority, 
IEC, or Sponsor. 
After implementation of such measure, the Investigator must notify Biotrials PM and the 
Sponsor within 24 hours and follow any local regulatory requirements. 
 
Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; no names will be 
transferred and records will use unique identifier with no information that reveals the identity 
of the participant. The participant must be informed that his/her personal study-related data 
will be used by the Sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant.  The participant must be informed that 
his/her medical records may be examined by Clinical Quality Assurance auditors or other 
authorised personnel appointed by the Sponsor, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities. 
 
Investigator’s Regulatory Obligations 
All clinical work under this protocol will be conducted according to GCP rules.  This 
includes that the study may be audited at any time by a Quality Assurance personnel 
designated by the Sponsor, or by regulatory bodies.  The Investigator must adhere to the GCP 
principles in addition to any applicable local regulations.   
If requested, the Investigator will provide the Sponsor, applicable regulatory agencies, and 
applicable Ethics Committee with direct access to any original source documents. 
The Investigator should demonstrate due diligence in recruitment and screening of potential 
study participants.  The enrolment rate should be sufficient to complete the study as agreed 
with the Sponsor.  The Sponsor should be notified of any projected delays, which may impact 
the completion of the study. 
 
Record Keeping 
The Investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes. 
Depending on the data collected and the type(s) of data, records will be kept for 25 years 
following storage, and archiving procedures agreed by the Sponsor and the Investigator site 
and any other parties involved in this study, and in accordance to any regulations that are 
applicable in the country where the study is conducted. 
 
Regulatory Considerations 
This study will be conducted in accordance with applicable laws and regulations, GCPs, 
GDPR and the ethical principles that have their origin in the Declaration of Helsinki. 
All or some of the obligations of the Sponsor will be assigned to a Clinical Research 
Organisation (CRO).  
An identification code assigned to each participant will be used in lieu of the participant’s 
name to protect the participant’s identity when reporting AEs and/or other trial-related data. 


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Final Report Signature 
The Investigator or designee will sign the CSR for this study, indicating agreement with the 
analyses, results, and conclusion of the report. 
Insurance 
The Sponsor declares that an insurance policy will be in place covering the participants in 
respect to risks involved in the study.  
Financial Agreement 
A financial agreement between the Sponsor and the Investigator will be signed prior to 
initiating the study. 
 
STUDY SUSPENSION, TERMINATION, AND COMPLETION 
The Sponsor may suspend or terminate the study or any part of the study at any time for any 
reason, and has an obligation to report stopping of the study to both EC/CA. 
If the Investigator suspends or terminates the study, the Investigator will promptly inform the 
Sponsor, the IEC and the regulatory authorities and provide them with a detailed written 
explanation. The Investigator will also return all test articles, test article containers, and other 
study materials to the Sponsor. 
Upon study completion, the Investigator will approve and will provide the Sponsor and 
IRB/IEC with final reports and summaries as required by regulations. 
Additional conditions, besides the discovery of an unexpected, relevant, or unacceptable risk 
to the participants enrolled in the study, that may warrant termination of the study include, 
but are not limited to: 
- 
Other ethical issues 
- 
Inaccurate or incomplete data recording 
- 
Noncompliance 
- 
Unsatisfactory enrolment with respect to quality or quantity 
- 
A decision of the Sponsor to suspend or discontinue development of the IMP 
 
If the study is prematurely discontinued, all study data must be returned to the Sponsor. In 
addition, arrangements will be made for all unused investigational product(s) in accordance 
with the Sponsor’s applicable procedures for the study. Financial compensation to the 
investigator and participant indemnification will be in accordance with the agreement 
established between the investigator and the Sponsor. 
 


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ETHICS AND REGULATORY ASPECTS  
Current texts 
The investigator will ensure that this study is conducted in full conformity with the current 
revision of the Declaration of Helsinki, with the International Conference for Harmonisation 
Good Clinical Practice (ICH-GCP) regulations and guidelines, and with local rules and 
regulations of the country where the study is conducted, whichever affords the greater 
protection to the patient. In particular, the study will be carried out in accordance with: 
- 
The most recent recommendations of the World Medical Association (WMA). 
- 
The ICH recommendations: Good Clinical Practice [E6 (R2)], (CPMP/ICH/135/95), 
2016. 
- 
Directive 2001/20/EC translated in Belgian Law of 07 May 2004 with regards to the 
experiments on the human person.  
- 
The Belgian Law of 8 December 1992 relative to the protection of privacy in relation to 
the processing of personal data, the Belgian Law of 22 August 2002 on patient rights and 
the GDPR (EU) 2016/679. 
- 
European directive 2005/28/EC translated in Belgian Law of 18 May 2006 setting the 
GCP for biomedical research on drugs for human use. 
- 
EMEA Guideline on strategies to identify and mitigate risks for first-in-human and early 
clinical trials with investigational medicinal products; EMEA/CHMP/SWP/28367/07 Rev. 
1; Jul 2017. 
The Investigator will supply the following documents to the relevant Ethics Committee for 
review and approval to conduct the study (this list may not be exhaustive): 
- 
Protocol approved by the Sponsor, 
- 
Currently applicable Investigator’s Brochure or package labelling and updates during the 
course of the study, 
- 
Informed consent document(s), 
- 
Relevant Investigator’s curriculum vitae, 
- 
Participant information and informed consent form, 
- 
Recruitment materials (advertisements). 
 
The EC will review all submission documents as required, and the EC decision on the 
conduct of the study will be made in writing to the Investigator.  This document must be 
dated and clearly identify the version number and date of the documents submitted. 
The study may begin at the investigative site only after receiving the dated and signed 
documentation of the EC approval of the protocol and the informed consent documents. 
During the study the following documents will be sent to the EC for their information, or for 
review and approval: (1) update(s) to the Investigator’s Brochure; (2) reports of SAEs; (3) all 
substantial protocol amendments and revised informed consent(s), if any. 
At the end of the study, the Investigator will notify the EC about the study completion. 
 
 
 


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Participant Information and Consent 
An unconditional prerequisite for a participant’s participation in the trial is his written 
informed consent. The participant’s written informed consent to participate in the trial must 
be given before any trial-related activities are carried out.  
Participants will be verbally informed by an investigator of all pertinent aspects of the trial: 
the nature of the study, its aim, its possible risks and restrictions, its duration and the fee that 
they will receive. The protocol will be explained during a meeting prior to the study and each 
participant must be informed that participation in the study is voluntary and that they may 
withdraw from the study at any time. At this meeting, an information sheet will be given to 
each participant. The language used in doing so must be chosen so that the information can 
be fully and readily understood by lay persons.  
The Investigator is responsible for ensuring that the participant understands the potential risks 
and benefits of participating in the study, including answering, orally and/or in writing, to any 
questions the participant may have throughout the study and sharing any new information 
that may be relevant to the participant’s willingness to continue his or her participation in the 
study in a timely manner. 
The participant information sheet and consent document will be used to explain the potential 
risks and benefits of study participation to the participant in simple terms before the 
participant is entered into the study, and to document that the participant is satisfied with his 
or her understanding of the study and desires to participate.  The participant information sheet 
and consent document will also contain information related to Article 13 of the General Data 
Protection Regulation (GDPR) to comply with the transparency agreement. The Investigator 
is ultimately responsible for ensuring that the EC-approved informed consent is appropriately 
signed and dated by each participant prior to the performance of any study procedures.  
Informed consent obtained under special circumstances may occur only if allowed by local 
laws and regulations. 
The completed “participant screen log” will be signed by the Investigator to attest that 
consent has been obtained from all participants. 
Whenever important new information becomes available that may be relevant to the 
participant’s consent, the written participant information sheet and any other written 
information provided to participants will be revised by the Sponsor and be submitted again to 
the IEC/IRB for review and favorable opinion/authorisation. The agreed, revised information 
will be provided to each participant in the trial for signing and dating. The Investigator will 
explain the changes from the previous version.  
Participant card 
A participant card will be provided to each participant that is registered in the study. The 
information to be provided on the participant card will include the contact details of the 
treating physician/hospital and any other relevant study-related information 
Submission to the authorities 
Each clinical trial protocol is identified at European level with a unique number. This number 
has to be asked by the requesting company in the EudraCT database before submission of any 
demand. The European application form, which is part of the dossier, has also to be 
completed in the EudraCT database. 
A clinical trial can only start after receiving a favourable opinion from the recognized Ethics 
Committee and if the relevant authority (FAMHP: R&D) has not indicated any major 


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insufficiency within the legal timeframe provided for in the law dated 7th May 2004 related to 
experiments on human people. 
An application for the FAMHP is a full electronic file and a cover letter. The application 
must be sent via CESP. 


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DATA PROCESSING AND ARCHIVING OF DOCUMENTS AND DATA RELATIVE 
TO THE RESARCH 
After the study, the Investigator will keep all information relevant to the study for 25 years, 
or according to the Sponsor’s procedures, whichever is longer. 
The Investigator will contact the Sponsor for authorization prior to the destruction of any 
study records or in the event of accidental loss or destruction of any study records. 
The Investigator will also notify the Sponsor should he/she relocate or move the study-related 
files to a location other than that specified in the Sponsor’s study master file. 
 
CONFIDENTIALITY AND AGREEMENTS 
Before starting the study, the Investigator must confirm receipt of adequate documentation 
from the Sponsor so as to be able to decide whether or not to perform the study. 
All documents and information given to the Investigator by the Sponsor with respect to the 
study are strictly confidential. 
The Investigator and his colleagues agree to use them only with the framework of this study, 
in order to carry out the protocol. This agreement is binding as long as the confidential 
information has not been disclosed to the public by the Sponsor. 
The Investigator may use the technical protocol to obtain the informed consent of study 
participants. It must not be disclosed to other parties without the written authorisation of the 
Sponsor. 
The Investigator keeps a confidential participant identification list for the study to permit 
easy identification of each participant during and after the study. This document will be 
reviewed by the sponsor site contact for completeness. 
The participant identification and enrollment log will be treated as confidential and will be 
filed by the investigator in the study file. To ensure participant confidentiality, no copy will 
be made. All reports and communications relating to the study will identify participants by 
initials and/or assigned number only. 
The Investigator must also complete a participant-screening log, which reports on all 
participants who were seen to determine eligibility for inclusion in the study. 
The Investigator must maintain source documents for each participant in the study. 
Data on participants collected in CRFs during the study will be documented in an anonymous 
fashion. All information in the eCRFs must be traceable to these source documents. 
 
REPORT AND PUBLICATION 
Report 
The results of the study will be reported in a CSR. This report will be prepared by Biotrial 
according to existing Standard Operating Procedures (ICH Biotrial or Sponsor own format). 
In compliance with the regulations, the final report will be produced within one year of 
completing the study and in agreement with the work order. The final CSR will include the 
data up to the D180 visit date, and when all results from the additional ADA samplings are 
collected, the final CSR will be amended to add the ADA results as an additional appended 
listing. 
The final report will be provided to all Investigators having included participants in the study. 


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The Clinical Study Report will be provided as Word and PDF files. Also, SAS transfer files 
of the data will be provided electronically. All data will be presented CTD-compliant. 
 
Publication 
The Investigator will only use the information in the context of the study. The information 
cannot be used without the Sponsor’s authorisation. Hence, all or part of the information 
should only be divulged, submitted for publication or claimed for industrial proprietary act 
with the written consent of the Sponsor. 
 


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Appendix 2: Adverse event and serious adverse event definitions 
Definitions 
• Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a participant to whom a 
medicinal product is administered and which does not necessarily have a causal relationship 
with this treatment. 
An 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 related to the medicinal product or not. 
An AE includes, but is not limited to, the following: 
• Any clinically significant worsening of a pre-existing condition, 
• An AE occurring from overdose of an IMP, whether accidental or intentional. 
Overdose is a dose greater than specified in the protocol, 
• An AE occurring from abuse (e.g., use for nonclinical reasons) of an IMP, 
• An AE that has been associated with the discontinuation of the use of an IMP. 
Laboratory/ECG/vital signs abnormalities should not be documented as AEs unless they are 
considered clinically relevant, require treatment, fulfil any serious AE (SAE) criterion, or 
cause the participants to change the study schedule. 
In the case of laboratory/ECG abnormalities that are a sign of a medical condition, the 
condition should be reported as an AE and not the sign. 
Events occurring in participants in the course of a clinical study during treatment-free periods 
or on treatment with placebo or a comparative medicine are also to be considered AEs. 
• Adverse Event of Specific Interest 
For the purpose of this study, AEs related to bleeding (e.g. positive Hemoccult® testing, 
gingival bleeding, bruising/haematoma, conjunctival bleeding, prolonged bleeding after 
trauma) will be considered as Adverse Events of Specific Interest (AESIs). 
In case of extreme bleeding or emergencies, Fresh Frozen Plasma can be tried to mitigate the 
bleeding. Dialysis will eliminate the protein from the body. 
Also considered as AESI are all infusion site reactions, including hypersensitivity reactions 
that would occur during or after study drug administration. 
• Adverse Drug Reactions 
An Adverse Drug Reaction (ADR) is a response to a drug that is noxious and unintended and 
that occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or 
for modification of physiological function. 
All AEs judged by either the reporting Investigator or the Sponsor as having a reasonable 
causal relationship to a medicinal product qualify as an ADR. 
All AEs for which the judgement of relationship to study medication is “possible” or higher 
will be considered ADRs. 
• Treatment-Emergent Adverse Events  
A treatment-emergent AE is an AE that occurs after IMP dosing or that was present prior to 
dosing but becomes exacerbated between dosing during a treatment period and the end of the 
study.  


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• Abuse, Misuse, Medication Error and Overdose 
Abuse is defined as persistent or sporadic, intentional excessive use of IMP which is 
accompanied by harmful physical or psychological effects. 
Misuse is defined as situations where an IMP is intentionally and inappropriately used not in 
accordance with the terms of the study protocol. 
Medication error is defined as an unintended failure in the IMP administration process that 
leads to, or has the potential to lead to, harm to the participant. 
Overdose is defined as intake of a quantity of an IMP given per administration or 
cumulatively which is above the maximum dose recommended in the study protocol. 
Serious Adverse Events or Serious Adverse Drug Reactions 
• General definitions 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 
• results in death, 
• is life threatening, 
• requires inpatient hospitalisation or prolongation of existing hospitalisation*, 
• results in persistent or significant disability/incapacity, 
• is a congenital anomaly/birth defect, or 
• is an important medical event that requires intervention to prevent one of the above. 
* “Inpatient hospitalisation” is defined as 24hours in the hospital or an overnight stay. 
Additionally, a Serious Adverse Drug Reaction (SADR) is a SAE that occurs after IMP 
administration and is considered to have any potential causal relationship with the IMP 
according to the Investigator or the Sponsor. 
Additionally, important medical events that may not result in death, be life-threatening, or 
require hospitalisation may be considered SAEs when, based on appropriate medical 
judgment, they may jeopardize the participant and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in hospitalisation, or development of 
drug dependency or drug abuse. 
Life-threatening refers to immediate risk of death as the event occurred per the reporter. A 
life-threatening experience does not include an experience, had it occurred in a more severe 
form, might have caused death, but as it actually occurred, did not create an immediate risk of 
death. For example, hepatitis that resolved without evidence of hepatic failure would not be 
considered life-threatening, even though hepatitis of a more severe nature can be fatal. 
Similarly, an allergic reaction resulting in angioedema of the face would not be life-
threatening, even though angioedema of the larynx, allergic bronchospasm, or anaphylaxis 
can be fatal. 
Hospitalisation is official admission to a hospital. Hospitalisation or prolongation of 
hospitalisation constitutes criteria for an AE to be serious; however, it is not in itself 
considered a serious adverse event (SAE). In absence of an AE, hospitalisation or 
prolongation of hospitalisation should not be reported as an SAE. This is the case in the 
following situations: 


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- 
The hospitalisation or prolongation of hospitalisation is needed for a procedure required 
by the protocol.  
- 
The hospitalisation or prolongation of hospitalisation is part of a routine procedure 
followed by the centre (e.g., stent removal after surgery). This should be recorded in the 
study file. 
In addition, hospitalisation for a pre-existing condition that has not worsened does not 
constitute an SAE. 
Disability is defined as a substantial disruption in a person’s ability to conduct normal life 
functions. 
If there is any doubt about whether the information constitutes an SAE, the information is 
treated as an SAE. 
Other Reportable Information: Certain information, although not considered an SAE, must 
be recorded, reported, and followed up as indicated for an SAE. This includes:  
- 
Overdose of an investigational product as specified in this protocol with or without an 
AE. 
- 
Inadvertent or accidental exposure with or without an AE. 
• Expected and unexpected adverse events 
Expected AEs with the IMP are those described in the current Investigator’s brochure [1]. An 
unexpected AE is an experience not previously reported in or the nature or severity of which 
is not consistent with the current prescribing information. Suspected Unexpected Serious 
Adverse Reactions (SUSARs) are unexpected SAEs having a reasonable possibility of a 
causal relationship with the study drug. 
• Adverse Event of Special Interest 
Adverse Events of Special Interest (AESIs) are AEs (serious or non-serious) that need to be 
monitored, documented, and managed in a pre-specified manner. For the tested drug, AEs 
related to bleeding (e.g. positive Hemoccult® testing, gingival bleeding, bruising/haematoma, 
conjunctival bleeding, prolonged bleeding after trauma), and all infusion site reactions, 
regardless of causality, including hypersensitivity reactions that would occur during or after 
study drug administration, will be considered as AESIs. 
Participants that report an AESI will be followed until stabilisation of the symptoms. 
 
• Severity 
The maximum intensity of an AE during a day should be graded according to the definitions 
below and recorded in details as indicated on the eCRF. If the intensity of an AE changes 
over a number of days, then separate entries should be made having distinct onset dates. 
1. Mild: AEs are usually transient, requiring no special treatment, and do not interfere with 
patient’s daily activities. 
2. Moderate: AEs typically introduce a low level of inconvenience or concern to the patient 
and may interfere with daily activities, but are usually ameliorated by simple therapeutic 
measures. 
3. Severe: AEs interrupt a patient’s usual daily activity and traditionally require systemic 
drug therapy or other treatment. 
 


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• Causal relationship with trial medication 
The relationship of an AE to the investigational product is a clinical decision by the 
Investigator based on all available information at the time of the completion of the eCRF and 
is graded as follows: 
1. Not related (no reasonable possibility): a reaction for which sufficient information 
exists to indicate that the etiology is unrelated to the IMP; the participant did not receive 
the study medication or the temporal sequence of the AE onset relative to administration 
of the study medication is not reasonable or the event is clearly related to other factors 
such as the participant’s clinical state, therapeutic intervention or concomitant therapy. 
2. Unlikely (reasonable possibility): a clinical event, including a laboratory test 
abnormality, with a temporal relationship to drug administration which makes a causal 
relationship improbable and in which other drugs, chemicals or underlying disease 
provide plausible explanations. 
3. Possible (reasonable possibility): a clinical event, including a laboratory test 
abnormality, with a reasonable time sequence to administration of the drug but which 
could also be explained by concurrent disease or other drugs or chemicals, information on 
drug withdrawals may be lacking are unclear. 
4. Probable (reasonable possibility): a clinical event, including a laboratory test 
abnormality, with a reasonable time sequence to administration of the drug, unlikely to be 
attributed to concurrent disease or other drugs or chemicals and which follows a clinically 
reasonable response on withdrawal (de-challenge): re-challenge information is not 
required to fulfil this definition. 
5. Definite (reasonable possibility): a reaction that follows a reasonable temporal sequence 
from administration of the drug or in which the drug level has been established in body 
fluids or tissues, that follows a known or expected response pattern to the suspected drug, 
and that is confirmed by improvement on stopping or reducing the dosage of the drug, 
and reappearance of the reaction on repeated exposure (re-challenge). 
 
 

SAP_001.pdf: 
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STATISTICAL ANALYSIS PLAN 
 
 
 
Study protocol code 
Clin_IrCPI_101 
Biotrial code 
2BIOXO1 
ATC study code 
M2154 
Study title 
A Phase I, Double Blind, Placebo Controlled, 
Single Ascending Dose Study of Intravenously 
Administered 
Ir-CPI 
to 
Evaluate 
Pharmacokinetics, Pharmacodynamics, Safety and 
Tolerability in Healthy Male Volunteers.  
Study investigational medicinal product 
Ixodes ricinus-Contact Phase Inhibitor (Ir-CPI) 
Development phase 
Phase I 
Sponsor 
BIOXODES SA 
Parc d’activités économiques du Wex 
Rue de la Plaine, 11 
6900 Marche-en-Famene 
BELGIUM 
Version of the statistical analysis plan 
Final version 1.0 
Date of the statistical analysis plan 
09 July 2020 
 
 
 
 
 
This document contains confidential information that should only be disclosed to those persons responsible for 
the study. This information must not be disclosed to any third party without prior written authorisation from the 
Sponsor. 
 
 




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REVISION HISTORY 
 
Date 
Version number 
Reason for change 
Authored by 
12JUN2020 
Draft 0.1 
Initial version 
C. MAUDET 
26JUN2020 
Draft 0.2 
Integration of BIOXODES comments 
C. MAUDET 
09JUL2020 
Final version 1.0 
. Integration of BIOXODES comments 
. Addition of QTcB formula 
. Addition of Steven RAMAEL in the 
signatory list 
C. MAUDET 


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TABLE OF CONTENTS 
 
1. 
Introduction .................................................................................................................... 9 
2. 
Study objectives ............................................................................................................... 9 
2.1. 
Primary objectives ....................................................................................................... 9 
2.2. 
Secondary objectives ................................................................................................... 9 
2.3. 
Exploratory objectives ................................................................................................. 9 
3. 
Study methodology ....................................................................................................... 10 
3.1. 
Study design .............................................................................................................. 10 
3.2. 
Randomisation ........................................................................................................... 10 
3.3. 
Treatment(s) received ................................................................................................ 10 
3.4. 
Visits .......................................................................................................................... 11 
4. 
Sample Size ................................................................................................................... 11 
5. 
Changes to the planned analysis from protocol .......................................................... 11 
6. 
Statistical considerations .............................................................................................. 12 
6.1. 
Software environment ................................................................................................ 12 
6.2. 
Descriptive statistics and data listings ....................................................................... 12 
6.3. 
Handling of missing and retest values ....................................................................... 12 
6.4. 
Handling of incomplete dates .................................................................................... 13 
6.5. 
Baseline definition ..................................................................................................... 13 
6.6. 
Duration ..................................................................................................................... 13 
6.7. 
Type I error rate ......................................................................................................... 13 
7. 
Description of study subjects ........................................................................................ 13 
7.1. 
Definition of analysis sets .......................................................................................... 13 
7.2. 
Subject disposition ..................................................................................................... 14 
7.3. 
Protocol deviations .................................................................................................... 14 
8. 
Demographic data and baseline characteristics .......................................................... 14 
8.1. 
Demographic data ...................................................................................................... 14 
8.2. 
Other baseline characteristics .................................................................................... 14 
8.3. 
Medical and surgical history and procedures ............................................................ 14 
8.4. 
Previous and concomitant medications ..................................................................... 15 
8.5. 
Compliance ................................................................................................................ 15 
9. 
Pharmacokinetic data ................................................................................................... 15 
9.1. 
Generalities ................................................................................................................ 15 


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9.2. 
Plasma concentrations and pharmacokinetic parameters .......................................... 17 
9.2.1. 
Plasma PK parameters ........................................................................................ 17 
9.2.2. 
Plasma pharmacokinetic analysis ....................................................................... 18 
10. 
Pharmacodynamics data .............................................................................................. 19 
11. 
Exploratory Pharmacokinetic / Pharmacodynamic analysis ..................................... 20 
12. 
Exploratory Biomarkers Evaluation ............................................................................ 20 
13. 
Safety data ..................................................................................................................... 21 
13.1. Adverse events ........................................................................................................... 21 
13.2. Clinical laboratory data ............................................................................................. 22 
13.3. Other safety parameters ............................................................................................. 23 
13.3.1. 
Vital signs data ................................................................................................... 23 
13.3.2. 
Electrocardiogram data ...................................................................................... 23 
13.3.3. 
Physical examination .......................................................................................... 24 
13.3.4. 
Telemetry monitoring (including SpO2) ............................................................ 24 
13.3.5. 
Occult blood in faeces ........................................................................................ 24 
13.3.6. 
Exposure to tick bites ......................................................................................... 24 
14. 
Reporting conventions .................................................................................................. 25 
15. 
References ..................................................................................................................... 26 
16. 
Appendices .................................................................................................................... 27 
16.1. Appendix 1 - Flow chart/Schedule of assessments of the study ................................ 27 
16.1.1. 
Part 1: Single 6-hour infusion for Cohorts A, B and C ...................................... 27 
16.1.2. 
Part 1: Single 6-hour infusion for Cohort D ....................................................... 30 
16.2. Appendix 2 - Criteria for Potentially Clinically Significant Abnormalities (PCSA) 33 
16.3. Appendix 3 – Normal ranges for vital signs and ECG parameters ........................... 34 
16.4. Appendix 4 - List of tables, listings and figures included in the clinical study report
 
35 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ABBREVIATION 
DEFINITION 
ADA 
Anti-Drug Antibodies 
ADPP 
ADaM Pharmacokinetic Parameters 
AE 
Adverse Event 
AESI 
Adverse Event of Specific Interest 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of Variance 
aPTT 
activated Partial Thromboplastin Time 
AST 
Aspartate aminotransferase 
ATC 
Anatomic Therapeutic Chemical 
AUC 
Area Under the Curve 
AUC0-6h 
Area Under the Curve from time zero to 6h 
AUC0-last 
Area Under the Curve from time zero to last measurable plasma 
concentration 
AUC0-inf 
Area Under the Curve from time zero to infinity 
BLQ 
Below the Limit of Quantification 
BMI 
Body Mass Index 
Clast 
Last measurable plasma concentration 
Cmax 
Maximum observed plasma concentration 
CI 
Confidence Interval 
CL 
Total body clearance 
CysC 
Cystatin C 
CRF 
Case Report Form 
CV 
Coefficient of Variation 
DBP 
Diastolic Blood Pressure 
ECG 
ElectroCardioGram 
FDA 
Food and Drug Administration – U.S. authority 
FIH 
First-In-Human 
FXI 
Factor XI 
FXII 
Factor XII 
GGT 
Gamma Glutamyl Transferase 
hsCRP 
high sensitivity C-Reactive Protein 
HBsAg 
Hepatitis B surface Antigen 
HCV 
Hepatitis C Virus 


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ABBREVIATION 
DEFINITION 
HIV 
Human Immunodeficiency Virus 
i.e. 
id est 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IMP 
Investigational Medicinal Product (synonymous with “study drug”) 
Ir-CPI 
Ixodes ricinus-Contact Phase Inhibitor 
IS 
Included Set 
!z 
Terminal elimination rate constant 
KIM 
Kidney Injury Molecule 
LDH 
Lactate Dehydrogenase 
LLN 
Lower Limit of Normal range 
LLOQ 
Lower Limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
ND 
Not Determined 
NGAL 
Neutrophil Gelatinase-Associated Lipocalin 
NOAEL 
No Observed Adverse Effect Level 
PCSA 
Potentially Clinically Significant Abnormalities 
PD 
PharmacoDynamics 
PDS 
PharmacoDynamics Set 
PK 
PharmacoKinetics 
PKS 
PharmacoKinetic Set 
PT 
Preferred Term 
QRS 
QRS interval duration 
QT 
Time interval for ventricular depolarisation and repolarisation 
QTc 
Corrected QT interval 
QTcB 
QT interval corrected using Bazett’s formula 
QTcF 
QT interval corrected using Fridericia’s formula 
RS 
Randomised Set 
SAD 
Single Ascending Dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS® 
Statistical Analysis System® 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 


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ABBREVIATION 
DEFINITION 
SEM 
Standard Error of the Mean 
SOC 
System Organ Class 
SpO2 
Peripheral Capillary Oxygen Saturation 
SRC 
Safety Review Committee 
SS 
Safety Set 
SVT 
SupraVentricular Tachycardia 
t1/2 
Terminal elimination half-life 
tmax 
time to reach maximum observed plasma concentration 
TEAE 
Treatment-Emergent Adverse Event 
TNF 
Tumor Necrosis Factor 
ULN 
Upper Limit of Normal range 
Vdz 
Volume of distribution 
VT 
Ventricular Tachycardia 
WHO 
World Health Organisation 
 
 


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1. Introduction 
The Statistical Analysis Plan (SAP) details the statistical methodology to be used in analysing 
study data and outlines the statistical programming specifications, tables, figures and listings. 
It describes the pharmacokinetics, pharmacodynamics, safety and tolerability variables and 
populations, anticipated data transformations and manipulations, and other details of the 
analyses not provided in the study protocol. 
The analyses described are based upon the final clinical study protocol V4.0 dated 06 
December 2019 and minutes of Safety Review Committee (SRC) meetings, and are prepared 
in accordance with the International Conference on Harmonisation (ICH) E9 Step 4 version 
dated 05 February 1998 [1]. 
The statistical analyses will be performed by the Biostatistics unit of BIOTRIAL 
BIOMETRICS in agreement with the Sponsor. 
The SAP will be validated and signed before the study database is locked. 
 
2. Study objectives 
2.1. Primary objectives 
The primary objectives are:  
o Part 1: To assess the safety and tolerability of Ir-CPI following a single ascending 6-
hour intravenous infusion in healthy male participants. 
o Part 2: To assess the safety and tolerability of Ir-CPI following a combination of rapid 
(30 minutes) and slow (5.5 hours) intravenous infusion over a total of 6 hours in 
healthy male participants (see Note at the end of this section). 
2.2. Secondary objectives 
Secondary objectives are: 
o Part 1: To assess the pharmacokinetics (PK) of Ir-CPI following single ascending 6-
hour intravenous infusion in healthy male participants. 
o Part 2: To assess the PK of Ir-CPI following a combination of rapid (30 minutes) and 
slow (5.5 hours) intravenous infusion over a total of 6 hours in healthy male 
participants (see Note at the end of this section). 
o Investigate the preliminary pharmacodynamics (PD) of Ir-CPI in healthy male 
participants using a validated method according to the Food and Drug Administration 
(FDA) guidelines 2018 for activated Partial Thromboplastin Time (aPTT). Inhibition 
of Factor XI (FXI) and Factor XII (FXII) procoagulant activities will also be assessed 
to support the aPTT dynamics. 
2.3. Exploratory objectives 
Exploratory objectives are: 
o Investigate the potential of Ir-CPI to induce the formation of anti-drug antibodies 
(ADA), including their capability to neutralize drug activity. 
o Investigate the effect of Ir-CPI on markers related to the coagulation system. 
o Investigate the effect of Ir-CPI on biomarkers of renal injury. 
o Investigate the effect of Ir-CPI on inflammatory markers. 


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o Assess the PK of Ir-CPI in urine. 
o PK PD relationship (graphical analyses). 
 
Note: Only the Part 1 was performed with 4 cohorts (A, B, C and D) (instead of Part 1 with 5 
cohorts and Part 2 with 3 cohorts) and with the following doses discussed during SRC 
meetings: 
· Cohort A: Ir-CPI 1.5 mg/kg; 
· Cohort B: Ir-CPI 3 mg/kg; 
· Cohort C: Ir-CPI 6 mg/kg; 
· Cohort D: Ir-CPI 9 mg/kg. 
Consequently, in all the following descriptions, only the Part 1 will be detailed in this SAP. 
 
3. Study methodology 
3.1. Study design 
This study is a First-In-Human (FIH) Phase 1, double-blind, placebo controlled, single dose 
escalation study of Ir-CPI in healthy male participants. 
 
The study will consist of: 
Ø Part 1: an Ir-CPI or matching placebo single ascending dose administration in healthy 
male participants using a continuous 6-hour intravenous infusion. 
 
The flowchart of this study is detailed in section 16.1. 
 
In all the following descriptions, the term postdose is defined as « after start of infusion ». 
The terms panel and cohort can be used interchangeably. 
3.2. Randomisation 
For this double blind, placebo-controlled, ascending dose trial of single dose infusions of Ir-
CPI/Placebo, the participants will be randomised taking into account the specific requirements 
for the sentinel groups. 
 
Four (4) panels (A to D), each consisting of eight (8) healthy male participants will be 
randomised to receive either Ir-CPI or matching placebo: first, 2 sentinel participants (1:1 
active / placebo) then for the rest of the group, a 5:1 ratio (active / placebo). The four (4) 
panels will be administered Ir-CPI/Placebo in a sequential group design.  
 
3.3. Treatment(s) received 
An Ir-CPI or matching placebo single ascending dose will be administered to the participants 
using a continuous 6-hour intravenous infusion. 
Each of the four (4) panels will receive: 
- 
Cohort A: Ir-CPI 1.5 mg/kg; 
- 
Cohort B: Ir-CPI 3 mg/kg; 
- 
Cohort C: Ir-CPI 6 mg/kg; 
- 
Cohort D: Ir-CPI 9 mg/kg. 
 


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3.4. Visits 
For cohorts from A to D, the study will include the following visits (see section 16.1.1): 
 
Cohorts A, B and C 
Cohort D 
Screening 
from Day-28 to Day -2 (Visit V1) 
Randomisation 
Day 1 (pre-dose, Visit V3) 
Treatment period 
from Day -1 (Visit V2) to 
Day 5 (Visit V7) 
from Day -1 (Visit V2) to 
Day 7 (Visit V8) 
Discharge visit 
Day 10 (± 2 days) (Visit V8) 
Day 10 (± 2 days) (Visit V9) 
Extra ambulatory visits for 
ADA analysis 
Day 30 (± 3 days) (1 month, 
Visit V9) 
Day 90 (± 7 days) (3 months, 
Visit V10) 
Day 180 (± 7 days) (6 
months, Visit V11) 
Day 30 (± 3 days) (1 month, 
Visit V10) 
Day 90 (± 7 days) (3 months, 
Visit V11) 
Day 180 (± 7 days) (6 
months, Visit V12) 
All participants will receive a single intravenous dose of Ir-CPI/Placebo at Day 1, given as a 
6-hour infusion. 
 
4. Sample Size 
The number of participants is not based on statistical power considerations. A sample size of 
8 participants per panel (i.e., 6 active and 2 placebo) was chosen based on the design of 
similar SAD studies and is considered adequate to provide an initial assessment of the safety 
and tolerability profile of Ir-CPI. 
 
5. Changes to the planned analysis from protocol  
The following changes are added compared to the planned analysis detailed in the study 
protocol: 
o Addition of the Screened set (defined as all of the subjects having signed an informed 
consent form) (see section 7.1). 
o Orthostatic hypotension and abnormal HR will not be derived because there are not 
standing vital signs measured during the study. 
o Only the Part 1 was performed with 4 cohorts (A, B, C and D) (instead of Part 1 with 
5 cohorts and Part 2 with 3 cohorts) and with the following dose modifications 
discussed during SRC meetings (see minutes of these meetings): 
- 
Cohort A: Ir-CPI 1.5 mg/kg; 
- 
Cohort B: Ir-CPI 3 mg/kg; 
- 
Cohort C: Ir-CPI 6 mg/kg; 
- 
Cohort D: Ir-CPI 9 mg/kg. 
o In exploratory objectives, the investigation of the ADA capability to neutralize drug 
activity was not performed, and the assessment of the PK of Ir-CPI in urine was also 
not done. 
o Addition of statistical analysis of AUC0-96h and AUC0-last (see section 9.2.2). 


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6.  Statistical considerations 
6.1. Software environment 
Statistical analyses (demography, pharmacodynamics, safety and tolerability data) will be 
performed using SASâ software version 9.4 (SAS institute Inc. Cary NC USA). 
PK parameters will be calculated using Phoenixâ WinNonlinâ version 8.1 (Certara USA, Inc., 
Princeton, NJ) and will be analysed using SASâ version 9.4 (SAS Institute Inc., Cary, NC, 
USA). 
 
6.2. Descriptive statistics and data listings 
Descriptive statistics will be supplied according to the nature of the criteria: 
- 
Quantitative variable: sample size, arithmetic mean, standard deviation (SD), standard 
error of the mean (SEM), minimum, median and maximum, and [quartiles if necessary 
with geometric mean, arithmetic and geometric coefficients of variation (CV), and 
quartiles for PK parameters]. 
- 
Qualitative variable: sample size, absolute and relative frequencies per class. Percentages 
will be provided with one decimal place. 
If the sample size of one treatment group is less than or equal to 2, only the number of 
observed values, the minimum and the maximum will be presented for quantitative variables 
and the percentage of subjects will not be presented for qualitative variables. 
Unless specified otherwise, the calculation of percentages will be based on the number of 
observed values. Therefore, counts of missing values will be included in the denominator and 
displayed as a separate category if any. 
 
Data will be organised by treatment group: 
· Pooled Placebo; 
· Ir-CPI 1.5 mg/kg; 
· Ir-CPI 3 mg/kg; 
· Ir-CPI 6 mg/kg; 
· Ir-CPI 9 mg/kg. 
 
All demographic, pharmacokinetics, pharmacodynamics, safety and tolerability listings will 
be sorted by treatment group, subject and measurement time if applicable. 
All listings containing an evaluation date will display the study day defined as the day relative 
to the administration of study drug: 
- Study day 1 will be defined as the day of the study product administration date; 
- Study day -1 will be defined as the day prior to the study product administration date; 
- There will be no study day 0. 
6.3. Handling of missing and retest values 
No management of missing values or values below/above a limit of detection/quantification 
will be performed, except for pharmacokinetic values (see section 0). 
For all parameters and for subjects with retest values, the last reliable value will be used for 
the measurement time before the study drug administration (provided it was measured before 


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the study drug administration) and the first reliable value will be used for the measurement 
time after the study drug administration. 
6.4. Handling of incomplete dates 
No management of incomplete dates will be performed. The incomplete dates will be labelled 
as such in the listings.  
If the start date of a medication or an adverse event is missing or incomplete and the end date 
is missing, on or after the study drug administration, it will be considered as 
concomitant/treatment emergent. 
6.5. Baseline definition 
For all parameters, baseline will be defined as the last available measurement prior to the IMP 
administration. 
6.6. Duration 
Duration (in days, hh:mm) will be calculated by the difference between the start and stop date 
and time (e.g. duration of AE [days, hh:mm] = end of AE date and time – AE onset date and 
time). 
Duration (in days) will be calculated by the difference between the start and stop date + 1 
(e.g. duration of a medication [days] = end of medication date – onset of medication date + 1). 
6.7. Type I error rate 
Unless stated otherwise, statistical tests will be two-sided and will be carried out at the 5 % 
level of significance. 
 
7. Description of study subjects 
7.1. Definition of analysis sets 
The following analysis sets will be defined: 
· Screened set: all of the subjects having signed an informed consent form (ICF). 
· Included set (IS): all the included participants who have signed an ICF. 
· Randomised set (RS): all the randomised participants. 
· Safety set (SS): all the included participants who have received at least a partial dose 
of IMP (Ir-CPI or placebo). 
· Pharmacodynamic set (PDS): all the included participants who have completed the 
study without any protocol deviation affecting PD evaluation and with at least one 
available post-baseline PD data. 
· Pharmacokinetic set (PKS): all of the included participants who have been 
administered a complete infusion of IMP without major protocol deviation affecting 
PK evaluation. The inclusion of the subjects with incomplete PK profile(s) or 
incomplete infusion will be discussed before the PK concentration dataset is locked. 
The analysis sets will be precisely defined and validated during the blind review meeting. 
The safety and pharmacokinetic sets will be analysed using subjects as treated. The 
randomised and pharmacodynamic sets will be analysed using subjects as randomised. 


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7.2. Subject disposition 
Subject disposition will be described. 
A summary table with the description of the number of screened participants, the number of 
included participants, the number of randomised participants, the number of participants who 
completed the study and the number of participants who discontinued the study, classified by 
main reason of withdrawal, will be prepared by treatment group and overall for the subjects in 
the IS. Corresponding individual listings will be provided.  
A summary table with the description of the number and percentage of subjects in each 
analysis set (IS, RS, SS, PDS and PKS) will be prepared by treatment group and overall. A 
specific listing of subjects excluded from analysis sets will be provided with the reason(s) for 
exclusion. 
A summary table with the number and percentage of subjects at each visit will be prepared by 
treatment group and overall on the subjects in the RS. A specific listing with discontinued 
participants will be prepared. Listings with analysis sets, end of study status and visit dates 
will also be generated.  
7.3. Protocol deviations 
A summary table by treatment group and overall with the number and percentage of subjects 
presenting deviations relating to inclusion/exclusion criteria will be prepared for the subjects 
in the RS. A summary table by treatment group and overall with the number and percentage 
of subjects presenting other protocol deviations (all deviations judged relevant during the 
blind review meeting) will also be prepared by status of the deviations (minor/major). The 
corresponding listings will be provided with the status of the deviations. 
8. Demographic data and baseline characteristics 
The analyses of the demographic and baseline characteristics will be performed on the 
Randomised set. 
8.1. Demographic data 
The participants’ demographic characteristics (age, sex, ethnicity, race, height, weight and 
BMI recorded at screening) will be summarised by treatment group and overall, and listed. 
8.2. Other baseline characteristics 
All parameters recorded before dosing (subjects’ habits like tobacco, alcohol and caffeine 
consumption, diet) will be summarised by treatment group and overall, and listed. 
Abnormal or positive results as well as all individual data for serology (presence of HIV 
antibodies, hepatitis B surface antigen (HBsAg), and hepatitis C virus (HCV) antibodies), 
urine drug screen (amphetamines, benzodiazepine, cocaine, opiates, barbiturate and 
cannabinoids) and alcohol breath test will be listed. 
Birth control method will also be listed. 
8.3. Medical and surgical history and procedures 
Information on medical and surgical history (including blood donation) recorded at the 
screening visit and procedures will be coded according to the Medical Dictionary for 
Regulatory Activities (MedDRA) Version 22.0. 


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A table with the number and percentage of subjects having at least one previous/ongoing 
medical history or one surgical history will be generated by treatment group and overall. 
Previous/ongoing medical history will be listed as well as prior surgeries and concomitant 
surgeries. 
8.4. Previous and concomitant medications 
Information on previous and concomitant medications will be coded according to the WHO 
drug Dictionary version of March 2019. 
A previous medication will be defined as a relevant treatment received by the participant 
within 2 weeks before the study product administration. A concomitant medication will be 
defined as a medication the participant takes during the study and until the  last extra 
ambulatory V11 visit only if related to a reported AE, other than the study drugs, including 
any prescription or over-the counter drug (including vitamins, herbal and mineral 
supplements). If the date value does not allow allocation of a medication to the previous or 
concomitant category (missing or incomplete start or end date), this medication will be 
considered concomitant. 
A table with the number and percentage of subjects having taken at least one previous 
medication and a table with the number and percentage of subjects having taken at least one 
concomitant medication will be generated by treatment group and overall (overall and by 
medication class [2nd level of Anatomical Therapeutic Chemical (ATC)] and medication drug 
name). Previous and concomitant medications will be listed separately.  
8.5. Compliance 
A listing with IMP administration dates and times will be generated. Time of meals intake 
will also be listed. 
 
9. Pharmacokinetic data 
The pharmacokinetic analysis will be performed on the PKS. 
9.1. Generalities 
The following rules for PK parameter calculation will be used: 
- 
Actual sampling times will be used for deriving PK parameters. 
- 
If an entire concentration-time profile is below the limit of quantification (BLQ), BLQ 
values will not be replaced and the profile will be excluded from the PK analysis. 
- 
 For plasma concentrations, all BLQ values occurring prior to the first detectable 
concentration and negative values will be replaced by “0”. 
- 
 Embedded BLQ values (BLQ values between two measurable concentrations) will be 
treated as missing. 
- 
All BLQ values occurring after the first detectable plasma concentration at the end of 
infusion: if there are several consecutives ones, the first one will be replaced by the lower 
limit of quantification (LLOQ) divided by 2 (“LLOQ/2”) and the following ones by 
missing.  
- 
If the pre-dose concentration is • 5 % of the Cmax value for a particular subject, that 
subject’s data, without any adjustments, may be included in all pharmacokinetic and 


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statistical analysis. If the pre-dose value is > 5 % of Cmax, two analyses will be performed: 
one with the pre-dose value and the other one with the pre-dose value replaced by 0. 
- 
If there are late positive concentration values following 2 BLQ concentration values in the 
terminal phase, these values will be evaluated. If these values are considered to be 
anomalous, they will be set to missing. 
- 
Some conditions for PK parameters have to be fulfilled: 
1) the percentage of the extrapolated AUC should not exceed 20 % of the AUC0-inf of 
each individual profile, 
2) the elimination rate constant should be determined over a time interval equal to at least 
2 x t1/2, 
3) the determination of "z should use only those data points judged to describe the 
terminal log-linear decline resulting in an adjusted coefficient of determination value 
R² > 0.7, and a minimum of 3 data points will be used in calculating "z excluding Cmax. 
If these conditions are not fulfilled, the following unreliable PK parameters will not be 
calculated, will be considered not determined (ND) in the listings and will be excluded 
from the analysis: 
1) if extrapolated AUC > 20 %: AUCext, AUC0-inf, CL and Vdz; 
2) if the time interval used for the determination of the elimination rate constant is 
inferior to 2 x t1/2 or if the adjusted R² < 0.7: "z, t1/2, AUC0-inf, R², CL and Vdz. 
 
The following rules for plasma concentration versus time graphic representation will be 
used: 
- 
No graphic representation will be done if all values are BLQ. 
- 
BLQ values occurring prior to the first detectable concentration will be replaced by “0”. 
- 
 Embedded BLQ values (BLQ values between two measurable concentrations) will be 
treated as missing. 
- 
All BLQ values occurring after the first detectable plasma concentration at the end of 
infusion: if there are several consecutives ones, the first one will be replaced by the lower 
limit of quantification (LLOQ) divided by 2 (“LLOQ/2”) and the following ones by 
missing. 
 
The following rules for mean plasma concentration calculation will be used: 
For BLQ concentrations before the first detectable concentration: 
- 
If more than (or equal to) half of the values are either BLQ values replaceable by zero 
and/or numeric values: statistics will be calculated with the replaceable and numeric 
values. 
- 
 If more than half of the values are BLQ values not replaceable by zero (i.e., subjects for 
whom all values are BLQ): only the maximum will be presented and the other statistics 
will be considered BLQ. 
For BLQ concentrations after the first detectable concentration: 
- 
If more than (or equal to) half of the values are not BLQ: statistics will be calculated with 
missing and replaced BLQ values. 


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- 
 If more than half of the values are BLQ: only the maximum will be presented and the 
other statistics will be considered BLQ. 
 
For summary statistics for PK parameters: 
- 
 If more than (or equal to) half of the values are not ND and not missing: statistics will be 
calculated with the available values. 
- 
If more than half of the values are ND or missing: only the minimum, median and 
maximum of the available numeric values will be presented. All other statistics will not be 
calculated and will be presented as ND. 
All BLQ concentrations and missing data will be labelled as such in the concentration data 
listings. 
 
9.2. Plasma concentrations and pharmacokinetic parameters 
9.2.1. Plasma PK parameters 
Blood samples will be drawn (see section 16.1):  
Ø For cohorts A, B and C:  
- 
on Day 1 at pre-dose then post-dose (after start of infusion) at H0.5, H1, H1.5, H2, 
H4, H6, H6.5, H7, H7.5, H8, H10, H12, H16, then at D2 (H24), D3 (H48), D4 
(H72) and D5 (H96).  
In case of infusion less than 6 hours, blood sample for Ir-CPI pharmacokinetics 
will be done at the end of infusion then H0.5, H1, H1.5, H2, H4, H6, H10, H18, 
H42, H66 and H90 after the end of infusion. 
 
Ø For cohort D: 
- 
on Day 1 at pre-dose then post-dose (after start of infusion) at H0.5, H1, H1.5, H2, 
H4, H6, H6.5, H7, H7.5, H8, H10, H12, H16, then at D2 (H24), D3 (H48), D4 
(H72), D5 (H96) and D7 (H144).  
In case of infusion less than 6 hours, blood sample for Ir-CPI pharmacokinetics 
will be done at the end of infusion then H0.5, H1, H1.5, H2, H4, H6, H10, H18, 
H42, H66, H90 and H138 after the end of infusion. 
 
Relevant plasma pharmacokinetic (PK) parameters will be calculated for Ir-CPI by non-
compartmental methods, as appropriate for those participants with sufficient plasma 
concentration data. The rules defined in the previous section (0) will be used. 
The different areas under the concentration-time curve (AUC) will be calculated using the 
linear trapezoidal summation (both the ascending phase and the descending phase). 
 
The following plasma pharmacokinetic parameters will be calculated for Ir-CPI:  
Parameters (unit) 
Definition 
Cmax (ng.mL) 
Maximum observed plasma concentration 
tmax (h) 
Time to reach maximum observed plasma concentration 
AUC0-6h (ng/mL.h) 
Area under the plasma concentration-time curve from time zero to 6 
hours 
AUC0-last (ng/mL.h) 
Area under the plasma concentration-time curve from time zero to the 
last measurable plasma concentration 


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Parameters (unit) 
Definition 
AUC0-96h (ng/mL.h) 
Area under the plasma concentration-time curve from time zero to 96 
hours (in order to be comparable between all the 4 cohorts) 
AUC0-144h (ng/mL.h) 
Area under the plasma concentration-time curve from time zero to 
144 hours (only for Cohort D) 
AUC0-inf (ng/mL.h) 
Area under the plasma concentration-time curve from time zero to 
infinity, calculated as follows:  
AUC0-inf = AUC0-last + Clast/ z, 
where Clast is the last quantifiable concentration 
t1/2 (h) 
Terminal elimination half-life, calculated as follows:  
t1/2 =!Ln(2)/ z 
 z (h-1) 
Terminal elimination rate constant 
CL (L/h) 
Total body clearance, calculated as follows: 
CL = Dose / AUC0-inf 
Vdz (L) 
Volume of distribution, calculated as follows: 
Vdz =!CL!/! z 
9.2.2. Plasma pharmacokinetic analysis 
The plasma pharmacokinetic analysis will be performed on the PKS set. 
 
Subjects receiving placebo will not be included in the summary and analysis of PK 
parameters. Listings with plasma concentrations (including dates and times of PK blood 
sampling) and PK parameters will be provided by treatment group and subject. These listings 
will be generated for all subjects with an available PK profile (complete or incomplete), 
including those who are excluded from the PKS. 
 
Plasma concentrations and PK parameters of Ir-CPI including descriptive statistics will be 
presented in tables separately for each treatment group. 
Individual plasma concentration versus time profiles of Ir-CPI will be presented graphically 
on linear and log/linear coordinates for each subject. 
The graph of arithmetic mean ± SEM over time will be provided for plasma concentration of 
Ir-CPI on linear and log/linear coordinates with all treatment groups (cohorts A, B, C and D) 
on the same graph. A reference line corresponding to the lowest Cmax values at the NOAEL 
(No Observed Adverse Effect Level), i.e. 53.7µg/mL will be added on the graph of mean and 
individual concentration-time profiles on log/linear coordinated only. 
A graph of arithmetic mean ± SEM with min-max curves over time will be provided for 
plasma concentration of Ir-CPI for each treatment group on linear coordinates.  
Individual plasma concentration-time profiles (spaghetti plots) of Ir-CPI will also be 
presented for each treatment group on linear coordinates. 
Box whisker plots will be generated for the comparison of Cmax, AUC0-6h , AUC0-96h, AUC0-last 
and AUC0-inf. 
 
The linear dose-proportionality of the maximum concentration (Cmax) and the areas under the 
concentration-time curve (AUC0-6h, AUC0-96h, AUC0-last and AUC0-inf) will be assessed for Ir-
CPI using an exponential regression model ("power model") that measures the degree of non-
linear proportionality [2]. The PK parameter and dose values will be logarithmically 


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transformed prior to analysis and evaluated using a 1-factor analysis of variance (ANOVA) 
including log (dose) as fixed effect and subject as random effect. 
Linear dose-proportionality will be concluded if the two-sided 90 % confidence interval (CI) 
for the slope value of the log-transformed dose is within the critical [(1+ln(LL)/ln(r)) ; 
(1+ln(UL)/ln(r))] region, where r = Dose Maximum/Dose Minimum, LL = 0.8 and UL = 1.25 
[2]. 
The following SAS® code will be used: 
proc mixed data=ADPP method=REML; 
 
by PARAMCD; 
class USUBJID; 
 
model ln(AVAL) = ln(dose) / solution cl alpha=0.10 ddfm=kr; 
 
random USUBJID; 
run; 
 
10. Pharmacodynamics data 
The pharmacodynamic analysis will be performed on the PDS set. 
PD aPTT, Factor XI and Factor XII inhibition will be measured by the change from baseline 
(central lab). PD aPTT and FXI/FXII parameters will be measured (see section 16.1): 
Ø For cohorts A, B and C: 
- 
on D1, pre-dose then at 30min, 60min, 90min, 2h, 4h, 6h, 6h30, 7h, 7h30, 8h, 10h, 
12h, 16h post-dose, then on D2 (24h), D3 (48h), D4 (72h), D5 (96h) and discharge 
visit (D10 ± 2 days) (see section 16.1).  
In case of infusion less than 6 hours and besides assessment at pre-dose, 30 min, 
60 min, 90 min, 2h and 4h after start of infusion, parameters should be measured at 
the end of infusion, then 30min, 60 min, 90min, 2h, 4h, 6h, 10h, then 18h, 42h, 
66h and 90h after the end of infusion and then at the discharge visit. 
 
Ø For cohort D: 
- 
on D1, pre-dose then at 30min, 60min, 90min, 2h, 4h, 6h, 6h30, 7h, 7h30, 8h, 10h, 
12h, 16h post-dose, then on D2 (24h), D3 (48h), D4 (72h), D5 (96h), D7 (144h) 
and discharge visit (D10 ± 2 days) (see section 16.1).  
In case of infusion less than 6 hours and besides assessment at pre-dose, 30 min, 
60 min, 90 min, 2h and 4h after start of infusion, parameters should be measured at 
the end of infusion, then 30min, 60min, 90min, 2h, 4h, 6h, 10h, then 18h, 42h, 
66h, 90h and 138h after the end of infusion and then at the discharge visit. 
For each time point, including the baseline time point, an aPTT ratio will be calculated by 
dividing the aPTT value (in sec) of the specific time point (aPTT*) by the baseline aPTT 
value (in sec) (aPTT°) of the same volunteer (aPTT ratio = aPTT*/aPTT°). The baseline time-
point is considered as having an aPTT ratio of 1. A graphical representation of aPTT ratio in 
function of the time will be done per volunteer. The mean ± SEM, min and max curves will 
be also represented for each cohort on separate graphs. The mean ± SEM curves of all cohorts 
(A, B, C, D) will be also represented on one graph. 
Concerning FXI and FXII PD parameters, a graphical representation of individual data of FXI 
activity in each cohort, in function of the time, will be done. Another graphical representation 
of FXII activity in each cohort, in function of the time, will be done. In these graphs, the 
normal lower ranges of FXI and FXII activities will be indicated as horizontal lines. 


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Moreover, FXI or FXII inhibition, expressed in percentages, for each time point (including 
the baseline time point), has to be calculated for each volunteer. To do so, the calculation is 
the following: 
· Percentage of FXI inhibition= (100-((FXI*/FXI°)*100) 
· Percentage of FXII inhibition= (100-((FXII*/FXII°)*100) 
FXI* or FXII*: FXI or FXII percentage of inhibition of a specific time point 
FXI° or FXII°: FXI or FXII percentage of inhibition of the baseline time point 
The baseline time point is considered as 0 % of FXI or FXII inhibition. A graphical 
representation of FXI or FXII inhibition, expressed as percentages, in function of the time will 
be done per volunteer. The mean ± SEM, min and max curves will be also represented for 
each cohort on separate graphs. The mean ± SEM curves of all cohorts (A, B, C, D) will be 
also represented on a same graph. 
Descriptive statistics of changes from baseline will be provided by treatment group and each 
measurement time for changes from baseline of aPTT ratio and absolute values. 
Descriptive statistics will be provided by treatment group on each measurement time for 
aPTT values (absolute values and changes from baseline), aPTT ratio (ratio values and 
changes from baseline of ratios) and percentage of FXI or FXII inhibition (calculated 
percentages and changes from baseline of percentages). 
All pharmacodynamics parameters will be listed. 
 
11. Exploratory Pharmacokinetic / Pharmacodynamic analysis 
Evaluation of the relationship between concentrations of Ir-CPI and the PD parameters: the 
change from baseline in coagulation parameters (i.e. aPTT ratio) defined above, FXI and FXII 
inhibition will be graphically investigated and displayed. The analysis will be performed on 
the PDS. 
 
12. Exploratory Biomarkers Evaluation 
The exploratory biomarkers evaluation will be performed on the PDS. 
The following exploratory outcome measurements are defined: 
- 
In blood: D-dimers, fibrinogen, prothrombin time PT (expressed in seconds and as 
INR), TNF , hsCRP, cystatin C (CysC), ADA. 
- 
In urine: Urinary microalbumin, Kidney Injury Molecule (KIM-1), Urinary 
Neutrophil Gelatinase-Associated Lopocalin (NGAL).  
Samples for D-dimers, fibrinogen, PT, hsCRP and TNF  will be collected at pre-dose on D1 
and then 2h, 4h, 6h, 8h, 12h post-dose, at 24h (D2), at 48h (D3), at 72h (D4) discharge visit 
(D10 ± 2 days) (see section 16.1). 
CysC samples will be collected at screening, then from D1 to D4: pre-dose (D1), 24h (D2), 
72h postdose (D4), and then at the discharge visit (D10±2 days) (see section 16.1). 
ADA analysis samples will be collected at pre-dose on the day of infusion, at the discharge 
visit (D10 ± 2 days), on D30 and on D90. If ADAs are detected in D90 samples, ADA 
analysis samples will be collected also at D180 (see section 16.1). 


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Urine collections will be done at these intervals pre-dose, [0-6h[, [6-12h[ and [12-24h[ after 
start of infusion. Urinary NGAL, microalbuminuria and KIM-1 will be assessed (see section 
16.1). 
 
For each parameter, descriptive statistics will be provided by treatment group on absolute 
values and changes from baseline for each measurement time. Graph over time by treatment 
group will be also produced. 
Presence of ADA (and their titration for ADA+ samples) and sub-classes determination 
(isotype) will be described by treatment group and measurement time. 
All exploratory parameters will be listed. 
 
13. Safety data 
The safety analyses will be performed on the SS. 
13.1. Adverse events 
Adverse events, including pre-treatment events, will be recorded from the time of consent 
through the end of the study. 
Adverse events will be coded according to MedDRA Version 22.0. 
A treatment-emergent adverse event (TEAE) is an adverse event that occurs after IMP dosing 
or that was present prior to dosing but was exacerbated between dosing during a treatment 
period and the end of the study. 
 
Adverse events (including AESIs) will be summarised in tables as follows [overall and by 
System Organ Class (SOC) and Preferred Term (PT)]: 
- 
Number and percentage of subjects with at least one adverse event and number of 
occurrences of an adverse event by treatment group and overall, 
- 
Number and percentage of subjects with at least one TEAE and number of 
occurrences of a TEAE by treatment group and overall, 
- 
By intensity, with the number and percentage of subjects with at least one TEAE and 
number of occurrences of a TEAE by treatment group and overall, 
- 
By causality, with the number and percentage of subjects with at least one TEAE and 
number of occurrences of a TEAE by treatment group and overall. 
If there are only a few adverse events (! 10), only a listing will be generated. 
All adverse events reported in the Case Report Form (CRF) will be listed with the SOC, the 
PT and the Investigator's verbatim. All TEAEs will also be listed with the SOC and the PT. 
An additional listing will be provided for AEs leading to death and other serious and 
significant AEs (SAEs or AEs leading to study withdrawal). 
Note: In case of a change of intensity or causality for an event during the treatment period, 
the intensity will be the highest recorded intensity and the causality will be the highest 
likelihood recorded. 


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13.2. Clinical laboratory data 
The following clinical laboratory parameters will be measured at screening, then from D1 to 
D4: pre-dose (D1), 24h (D2), 72h post-dose (D4), and then at the discharge visit (D10 ± 2 
days) (see section 16.1). 
Haematology parameters will be listed and grouped as follows: 
- Red blood cells: erythrocytes (10^12/L), haematocrit (ratio), hemoglobin (g/L); 
- White blood cells: basophils (10^9/L), basophils/leukocytes (%), eosinophils (10^9/L), 
eosinophils/leukocytes 
(%), 
leukocytes 
(10^9/L), 
lymphocytes 
(10^9/L), 
lymphocytes/leukocytes (%), monocytes (10^9/L), monocytes/leukocytes (%), neutrophils 
(10^9/L) and neutrophils/leukocytes (%); 
- Other parameters: platelets (10^9/L). 
Coagulation parameters will be listed and grouped as follows: 
- Coagulation parameters: activated Partial Thromboplastin Time (sec) and aPTT ratio (see 
calculation in section 10). 
Blood chemistry parameters will be listed and grouped as follows: 
- Liver function: alanine aminotransferase (ALT) (IU/L), alkaline phosphatase (IU/L), 
aspartate aminotransferase (AST) (IU/L), total bilirubin (fraction of direct bilirubin in case > 
1.25 x ULN) (µmol/L) and gamma glutamyl transferase (GGT) (IU/L), lactate dehydrogenase 
(LDH) (IU/L); 
- Renal chemistry: creatinine (µmol/L) and urea (mmol/L); 
- Electrolytes: bicarbonate, calcium, chloride, phosphorus, potassium and sodium (all 
electrolytes expressed in mmol/L); 
- Metabolism parameters: fasting glucose (mmol/L); 
- Other proteins: albumin (g/L), creatine kinase (and fraction of CK-MB if > 1.5 x ULN) 
(IU/L) and total protein (g/L). 
Urinalysis parameters will be listed and grouped as follows: 
- Planned urinalysis parameters: cylinders, erythrocytes and leucocytes. 
 
For haematology, blood chemistry and coagulation, absolute values and changes from 
baseline will be described by treatment group (and overall) and measurement time.  
For urinalysis, absolute values will be described by summary statistics or frequency tables by 
treatment group and measurement time. 
For haematology, blood chemistry, coagulation and urinalysis, values higher or lower than the 
laboratory reference range (H, L) will be listed. 
For haematology and blood chemistry, a summary table with the number and percentage of 
subjects with potentially clinically significant abnormal (PCSA) values (defined in section 
16.2) will be generated by treatment group (and overall) and measurement time.  
For haematology and blood chemistry, shift tables with the number of subjects having values 
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(defined in section 16.2) according to the baseline position will be prepared by treatment 
group and measurement time. 
A specific listing of subjects with PCSA values will be generated. 
Values (absolute values and changes from baseline) will be listed and data out of 
normal/PCSA ranges will be flagged with clinical significance information. 
Urinalysis values will be listed. 
13.3. Other safety parameters 
13.3.1. Vital signs data 
Supine systolic and diastolic blood pressure (mmHg), heart rate (beats/min) and body 
temperature (C°) will be measured at screening, then from D1 to D4 (pre-dose, 60min, 2h, 4h, 
6h, 8h, 10h, 12h, 24h, 48h, 72h post-dose), and the discharge visit (D10 ± 2 days) (see section 
16.1). 
Weight will be measured at screening and the discharge visit (D10 ± 2 days). 
Absolute values and changes from baseline will be described by treatment group (and overall) 
and measurement time.  
Graphs of median ± SEM over time will be provided for changes from baseline with all 
treatment groups on the same graph. The median of all treatment groups will be also 
represented. 
A summary table with the number and percentage of subjects with PCSA values (defined in 
section 16.2) will be generated by treatment group and measurement time. 
A specific listing of subjects with PCSA values will be generated. 
Values (absolute values and changes from baseline) will be listed and PCSA values will be 
flagged with clinical significance information. 
13.3.2. Electrocardiogram data 
Supine 12-lead ECG parameters [including heart rate (beats/min), PR interval (msec), QRS 
duration (msec), QRS axis (deg), QTc interval (msec), Bazett QTc interval (QTcB) (msec) 
and Fridericia QTc interval (QTcF) (msec)] and ECG abnormalities will be recorded at 
screening, then on D1 (pre-dose, 2h, 4h, 6h, 8h, 12h), 24h (D2), 48h (D3), 72h (D4) post-dose 
and at the discharge visit (D10 ± 2 days) (see section 16.1). 
Only interpretable ECGs will be analysed. 
QTcB will be derived using the following formula:  
 
Absolute values and changes from baseline (except for QRS axis in degrees and ECG 
abnormalities) will be described by treatment group (and overall) and measurement time. 
Graphs of median ± SEM over time will be provided for changes from baseline with all 
treatment groups on the same graph. The median of all treatment groups will be also 
represented. 
A summary table with the number and percentage of subjects with PCSA values (defined in 
section 16.2) will be generated by treatment group and measurement time. 


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Shift tables with the number of subjects having values lower than the lower PCSA limit 
(Low), normal and higher than the upper PCSA limit (High) (defined in section 16.2) 
according to the baseline position will be prepared by treatment group and measurement time.  
A specific listing of subjects with PCSA values will be generated. 
Values [absolute values/ECG abnormalities and changes from baseline (except for QRS axis 
in degrees)] will be listed and data out of the PCSA ranges will be flagged with clinical 
significance information. 
13.3.3. Physical examination 
Physical examination will be performed at screening, D-1, D2, D3 (only for cohort D) and the 
discharge visit (D10 ± 2 days) (see section 16.1). 
Physical examination includes basic neurological testing for isocoria, light reflexes, gait and 
balance). 
Abnormal results for physical examination will be listed with clinical significance 
information. All individual data for physical examination will be listed and abnormalities will 
be flagged. 
13.3.4. Telemetry monitoring (including SpO2) 
Cardiac monitoring using telemetry (3-lead minimum and including SpO2) will be performed 
at Day 1 from 1h pre-dose up to 12h post-dose (see section 16.1). 
SpO2, non-artifact events [arrhythmias, bradycardia, tachycardia, pause, ventricular 
tachycardia (VT), supraventricular tachycardia (SVT)] will be described by treatment group 
(and overall) and measurement time. 
Abnormal results will be listed with clinical significance information. All individual data will 
be listed and abnormalities will be flagged. 
 
13.3.5. Occult blood in faeces 
Hemoccult® testing will be performed to investigate any presence of occult blood in faeces at 
screening and from D2 to D4 (see section 16.1). 
Absence/presence of occult blood in faeces will be described by treatment group (and overall) 
and measurement time. 
Abnormal results will be listed with clinical significance information. All individual data will 
be listed and abnormalities will be flagged. 
 
13.3.6. Exposure to tick bites 
Any absence/presence of exposure to tick bites at D1 pre-dose, the discharge visit (D10 ± 2 
days), and the extra ambulatory visits for ADA analysis (D30 ± 3 days, D90 ± 7 days and 
D180 ± 7 days) (see section 16.1) will be collected.  
An extra serology sample will be also collected at baseline for anti-Borrelia IgG and IgM 
assays for archiving only. Consequently, no statistical description will be performed. 
 
Absence/presence of exposure to tick bites will be described by treatment group (and overall) 
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14. Reporting conventions 
All tables, figures and listings are detailed in section 16.4. They will be prepared using SASâ 
software as rtf files and the rtf files will be compiled as PDF files (one PDF file by main 
section). 
The footers will be presented as follows: --- STUDY Clin_IrCPI_101 / <name of the 
program>.SAS / <name of the output>.RTF / DDMMMYY HH:MM ---. 
Table and Listing Page Set Up Requirements: 
- 
Font Type = Courier New 
- 
Font Size = 8 pt (at a minimum) 
- 
Page Margins: Top=2 cm; Bottom=2 cm; Left=2 cm; Right=2 cm 
- 
Paper Size = A4 (21 cm x 29.7 cm) 
- 
Page Orientation: Landscape 
- 
Graphs: Portable Network Graphics (PNG) format 
Summary statistics will be presented as follows.  
Parameter (unit) 
Statistics 
/ Category 
Group X 
(N=xx) 
Quantitative variable (unit)* 
n 
xx 
 
Mean+ 
xx.xx 
 
SD 
xx.xx 
 
SEM 
xx.xx 
 
Geometric Mean& 
xx.xx 
 
CV% Geometric mean& 
xx.xxx 
 
Median 
xx.xx 
 
Q1 ; Q3& 
xx.x ; xx.x 
 
Min ; Max 
xx.x ; xx.x 
Qualitative variable 
Class 1  n (%) 
xx (xx.x) 
 
Class 2  n (%) 
xx (xx.x) 
 
… 
… 
* All statistics, except the minimum and the maximum, will be provided with an additional 
decimal place compared to the variable itself. PK parameter coefficients of variation will be 
provided with one decimal place. 
+ For PK parameters only, “Arithmetic Mean” term will be specified in order to distinguish with 
the geometric mean. 
& To provide for PK parameters only. 
Box plots will be built as follows: 


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15. References 
[1] International Conference on Harmonisation of technical requirements for registration of 
pharmaceuticals for human use. ICH Harmonised tripartite guideline. Statistical Principles for 
Clinical Trials E9 – Current step 4 dated 5 February 1998. 
[2] Brian P. Smith, et al. Confidence interval criteria for assessment of dose proportionality. 
Pharmaceutical research. 2000 Oct;17(10):1278-1283. 
 
 


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16. Appendices  
16.1. Appendix 1 - Flow chart/Schedule of assessments of the study 
16.1.1. Part 1: Single 6-hour infusion for Cohorts A, B and C 
 


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16.1.2. Part 1: Single 6-hour infusion for Cohort D 
 


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16.2. Appendix 2 - Criteria for Potentially Clinically Significant Abnormalities (PCSA) 
PARAMETER 
LOWER PCSA VALUE 
UPPER PCSA VALUE 
Laboratory parameters 
AST 
 
³ 3 ULN and < 5 ULN (High) 
• 5 ULN and < 10 ULN (High+) 
• 10 ULN and < 20 ULN (High++) 
³ 20 ULN (High+++) 
ALT 
 
³ 3 ULN and < 5 ULN (High) 
• 5 ULN and < 10 ULN (High+) 
• 10 ULN and < 20 ULN (High++) 
• 20 ULN (High+++) 
Gamma GT 
 
³ 3 ULN 
Alkaline phosphatase 
 
³ 2 ULN 
Total bilirubin 
 
³ 2 ULN 
Creatinine 
 
³ 150 µmol/L 
Sodium 
£ 129 mmol/L 
³ 160 mmol/L 
Potassium 
< 3 mmol/L 
³ 5.5 mmol/L 
Glucose 
£ 3.9 mmol/L and < LLN  
³ 7 mmol/L  
Hemoglobin 
£ 100 g/L 
 
Platelets 
< 100 10^9/L 
 
Leukocytes 
< 3 10^9/L (< 2 10^9/L for Black 
or African American) 
 
Neutrophils 
< 1.5 10^9/L (< 1 10^9/L for Black 
or African American) 
 
Eosinophils 
 
> 0.5 10^9/L or > ULN if ULN > 0.5 
10^9/L 
aPTT value 
 
> 180 sec 
aPTT ratio 
 
> 3 
Vital signs 
Supine HR 
£ 40 beats/min and change from 
baseline £ -20 beats/min 
³ 100 beats/min and change from 
baseline ³ 20 beats/min 
Supine SBP 
£ 95 mmHg and change from 
baseline £ -20 mmHg 
³ 140 mmHg and change from baseline 
³ 20 mmHg 
Supine DBP 
£ 45 mmHg and change from 
baseline £ -10 mmHg 
³ 90 mmHg and change from baseline ³ 
10 mmHg 
ECG parameters 
HR 
£ 40 beats/min and change from 
baseline £ -20 beats/min 
³ 100 beats/min and change from 
baseline ³ 20 beats/min 
PR 
 
³ 220 msec  
QRS 
 
³ 120 msec 
QTc 
 
> 450 msec and • 500 msec (High) 
> 500 msec (High+) 
change from baseline > 30 msec and 
change from baseline • 60 msec (High) 
change from baseline > 60 msec (High+) 
 
 
 


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16.3. Appendix 3 – Normal ranges for vital signs and ECG parameters 
Vital signs 
Supine SBP 
90 • SBP • 150 mmHg 
Supine DBP 
50 • DBP • 90 mmHg 
Heart rate 
40 • HR • 100 
Tympanic temperature 
36.0 • T • 37.5 
ECG parameters 
HR 
40 bpm • HR • 100 bpm 
PR 
110 ms • PR • 220 ms 
QRS 
QRS • 120 ms 
QTcF 
QTc •  450 ms 
 
 


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16.4. Appendix 4 - List of tables, listings and figures included in the clinical study report 
NUMBER 
TITLE 
14 
TABLES, FIGURES AND GRAPHS REFERRED TO BUT NOT 
INCLUDED IN THE TEXT 
14.1 
Demographic data 
14.1.1 
Description of study subjects 
14.1.1.1 
Subject disposition – Included set 
14.1.1.2 
Analysis sets – Included set  
14.1.1.3 
Study visits – Randomised set 
14.1.2 
Protocol deviations 
14.1.2.1 
Deviations relating to inclusion/exclusion criteria – Randomised set 
14.1.2.2 
Other deviations – Randomised set 
14.1.3 
Demographic data and baseline characteristics 
14.1.3.1 
Demographic data – Randomised set 
14.1.3.2 
Other baseline characteristics 
14.1.3.2.1 
Subjects’ habits – Randomised set 
14.1.3.2.2 
Listing of positive serology results – Randomised set 
14.1.3.2.3 
Listing of positive urine drug screen results – Randomised set 
14.1.3.2.4 
Listing of positive alcohol breath tests – Randomised set 
14.1.3.3 
Medical and surgical history – Randomised set 
14.1.4 
Previous and concomitant medications 
14.1.4.1 
Previous medications – Randomised set 
14.1.4.2 
Concomitant medications – Randomised set 
14.2 
Pharmacokinetic and Pharmacodynamics data 
14.2.1 
Pharmacokinetic data 
14.2.1.1 
Plasma concentrations 
14.2.1.1.1 
Plasma concentrations for Ir-CPI – Pharmacokinetic set 
14.2.1.1.2 
Graphs of plasma concentration means (±SEM), min-max curves over 
time by treatment groups for Ir-CPI – Pharmacokinetic set 
14.2.1.1.3 
Graphs of plasma concentration means (±SEM) over time for Ir-CPI – 
Pharmacokinetic set 
14.2.1.1.4 
Individual plasma concentration-time profiles (spaghetti plots) for Ir-
CPI – Pharmacokinetic set 
14.2.1.2 
PK parameters in plasma 
14.2.1.2.1 
PK parameters in plasma for Ir-CPI – Pharmacokinetic set 
14.2.1.2.2 
Analysis of dose-proportionality for Cmax, AUC0-6h, AUC0-96h and 
AUC0-inf for Ir-CPI – Pharmacokinetic set 
14.2.1.2.3 
Box whisker plots of Cmax, AUC0-6h, AUC0-96h and AUC0-inf for Ir-CPI – 
Pharmacokinetic set 
14.2.2 
Pharmacodynamics data 


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NUMBER 
TITLE 
14.2.2.1 
Pharmacodynamic parameters for Ir-CPI – Pharmacodynamic set 
14.2.2.2 
Graphs of aPTT ratio means (± SEM), min and max curves over time 
by treatment groups – Pharmacodynamic set  
14.2.2.3 
Graphs of aPTT ratio means (± SEM) over time – Pharmacodynamic 
set 
14.2.2.4 
Graph of FXI and FXII inhibition means (± SEM), min and max values 
over time by treatment groups – Pharmacodynamic set 
14.2.2.5 
Graph FXI and FXII inhibition means (± SEM) values over time – 
Pharmacodynamic set 
14.2.2.6 
Individual aPTT ratio, FXI and FXII activities, FXI and FXII inhibition 
profiles (spaghetti plots) over time by treatment groups – 
Pharmacodynamic set 
14.2.3 
Exploratory analysis  
14.2.3.1 
Exploratory analysis Pharmacokinetic / Pharmacodynamic analysis 
14.2.3.1.1 
Graph of the relationship between treatment groups and concentrations 
of Ir-CPI and the change from baseline in coagulation parameters – 
Pharmacodynamic set 
14.2.3.2 
Exploratory Biomarker’s Evaluation 
14.2.3.2.1 
Biomarker parameters for Ir-CPI – Pharmacodynamic set 
14.2.3.2.2 
Graphs of biomarker means (±SEM) over time for Ir-CPI by treatment 
group – Pharmacodynamic set 
14.2.3.2.3 
Presence of ADA and their titration for ADA+ samples – 
Pharmacodynamic set 
14.2.3.2.4 
Sub-classes determination – Pharmacodynamic set 
14.3 
Safety data 
14.3.1 
Adverse events 
14.3.1.1 
Adverse events – Safety set 
14.3.1.2 
Treatment-emergent adverse events 
14.3.1.2.1 
Treatment-emergent adverse events – Safety set 
14.3.1.2.2 
Treatment-emergent adverse events by intensity – Safety set 
14.3.1.2.3 
Treatment-emergent adverse events by causality – Safety set 
14.3.1.3 
Adverse events of special interest – Safety set 
14.3.2 
Listing of deaths, other serious and significant adverse events – 
Safety set 
14.3.3 
Clinical laboratory data 
14.3.3.1 
Haematology 
14.3.3.1.1 
Summary statistics – Safety set 
14.3.3.1.2 
Listing of subjects presenting abnormal values – Safety set 
14.3.3.1.3 
Number and percentage of subjects with PCSA values – Safety set 
14.3.3.1.4 
Shift tables (PCSA values) – Safety set 


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NUMBER 
TITLE 
14.3.3.1.5 
Listing of subjects presenting PCSA values – Safety set 
14.3.3.2 
Blood chemistry 
14.3.3.2.1 
Summary statistics – Safety set 
14.3.3.2.2 
Listing of subjects presenting abnormal values – Safety set 
14.3.3.2.3 
Number and percentage of subjects with PCSA values – Safety set 
14.3.3.2.4 
Shift tables (PCSA values) – Safety set 
14.3.3.2.5 
Listing of subjects presenting PCSA values – Safety set 
14.3.3.3 
Coagulation 
14.3.3.3.1 
Summary statistics – Safety set 
14.3.3.3.2 
Listing of subjects presenting abnormal values – Safety set 
14.3.3.4 
Urinalysis 
14.3.3.4.1 
Summary statistics – Safety set 
14.3.3.4.2 
Listing of subjects presenting abnormal values – Safety set 
14.3.4 
Other safety parameters 
14.3.4.1 
Vital signs data 
14.3.4.1.1 
Summary statistics – Safety set 
14.3.4.1.2 
Graphs of vital signs (median ± SEM) over time (changes from 
baseline) – Safety set 
14.3.4.1.3 
Number and percentage of subjects with PCSA values – Safety set 
14.3.4.1.4 
Listing of subjects presenting PCSA values – Safety set 
14.3.4.2 
Electrocardiogram data – Standard 12-lead ECG parameters 
14.3.4.2.1 
Summary statistics – Safety set 
14.3.4.2.2 
Graphs of ECG parameters (median ± SEM) over time (changes from 
baseline) – Safety set 
14.3.4.2.3 
Number and percentage of subjects with PCSA values – Safety set 
14.3.4.2.4 
Shift tables (PCSA values) – Safety set 
14.3.4.2.5 
Listing of subjects presenting PCSA values – Safety set 
14.3.4.3 
Physical examination 
14.3.4.3.1 
Listing of subjects presenting abnormal results – Safety set 
14.3.4.4 
Telemetry monitoring 
14.3.4.4.1 
Summary statistics – Safety set 
14.3.4.4.2 
Listing of subjects presenting abnormal results – Safety set 
14.3.4.5 
Occult blood in faeces 
14.3.4.5.1 
Summary statistics – Safety set 
14.3.4.5.2 
Listing of subjects presenting abnormal results – Safety set 


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NUMBER 
TITLE 
14.3.4.6 
Exposure to tick bites – Safety set 
16.1 
STUDY INFORMATION 
16.1.7 
Randomisation scheme and codes (subject identification and 
treatment assigned) – Randomised set 
16.1.9 
Documentation of statistical methods 
16.1.9.1 
Statistical analysis plan (integrated by the medical writer during the 
creation of the appendices of the clinical study report) 
16.1.9.2. 
ANOVA: Analysis of dose-proportionality for Cmax, AUC0-6h, AUC0-96h 
and AUC0-inf for Ir-CPI – Pharmacokinetic set 
16.2 
SUBJECT DATA LISTINGS 
16.2.1 
Subject disposition 
16.2.1.1 
Discontinued subjects – Included set 
16.2.1.2 
Subject disposition and analysis sets – Included set 
16.2.1.3 
End of study status – Included set 
16.2.1.4 
Subject visit dates – Included set 
16.2.1.5 
Screen failures – Screened set 
16.2.2 
Protocol deviations 
16.2.2.1 
Deviations relating to inclusion/exclusion criteria – Randomised set 
16.2.2.2 
Other deviations – Randomised set 
16.2.3 
Subjects excluded from analysis sets – Randomised set 
16.2.4 
Demographic data and baseline characteristics 
16.2.4.1 
Demographic data – Randomised set 
16.2.4.2 
Other baseline characteristics 
16.2.4.2.1 
Subjects’ habits – Randomised set 
16.2.4.2.2 
Serology – Randomised set 
16.2.4.2.3 
Urine drug screen – Randomised set 
16.2.4.2.4 
Alcohol breath test – Randomised set 
16.2.4.2.5 
Birth control method – Randomised set 
16.2.4.3 
Medical and surgical history and procedures 
16.2.4.3.1 
Medical history – Randomised set 
16.2.4.3.2 
Surgical history – Randomised set 
16.2.4.3.3 
Concomitant procedures – Randomised set 
16.2.4.4 
Previous and concomitant medications 
16.2.4.4.1 
Previous medications – Randomised set 
16.2.4.4.2 
Concomitant medications – Randomised set 


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NUMBER 
TITLE 
16.2.5 
Compliance and/or drug concentration data 
16.2.5.1 
Compliance and dosing data  
16.2.5.1.1 
IMP administration – Randomised set 
16.2.5.1.2 
Meals intake – Randomised set 
16.2.5.2 
Pharmacokinetic data 
16.2.5.2.1 
Plasma concentrations and pharmacokinetic parameters 
16.2.5.2.1.1 
Plasma concentrations – Randomised set 
16.2.5.2.1.2 
Individual plasma concentration-time curves – Pharmacokinetic set 
16.2.5.2.1.3 
PK parameters in plasma – Randomised set 
16.2.6 
Pharmacodynamics data 
16.2.6.1 
Pharmacodynamic parameters – Pharmacodynamic set 
16.2.6.2 
Exploratory biomarker parameters – Pharmacodynamic set 
16.2.7 
Adverse event listings 
16.2.7.1 
Treatment-emergent adverse events – Randomised set 
16.2.7.2 
Adverse events for special interest – Randomised set 
16.2.7.3 
All adverse events – Randomised set 
16.2.8 
Clinical laboratory data  
16.2.8.1 
Haematology 
16.2.8.1.1 
Normal ranges for SI units and local units 
16.2.8.1.2 
PCSA ranges 
16.2.8.1.3 
All haematology values (SI unit) – Randomised set 
16.2.8.2 
Blood chemistry 
16.2.8.2.1 
Normal ranges for SI units and local units 
16.2.8.2.2 
PCSA ranges 
16.2.8.2.3 
All blood chemistry values (SI unit) – Randomised set 
16.2.8.3 
Coagulation 
16.2.8.3.1 
Normal ranges for SI units and local units 
16.2.8.3.2 
PCSA ranges 
16.2.8.3.3 
All coagulation values (SI unit) – Randomised set 
16.2.8.4 
Urinalysis – Randomised set 
16.2.9 
Other safety parameters 
16.2.9.1 
Vital signs data – Randomised set 
16.2.9.2 
Electrocardiogram data - Standard 12-lead ECG parameters – 
Randomised set 


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NUMBER 
TITLE 
16.2.9.3 
Physical examination – Randomised set 
16.2.9.4 
Telemetry monitoring – Randomised set 
16.2.9.5 
Occult blood in faeces – Randomised set 
16.2.9.6 
Exposure to tick bites– Randomised set 
 


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B I O T R I A L DRUG EVALUATION AND PHARMACOLOGY RESEARCH
 
Protocol Number: Clin_IrCPI_101 
 
Version and date: 4.0 – 06DEC2019 
 
TITLE: Appendix to the final Statistical Analysis Plan for 
compartmental pharmacokinetic analysis of Ir-CPI plasma 
concentrations, Pharmacokinetic-Pharmacodynamic analysis and Anti-
Drug Antibodies analysis 
Date: 13AUG2020 - Version: Final version 1.0 
 
1. Introduction 
This appendix covers the details of the post-hoc analyses on Pharmacokinetics (PK), 
pharmacokinetics/pharmacodynamics (PK/PD) and Anti-Drug Antibodies (ADA) data from 
Clin_IrCPI_101 study as well as anticipated data transformations and manipulations. It 
completes the final Statistical Analysis Plan (SAP) (version V1.0 dated 09 July 2020) and it is 
based on Sponsor requests.  
This SAP will support additional post-hoc analyses on: 
- 
PK data and PK/PD endpoints performed by the Pharmacokineticist of BIOTRIAL in 
agreement with the Sponsor.  
- 
ADA data (presence, titration, sub-classes and the capability to neutralize drug 
activity) performed by the Biostatistics unit of BIOTRIAL BIOMETRICS in 
agreement with the Sponsor. 
PK and PK/PD parameters will be calculated using Phoenix® WinNonlin® version 8.1 Certara 
USA, Inc., Princeton, NJ) and ADA analysis will be performed using SAS software version 
9.4 (SAS institute Inc. Cary NC USA). 
 
In accordance with the Sponsor, negative values, identified after the calculation of Factor XI 
and Factor XII inhibition in the main analysis, will be replaced by 0. 
 
2. Compartmental pharmacokinetic analysis 
The rules defined in the section Erreur ! Source du renvoi introuvable. of the final SAP 
will be used. 
The actual blood sampling time and infusion duration will be used. The theoretical dose 
(mg/kg) will be used. 


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2.1. Plasma PK endpoints 
Blood samples will be drawn: 
 For cohorts A, B and C: 
- 
on Day 1 at pre-dose then post-dose (after start of infusion) at H0.5, H1, H1.5, H2, 
H4, H6, H6.5, H7, H7.5, H8, H10, H12, H16, then at D2 (H24), D3 (H48), D4 
(H72) and D5 (H96).  
In case of infusion less than 6 hours, blood sample for Ir-CPI pharmacokinetics 
will be done at the end of infusion then H0.5, H1, H1.5, H2, H4, H6, H10, H18, 
H42, H66 and H90 after the end of infusion. 
 For cohort D: 
- 
on Day 1 at pre-dose then post-dose (after start of infusion) at H0.5, H1, H1.5, H2, 
H4, H6, H6.5, H7, H7.5, H8, H10, H12, H16, then at D2 (H24), D3 (H48), D4 
(H72), D5 (H96) and D7 (H144).  
In case of infusion less than 6 hours, blood sample for Ir-CPI pharmacokinetics 
will be done at the end of infusion then H0.5, H1, H1.5, H2, H4, H6, H10, H18, 
H42, H66, H90 and H138 after the end of infusion. 
2.2. Plasma pharmacokinetic analysis 
The compartmental pharmacokinetic analysis will be performed on the Pharmacokinetic set 
(PKS) defined in the final SAP as all of the included participants who have been administered 
a complete infusion of IMP without major protocol deviation affecting PK evaluation. 
Subjects receiving placebo will not be included in the summary and analysis of PK 
parameters.  
Graphical exploration of plasma concentrations versus time profiles will be performed by 
subject and by group.  
For the description of individual plasma concentration-time profiles, one-, two- and three 
compartment models will be investigated using non-linear regression from models of the 
Phoenix WinNonlin library.  
To assess how the compartmental model explains the individual concentration data:  
- 
The evaluation of the goodness of fit and the estimated parameters will be based, 
but not only, on the Akaike information criterion, the Schwarz Bayesian Criterion 
(SBC), the coefficient of variability (CV) of the parameter estimates, the random 
distribution of residuals (weighted or not) between measured and predicted 
concentrations with respect to time, correlation between independent model 
parameters (<0.95) will be checked to select the model that best fits the observed 
data. 
- 
Individual plots of observed and predicted concentrations, residual versus (vs.) 
predicted concentrations and residual vs. time profiles of Ir-CPI will be presented 
graphically on linear and log/linear coordinates with the PK model selected to best 
fits the observed data. 
- 
Relevant plasma PK parameters will be calculated for Ir-CPI by compartmental 
methods, as appropriate for those participants with sufficient plasma concentration 
data. PK parameters obtained by compartmental analysis including descriptive 
statistics will be presented in tables separately for each treatment group.  
 


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3. Pharmacokinetic-Pharmacodynamic analysis 
The evaluation of the relationship between plasma concentrations of Ir-CPI and the PD 
parameters, i.e. the change from baseline in coagulation parameters (i.e. aPTT ratio), FXI and 
FXII inhibition are graphically investigated and displayed according to the final SAP. 
3.1. Plasma PD endpoints 
Effect of Ir-CPI on PD aPTT, Factor XI and Factor XII inhibition will be measured by the 
change from baseline (central lab). PD aPTT and FXI/FXII parameters will be measured: 
 For cohorts A, B and C: 
- 
on D1, pre-dose then at 30min, 60min, 90min, 2h, 4h, 6h, 6h30, 7h, 7h30, 8h, 10h, 
12h, 16h post-dose, then on D2 (24h), D3 (48h), D4 (72h), D5 (96h) and discharge 
visit (D10 ± 2 days).  
In case of infusion less than 6 hours and besides assessment at pre-dose, 30 min, 
60 min, 90 min, 2h and 4h after start of infusion, parameters should be measured at 
the end of infusion, then 30min, 60 min, 90min, 2h, 4h, 6h, 10h, then 18h, 42h, 
66h and 90h after the end of infusion and then at the discharge visit. 
 
 For cohort D: 
- 
on D1, pre-dose then at 30min, 60min, 90min, 2h, 4h, 6h, 6h30, 7h, 7h30, 8h, 10h, 
12h, 16h post-dose, then on D2 (24h), D3 (48h), D4 (72h), D5 (96h), D7 (144h) 
and discharge visit (D10 ± 2 days).  
In case of infusion less than 6 hours and besides assessment at pre-dose, 30 min, 
60 min, 90 min, 2h and 4h after start of infusion, parameters should be measured at 
the end of infusion, then 30min, 60min, 90min, 2h, 4h, 6h, 10h, then 18h, 42h, 
66h, 90h and 138h after the end of infusion and then at the discharge visit. 
For each time point, including the baseline time point, an aPTT ratio was calculated by 
dividing the aPTT value (in sec) of the specific time point (aPTT*) by the baseline aPTT 
value (in sec) (aPTT°) of the same volunteer (aPTT ratio = aPTT*/aPTT°). This ratio in 
function of the time will be used. The baseline time-point is considered as having an aPTT 
ratio of 1.  
Concerning FXI and FXII PD parameters, individual data of FXI activity and FXII activity in 
function of the time will be used. Moreover, FXI or FXII inhibition, expressed in percentages, 
for each time point (including the baseline time point), were calculated for each volunteer 
according to the main SAP:  
 Percentage of FXI inhibition= 100-[(FXI*/FXI°)*100] 
 Percentage of FXII inhibition= 100-[(FXII*/FXII°)*100] 
In case of negative values, these values will be replaced by 0 (for the main and post-hoc 
analyses). 
FXI* or FXII*: FXI or FXII percentage of inhibition of a specific time point 
FXI° or FXII°: FXI or FXII percentage of inhibition of the baseline time point 
The baseline time point is considered as 0 % of FXI or FXII inhibition.  
 
 


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3.2. PK-PD analysis 
The pharmacokinetic-pharmacodynamic analysis will be performed on the Pharmacodynamic 
set (PDS) defined in the final SAP as all the included participants who have completed the 
study without any protocol deviation affecting PD evaluation and with at least one available 
post-baseline data.  
Subjects receiving placebo will be included in the summary and analysis of PK-PD 
relationship. 
The rationale for PK/PD analysis is to link pharmacokinetics and pharmacodynamics in order 
to establish and evaluate dose-concentration-response relationships and subsequently describe 
and predict the effect-time courses resulting from a drug dose. PK-PD relationship will be 
investigated mainly to assess potential correlation between Ir-CPI exposure and the aPTT 
ratio.  
The pharmacokinetic-pharmacodynamic analysis dedicated to FXI and FXII responses will be 
investigated (or not if considered not appropriate) based on exploratory analysis of the main 
SAP.  
The preliminary graphical exploration will be performed in order to assess the effect of Ir-CPI 
on aPTT ratio with the dose, the pattern of the relationship for the previous PD model, the 
linearity assumption and the potential hysteresis between concentrations and response. 
The model development will be based on the evaluation of the relation between effect and 
concentration using non-linear regression from model of the Phoenix WinNonlin library. A 
direct effect relationship was assumed for aPTT according to the safety aPTT data from 
interim analysis. 
To compare structural models, the evaluation of the goodness of fit and the estimated 
parameters will be based, but not only, on the Akaike information criterion, the coefficient of 
variability (CV) of the parameter estimates, the random distribution of residuals between 
measured and predicted concentrations with respect to time, correlation between independent 
model parameters (<0.95) will be checked.  
Plots of concentration-effect relationship between concentrations versus the corresponding 
aPTT ratio after Ir-CPI administration will be presented graphically with the PK-PD model 
selected to best fits the observed data (observed and fitted data). 
Relevant PK-PD parameters estimated from the selected model will be described. 
 
4. ADA analysis 
ADA analysis samples will be collected at pre-dose on the day of infusion, at the discharge 
visit (D10 ± 2 days), on D30 and on D90. If ADAs are detected in D90 samples, ADA 
analysis samples will be collected also at D180. 
 
Samples are determined as ADA-positive or -negative according to the results of the 
screening and/or confirmatory ADA assays. Only samples confirmed as positive by the 
confirmatory assay were considered for titration and sub-classes assays. 
Titers of anti-Ir-CPI antibodies in study samples (titration assay) are determined as the last 
dilution factor with a result above the Floating Cut Point (FCP) determined for ADA assay. 


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The results are expressed in Dil-1 and reported for each ADA-positive volunteer at each time 
point. 
In addition, for each ADA-positive volunteers, the presence or absence of the 3 ADA sub-
classes (i.e. IgG, IgM and IgE) are determined. The results are expressed as Negative, 
Positive or NA (Not applicable, ADA negative sample not analyzed for Ig sub-classes).  
As specified in the final SAP, presence of ADA, their titration and sub-classes determination 
(isotype) for ADA+ sampleswill be described by treatment group and measurement time. All 
data will be listed. 
 
Within each treatment group, pairwise comparisons (predose vs each ADA+ timepoint) will 
be performed using Dunnett’s adjustment due to multiple testing. 
Ability of ADA to neutralize the activity of Ir-CPI will be determined in a coagulation assay. 
Baseline plasma samples and ADA-positive samples of the same volunteer will be spiked 
with known concentration of Ir-CPI increasing the coagulation time. Coagulation time of 
spiked baseline and ADA-positive plasma will be compared in order to define if the ADAs 
interfere with the activity of Ir-CPI. A titration will be performed to define the proportion of 
ADAs in the samples having neutralizing abilities. 
ADA neutralizing drug activity will be described by treatment group.  
 
 
Biotrial (to be completed manually): 
Name 
 
Title 
 
Date 
 
Signature 
 
 
Biotrial (to be completed manually): 
Name 
 
Title 
 
Date 
 
Signature 
 
 
Sponsor (to be completed manually): 
Name 
 
Title 
 
Date 
 
Signature 
 
 


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B I O T R I A L DRUG EVALUATION AND PHARMACOLOGY RESEARCH
 
Protocol Number: Clin_IrCPI_101 
 
Version and date: 5.0 – 15OCT2020 
 
TITLE: Appendix n°2 to the final Statistical Analysis Plan for 
Descriptive analysis of Pharmacokinetic-Pharmacodynamic and safety 
parameters by ADA group 
Date: 12NOV2020 - Version: Final version 1.0 
 
1. Introduction 
This appendix covers the details of the post-hoc analysis n°2 on pharmacokinetics, 
pharmacodynamics and safety endpoints from the Clin_IrCPI_101 study. It completes the 
final Statistical Analysis Plan (SAP) (version V1.0 dated 09 July 2020) and it is based on 
Sponsor requests. 
This SAP will support the post-hoc analysis on PK (based on compartmental PK analysis) and 
safety endpoints by Anti-Drug Antibodies (ADA) group. 
This additional analysis will be performed using SAS software version 9.4 (SAS institute 
Inc. Cary NC USA). 
 
2. Statistical analysis 
The ADA group will be defined using data on the presence of ADA (defined as screening + 
confirmatory positive results) whatever the study day. If a subject is positive for the presence 
of ADA at a specific day, he will be included in the ADA+ group. 
Additional analyses will be performed on the following PK and safety endpoints: 
- 
PK parameters: Alpha_HL, Beta_HL, total body clearance (CL), volume of 
distribution at steady-state (Vss) and AUC (Area under the concentration versus time 
curve); 
Note: AUC will be normalized by theoretical Ir-CPI dose (1.5, 3, 6 or 9 mg/kg) using the 
following formula: nAUC0-x = AUC0-x / theoretical Ir-CPI dose. 
- 
PD and safety aPTT ratio at the following selected timepoints: 2h, 4h, 6h, 8h, 12h, 
24h, 48h and 72h. 
 
Descriptive statistics will be generated on all aforementioned endpoints, by ADA group 
(ADA+ and ADA-) and treatment group (Ir-CPI 1.5 mg/kg, Ir-CPI 3 mg/kg, Ir-CPI 6 mg/kg 
and Ir-CPI 9 mg/kg).  
 


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The following descriptive statistics will be supplied: sample size, arithmetic mean, standard 
deviation (SD), standard error of the mean (SEM), minimum, median and maximum, and 
[quartiles if necessary with geometric mean, arithmetic and geometric coefficients of variation 
(CV), and quartiles for PK parameters]. If the sample size of one treatment group is less than 
or equal to 2, only the number of observed values, the minimum and the maximum will be 
presented. 
No inferential analysis will be performed due to the small sample size in each treatment 
group/ADA+.  
 
 
Biotrial (to be completed manually): 
Name 
 
Title 
 
Date 
 
Signature 
 
 
Biotrial (to be completed manually): 
Name 
 
Title 
 
Date 
 
Signature 
 
 
Sponsor (to be completed manually): 
Name 
 
Title 
 
Date 
 
Signature