Clinical trial NCT03463044
Conditions: Healthy Subjects
Sponsor: Inotrem
Start date: 2016-04-01; Completion date: 2016-08-25
Enrollment: 27 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a single center, randomized, placebo-controlled study with a sequential i.v. dose escalation cohorts design, to assess safety, tolerability and pharmacokinetics of MOTREM (nangibotide) in healthy volunteers

Detailed description:
This was a dose escalation study in healthy volunteers to evaluate the safety and pharmacokinetics of nangibotide in humans

Arms: arm 1: Matched placebo arm 2: nangibotide dose 1 arm 3: Nangibotide dose 2 arm 4: Nangibotide dose 3 arm 5: Nangibotide dose 4 arm 6: Nangibotide dose 5 arm 7: Nangibotide dose 6 arm 8: Nangibotide dose 7 arm 9: Nangibotide dose 8
Interventions: intervention 1: nangibotide intervention 2: Placebo
Intervention descriptions: intervention 1: Continous i.v. infusion intervention 2: Placebo

Protocol documents:
Prot_SAP_000.pdf: 
Final Clinical Study Report (Protocol MOT-C-104)  
 
16.1 
STUDY INFORMATION 
16.1.1 Protocol and Protocol Amendments 
• Final Study Protocol (Version 03, 13 May 2016) 
• Amendment 2 (03 May 2016) 
• Amendment 3 (12 May 2016) 
• Amendment 4 (22 July 2016) 
 
 
 


 
 
 
 
STUDY PROTOCOL 
 
Including Amendments 1-3 
 
A Phase I, randomised, placebo controlled study to assess the safety, tolerability and 
pharmacokinetic profiles of ascending, single, intravenous doses of MOTREM (LR12) in 
healthy male subjects 
 
Investigational medicinal product: MOTREM (LR12) 
Development phase: Ia  
 
Version: 3.0 Final 
Date: 13 May 2016 
 
 
Sponsor Study Code: 
CRO Study Code 
EudraCT Number 
MOT-C-104 
C15030 
2015-005654-35 
 
 
Sponsor 
INOTREM SA 
114 Rue La Boétie 
75008 Paris, France 
Sponsor’s Officer 
Jean-Jacques GARAUD, MD 
Chief Executive Officer 
114 Rue La Boétie 
75008 Paris, France 
Principal Investigator 
Dr Ulrike Lorch, MD FRCA FFPM  
Richmond Pharmacology Ltd. 
St George’s University of London 
Cranmer Terrace, Tooting 
London SW17 0RE, UK 
Study Site 
Richmond Pharmacology Ltd. 
Croydon University Hospital, Thornton Wing,  
530 London Road,  
Croydon, CR7 7YE, UK 
 
 
Information in this protocol is confidential and should not be disclosed, other than to 
those directly involved in the execution or the ethical/regulatory review of the study, 
without written authorisation from INOTREM SA or its affiliates. 


INOTREM SA. 
CONFIDENTIAL 
13 May 2016 
Protocol Ref: MOT-C-104 
Final Version 3.0 
Page 2 of 66 
 
HISTORY OF CHANGES 
The following changes to the second version of the study protocol (22 FEB 2016) were 
implemented with study protocol amendment 3. These changes are non-substantial.  
 Reduction of the number of PK samples in line with the adaptive feature no 13  
Limit I & II. 
 Correction of minor errors 
 Administrative change (provider for PK analysis): Dynakin was replaced by Phinc. 
 
The following changes to the second version of the study protocol (22 FEB 2016) were 
implemented with study protocol amendment 2. These changes are non-substantial. A new 
version of the study protocol was not issued for this amendment. 
 100% extension of Group 2 (Part A) in line with the Adaptive feature no 8, Limit I-III. 
This was made to gather additional pharmacokinetic information. 
 
The following changes to the first version of the study protocol (19 JAN 2016) were 
implemented with study protocol amendment 1. These changes are non-substantial. 
 Addition of exclusion criterion to exclude volunteers with pregnant partners due to the 
request oft he ethics committee 
 Clarification of vital signs measurements 
 Clarification of holter ECG measurements 
 




INOTREM SA. 
CONFIDENTIAL 
13 May 2016 
Protocol Ref: MOT-C-104 
Final Version 3.0 
Page 4 of 66 
 
1.2 
Investigator’s Agreement 
I have read this INOTREM SA Protocol No. MOT-C-104 
A Phase I, randomised, placebo controlled study to assess the safety, tolerability and 
pharmacokinetic profiles of ascending, single, intravenous doses of MOTREM (LR12) in 
healthy male subjects 
I have fully discussed the objectives of this trial and the contents of this protocol with 
INOTREM SA representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the ethical/regulatory review of the 
trial, without written authorisation from. It is, however, permissible to provide information to 
a subject in order to obtain consent. 
I agree to conduct this trial according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the trial in 
accordance with ICH guidelines on GCP and with the applicable regulatory requirements. 
I understand that INOTREM SA may decide to suspend or prematurely terminate the trial at 
any time for whatever reason; such a decision will be communicated to me in writing. 
Conversely, should I decide to withdraw from execution of the trial I will communicate my 
intention immediately in writing to INOTREM SA 
 
 
 
Principal Investigator 
Dr Ulrike Lorch, MD FRCA FFPM 
Date: 
Signature: 
 
 


INOTREM SA. 
CONFIDENTIAL 
13 May 2016 
Protocol Ref: MOT-C-104 
Final Version 3.0 
Page 5 of 66 
 
2 
STUDY PERSONNEL 
Sponsor’s Representative and  
Medical Officer 
Jean-Jacques Garaud, MD 
Chief Executive Officer 
Email: jjg@inotrem.com 
Tel: +33 6 30 62 86 51 
Sponsor’s Main Contact 
Valérie Cuvier 
Project Manager 
Email: vc@inotrem.com 
Tel: +33 6 80 61 52 05 
Sponsor Site 
INOTREM SA 
114 Rue La Boétie 
75008 Paris, France 
Principal Investigator 
Dr Ulrike Lorch MD FRCA FFPM 
Tel: +44 (0)20 8664 5200 
Email: u.lorch@richmondpharmacology.com 
Study Site 
Richmond Pharmacology Ltd. 
Croydon University Hospital, Thornton Wing, 
530 London Road,  
Croydon, CR7 7YE, UK 
Clinical Laboratory 
The Doctor’s Laboratory 
60 Whitfield Street 
London W1T 4EU, UK 
Study Statistician 
Aude Lasfargues 
ASCOPHARM Groupe NOVASCO 
56 rue de Londres 
75008 Paris, France 
Tel: +33 1 56 33 15 48 
Fax: +33 1 56 33 35 50 
Email: a.lasfargues@novasco.fr 
Pharmacovigilance Provider 
For Drug Consulting 
6, rue Rouget de Lisle 
92240 MALAKOFF 
Tel: +33 (0) 1 46 55 27 11 
Fax: +33 (0) 1 47 46 18 48 
Email: safety@fordrugconsulting.fr 
Bioanalytical Laboratory: 
Cédric Charrier 
BERTIN Pharma 
L.E.E.M 
DSV/iBiTec-S/SPI 
CEA-Saclay-Bâtiment 136 
91191 Gif sur Yvette Cedex, France 
Tel: +33 (0)1 69 08 97 09 
Fax: +33 (0)1 69 08 59 07 
Email : cedric.charrier@bertinpharma.com 
 
 


INOTREM SA. 
CONFIDENTIAL 
13 May 2016 
Protocol Ref: MOT-C-104 
Final Version 3.0 
Page 6 of 66 
 
PK Analysis: 
Bernard Orlandini, MSc Biology 
PHINC 
Immeuble Le Classéa 
36, Rue Victor Basch 
91300 Massy, France 
Tel: +33 (0)1 76 91 24 66 
Fax: +33 (0)1 76 91 24 61 
Mobile: +33 (0)6 43 85 18 31 
Email:  bernard.orlandini@phinc.fr 
Immunogenicity (ADA): 
Dr. Jean-Paul Freche, Eurofins ADME 
BioanalysesBiotech 
75, chemin de Sommières 
F - 30310 Vergèze, France 
Tel: +33 4 66 73 15 55 
Fax: +33 (0)4 66 73 17 74 
Email: Jean-PaulFreche@eurofins.com 
IMP Management: 
Bio-Connection (Proxy) 
M.C. Kooij (Qualified Person) 
Proxy laboratories B.V., Archimedesweg 25,  
2333 CM Leiden, The Netherlands 
Tel: +31(0)71 524 4080 
Fax: +31(0)71 528 4213 
 
 


INOTREM SA. 
CONFIDENTIAL 
13 May 2016 
Protocol Ref: MOT-C-104 
Final Version 3.0 
Page 7 of 66 
 
3 
TABLE OF CONTENTS 
 
1 
PROTOCOL APPROVAL SIGNATURES ........................................................................ 3 
1.1 
Sponsor’s Approval ...................................................................................................... 3 
1.2 
Investigator’s Agreement ............................................................................................. 4 
2 
STUDY PERSONNEL ....................................................................................................... 5 
3 
TABLE OF CONTENTS .................................................................................................... 7 
4 
LIST OF ABBREVIATIONS ........................................................................................... 11 
5 
STUDY SYNOPSIS .......................................................................................................... 13 
6 
INTRODUCTION ............................................................................................................. 16 
6.1 
Mode of Action: ......................................................................................................... 16 
6.2 
Pharmacology: ........................................................................................................... 16 
6.3 
Rationale for Conducting Study ................................................................................. 17 
6.4 
Risk-Benefit Evaluation ............................................................................................. 17 
6.4.1 
Potential Benefits ............................................................................................... 17 
6.4.2 
Potential Risks .................................................................................................... 17 
7 
STUDY OBJECTIVES ..................................................................................................... 19 
7.1 
Primary Objectives ..................................................................................................... 19 
7.2 
Secondary Objectives ................................................................................................. 19 
8 
STUDY DESIGN .............................................................................................................. 19 
8.1 
Overall Study Design and Procedure ......................................................................... 19 
8.2 
Rules for Dose Escalation/Progression ...................................................................... 27 
8.2.1 
Safety Review Committee .................................................................................. 27 
8.2.2 
Data Requirements ............................................................................................. 27 
8.2.3 
SRC Meeting ...................................................................................................... 28 
8.2.4 
Dose Escalation/Progression .............................................................................. 28 
8.3 
Toxicity Rules ............................................................................................................ 28 
8.4 
Rationale for Study Design, Doses and Control Groups ........................................... 32 
8.4.1 
Justification of Safe Starting Dose ..................................................................... 32 
8.4.2 
Choice of Subjects for Study .............................................................................. 36 
8.4.3 
Route and Rate of Administration ...................................................................... 37 
8.4.4 
Precautions to be Applied for Dosing Between Subjects within a Cohort ......... 37 
8.4.5 
Precautions to be Applied for Dosing Between Different Cohorts .................... 37 
8.4.6 
Monitoring and Communication of Adverse Events / Reactions ....................... 37 
8.4.7 
Investigator Site Facilities and Personnel .......................................................... 38 
9 
SELECTION AND WITHDRAWAL OF SUBJECTS .................................................... 38 
9.1 
Number and Source of Subjects ................................................................................. 38 
9.2 
Inclusion Criteria ........................................................................................................ 38 
9.3 
Exclusion criteria ....................................................................................................... 39 
9.4 
Subject Restrictions .................................................................................................... 40 
9.5 
Subject Inclusion and Randomisation ........................................................................ 41 
9.6 
Criteria for withdrawal ............................................................................................... 41 
9.6.1 
Handling of Withdrawals ................................................................................... 42 
10  STUDY AND CONCOMITANT TREATMENTS .......................................................... 42 


INOTREM SA. 
CONFIDENTIAL 
13 May 2016 
Protocol Ref: MOT-C-104 
Final Version 3.0 
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10.1  Investigational Medicinal Products (IMPs) ............................................................... 42 
10.1.1  Doses and Treatment Regimen .......................................................................... 43 
10.2  Labelling of IMPs ...................................................................................................... 44 
10.3  Drug Accountability ................................................................................................... 44 
10.4  Blinding and Procedures for Unblinding the Study ................................................... 45 
10.4.1  Methods for Ensuring Blinding .......................................................................... 45 
10.4.2  Methods for Unblinding the Study ..................................................................... 45 
10.4.3  Concomitant Medications/Permitted medications ............................................. 45 
11  STUDY PROCEDURES .................................................................................................. 46 
11.1  Schedule of Study Procedures .................................................................................... 46 
12  STUDY METHODOLOGY ............................................................................................. 46 
12.1.1  Meals .................................................................................................................. 46 
12.1.2  Haematology and Biochemistry ......................................................................... 46 
12.1.3  Serology ............................................................................................................. 47 
12.1.4  Urinalysis ........................................................................................................... 47 
12.1.5  Drugs of Abuse ................................................................................................... 47 
12.1.6  Alcohol Breath Test ........................................................................................... 48 
12.2  Vital Signs .................................................................................................................. 48 
12.2.1  Blood Pressure, Heart Rate and Tympanic Temperature ................................... 48 
12.3  Electrocardiographic (ECG) Measurements .............................................................. 48 
12.3.1  Recording of 12-lead ECGs ............................................................................... 48 
12.3.2  Real Time Display (ECG Telemetry) ................................................................. 49 
12.3.3  24-hour Holter ECG ........................................................................................... 49 
12.4  Physical Examination, Height and Weight ................................................................ 49 
12.5  Pharmacokinetic Assessments ................................................................................... 49 
12.5.1  PK Blood Samples ............................................................................................. 49 
12.6  Immunogenicity ......................................................................................................... 50 
12.7  Volume of Blood Sampling ....................................................................................... 50 
13  ADVERSE EVENTS ........................................................................................................ 50 
13.1  Serious Adverse Events (SAE) and Suspected Unexpected Serious Adverse Reaction 
(SUSAR) .................................................................................................................... 51 
13.1.1  Definitions .......................................................................................................... 51 
13.1.2  Recording of Adverse Events and Follow-Up ................................................... 52 
13.1.3  Reporting of serious adverse events ................................................................... 53 
14  QUALITY ASSURANCE AND QUALITY CONTROL ................................................ 54 
14.1  Quality Assurance and Quality Control ..................................................................... 54 
14.2  Monitoring ................................................................................................................. 54 
15  STATISTICAL METHODS PLANNED AND DETERMINATION OF SAMPLE SIZE
 55 
15.1  Statistical and Analytical Plans .................................................................................. 55 
15.1.1  Data Sets Analysed ............................................................................................. 55 
15.1.2  Demographic and other Baseline Characteristics ............................................... 55 
15.1.3  Safety analyses ................................................................................................... 56 
15.2  Pharmacokinetics ....................................................................................................... 57 
15.2.1  Evaluation of Pharmacokinetic Parameters ........................................................ 57 


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CONFIDENTIAL 
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Protocol Ref: MOT-C-104 
Final Version 3.0 
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15.2.2  Statistical Analysis on PK Parameters ............................................................... 58 
15.3  Handling of Missing and Incomplete Data ................................................................ 58 
15.4  Determination of Sample Size ................................................................................... 58 
15.5  Interim Analysis ......................................................................................................... 58 
16  DATA MANAGEMENT .................................................................................................. 58 
16.1  Case Report Forms ..................................................................................................... 59 
17  SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES ...................................... 59 
17.1  Sponsor’s Responsibilities ......................................................................................... 59 
17.1.1  GCP Compliance ................................................................................................ 60 
17.1.2  Regulatory Approval .......................................................................................... 60 
17.1.3  Indemnity/Liability and Insurance ..................................................................... 60 
17.1.4  Protocol Management ........................................................................................ 60 
17.1.5  End of Trial Notification .................................................................................... 60 
17.1.6  Submission of Summary of Clinical Trial Report to Competent Authorities of 
Member States Concerned and Regulatory Approval ...................................................... 60 
17.2  Investigator’s Responsibilities ................................................................................... 61 
17.2.1  GCP Compliance ................................................................................................ 61 
17.2.2  Protocol Adherence and Investigator Agreement .............................................. 61 
17.2.3  Documentation and Retention of Records ......................................................... 61 
17.3  Ethical Considerations ............................................................................................... 61 
17.3.1  Informed Consent ............................................................................................... 62 
17.3.2  Research Ethics Committee (REC) Approval .................................................... 62 
17.4  Confidentiality ........................................................................................................... 62 
17.5  Publication Policy ...................................................................................................... 63 
18  REFERENCES .................................................................................................................. 64 
19  Appendices ........................................................................................................................ 65 
19.1  UK Treatment Guideline for Anaphylaxis ................................................................. 65 
19.2  Acute Infusion Reactions Algorithm ......................................................................... 66 
 
List of Tables 
Table 1. Adaptive Protocol Features. ....................................................................................... 20 
Table 2. Study Plan – Part A (Groups 1 and 2). ....................................................................... 24 
Table 3. Study Plan – Part B (Groups 3 to 8). .......................................................................... 25 
Table 4. Group Toxicity Rules. ................................................................................................ 30 
Table 5. Individual Toxicity Rules. .......................................................................................... 31 
Table 6. NOAEL and HED BS. ............................................................................................... 34 
Table 7. Highest Loading Dose and HED BS. ......................................................................... 34 
Table 8. Planned Dose Escalation Scheme. ............................................................................. 35 
Table 9. Number of subjects .................................................................................................... 38 
Table 10. Composition of MOTREM Drug Product and as Reconstituted Solution ............... 43 
Table 11. Daily dose of IMP (MOTREM or matching placebo) for each dose group. ............ 44 
Table 12. Laboratory parameters. ............................................................................................ 46 
 
 


INOTREM SA. 
CONFIDENTIAL 
13 May 2016 
Protocol Ref: MOT-C-104 
Final Version 3.0 
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List of Figures 
Figure 1: Study Flow Chart. ..................................................................................................... 23 
 


INOTREM SA. 
CONFIDENTIAL 
13 May 2016 
Protocol Ref: MOT-C-104 
Final Version 3.0 
Page 11 of 66 
 
4 
LIST OF ABBREVIATIONS 
GT 
: Gamma glutamyl transpeptidase 
ADA 
: Anti-Drug Antibody 
AE 
: Adverse event 
Ae (0-24h) 
: Cumulative amount excreted in urine from time 0 to time 24 h 
ALAT 
: Alanine amino transferase 
ALP 
: Alkaline phosphatase 
API 
: Active Pharmaceutical Ingredient 
aPTT 
: activated Partial Thromboplastin Time 
ASAT  
: Aspartate amino transferase 
ATC 
: Anatomic Therapeutic Class 
AUC(0-8h) 
: Area under the plasma concentration-time curve from time 0 to time 8 h 
AUC(0-t) 
: Area under the plasma concentration-time curve from time 0 to the time of the 
last quantifiable concentration 
AUC(0-inf)or 
AUC(0-∞) 
: Area under the plasma concentration time curve extrapolated to time infinity 
AR 
: Adverse reaction 
BMI 
: Body mass index 
bpm 
 
: beat per minute 
CL 
: Plasma clearance 
C0.25h 
: Concentration at the end of the loading infusion 
C8h 
: Concentration at the end of the maintenance infusion 
Cmax 
: Maximal plasma concentration 
Cox-1 / 2 
: Cyclo-oxygenase 1/ 2 
CPK 
: Creatine phosphokinase 
CRF 
: Case report form 
Css inf 
: Steady state concentration during the maintenance infusion 
CV 
: Coefficient of variation 
DBP 
DHP 
: Diastolic blood pressure 
: Data Handling Protocol 
EC 
: Ethics Committee 
ECG 
: Electrocardiogram 
FIH 
: First in Human 
h 
: hour(s) 
HBsAg 
: Hepatitis B surface antigen 
HCV 
: Hepatitis C virus 
HED 
: Human Equivalent Dose 
HIV 
: Human immunodeficiency virus 
HR 
: Heart rate 
IL 
: Interleukin 
IMP 
: Investigational medicinal product 
iNOS 
: inducible Nitric Oxide Synthase 
INR 
: International Normalised Ratio 
ITT 
: Intent-to-treat 
i.p. 
: intraperitoneal 
i.v. 
: intravenous 
IWRS 
: Interactive Web Randomisation System 
Kinf 
: Infusion rate 
LPS 
LR12 
LSLV 
: Lipopolysaccharide 
: 12 amino-acid peptidic fragment of sTLT-1 
: Last Subject Last Visit 


INOTREM SA. 
CONFIDENTIAL 
13 May 2016 
Protocol Ref: MOT-C-104 
Final Version 3.0 
Page 12 of 66 
 
λz 
: Terminal elimination rate 
MCHC  
: Mean corpuscular haemoglobin concentration 
MCV 
: Mean corpuscular volume 
MedDRA 
: Medical dictionary for regulatory activities 
MHC 
MOTREM 
: Mean haemoglobin concentration 
: Investigational Medicinal Product (formulation of the active ingredient LR12) 
MTD 
: Maximum tolerated dose 
MS 
: Mass Spectrometry  
NOAEL 
: No-observed-adverse-effect level 
PK 
: Pharmacokinetics 
QTcB 
: QT corrected Bassett:  
QTcF 
: QT corrected Fridericia 
SAE 
: Serious adverse event 
SAS® 
: Statistical analysis system 
SBP 
: Systolic blood pressure 
SD 
: Standard deviation 
SOC 
: System organ class  
SOM 
: Study Operations Manual 
SRC 
: Safety Review Committee 
SUSAR 
: Suspected Unexpected Severe Adverse Reaction 
t 1/2 
: Terminal elimination half life 
T° 
: Temperature 
TEAE 
: Treatment-emergent adverse event 
TLRs 
: Toll-like Receptors 
TLT-1 
: TREM-Like Transcript-1 
TREM-1 
: Triggering receptor expressed on myeloid cells 1 
tmax 
: Time at which the plasma concentration maximum occurs 
USP 
: U.S. Pharmacopeial Convention 
Vd 
: Volume of distribution (CL/λz) 
 
 
 
 


INOTREM SA. 
CONFIDENTIAL 
13 May 2016 
Protocol Ref: MOT-C-104 
Final Version 3.0 
Page 13 of 66 
 
5 
STUDY SYNOPSIS 
Protocol No. MOT-C-104 
Study Drug: MOTREM (LR12) 
Title of the Study:  
A Phase I, randomised, placebo controlled study to assess the safety, tolerability and pharmacokinetic profiles of 
ascending, single, intravenous doses of MOTREM (LR12) in healthy male subjects 
Principal Investigator:  
Dr Ulrike Lorch, MD FRCA FFPM 
Study Centre:  
Richmond Pharmacology Ltd. 
St George’s University of London, Cranmer Terrace, Tooting, London, SW17 0RE, UK 
Croydon University Hospital, Thornton Wing, 530 London Road, Croydon, CR7 7YE, UK 
Study Period: 
- First enrolment expected: February 2016 
- Completion date expected: June 2016 
Clinical Phase: Ia 
(The study does not have therapeutic or prophylactic 
intent and does not plan to assess efficacy) 
Objectives: 
Primary 
- To assess the safety and tolerability of MOTREM (LR12) in comparison with placebo, after single 
intravenous (i.v.) dose administration in healthy young male subjects 
Secondary 
- To assess the pharmacokinetics (PK) of MOTREM (LR12) after single i.v. dose administration in healthy 
young male subjects. 
- To investigate the presence of anti-MOTREM (LR12) antibodies after single i.v. dose administration in 
healthy young male subjects. 
Study Design: 
This study is a single center, randomised, placebo-controlled (Part B) with sequential i.v. dose escalation groups 
design. 
Single doses of MOTREM (LR12) or matching placebo (Part B) are planned to be administered following a 
sequential group design in 26 healthy young male subjects aged from 18 to 45 years: Part A (Groups 1 and 2 of 1 
subject) followed by Part B (Groups 3 to 8 of 4 subjects each). For Part A (Groups 1 and 2), one subject each 
will receive MOTREM. For Part B (Groups 3 to 8) 3 subjects will receive MOTREM and 1 subject will receive 
placebo (3:1 ratio). Dose escalation to the following scheduled dose will only occur after satisfactory review of 
all safety and tolerability data by the Safety Review Committee in accordance with Table 1, protocol sections 8.2 
Rules for dose escalation/progression and 8.3 Toxicity rules. 
Subjects will be screened within 14 days and screening may be performed over multiple days prior to entering 
the study on Day -1. Each subject will receive verbal and written information followed by signing of the 
Informed Consent Form (ICF) prior to any screening procedures taking place. Subjects will be admitted on Day-
1. All the subjects from Part A (Groups 1 and 2) and Part B (groups 3 to 8) will be discharged on Day 2 after 24h 
post-dose (start of infusion). They will attend the unit for a follow-up visit on Day 8±1. The End of Study visit 
will take place on Day 28±2. All the assessments performed during the study are detailed in the Study Plan 
(Table 2 and Table 3). Study design features as well as number of subjects may be adapted according to Table 1. 


INOTREM SA. 
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13 May 2016 
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Final Version 3.0 
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Study Flowchart: 
 
Number of Subjects: 
26 subjects are planned (i.e. 2 first groups of 1 healthy male subject each and 6 groups of 4 healthy male 
subjects). Dose groups may be amended in accordance with Table 1 to collect relevant data. The total number of 
subjects will not exceed 72 subjects. 
Diagnosis and Main Criteria for Admission: 
Subjects will be included if they are healthy male, ≥18 to ≤45 with a BMI between 18-30 kg/m² inclusive having 
freely given their written informed consent to participate. 
Main exclusion criteria are: any clinically relevant acute or chronic diseases which could interfere with the 
subjects’ safety during the trial, or expose them to undue risk, or which could interfere with the study objectives. 
Any history of drug or alcohol abuse or clinical significant disease as determined by medical history, physical 
examination or other evaluations. 
Part A: 
Group 1: 1 mg (loading dose) over 15 minutes i.v.; 
Group 2: 10 mg (loading dose) over 15 minutes i.v.;  
Part B: 
Group 3: 0.5 mg/kg i.v. loading dose and 0.03 mg/kg/h maintenance dose i.v. over 7 hours and 45 min;  
Group 4: 1 mg/kg i.v. loading dose and 0.1 mg/kg/h maintenance dose i.v. over 7 hours and 45 min; 
Group 5: 2 mg/kg i.v. loading dose and 0.3 mg/kg/h maintenance dose i.v. over 7 hours and 45 min;  
Group 6: 5 mg/kg i.v. loading dose and 1 mg/kg/h maintenance dose i.v. over 7 hours and 45 min;  
Group 7: 5 mg/kg i.v. loading dose and 3 mg/kg/h maintenance dose i.v. over 7 hours and 45 min;  
Group 8: 5 mg/kg i.v. loading dose and 9 mg/kg/h maintenance dose i.v. over 7 hours and 45 min. 
Please refer to Table 1. 
 
Reference Treatment(s) and Mode of Administration: 
Placebo solution: saline; i.v. administration 
Anticipated Duration of Treatment: 
Single dose administration. 
Part A (Groups 1 and 2): 15 minutes i.v. dose 
Part B (Groups 3 to 8): 7 hours and 45 minutes continuous i.v. administration after a 15 minutes i.v. loading 
dose. 
Criteria for Evaluation: 
Please refer to the Study Plan (Table 2 and Table 3) for detailed timing of the evaluations. 
 
Safety Parameters: 
- Vital signs: systolic (SBP) and diastolic (DBP) blood pressure, heart rate, and body temperature (tympanic). 
- ECG (12-lead ECG, telemetry and Holter)  
- Physical examination. 


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- Safety laboratory tests: haematology, coagulation, plasma biochemistry, urinalysis.  
- Local tolerability at the infusion site. 
- Presence of anti-LR12 antibodies  
- Adverse events: from screening until study completion. 
 
Pharmacokinetics: 
Plasma concentrations of LR12 will be measured by a validated LC-MS/MS assay and analysed using non-
compartmental methods to obtain estimates of the following PK parameters: 
Cmax, tmax, C0.25h, C8h, Css inf, AUC0-0.25h, AUC0-8h, AUC0-t, AUC0-∞, t1/2, λz, CL, Vd. 
Statistical Methods:  
Adverse Events: 
Adverse events will be coded using the MedDRA dictionary version 17.1 or higher. They will be classified by 
System Organ Class and Preferred Term. 
The number and percentage of subjects with at least one adverse event will be provided. 
Analysis of treatment-emergent adverse events (TEAE) 
TEAEs will be summarised and described for the following criteria: 
- 
Number and percentages of subjects with at least one TEAE 
- 
Number and percentages of subjects with at least one severe TEAE 
- 
Number and percentages of subjects with at least one study treatment related TEAE  
- 
Number and percentages of subjects with at least one serious TEAE  
- 
Number and percentages of subjects with at least one TEAE leading to treatment withdrawal 
The maximum intensity encountered during the evaluation period will be recorded. 
The number of TEAEs of each category will also be provided by system organ class and preferred term. 
 
Analysis of Deaths and Other Serious Adverse Events 
A listing of deaths will be provided. 
A summary table of the other serious adverse events should be provided. In case of a low incidence of serious 
adverse events, only a listing will be done. 
 
Vital Signs, ECG, Physical Examination and Laboratory Data: 
Vital signs (SBP, DBP, heart rate and body temperature), ECG (12-lead ECG, telemetry and Holter), physical 
examination and laboratory data will be described at each visit/time. Changes from baseline will be described. 
Abnormal values will be identified in subject’s data listings. 
 
Concomitant Treatments: 
Concomitant treatments are coded using the WHO-DRUG dictionary version 2014-3. All treatments continued 
after the inclusion or appeared during the study will be summarised by Anatomical Therapeutic Class (ATC) and 
substance name.  
 
Pharmacokinetics:  
Individual and mean concentration versus time will be plotted on linear and semi logarithmic scales. Plasma 
concentrations and plasma PK parameters will be listed for LR12. Summary statistics of PK parameters 
including means, geometric means, medians, ranges, standard deviations, coefficients of variation will be 
presented for each dose.  
Analysis of variance models will be applied to the dose normalised and logarithmically transformed 
pharmacokinetic parameters to investigate possible deviations from dose proportionality 


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6 
INTRODUCTION 
MOTREM (formulated LR12) is developed for the treatment of sepsis and myocardial 
infarction. MOTREM is to be introduced into Phase I clinical studies to assess safety, 
tolerance, pharmacokinetics, and pharmacodynamic profile. 
MOTREM is the formulation of the active ingredient LR12, which is a 12 amino-acid peptide 
prepared by chemical synthesis. The investigational drug product MOTREM is prepared as a 
stable lyophilised product of LR12 peptide in sodium citrate and arginine. The powder is to be 
solubilised with 40 mL of saline solution for injection to yield a clear and colourless solution 
of LR12 at 10 mg/mL and at pH 5.5. 
The manufacturing of MOTREM for administration to humans is in compliance with the 
principles of good manufacturing practice (GMP). 
MOTREM is expected to be administered as a continuous i.v. infusion in the critical care 
setting for an average duration of 3 to 5 days. 
 
6.1 
Mode of Action:  
The Triggering Receptor Expressed on Myeloid Cells 1 (TREM-1) is an immunomodulatory 
receptor expressed on innate immune cells (1–4) The biological function of TREM-1 is the 
amplification of inflammation. In sepsis, this amplification may result in an exuberant and 
hyperactivated immune state (“genomic storm”) (5), which is responsible for the onset and 
progression of the disease.  
LR12 is a 12 amino-acid peptidic fragment derived from TREM-Like Transcript-1 (TLT-1), a 
receptor protein belonging to the TREM-1 family. LR12 can bind to (“trap”) TREM-1 ligand 
and thereby inhibit the amplification of the immune response caused by the activation of 
TREM-1 both in sepsis and myocardial infarction (6,7). 
 
6.2 
Pharmacology:  
In vitro, LR12 was shown to be a competitive inhibitor of TREM-1, able to inhibit TREM-1-
induced activation of several intracellular proteins implicated in inflammation as well as 
cytokine production by human neutrophils and monocytes in a dose dependent manner. 
However, the in vitro incubation of LR12 alone with leucocytes in resting conditions did not 
induce the spontaneous activation of any of the studied intracellular signalling pathways. 
As sepsis is a life-threatening disease characterised by a hyperactivated immune response, it is 
of paramount importance to consider the safety of LR12, when administered in a condition in 
which the immune system is activated. In every preclinical model of sepsis and septic shock 
studied, the administration of LR12 was associated with protective effects especially on the 
intensity of inflammation, cardiovascular system and survival: 
In animal models of peritonitis (mouse and rat), a mortality of 90 to 95% was observed within 
7 days following the onset of sepsis. The administration of LR12 decreased mortality with a 
strong reduction (not abrogation) of the inflammatory response markers, sepsis-induced tissue 
abnormalities and showed protective effects on the cardiovascular system. In a mini-pig 
model of peritonitis, the administration of LR12 led to a decreased need of vasopressor 
(norepinephrine) which translates to a substantial protective effect of the cardiovascular 
system. LR12 also prevented sepsis-induced tissue abnormalities and dysfunctions. 


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Protocol Ref: MOT-C-104 
Final Version 3.0 
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The TREM-1 signalling pathway belongs to the 10 most upregulated pathways during the 
“genomic storm” that can be observed in patients with septic shock. During experimental 
Monkey endotoxemia, the administration of LR12 attenuated the endotoxin-induced blood 
pressure decrease and release of several inflammatory cytokines in blood. The transcription of 
a wide range of genes related to the “genomic storm” was also attenuated by LR12 
administration. 
In addition, LR12 was evaluated in animal models of myocardial infarction: In a rat model of 
myocardial ischemia-reperfusion, treatment with LR12 reduced the ventricular dilation and 
improved systolic and diastolic ventricular functions. In a mini-pig model of cardiogenic 
shock, treatment with LR12 was linked to a strong protection of the cardiovascular system 
and decreasing the infarct size.  
For details please refer to the current Investigator’s Brochure. 
 
6.3 
Rationale for Conducting Study 
The aim of this First-in-Human (FIH) study is to obtain information on the safety, tolerability 
and pharmacokinetics of single ascending doses of MOTREM in healthy young male subjects.  
The rationale for taking MOTREM into further development is the expectation that this 
compound could be an effective new anti-sepsis therapeutic agent. Prior to initial testing in 
patients, the safety and the pharmacokinetic characteristics of the drug in healthy humans 
must be investigated. 
Data from this study will help to design subsequent studies in patient populations clinically 
and therapeutically relevant with this new class of compound. 
 
6.4 
Risk-Benefit Evaluation 
6.4.1 Potential Benefits 
MOTREM (LR12) will be given to healthy subjects purely for research and development 
purposes and those subjects receiving IMP will experience no medical benefit except for a 
general health examination. 
 
6.4.2 Potential Risks 
6.4.2.1 Nonclinical Safety Pharmacology and Toxicology:  
Toxicity studies were only conducted in one species in accordance with ICH guidance 
documents S6(R1) and M3(R2) as well as to EMA’s guidance on repeated dose toxicity 
(EMEA/CHMP/SWP/488313/2007). Safety pharmacology also followed the ICH S7A and 
S7B guidance. 
A cardiovascular safety study in Cynomolgus monkeys did not identify any adverse 
cardio¬vascular effect of LR12, when administered as an intravenous infusion of 18-times the 
expected pharmacologically active dose. In addition, the central nervous and pulmonary 
systems were explored during the toxicity studies and did not unveil untoward effects.  
Receptor binding assays with a wide range of receptors did not show any relevant off target 
effects in vitro.  


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13 May 2016 
Protocol Ref: MOT-C-104 
Final Version 3.0 
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A bacterial reverse mutation test (Ames test) and a chromosome aberration test did not show 
any evidence for genotoxicity of LR12. 
Toxicokinetic studies showed dose-dependent kinetics and suggested a clearance of the 
product within 15 to 30 minutes depending on the dose. 
A series of toxicity studies was conducted with LR12 in cynomolgus monkey, as this 
represents the only relevant species. In the pivotal 14-day toxicology study with the clinical 
formulation, the administration of LR12 was safe and well tolerated at doses 7.2, 24 and 140 
mg/kg/day. No adverse events were observed up to the highest dose level. In addition, a dose 
of 440 mg/kg/day in a preliminary formulation was found to be safe and well tolerated in a 
14-day study. 
Severe time dependent adverse events, likely related to immunogenicity, were observed in the 
low- dose arm of an early toxicity study conducted with an experimental frozen formulation 
that was diluted with a technical, non USP grade buffer. Further toxicology studies with a 
suitable buffer or the API alone and with the final clinical formulation did not reproduce these 
findings. 
 
6.4.2.2 Clinical Studies 
There is currently no clinical experience with MOTREM. Potential risks will be closely 
monitored for as part of the safety evaluations being performed in this study. 
Measures to minimise the risks to volunteers will include: 
 Selection of a starting dose well below a dose level for which effects are expected 
Please refer to protocol section 8.4.1. 
 Sentinel dosing of subjects. Please refer to protocol section 8.4.4.  
 Progression to next dose level only after evaluation of data from previous 
groups/cohorts and approval from Safety Review Committee (SRC). Please refer to 
protocol section 8.2.3 and 8.2.4.  
 Clinical and laboratory monitoring of study subjects. Please refer to protocol section 
8.2.2 and 12.1.2. 
 Exposure to study drug limited to 8 hours. Please refer to protocol section 8.4.1. 
 
6.4.2.3 Allergic Reactions, Infusion Reactions and Anaphylaxis 
As with all protein products, administration of MOTREM may result in hypersensitivity 
reactions including anaphylaxis, or infusion site associated reactions. 
Subjects will be closely monitored during and after IMP administration for any symptoms of 
anaphylaxis and other hypersensitivity reactions, including circulatory and/or respiratory 
changes or arrest, or urticaria, arthralgia, myalgia or other signs of related reactions. Adequate 
treatment will be immediately available. Infusion-associated AEs may occur, and depending 
on its type and severity, discontinuation of infusion may be required. Subjects will be 
informed of early symptoms and signs of hypersensitivity reactions including hives, swollen 
face, eyelids, lips, or tongue, or trouble with breathing. An acute infusion reaction algorithm 
will be used to manage infusion related reactions (refer to Appendix 19.2). In this study 
regular assessments to monitor infusion reactions and infusion site reactions will be done.. A 
mandatory sentinel dosing strategy of dosing one subject on IMP on the first day will be used 


INOTREM SA. 
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13 May 2016 
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Final Version 3.0 
Page 19 of 66 
 
for each cohort. If safety and tolerability is acceptable the remaining subjects of each cohort 
will be dosed in group sizes of no more than three with a minimum interval of 24 hours 
between the start of dosing in the first subject on the previous day and the start of dosing on 
the next day. In addition, during a dosing day, there will be a minimum interval of 60 minutes 
between the start of (maintenance) dosing in a subject and the start of dosing in the next 
subject to ensure that reactions can be dealt with promptly. Any reactions will be treated and 
taken into account in the dose progression/escalation and toxicity rules. If anaphylactic 
reactions occur the current “UK Treatment Guideline for Anaphylactic Reactions” of the UK 
Resuscitation Council will be followed (refer to Appendix 19.1). 
 
6.4.2.4 Product-Specific Antibody Development 
LR12 is a peptide derived from a highly conserved human protein; it is expected to have a low 
immunogenic profile. An exposure to study drug of 8 hours is not expected to result in 
triggering an immune response in the study subjects. However, the possibility of triggering an 
immune response against it in humans still exists. Therefore, all subjects will be carefully 
monitored for 28 days. Should any subject develop ADA against LR12, they will be followed 
up for at least 3 months or until the antibody response is no longer detected. 
 
7 
STUDY OBJECTIVES 
7.1 
Primary Objectives 
 To assess the safety and tolerability of MOTREM in comparison with placebo, after 
single intravenous (i.v.) dose administration in healthy young male subjects. 
 
7.2 
Secondary Objectives 
 To assess the pharmacokinetics of LR12 after single i.v. dose administration in healthy 
young male subjects 
 To investigate the presence of anti-LR12 antibodies after single i.v. dose administration 
in healthy young male subjects 
 
8 
STUDY DESIGN 
8.1 
Overall Study Design and Procedure 
This will be a First in Human (FIH), randomised, placebo-controlled study, with sequential 
single ascending intravenous dose groups. Single doses of MOTREM (LR12) or matching 
placebo are planned to be administered following a sequential group design in 26 healthy 
young male subjects aged from 18 to 45 years. 
This study incorporates the use of an adaptive design (8). Study specific adaptive features and 
their limits are described in Table 1. 
Dose escalation and progression will be limited by evaluation of safety and tolerability data 
governed by toxicity rules (Section 8.3) and will only occur after satisfactory review of all 
safety and tolerability data by the Safety Review Committee (Section 8.2.3). 
 


INOTREM SA. 
CONFIDENTIAL 
13 May 2016 
Protocol Ref: MOT-C-104 
Final Version 3.0 
Page 20 of 66 
 
Table 1. Adaptive Protocol Features. 
Adaptive Study 
Design Areas  
Features 
Limits 
Dose 
1. All anticipated dose levels/dosing 
regimens in Parts A and B can be 
adjusted in accordance with PK, 
safety and tolerability data collected 
up to the decision making time-
point.  
 
I. 
The starting dose for Part A of the 
study will not exceed 1 mg.  
II. 
The maximum dose for Part A will not 
exceed 10 mg. 
III. 
The starting loading dose in Part B will 
not exceed 0.5mg/kg.  
IV. 
The starting maintenance dose in Part 
B will not exceed 0.03 mg/kg/h. 
V. 
The dose increments between the dose 
levels 1 to 2 in Part A will be no more 
than 10-fold. 
VI. 
The loading dose increments between 
the dose levels in Part B will be no 
more than 2.5-fold. 
VII. 
The maintenance dose increments 
between the dose levels in Part B will 
be no more than 3.5-fold. 
 
2. In Part B, the anticipated dosing 
regimens can be adjusted in 
accordance with PK, safety and 
tolerability data collected up to the 
decision making time-point. 
3. The term dosing regimen includes 
(1) the dose level administered as 
loading dose, (2) the dose level 
administered as maintenance dose 
(3) the duration of the loading dose 
and (4) the duration of the 
maintenance dose. Accordingly, 
these can be adjusted individually or 
in combination. 
I. 
The treatment duration will not exceed 
8 hours.  
II. 
Minimum duration of loading dose will 
be of 15 min. 
III. 
Limits outlined under adaptive feature 
1 apply.  
Timing 
4. Dosing regimens may overlap.  
I. 
Protocol specific minimum study 
progression/escalation requirements for 
the SRC must be met before dose 
progression/escalation as described in 
section 8.2.  
 
5. Cohorts/dosing regimens may be 
split into sub-groups 
I. 
A mandatory sentinel dosing strategy 
of dosing one subject on IMP on the 
first day will be used for each cohort. If 
safety and tolerability is acceptable the 
remaining subjects of each cohort will 
be dosed in group sizes of no more than 
three with a minimum interval of 24 
hours between the start of dosing in the 
first subject on the previous day and the 
start of dosing on the next day.  
II. 
During a dosing day, there will be a 
minimum interval of 60 minutes 
between the start of (maintenance) 
dosing in a subject and the start of 
dosing in the next subject.  
III. 
Additional sentinel or sequential dosing 
for all cohorts and study parts can be 
performed at the discretion of sponsor 


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Final Version 3.0 
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Adaptive Study 
Design Areas  
Features 
Limits 
and investigator. 
Flexible Cohort 
Sizes 
6. Withdrawn subjects can be replaced 
at the discretion of the sponsor and 
investigator, if not withdrawn for 
safety reasons. 
7. Replacement subjects may be 
enrolled in an ongoing cohort, or 
dosed together as a group or dosed 
separately.  
8. The number of subjects in a dose 
cohort can be extended to gather 
further information on a dosing 
regimen.  
I. 
The maximum extension is 100% of 
the original group/cohort size at the 
selected dose level. 
II. 
The randomisation will follow the 
randomisation system of the originally 
planned dose cohort. 
III. 
Study specific toxicity rules (Table 4) 
apply. 
Optional Study 
Parts/Cohorts 
9. Optional groups/cohorts may be 
included to explore additional dose 
levels and/or dosing regimen.  
I. 
Up to 2 additional groups/cohorts may 
be included into each, Part A and B. 
II. 
The size of the optional groups/cohorts 
will not exceed the limits outlined 
under adaptive features 6-8. 
Samples and 
Assessments 
 
10. The in-house stay or follow-up 
period may be prolonged if: 
a. It is considered clinically 
necessary by the PI or delegate 
for individuals on a case-by-
case basis. 
b. The Safety Review Committee 
(SRC) considers it necessary 
from a safety/tolerability point 
for an upcoming dose 
group/cohort. 
c. The follow-up period for a dose 
cohort may be prolonged if 
evolving PK data require a 
longer follow-up period. 
I. 
A maximum extended in-house or 
follow-up period cannot be defined as 
the extension will be as long as 
necessary to ensure the safety of the 
individual participant(s).  
II. 
The maximum extended in-house or 
follow-up period for study cohorts will 
be based on evolving safety, 
tolerability and PK data and will not 
usually exceed 10 x t½ of the IMP 
following the last dose.  
III. 
Extension of in-house or follow-up 
period does not constitute an SAE, 
unless a subject is hospitalised as 
patient of the National Health Service 
or the AE meets other SAE criteria.  
 
11. Additional safety blood and/or urine 
samples/variables may be taken or 
analysed if: 
a. It is considered clinically 
necessary by the PI or delegate 
for individuals on a case-by-
case basis. 
b. The SRC considers it necessary 
from a safety/tolerability point 
for an upcoming dose cohort. 
I. 
For individuals, a maximum number of 
safety blood samples will be 
determined on a case-by-case basis and 
cannot be pre-defined as investigations 
will be performed as necessary to 
ensure the safety of the individual 
participants.  
II. 
For dose cohorts, study specific 
maximum blood volumes will not be 
exceeded (see section 12.7).  
 
12. Timing of PK and/or 
immunogenicity samples may be 
adjusted in accordance with 
evolving data and dosing schedule. 
13. Additional or less PK and/or 
immunogenicity samples may be 
taken in accordance with evolving 
data and dosing schedule. 
I. 
Minimum: sufficient PK samples to 
establish full protocol specific serum 
PK profile. Sufficient immunogenicity 
samples to enable evaluation of de 
novo antibody development. 
II. 
Study specific maximum blood volume 
will not be exceeded (see section 12.7).  
 
14. Timing of safety assessments 
including but not limited to 
laboratory safety samples, vital 
I. 
Alterations in timing of the safety 
assessments need to be a reflection of 
the established PK, safety and 


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13 May 2016 
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Final Version 3.0 
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Adaptive Study 
Design Areas  
Features 
Limits 
signs and ECGs may be adjusted in 
accordance with evolving data and 
dosing schedule. 
15. Additional safety assessments 
including but not limited to 
laboratory safety samples, vital 
signs and ECGs may be taken in 
accordance with evolving data and 
dosing regimens. 
tolerability profile up to the decision 
making time-point. 
II. 
Alterations need to be made in the 
spirit of the current CSP (i.e. focus on 
the capture of essential and useful data) 
and not affect the risk profile of the 
study. 
 
16. Specialist referrals (e.g. to a 
cardiologist) may be made (and may 
include all relevant assessments and 
investigations) if it is considered 
clinically necessary by the PI or 
delegate or Sponsor or SRC for 
individuals on a case-by-case basis. 
I. 
A maximum for individuals will be 
determined on a case-by-case basis and 
cannot be pre-defined as investigations 
will be performed as necessary to 
ensure the safety of the individual 
participants. 
 
17. Except for those subjects that have 
been randomised, screening 
assessments, including Holter ECG 
recordings performed at Richmond 
Pharmacology Ltd on volunteers 
screened for another study can be 
used for this study to avoid 
unnecessary tests. 
I. 
The assessments must meet protocol 
criteria (e.g. the method to be used) 
II. 
The assessments must be performed 
within the protocol defined screening 
window 
III. 
The Holter ECG recordings are valid 
for a period of three months.  
AEs 
18. Allow for the study to continue 
under the originally approved CSP 
and IMPD in case of new pre-
clinical or clinical findings. 
I. 
Applicable only for findings which do 
not affect the risk profile or objectives 
of the study.   
 
Study Plan  
Single doses of MOTREM (LR12) or matching placebo (Part B) are planned to be 
administered following a sequential group design in 26 healthy young male subjects aged 
from 18 to 45 years: Part A (Groups 1 and 2 of 1 subject each) followed by Part B (Groups 3 
to 8 of 4 subjects each). For Part A (Groups 1 and 2), one subject each will receive 
MOTREM. For Part B (Groups 3 to 8) 3 subjects will receive MOTREM and 1 subject will 
receive placebo (3:1 ratio). Dose escalation to the following scheduled dose will only occur 
after satisfactory review of all safety and tolerability data by the Safety Review Committee in 
accordance with Table 1, protocol sections 8.2 Rules for dose escalation/progression and 8.3 
Toxicity rules. 
Subjects will be screened within 14 days and may be performed over multiple days prior to 
entering the study on Day -1. Each subject will receive verbal and written information 
followed by signing of the Informed Consent Form (ICF) prior to any screening procedures 
taking place. Subjects will be admitted on Day -1 and on Day 1 of the study each subject will 
receive MOTREM (LR12). All the subjects from Part A (Groups 1 and 2) and Part B (groups 
3 to 8) will be discharged on Day 2 after 24h post-dose (start of infusion). They will attend the 
unit for a follow-up visit on Day 8±1. The End of Study visit will take place on Day 28±2. All 
the assessments performed during the study are detailed in the Study Plan (Table 2 and Table 
3). Study design features as well as number of subjects may be adapted according to Table 1. 
The end of study is defined as the last subject, last visit (LSLV). 


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Protocol Ref: MOT-C-104 
Final Version 3.0 
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Figure 1: Study Flow Chart. 
 


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Protocol Ref: MOT-C-104 
Final Version 3.0 
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Table 2. Study Plan – Part A (Groups 1 and 2).  
Groups 1 and 2 
Screening 
 
Assessment Period 
FU 
Visit 
EOS 
Visit 
D-14 to D-2 
D-1 
D1 
D2 
D8±1 
D28±2 
Predose 
H0 
H1 
H2 
H3 
H4 
H5 
H6 
H7 
H8 
H24 
SCREENING PROCEDURES 
 
Signature 
of 
the 
informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medications 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X(1) 
 
 
 
 
 
 
 
 
 
 
X(1) 
X(1) 
X(1) 
Viral Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol breath test &  
Urine Drug Screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomisation 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
24h Holter 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hospitalisation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study treatment schedule 
 
 
 
T0' to T15' 
 
 
 
 
 
 
 
 
 
 
 
Meals(2) 
 
X 
X 
 
 
 
SAFETY ASSESSMENTS (3) 
 
Vital signs(4) 
(including BMI assessment at 
screening) 
X 
X 
X 
T0', T10', 
T20, T30, 
T40, T50' 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
X 
X 
T15' 
X 
X 
 
 
 
 
 
 
X 
 
 
Telemetry (5) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Haematology  
X 
X 
 
T15' 
 
 
 
X 
 
 
 
 
X 
 
 
Coagulation 
X 
X 
 
T15' 
 
 
 
X 
 
 
 
 
X 
 
 
Serum chemistry 
X 
X 
 
T15' 
 
 
 
X 
 
 
 
 
X 
 
 
Urinalysis 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Infusion site assessment 
 
 
X 
T15' (6) 
X 
 
 
X 
 
 
 
 
X 
 
 
Anti-LR12 antibody screening(7) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
Pharmacokinetics 
 
 
X 
T15' 
X 
 
 
 
 
 
 
 
 
 
 
Adverse Events  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(1) 
Brief physical examination. 
(2) 
Standard meals will be served at standard times. Meal at dismissal will be optional. 
(3) 
Time of procedures is relative to the start of infusion. 
(4) 
Tympanic temperature will be collected at predose and at H8 only. Vital signs at H0 will be measured only in supine position. 
(5) 
12-Lead telemetry will be recorded from pre-dose to 10 h post-dose. 
(6) 
The check of the local tolerability at H0 should be performed just after the loading infusion 
(7) 
Should any subject develop ADA against LR12, they will be followed up for at least 3 months or until the antibody response is no longer detected. 
. 
 


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13 May 2016 
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Final Version 3.0 
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Table 3. Study Plan – Part B (Groups 3 to 8). 
Groups 3 to 8 
Screening 
 
Assessment Period 
FU 
Visit 
EOS 
Visit 
D-14 to D-2 
D-1 
D1 
D2 
D8±1 
D28±2 
Predose 
H0 
H1 
H2 
H3 
H4 
H5 
H6 
H7 
H8 
H10 
H24 
SCREENING PROCEDURES 
Signature 
of 
the 
informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medications 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X(1) 
 
 
 
 
 
 
 
 
 
 
 
X(1) 
X(1) 
X(1) 
Viral Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol breath test &  
Urine Drug Screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomisation 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
24h Holter 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hospitalisation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study treatment schedule 
 
 
 
i.v. loading dose 
T0 to T15' 
i.v. maintenance dose over 7 hours and 45 minutes 
 
 
 
 
Meals(2) 
 
X 
X 
X 
 
 
SAFETY ASSESSMENTS (3) 
 
 
Vital signs(4) (including BMI 
assessment at screening) 
X 
X 
X 
T0', T10', T20, 
T30, T40, T50' 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
X 
X 
T15' 
X 
 
 
 
 
 
 
X 
X 
X 
 
 
Telemetry (5) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Haematology  
X 
X 
 
T15' 
 
 
 
X 
 
 
 
 
 
X 
 
 
Coagulation 
X 
X 
 
T15' 
 
 
 
X 
 
 
 
 
 
X 
 
 
Serum chemistry 
X 
X 
 
T15' 
 
 
 
X 
 
 
 
 
 
X 
 
 
Urinalysis 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Infusion site assessment 
 
 
X 
T15' (6) 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Anti-LR12 antibody screening(8) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Pharmacokinetics(7) 
 
 
X 
T5', T15', T18', 
T30', T45' 
X 
X 
 
X 
 
X 
 
T-15, T2’, 
T4', T7', T15', 
T30 
X 
 
 
 
Adverse Events  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(1) 
Brief physical examination.  
(2) 
Standard meals will be served at standard times. Meal at dismissal will be optional. 
(3) 
Time of procedures is relative to the start of infusion.  
(4) 
Tympanic temperature will be collected at pre-dose and at H8 only. Vital signs at H0 and H8 will be measured only in supine position. 
(5) 
12-Lead telemetry will be recorded from pre-dose to 10 h post-dose. 
(6) 
The check of the local tolerability at H0 should be performed just after the loading infusion. 
(7) 
PK sampling performed at the end of the 8 hours i.v. infusion will be as follows: 15 min before H8 (T-15’), then during 30 min after the end of the infusion as specified in the table. H0 timings refer to start of 
infusion. 


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(8) 
Should any subject develop ADA against LR12, they will be followed up for at least 3 months or until the antibody response is no longer detected. 


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8.2 
Rules for Dose Escalation/Progression 
A safety review committee (SRC) will review and assess at least the minimum required data 
from the previous group(s)/cohort(s) to make decisions on the dose(s) for the next dose 
levels/dosing regimen. The SRC will assess if any of the group or individual toxicity criteria 
are met and if the concerned AEs have a causal relationship with the IMP. If so, the SRC will 
take action in accordance with the rules stipulated in section 8.3.  
There is an option to have ad-hoc SRC meetings to discuss urgent issues should the need 
arise. 
 
8.2.1 Safety Review Committee 
The SRC will consist of, as a minimum: 
 Principal Investigator (RPL) or delegate 
 INOTREM SA Medical Officer or delegate 
 
Further internal or external experts such as a pharmacokineticist and/or a statistician, may be 
consulted by the SRC as necessary. Any additional information, if required will be included in 
the study operations manual (SOM). 
 
8.2.2 Data Requirements 
After each cohort the SRC will assess the minimum safety, tolerability and PK data required 
prior to dose escalation/progression (refer to dose escalation/progression section 8.2.4. Prior 
to each SRC meeting, an interim safety report will be prepared for that group/cohort 
presenting the relevant safety and tolerability data. These will be signed by the PI and/or 
delegate. PK data will be provided separately by the analytical laboratory. As the initial data 
review will be blinded, there will be no link between the safety data and the PK data. 
The following data will be required: 
Safety: 
 AEs 
 Vital sign variables (temperature, blood pressure, heart rate)  
 ECGs variables (12-lead ECG, telemetry and Holter) 
 Clinical laboratory variables (haematology, coagulation, biochemistry, urinalysis) 
 
PK  
For availability of PK data, refer to section 8.2.4. 
 
Additional data that may available at the time of report writing: 
 Other relevant clinical tests conducted on a case-by-case basis  
 


INOTREM SA. 
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13 May 2016 
Protocol Ref: MOT-C-104 
Final Version 3.0 
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8.2.3 SRC Meeting  
The SRC will determine dose escalations/progression according to the Clinical Study Protocol 
(CSP), anticipated doses, adaptive features and group toxicity rules. The decision will be 
signed by one of the Sponsor’s representatives and by the PI or delegate. For logistical 
reasons, the signature of the Sponsor or Investigator may be communicated via email. 
Initially the data will be reviewed blinded, but if the SRC consider it necessary due to a safety 
concern, either individual subjects or the entire cohort may be unblinded to enable their 
decision-making. Before breaking the code, the potential decisions and actions should be 
determined and documented. 
The decision of the SRC on the next dose will be taken in consensus between the members of 
the SRC. If consensus cannot be reached, then the most cautious approach will proceed. The 
decisions and decision-making of the SRC on the next dose level will be documented and 
provided to the PI and Pharmacist prior to the next scheduled dosing day. 
 
8.2.4 Dose Escalation/Progression 
Dose escalation /progression is defined as either of the following: 
1. Escalation to a higher exposure dosing regimen within Part A  
2. Progression from Part A to Part B  
3. Escalation to a higher exposure dosing regimen within Part B  
 
Minimum data requirements for dose escalation/progression are: 
1. Escalation to a higher exposure dosing regimen between Part A (Groups 1 and 2 
and optional groups) 
A minimum of 24 hours post-dose (start of infusion) safety and tolerability data from 
one subject of the cohort with the next lower mean exposure level will be required. 
2. Progression from Part A to Part B 
A minimum of 24 hours post-dose (start of infusion) safety and tolerability data from 
one subject on Part A’s 10mg dose level will be required. 
3. Escalation to a higher exposure dosing regimen between Part B (Groups 3 to 8 
and optional groups) 
A minimum of 24 h post-last dose (start of infusion) safety, tolerability and PK data 
from a minimum of three subjects who have received the active compound from a 
previous cohort that was on the next lower dosing regimen (and hence, next lower 
exposure (mean and individual Cmax) levels of loading dose and mean and individual 
Cmax and Css inf of maintenance doses) will be required. 
 
8.3 
Toxicity Rules 
Group toxicity rules 
For the purpose of this CSP, toxicity means clinically significant drug related adverse 
reaction(s).  


INOTREM SA. 
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13 May 2016 
Protocol Ref: MOT-C-104 
Final Version 3.0 
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For the purpose of this CSP the term ‘dose escalation’ means progression to a consecutive 
dose/dosing regimen or escalation to a dose/dosing regimen with an anticipated higher 
exposure in line with the dose progression/escalation rules and minimum data requirements. 
For the purpose of this CSP the term ‘suspension’ means that no further IMP will be 
administered at the dose level/dosing regimen concerned and that further dose 
escalation/progression will be suspended. If a dose level/dosing regimen is suspended, an ad 
hoc SRC meeting will be held. Any resumption at the same or a higher exposure dose 
level/dosing regimen will require a substantial amendment which has been approved by the 
Competent Authority and the REC.  
The group toxicity rules are described in Table 4. 


INOTREM SA. 
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13 May 2016 
Protocol Ref: MOT-C-104 
Final Version 3.0 
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Table 4. Group Toxicity Rules. 
CTCAE 
Grade 
Severity/  
Seriousness 
Reversibility 
Number of 
Subjects 
Affected 
Action 
Effect on Dose 
Progression/Escalation 
I 
Mild 
N/A 
N/A 
Next dose determined 
by SRC 
N/A 
II 
Moderate 
Showing signs 
of reversibility; 
i.e. event which 
shows signs of 
improvement in 
the judgment of 
investigator 
≤2 subjects in 
different SOC 
≤2 subjects in 
same SOC 
OR 
3 subjects in 
different SOC* 
Dose level may continue  
OR 
be extended 
AND  
Dose escalation on hold 
until results of 
continuation or 
extension are available 
Following continuation or 
extension, dose escalation may 
proceed as per clinical study 
protocol 
≥3 subjects in 
same SOC 
OR 
≥4 subjects in 
different SOC* 
Dose level suspended 
A lower (intermediate) dose 
level may be administered in 
the next cohort 
AND 
Dose continuation, extension, 
or escalation requires 
substantial amendment 
Showing no 
signs of  
reversibility 
≥2 subjects* 
III 
Severe, not 
serious 
Showing signs 
of reversibility; 
i.e. event which 
shows signs of 
improvement in 
the judgment of 
investigator 
1 subject*
 
 
Dose level may continue  
OR 
be extended 
AND  
Dose escalation on hold 
until results of 
continuation or 
extension are available 
Following continuation or 
expansion, dose escalation may 
proceed as per the clinical 
study protocol 
≥2 subjects* 
Dose level suspended
 
 
A lower (intermediate) dose 
level may be administered in 
the next cohort 
AND 
Dose continuation, extension, 
or escalation requires 
substantial amendment 
Showing no 
signs of 
reversibility 
≥1 subject  
 
Severe, 
serious 
N/A 
IV 
Life-
threatening 
N/A 
≥1 subject 
Study suspended 
Study continuation requires 
substantial amendment 
V 
Fatal  
Abbreviations:  AE=adverse event; N/A=not applicable; SOC=System Organ Class; SRC=Safety Review Committee 
* Within 2 weeks from each dose 
 


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13 May 2016 
Protocol Ref: MOT-C-104 
Final Version 3.0 
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Individual stopping criteria 
Individual stopping criteria are described in Table 5. 
Table 5. Individual Toxicity Rules.  
Individual toxicity rules 
Grade 
Severity/Seriousness  
Action 
I 
Mild 
No action required  
II 
Moderate 
IMP administration may be continued, amended, temporarily 
suspended or discontinued in accordance with Investigator’s 
clinical judgement and relevant algorithms for the treatment of 
toxicities   
III 
Severe, not serious 
IMP administration will be discontinued for the subject 
 
Severe, serious 
IMP administration will be discontinued for the subject 
IV 
Life-threatening 
IMP administration will be discontinued for the subject 
V 
Fatal 
 Not Applicable 
 
Standard toxicity grading according to the National Cancer Institute Common Terminology 
Criteria (NCI CTC) for AEs (NCI CTCAE, version 4.0) will be used to grade the AEs for the 
purpose of applying the toxicity rules. This is owing to the fact that these are the only 
standardised set of comprehensive criteria available and have proven useful in healthy 
volunteer and patient Phase 1 studies. Local laboratory normal values will be applied. 
Abnormal laboratory and other tests and measurements will be repeated whenever feasible 
and or appropriate, prior to grading in order to ensure consistency and to exclude technical 
errors. Diurnal variations in laboratory variables and other measurements as well as baseline 
status and conditions will be taken into account when assessing whether abnormalities 
constitute a drug related AE and when grading, if applicable. 
The CTCAE displays AE/toxicity Grades I through V with detailed clinical descriptions of 
severity for individual AEs based on a general guideline. The general grade definitions are 
described as follows: 
Grade I: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade II: Moderate; minimal, local or non-invasive intervention indicated; limiting age-
appropriate instrumental Activities of Daily Living (ADL)*. 
Grade III: Severe or medically significant but not immediately life-threatening; hospitalisation 
or prolongation of hospitalisation indicated; disabling; limiting self-care ADL**. 
Grade IV: Life-threatening consequences; urgent intervention indicated. 
Grade V: Death related to AE. 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden. 
The NCI CTCAE criteria and their interpretation are consistent with the standard intensity 
grading for AEs during clinical studies: Grade I: mild, Grade II: moderate, Grade III: severe 


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13 May 2016 
Protocol Ref: MOT-C-104 
Final Version 3.0 
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or medically significant but not immediately life-threatening, may constitute Serious Adverse 
events (SAE)/Suspected Unexpected Serious Adverse Reaction (SUSAR). Grades IV and V 
constitute SAE/SUSAR.  
Non-clinical data as well as potential class effects have identified the risks outlined in sections 
6.4.2.1, 6.4.2.3 and 6.4.2.4 (allergic reactions, infusion reactions and anaphylaxis; product 
specific antibody development).  
The grading of the NCI CTCAE criteria related to toxicities and potential AEs (including 
study related sections on: ‘infusion related reaction’, ‘injection site reaction’, ‘allergic 
reaction’ ‘anaphylaxis’, ‘Immune system disorders’ – specifically ‘autoimmune disorder’) is 
considered suitable for this particular IMP, study design and the study populations in 
conjunction with the CSP specific toxicity and dose progression/escalation rules.  No further 
qualifications are required.   
 
8.4 
Rationale for Study Design, Doses and Control Groups 
This study is the first time that MOTREM will be given to healthy young subjects.   
A standard single dose escalation design is used for this study to evaluate the safety, 
tolerability and PK of the investigational product in healthy subjects. The study is randomised 
and double blind (Part B only) to minimise bias and includes placebo to facilitate 
identification of effects related to administration of drug rather than the study procedures or 
situation. 
For the first two dose levels (Part A) there will be no placebo and only one subject will be 
dosed, as these dose levels are well below the expected therapeutic dose range and expected 
to be below the limit of quantification in human blood and therefore not considered 
informative (9). 
8.4.1 Justification of Safe Starting Dose  
Regulatory References 
Toxicity studies were performed at INOTREM in accordance with ICH guidance documents 
S6/R1 and M3 (R2) as well as to EMA’s guidance on repeated dose toxicity 
(EMEA/CHMP/SWP/488313/2007) and FDA guidance “Immunogenicity Assessment for 
Therapeutic Protein Products”.  
The safe starting dose of LR12 in the first-in-human study MOT-C-104 was estimated 
according to the principles laid out in the guidance documents “Guidance for Industry: 
Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in 
Adult Healthy Volunteers. FDA/CDER, July 2005” and the “Guideline on Strategies to 
Identify and Mitigate Risks for First-in Human Clinical Trials with Investigational Medicinal 
Products CHMP/SWP/28367/07”. 
Relevant Species Selection 
Since (i) LR12 sequence displays an identical amino acid sequence for both human and 
cynomolgus monkey TLT-1 protein and (ii) LR12 is pharmacologically active in this species, 
the cynomolgus monkey was selected as the relevant animal species to perform toxicity 
studies. In addition, the pharmacokinetic behaviour of LR12 is expected to be similar in 
cynomolgus monkeys and humans. The corresponding LR12 sequence of rodents differs from 
human and cynomolgus LR12 by two amino acids. 


INOTREM SA. 
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13 May 2016 
Protocol Ref: MOT-C-104 
Final Version 3.0 
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No Observed Adverse Effect Level (NOAEL) Determination 
For establishing the safe starting dose, only the 14-day GLP toxicity study in cynomolgus 
monkeys with the clinical formulation is considered (MOT-PT-10). In this study, monkeys 
were exposed to an initial high loading dose for 15 minutes followed by a maintenance dose 
administered by continuous IV infusion for 14 days. The NOAEL was then set as the highest 
dose administered in that study (140 mg/kg/day with a loading dose of 20 mg/kg/15 minutes, 
see Table 6 and Table 7). 
Human Equivalent Dose (HED) Calculation 
According to the “Guidance for Industry: Estimating the Maximum Safe Starting Dose in 
Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers. FDA/CDER, July 2005”, 
normalisation to body surface area is an appropriate method for extrapolating doses between 
species (hereafter referred to as “HED BS”). However, certain exceptions are made. It is 
considered that scaling based on body weight (i.e. setting the HED (mg/kg) = NOAEL 
(mg/kg) and referred to in this document as “HED BW”) may be appropriate for therapeutics 
that will have little distribution outside the intra-vascular compartment. There is some 
evidence that LR12 mainly remains in the i.v. compartment after administration. However, 
distribution of LR12 is not yet fully characterised. 
On the other hand, the clearance of LR12 is very fast in monkeys and it is expected to be 
similar in humans. Since LR12 is planned to be administered continuously by i.v. infusion to 
maintain steady state concentrations, as it has been done in efficacy pharmacology models, it 
is necessary to consider exposure time to LR12 at a given plasma concentration/infusion rate 
in order to determine appropriate safety margins.  
For the above mentioned reasons, both approaches HED BS and HED BW will be taken into 
consideration as well as rate of infusion and time of exposure in order to calculate the safety 
margin for this FIH study.  
 
8.4.1.1 Determination of Safe Starting Dose 
The safety factor recommended by regulatory guidance documents is 10. However, 
considering that LR12 is a novel therapeutic agent, we have increased greatly this safety 
margin.  
The first dose planned to be administered to humans is 1 mg as a “loading” dose infused i.v. 
for 15 minutes. This will be equivalent to a rate of infusion of 0.057 mg/kg/h and to 0.014 
mg/kg dose for an individual of 70 kg.  
The reference NOAEL and its conversion to HED BS is shown in Table 6. The reference 
“loading dose” and its conversion to HED BS for the group of animals that have received the 
highest loading dose in the toxicology study MOT-PT-10 is presented in Table 7. 


INOTREM SA. 
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13 May 2016 
Protocol Ref: MOT-C-104 
Final Version 3.0 
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Table 6. NOAEL and HED BS. 
Study 
Exposure  
Time1 
NOAEL 
mg/kg/day 
NOAEL 
mg/kg/hour 
HED BS2 
mg/kg/day 
HED BS1 
mgkg/hour 
MOT-PT-10 
24 h 
140 
5.83 
45.16 
1.88 
 
1: Refers to a period of 24h of a 14-day repeated toxicity study used here as the reference exposure period  
2: HED calculated according to FDA Guidance for Industry Estimating the Maximum Safe Starting Dose in Initial 
Clinical Trials for Therapeutics in Adult Healthy Volunteers (2005) body surface conversion table. Animal dose is 
divided by a factor of 3.1 for cynomolgus monkeys. 
 
Table 7. Highest Loading Dose and HED BS. 
Study 
Exposure 
time  
NOAEL 
mg/kg/15 min 
NOAEL 
mg/kg/hour 
HED BS1 
mg/kg/15 min 
HED BS1 
mg/kg/hour 
MOT-PT-10 
15 min 
20 
80 
6.45 
25.81 
 
1: HED calculated according to FDA Guidance for Industry Estimating the Maximum Safe Starting Dose in Initial 
Clinical Trials for Therapeutics in Adult Healthy Volunteers (2005) body surface conversion table. Animal dose is 
divided by a factor of 3.1 for cynomolgus monkeys. 
 
According to this, the starting dose rate in mg/kg/h will be 33 times lower than the NOAEL 
HED BS (1.88 versus 0.057) and 102 times lower than the NOAEL HED BW (5.83 versus 
0.057). In terms of total exposure, knowing that the reference taken in toxicology studies is of 
24 hours and that total exposure time for human starting dose will be 15 minutes, the total 
exposure in a one-day period in mg/kg will be 3226 times lower on the basis of HED BS 
(45.16 versus 0.014) and 10000 times lower on the basis of HED BW (140 versus 0.014). 
If the highest loading dose given during the toxicology study is considered, the starting dose 
rate in mg/kg/h will be 453 times lower by HED BS conversion (25.81 versus 0.057) and a 
1403 times lower by HED BW conversion (80 versus 0.057). In terms of total exposure, the 
total exposure in a 15-minute period in mg/kg will be 461 times lower on the basis of HED 
BS (6.45 versus 0.014) and 1429 times lower on the basis of HED BW (20 versus 0.014). 
These margins are considered to be sufficiently wide to assure safety of healthy volunteers 
who will receive LR12 for the first time. 
 


INOTREM SA. 
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13 May 2016 
Protocol Ref: MOT-C-104 
Final Version 3.0 
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8.4.1.2 Justification of Dose Escalation Steps 
The planned dose escalation scheme of the FIH study MOT-C-104 is summarised in Table 8: 
Table 8. Planned Dose Escalation Scheme. 
Group 
Loading dose 
Maintenance dose 
 
(mg/kg) 
15 min 
Rate 
(mg/kg/h) 
Total 
(mg)* 
Rate 
(mg/kg/h) 
Total 7h45 
(mg/kg) 
Total 7h45 
(mg)* 
1 
0.014 
0.057 
1 
- 
- 
- 
2 
0.140 
0.570 
10 
- 
- 
- 
3 
0.500 
2.000 
35 
0.03 
0.23 
16.3 
4 
1.000 
4.000 
70 
0.10 
0.78 
54.3 
5 
2.000 
8.000 
140 
0.30 
2.33 
162.8 
6 
5.000 
20.000 
350 
1.00 
7.75 
542.5 
7 
5.000 
20.000 
350 
3.00 
23.25 
1,627.5 
8 
5.000 
20.000 
350 
9.00 
69.75 
4,882.5 
*Assuming a body weight of 70kg 
 
The second dose planned to be administered to humans is 10 mg as a “loading” dose infused 
i.v. for 15 minutes. This will be equivalent to a rate of infusion of 0.57 mg/kg/h and to 0.14 
mg/kg dose for an individual of 70 kg.  
According to this, the second cohort dose rate in mg/kg/h will be 3.3 times lower than the 
NOAEL HED BS (1.88 versus 0.57) and 10 times lower than the NOAEL HED BW (5.83 
versus 0.57). In terms of total exposure, knowing that the reference taken in toxicology 
studies is of 24 hours and that total exposure time for this cohort will be 15 minutes, the total 
exposure in a one-day period in mg/kg will be 323 times lower on the basis of HED BS (45.16 
versus 0.14) and 1000 times lower on the basis of HED BW (140 versus 0.14). 
If the highest loading dose given during the toxicology study is considered, the second cohort 
dose in mg/kg/h will receive a 45 times lower dose by HED BS conversion (25.81 versus 
0.57) and a 140 times lower dose according to HED BW (80 versus 0.57). The total exposure 
in a 15 minutes period in mg/kg will be 46 times lower on the basis of HED BS (6.45 versus 
0.14) and 143 times lower on the basis of HED BW (20 versus 0.14). 
From cohorts 3 to 6, the loading dose will be increased incrementally by a factor 2 (or 2.50).  
The first maintenance dose rate will be introduced in cohort 3 and is of 16.3 mg at an infusion 
rate of 0.03 mg/kg/h for a total exposure time of 7h45. This corresponds to 0.23 mg/kg dose 
for an individual of 70 kg.  
According to this, the third dose rate for the maintenance dose in mg/kg/h will be 63 times 
lower than the NOAEL HED BS (1.88 versus 0.03) and 194 times lower than the NOAEL 
HED BW (5.83 versus 0.03). In terms of total exposure, knowing that the reference taken in 
toxicology studies is of 24 hours and that total exposure time for the maintenance dose in 
humans will be of 7 hours 45, the total exposure in a one day period in mg/kg will be 196 
times lower on the basis of HED BS (45.16 versus 0.23) and 609 times lower on the basis of 
HED BW (140 versus 0.23). 
From cohorts 3 to 8, the maintenance dose will be increased incrementally by a factor 3. 


INOTREM SA. 
CONFIDENTIAL 
13 May 2016 
Protocol Ref: MOT-C-104 
Final Version 3.0 
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For information, in preclinical efficacy pharmacology experiments in LPS-challenged 
cynomolgus monkeys, LR12 at a loading dose of 10 mg/kg/h for a period of 30 minutes and a 
maintenance dose of 1 mg/kg/h for 7.5 hours was pharmacologically active. In this model, this 
dose was able to avoid hypotension and diminish the increase of several pro-inflammatory 
cytokines by 20-50% in comparison with untreated animals. This dose would approximately 
correspond to the dose that will be administered to the cohort 5 of the present study if we 
consider the HED BS and to the dose that will be administered to the cohort 6 if we consider 
the HED BW. However, an LR12-induced pharmacological effect is not expected in healthy 
volunteers since their innate immune system would not be activated. 
Justification of highest dose level 
The anticipated highest dose regimen that will be tested (cohort 8) is a loading dose of 5 
mg/kg administered during 15 minutes (20 mg/kg/h) followed by a maintenance dose of 69.75 
mg/kg, administered during a period of 7h45 (9 mg/kg/h).  
The highest loading dose will be introduced in cohort 6 (Table 3). This dose in mg/kg/h will 
be 1.3 times lower by HED BS conversion (25.81 versus 20) and 4 times lower if HED BW is 
used (80 versus 20). For this cohort, the total exposure in a 15 minutes period in mg/kg will 
be 1.3 times lower on the basis of HED BS (6.45 versus 5) and 4 times lower on the basis of 
HED BW (20 versus 5). 
In a pilot toxicity study (MOT-PT-01), two monkeys received 18.75 mg/kg/h during a period 
of 24h, meaning 450 mg/kg (Twice higher rate than the maintenance dose planned in cohort 8 
if HED BW is considered). In this study no drug-related adverse event was observed. In terms 
of total dose in a period of one day, cohort 8 individuals will receive 69.75 mg/kg. In 
comparison to this pilot study, the total dose that will be administered to cohort 8 is around 
twice lower if HED BS is used (145.2 versus 69.75) and 6 times lower if HED BW is used 
(450 versus 69.75). In addition, in a GLP cardiovascular function safety pharmacology study 
(MOT-PT-02), four monkeys received 18.4 mg/kg/h during 24 hours (total dose of 442 
mg/kg) and did not show any drug-related adverse event. Therefore, the highest dose is 
expected to be safe.  
Of importance, in order to further minimise the risk to study subjects in study MOT-C-104, 
the safety of subjects will be monitored closely and escalation to higher dose levels will be 
allowed only after careful review by the Safety Review Committee of all clinical and 
laboratory analysis performed in volunteers (see sections 8.2 and 8.3). 
 
8.4.2 Choice of Subjects for Study 
Male subjects, aged between 18 and 45 years considered healthy for their age are planned to 
be included in Part A (Groups 1 and 2) and B (Groups 3 to 8). The selection criteria are 
defined such that subjects selected for participation in the study are known to be free from any 
significant illness which potentially could confound the study results. Healthy subjects are 
also unlikely to require concomitant treatments which could interfere with the study drug. 
Female volunteers are not included in this study because investigations on teratogenicity have 
not been performed. 
 


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13 May 2016 
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Final Version 3.0 
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8.4.3 Route and Rate of Administration 
MOTREM will be administered as an i.v. infusion. In this study, dose levels were calculated 
from pre-clinical data. Dose escalation will proceed with accordance with Table 1 of adaptive 
features and will not exceed the mean maximum exposure limits. 
 
8.4.4 Precautions to be Applied for Dosing Between Subjects within a Cohort 
For each cohort, treatment of subjects will begin on Day 1. 
Dose groups 1 and 2 will receive a single i.v. dose of MOTREM. Then, dose groups 3 to 8 
will receive a 15 minute i.v. loading dose of MOTREM followed by 7.45 hours of continued 
i.v. infusion or matching placebo.  
In order to avoid simultaneous exposure of all subjects on the same day to a given dose, each 
cohort will be split in two groups: a mandatory sentinel dosing strategy of dosing one subject 
on IMP on the first day will be used for each cohort. If safety and tolerability is acceptable the 
remaining subjects of each cohort will be dosed in group sizes of no more than three with a 
minimum interval of 24 hours between the start of dosing in the first subject on the previous 
day and the start of dosing on the next day. In addition, during a dosing day, there will be a 
minimum interval of 60 minutes between the start of (maintenance) dosing in a subject and 
the start of dosing in the next subject. Vital signs data recorded in each subject at T+50 min 
will be reviewed and AE checked before dosing the next subject. In case of significant 
abnormalities in these data, the next subject may not be dosed, or dosing may be delayed, 
according to the investigator’s judgment. 
The Investigator will document the decision to proceed from mandatory sentinel dosing to 
dosing of the remainder of a cohort in an e-mail to the Sponsor. The e-mail does not require 
Sponsor’s response, unless there is disagreement with the Investigator’s decision.  
 
8.4.5 Precautions to be Applied for Dosing Between Different Cohorts 
Please refer to section 8.2. 
 
8.4.6 Monitoring and Communication of Adverse Events / Reactions 
Adverse events (AEs) will be continuously monitored throughout the study from day of 
consent until the last follow up assessment. Each AE reported will be assessed by a trained 
Research Physician who will ensure that the event is dealt with as appropriate based on 
clinical need, study protocol, study operations manual and Richmond Pharmacology standard 
operating procedures (SOPs). Following discharge from the unit the subjects will be 
encouraged to phone the investigator immediately in case they experience any AEs and/or 
take any concomitant medication. AEs will be documented in the subjects’ Case Report 
Forms (CRFs) and reviewed regularly by the Research Physicians and the Investigator.  
If any information relating to the study drug in this study becomes available after the 
submission of a final protocol to the Competent Authority which may impact on the conduct 
of the study, including but not limited to the risk and benefit evaluations underpinning 
approvals and volunteer’s consent, INOTREM SA shall notify RPL in writing as soon as 
practically possible and the parties will agree, in writing, what steps need to be taken if any. 


INOTREM SA. 
CONFIDENTIAL 
13 May 2016 
Protocol Ref: MOT-C-104 
Final Version 3.0 
Page 38 of 66 
 
 
8.4.7 Investigator Site Facilities and Personnel 
This study will be conducted in a specialised early phase CPU within an acute hospital setting 
with Critical Care facilities, thus ensuring direct access to equipment and staff for 
resuscitating and stabilising subjects in acute medical conditions and emergencies. The study 
is conducted by an experienced PI and well trained medical, nursing and technical staff with 
ample experience in the conduct of early phase clinical trials. 
The study is designed to closely monitor, treat and communicate potential expected adverse 
reactions as well as potential unexpected adverse events.  
  
9 
SELECTION AND WITHDRAWAL OF SUBJECTS 
9.1 
Number and Source of Subjects 
26 subjects are planned (i.e. 2 first groups of one healthy male subject each and 6 groups of 4 
healthy male subjects). The number of subjects in a dose cohort can be extended to gather 
further information on a dosing regimen, withdrawn subjects can be replaced at the discretion 
of the sponsor and investigator, if not withdrawn for safety reasons and replacement subjects 
may be enrolled in an ongoing cohort, or dosed together as a group or dosed separately. The 
total number of subjects will not exceed 72 subjects (Table 9). 
 
Table 9. Number of subjects 
 
Part A 
Part B 
Total 
Planned cohorts 
2 (2x1=2) 
6(6x4=24) 
26 
Optional Cohorts 
2 (2x1=2) 
2(2x4=8) 
10 
Extended cohorts 
2 (2x1=2) 
2 (2x1=2) 
6(6x4=24) 
2(2x4=8) 
36 
Total 
8 
64 
72 
 
Optional groups/cohorts may be included to explore additional dose levels and/or dosing 
regimen. Please refer to Table 1. 
Inclusion and exclusion criteria for enrolling subjects in this trial are described in the 
following sections. 
 
9.2 
Inclusion Criteria 
Subjects must meet all of the following criteria to be eligible for enrolment in this study: 
1. Male subjects aged 18-45 years old (both ages included), 
2. Subjects must be in good health as determined by their medical history, physical 
examination, ECG, vital signs, and laboratory tests, 
3. Subjects with a body mass index within the range 18-30 kg/m2 (both inclusive), 
4. Subjects must agree with methods of contraception as outlined in Section 9.4,  


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13 May 2016 
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Final Version 3.0 
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5. Subjects must have signed an informed consent form indicating that they understand 
the purpose of and procedures required for the study and are willing to participate in 
the study and comply with the study procedures and restrictions, 
 
9.3 
Exclusion criteria 
Subjects will be excluded from enrolment in this study if they meet any of the following 
criteria: 
1. Subjects with any medical history, conditions or risks, which, in the opinion of the 
investigator, may interfere with the subject's full participation in the study, or 
compliance with the protocol, or pose any additional risk for the subject or confounds 
the assessment of the subject or outcome of the study. 
2. History of significant respiratory, renal, endocrinologic, hepatic, gastrointestinal, 
haematological, lymphatic, neurological, cardiovascular, psychiatric, musculoskeletal, 
genitourinary, immunological, dermatological or connective tissue disease or diseases, 
3. History of malignancy,  
4. History of relevant drug or other significant allergy, 
5. Likely to need any treatment (including dental care) during the study period,  
6. Significant infection or known inflammatory process at screening or Day -1,  
7. Recent vaccination in the previous 2 weeks (from screening), 
8. Donation or loss of more than 400 mL of blood within 90 days prior to the screening, 
9. Use of any prescribed or over-the-counter medication within 14 days prior to first 
dosing (not including paracetamol in the range of 1g/day) or within 6 times the 
elimination half-life of the medication prior to first dosing (whichever is longest),  
10. History or clinical evidence of alcohol or substance abuse. Alcohol abuse is defined as 
regular weekly intake of more than 21 units for males. 
11. Confirmed positive results from urine drug screen (methamphetamine, opiates, 
cocaine, cannabis) or from the alcohol breath test at screening and on admission. 
12. Current smokers (within 3 months prior to screening) and those who have a positive 
cotinine test, 
13. Subjects who do not have suitable veins for multiple venipunctures/cannulation as 
assessed by the investigator at screening, 
14. Supine blood pressure (BP) greater than 140/90 mmHg (systolic/diastolic) or less than 
90/60 mmHg confirmed by at least 2 repeated measurements at screening and D-1,  
15. Subjects who have clinically relevant ECG abnormalities (e.g. QTcB > 450 ms or 
notable sinus bradycardia with mean HR<40 bpm) confirmed by a repeat ECG at 
screening and D-1,  
16. Family history of congenital long QT syndrome or known congenital arrhythmia, 
17. Liver enzymes (ALAT, ASAT, ALP) exceeding the upper limit of normal range or 1.5 
times the upper limit on D-1,  


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18. Renal impairment or calculated glomerular filtration rate (according to Modification of 
Diet in Renal Disease (MDRD)) < 80 mL/min/1.73 m2 at screening,  
19. Positive results for serology test (HIV-1 and 2, Hepatitis B surface antigen (HBsAg), 
hepatitis C antibody (anti-HCV)), 
20. No legal capacity or limited legal capacity or unable to give an informed consent. 
21. Subjects with pregnant partners 
 
9.4 
Subject Restrictions  
Subjects will have to comply with the following restrictions during the study: 
1. Whenever subjects are confined in the ward, only the drinks and meals provided by 
the trial personnel will be allowed. 
2. Standard meals will be provided at the standard unit times as stated in the study plan, 
and meals should be completed each time. 
3. Subjects will be required to fast for a period of at least 8 hours before study drug 
administration. 
4. Intake of caffeine will not be allowed 12 hours before screening and then from 12 
hours prior to study drug administration until discharge. During the subjects’ 
outpatient periods, subjects should also limit their caffeine intake to equivalent of 3 
cups of coffee per day 
5. Abstain from consumption of energy drinks containing taurine or glucuronolactone 
from the day of enrolment until the end of study visit. 
6. Abstain from drinking alcohol from at least 48 hours before drug administration to end 
of study visit. 
7. Abstain from consumption of nicotine during the study. 
8. Not start any new physical training activities or increase the intensity of their usual 
physical training during the study.  
9. Avoid any medication (including over the counter (OTC) products and herbals, 
vitamins and minerals) from 14 days before IMP administration (with the exception of 
paracetamol in the range of 1g/day) until the end of the hospitalisation in order to 
avoid interference with study assessments. 
10. Abstain from blood and plasma donation during the study and up to three months after 
completion of the study. 
11. Subjects must use acceptable methods of contraception if the male subject’s partner 
could become pregnant from the time of the first administration of study medication 
until 3 months following administration of the last dose of study medication. One of 
the following acceptable methods of contraception must be utilised: 
 Surgical sterilisation (vasectomy with documentation of azoospermia) and a 
barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] used 
with spermicidal foam/gel/film/cream/suppository). 


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 The subject’s female partner uses oral contraceptives (combination 
estrogen/progesterone pills), injectable progesterone, or subdermal implants and 
a barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] 
used with spermicidal foam/gel/film/cream/suppository). 
 The subject’s female partner uses medically prescribed topically-applied 
transdermal contraceptive patch and a barrier method (condom or occlusive cap 
[diaphragm or cervical/vault caps] used with spermicidal 
foam/gel/film/cream/suppository). 
 The subject’s female partner has undergone documented tubal ligation (female 
steriliation). In addition, a barrier method (condom or occlusive cap [diaphragm 
or cervical/vault caps] with spermicidal foam/gel/film/cream/suppository) must 
be used. 
 The subject’s female partner has undergone documented placement of an IUD or 
IUS and the use of a barrier method (condom or occlusive cap [diaphragm or 
cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository). 
 True abstinence: When this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post 
ovulation methods) and withdrawal are not acceptable methods of contraception. 
Abstinent subjects have to agree to use one of the above-mentioned contraceptive 
methods, if they start sexual relationships during the study and for up to 3 months 
after the last dose of study drug. 
 Male subjects must use a condom with spermicidal 
foam/gel/film/cream/suppository if their female partner(s) is (are) pregnant or 
lactating from the time of the first administration of treatment or study 
medication until 3 months following administration of the last treatment or study 
medication administration. 
 
9.5 
Subject Inclusion and Randomisation  
Subjects in this study will be assigned to a treatment regimen according to a randomisation 
schedule generated by a statistician using PROC Plan. Details regarding the unique screening 
and subject number will be included in the SOM. 
For Part B (Groups 3 to 8), eligible subjects who meet the eligibility criteria will be randomly 
assigned on Day 1. Subjects will be randomly assigned in Part B (Groups 3 to 8) in a 3:1 ratio 
to either MOTREM (LR12) or Placebo. 
 
9.6 
Criteria for withdrawal  
The Investigator or designee will withdraw a subject from the study if the subject: 
 Is in major violation of the protocol 
 Meets individual stopping criteria 
 Use of/need for a prohibited medication which in the opinion of the Sponsor or 
Investigator may jeopardise the study results or represent a risk to the participant 
 Requests to be withdrawn from the study (subject withdrawal of consent) 
 Is found to be considerably non-compliant with the protocol-required dosing visits 
 In the Investigator’s opinion, is unable to continue study participation 


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 Is withdrawn from the study upon the request of Sponsor or the SRC, including if 
Sponsor terminates the study. 
 
9.6.1 Handling of Withdrawals 
In the event a subject withdraws or is withdrawn from the study, the Investigator will inform 
the Medical Monitor and the Sponsor immediately. The SRC will be notified. If there is a 
medical reason for withdrawal, the subject will remain under the supervision of the 
Investigator for protocol-specified safety follow up procedures.  
Should any of the subjects be withdrawn from the study after being dosed, all the relevant 
assessments should be completed as per protocol. 
Investigator and/or Sponsor may decide to perform additional assessments in accordance with 
Table 1 – Adaptive features 11, 12, 14, 16 and 17. 
 
A subject who fails to return for evaluations will be contacted by the site in an attempt to have 
the subject comply with the protocol in accordance with the site SOPs.  
When a subject withdraws from the study, the primary reason for discontinuation must be 
recorded in the appropriate section of the case report form (CRF). 
 
10 STUDY AND CONCOMITANT TREATMENTS 
10.1 Investigational Medicinal Products (IMPs)  
MOTREM is prepared as a stable lyophilised product in L50 type I glass vials containing 400 
mg of free base lyophilised LR12 peptide in sodium citrate and arginine buffer at pH 5.5. The 
powder is to be solubilised with 40 mL of saline solution for injection to yield a clear and 
colourless solution of MOTREM at 10 mg/mL. Table 10 shows the composition of 
MOTREM in vials and as reconstituted solution. IMP will be stored under appropriate 
conditions as described on the IMP vial label, in a reasonably secure +2 to +8°C refrigerator 
placed in a room of restricted access. 


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Table 10. Composition of MOTREM Drug Product and as Reconstituted Solution 
 
 
Drug 
Product1  
(per Vial) 
 
Reconstituted 
Solution 
Product 
Function  
 
 Solution after 
reconstitution with 
40 mL of 0.9% 
Sodium Chloride 
for Injection Ph 
Eur. 
LR12 
API 
400 mg 
 10 mg/mL (7.5 
mM) 
Trisodium citrate 
Buffer 
103 mg 
 2.6 mg/mL (10 
mM) 
Arginine 
Solubilisation 
and 
lyophilisation 
bulking agent 
139 mg 
 3.5 mg/mL (20 
mM) 
HCl 
pH adjustment 
q.s. pH 5.5 
 - 
 
Diluent 
Diluent: 
water for 
injection.  
 Diluent for 
reconstitution: 
NaCl 9 mg/mL 
(0.9%) 
1 : Manufactured Product 
 
 
The placebo used in this study will be a saline solution (i.e. NaCl 0.9%. Since placebo and 
IMP have both a clear appearance as formulated LR12 is diluted in saline solution, this 
assures the correct handling of the blinding. Placebo will be provided by the site. It will be a 
single batch dedicated for the purpose of the study (identical manufacturer and identical 
batch). 
 
10.1.1 Doses and Treatment Regimen 
Single doses of MOTREM (LR12) or matching placebo are planned to be administered i.v. as 
detailed in Table 11. 


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Table 11. Daily dose of IMP (MOTREM or matching placebo) for each dose group. 
Dose group 
 
i.v.  
loading dose  
T = 15’ 
Maintenance i.v. dose  
(mg/kg/h) 
T = 7h45’ 
Number of 
subjects 
Group 1 
1 mg 
- 
N = 1 
 
- 
 
Group 2 
10 mg 
- 
N = 1 
 
- 
 
Group 3 
0.5 mg/kg 
0.03 mg/kg/h 
N = 3 
Placebo 
Placebo 
N = 1 
Group 4 
1 mg/kg 
0.1 mg/kg/h 
N = 3 
Placebo 
Placebo 
N = 1 
Group 5 
2 mg/kg 
0.3 mg/kg/h 
N = 3 
Placebo 
Placebo 
N = 1 
Group 6 
5 mg/kg 
1 mg/kg/h 
N = 3 
Placebo 
Placebo 
N = 1 
Group 7 
5 mg/kg 
3 mg/kg/h 
N = 3 
Placebo 
Placebo 
N = 1 
Group 8 
5 mg/kg 
9 mg/kg/h 
N = 3 
Placebo 
Placebo 
N = 1 
 
IMOTREM or placebo will be administered by a Research Physician and the details of dosing 
will be recorded in the CRF. The dosing will be verified by another member of the 
Investigator’s staff.  
The study drugs will be dispensed by the pharmacy staff at the clinical study site. The 
pharmacy staff will be responsible for assembly and labelling of dosing containers according 
to randomisation schedules and assigned dose level. The amount/ volume of study drug to be 
administered will be determined based on the assigned dose level for a particular cohort. The 
procedure for preparing the study drugs and the volume to be prepared for each individual 
subject dose will be detailed in a Pharmacy Worksheet. 
Detailed instructions for dose administration will be included in the Study Operations Manual 
(SOM). 
 
10.2 Labelling of IMPs  
The labelling of the study drugs will be in compliance with Good Manufacturing Practice 
(GMP) specifications, as described in The Rules Governing Medicinal Products in the 
European Union, Volume 4, Annex 13, Investigational Medicinal Products, and any other or 
local applicable regulations. 
Sample label(s) will be submitted to the UK health authorities according to the submission 
requirements. 
 
10.3 Drug Accountability  
The designated pharmacy staff at the clinical study site will maintain accurate records of 
receipt and the condition of all study drugs, including dates of receipt. In addition, accurate 
records will be kept by the pharmacy staff of when and how much study drug is dispensed and 
used by each subject/patient in the study. Any reason for departure from the protocol 
dispensing regimen must also be recorded.  


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Drug accountability records and inventory will be available for verification by the Sponsor or 
designee. At the completion of the study, there will be a final reconciliation of all study drugs.   
Study drug must not be used for any purpose other than the present study. Remaining study 
drug will be returned to the Sponsor or its agent or destroyed at the clinical study site 
according to applicable regulations and only after receipt of written authorisation from the 
Sponsor. 
 
10.4 Blinding and Procedures for Unblinding the Study  
10.4.1 Methods for Ensuring Blinding 
The study will be conducted partly in a double-blind fashion (Part B only) whereby subjects 
and clinical study site staff are blinded to study drug/dose assignment. 
The pharmacy staff preparing the investigational products will not be blinded to study drug 
assignment. During the study, the randomisation codes will be kept in the site's clinical trials 
pharmacy, accessible to the pharmacy personnel only. Upon completion of the study, after the 
database lock and after the blind is revealed, the randomisation list will be filed in the Study 
Master File. 
 
10.4.2 Methods for Unblinding the Study 
In the event of an emergency, an envelope for each subject containing his study drug 
assignment will be available in the pharmacy at the clinical study site. Unblinding should only 
be considered for the safety of the subject. If unblinding is deemed necessary by the 
investigator, the investigator or designee can unblind the subject’s treatment allocation using 
the envelope available from the pharmacy. The investigator or designee must note the date, 
time and reason for unblinding and inform the sponsor of unblinding as soon as practicably 
possible. 
 
10.4.3 Concomitant Medications/Permitted medications  
Intake of any medication is prohibited from 14 days before IMP administration (with the 
exception of paracetamol in the range of 1g/day) until the end of the hospitalisation in order to 
avoid interference with study assessments. 
During the study, medications other than IMP must only be taken exceptionally and with the 
consent of the investigator. The need for other medication may lead to subject’s withdrawal 
from the study. In any case, the investigator will inform the sponsor about the concurrent 
medication given. 
Details of prior and concomitant medications should be recorded by the investigator on the 
CRF and source record.  
Emergency equipment and drugs will be available within the clinical unit as per current 
standard procedures. In the unlikely event that they are required, their use will be 
documented. 
 


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11 STUDY PROCEDURES 
11.1 Schedule of Study Procedures 
The study assessments are described in the sections below and the timing of these assessments 
are detailed in the study plan (Table 2 and Table 3). The sequence of assessments at particular 
time-points will be described in the SOM. 
 
12 STUDY METHODOLOGY 
12.1.1 Meals 
Standardised meals will be provided during the study period according to Study Plan (Table 2 
and Table 3). Subjects will be fasted eight hours prior to dosing. The composition of the 
meals will be specified in the SOM. 
 
12.1.2 Haematology and Biochemistry 
Blood samples for determination of biochemistry, haematology and coagulation parameters 
will be taken at the times given in the Study Plan (Table 2 and Table 3). The date and time of 
collection will be recorded on the appropriate CRF pages. The analyses will be done using 
routine methods. Further details will be described in the SOM.  
Laboratory values outside the reference limits, which are suspected to be of any clinical 
significance, will be repeated. Subjects in whom the suspected clinical significance is 
confirmed on repeated sampling will either not be included or, if already included, may be 
withdrawn from further participation in the study in accordance with the toxicity rules in 
section 8.3 and/or followed until normalisation or for as long as the Investigator considers 
necessary. 
Laboratory parameters to be measured are presented in Table 12. 
Table 12. Laboratory parameters. 
Biochemistry 
Haematology 
Urinalysis 
Serology 
Urine Screen for 
Drugs of Abuse 
Coagulation 
Aspartate 
aminotransferase 
Haemoglobin 
Leukocytes 
Hepatitis B 
surface 
antigen 
(HBsAG) 
Benzodiazepines 
Prothrombin 
time (INR) 
Alanine 
aminotransferase 
Haematocrit 
Nitrite 
Hepatitis B 
core antibody 
(anti-HBC 
IgG + IgM, if 
IgG positive) 
Opiates 
activated 
partial 
thromboplastin 
time (aPTT) 
Alkaline 
phosphatase 
Erythrocytes 
Urobilinogen 
Hepatitis C 
antibody 
(anti-HCV) 
Amphetamines 
Fibrinogen 
Total Bilirubin 
Mean 
corpuscular 
volume (MCV) 
Protein 
HIV I and II 
antibodies 
Methadone 
 
Creatinine 
Mean 
corpuscular 
haemoglobin 
concentration 
pH 
 
Cocaine 
 


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Biochemistry 
Haematology 
Urinalysis 
Serology 
Urine Screen for 
Drugs of Abuse 
Coagulation 
(MCHC) 
Urea 
Mean cell 
haemoglobin 
(MCH) 
Blood 
 
Cannabinoids 
 
Glucose 
Leucocytes 
Urine 
microscopy 
 
Barbiturates 
 
Sodium 
Basophils 
Ketones 
 
Cotinine 
 
Potassium 
Eosinophils 
Bilirubin 
 
 
 
Chloride 
Neutrophils 
Glucose 
 
 
 
Calcium 
Lymphocytes 
Specific 
gravity 
 
 
 
Inorganic 
phosphate 
Monocytes 
 
 
 
 
Total Protein 
Platelet count 
 
 
 
 
CRP 
Reticulocytes 
 
 
 
 
Albumin 
 
 
 
 
 
Albumin/globulin 
ratio 
 
 
 
 
 
Triglycerides 
 
 
 
 
 
Total Cholesterol 
 
 
 
 
 
eGFR* 
 
 
 
 
 
* eGFR is calculated by the Modification of Diet in Renal Disease (MDRD) equation:  
   186 x (Creat / 88.4)-1.154 x (Age)-0.203 x (0.742 if female) x (1.210 if black) 
 
12.1.3 Serology 
Serology will be performed at Screening as detailed in the Study Plan (Table 2 and Table 3). 
At the screening visit all subjects will be tested for the parameters listed in Table 12. This is 
done for the safety of the study personnel and the result from the tests will not be entered into 
the study database. If a volunteer is found to be confirmed positive in any of these tests, they 
will be referred for further examination/treatment and will not be included in the study, with 
the exception of volunteers with a confirmed positive anti-HBc IgG and negative anti-HBc 
IgM and HBsAg, indicative of natural immunity due to a past infection without active chronic 
or acute infection 
The serology tests will be analysed in the same blood sample used for biochemistry.  
 
12.1.4 Urinalysis 
Urine samples for determination of urinalysis parameters will be taken at the times given in 
the Study Plan (Table 2 and Table 3). If deemed necessary, based on a clinically significant 
positive test, microscopic examination of urine will be performed. 
 
12.1.5 Drugs of Abuse 
Urine will be tested for the drugs of abuse as described in the Study Plan (Table 2 and Table 
3). If a subject fails the drug abuse screen, they will be excluded from the study. A repeat drug 


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screen can only be done where methodological reasons are believed to have led to a false 
positive. Borderline positive results, unless covered by the preceding condition, are to be 
considered as positive and the subject excluded from the study. If subjects are found to be 
positive due to medication e.g. flu/cold remedies, they may undergo a repeat drug screen if 
they are still within the screening window. The results from the tests will not be entered into 
the database. 
 
12.1.6 Alcohol Breath Test 
An alcohol breath test will be done using an alcometer as described in the Study Plan (Table 2 
and Table 3). The results from this test will not be entered into the clinical study database. If a 
subject tests positive to the test they will be excluded from the study. 
 
12.2 Vital Signs 
12.2.1 Blood Pressure, Heart Rate and Tympanic Temperature 
Blood pressure and heart rate will be measured in supine position after the subject has rested 
comfortably for at least 5 minutes and in standing position after the subject has stood for 1 
minute, using automated Criticon Dynamap® monitors. In Part A at H0 and in Part B at H0 
and H8 vital signs will only be assessed in supine position, in order to prevent volunteers from 
standing up and lying down during infusions. Vital signs (blood pressure and heart rate) will 
be measured at the time points as detailed in the Study Plan (Table 2 and Table 3). 
Temperature will be measured using tympanic thermometers. 
 
12.3 Electrocardiographic (ECG) Measurements 
12.3.1 Recording of 12-lead ECGs 
12-lead ECGs will be recorded at the time-points described in Study Plan (Table 2 and Table 
3) using a GE Marquette MAC1200® /MAC1200ST® recorder connected via a fixed network 
connection to the MUSE® Cardiology Information System (MUSE).  ECGs recorded during 
screening will be stored electronically on the MUSE information system. Only ECG recorded 
electronically will be valid ECG for any purpose other than safety assessment.  ECG printouts 
may be filed in the subject’s CRF for medical safety reviews. 
Each ECG recorder will be set up to the required technical specifications and containing the 
information required to identify the records. Each ECG recording will be clearly identified 
(Subject ID, visit date, and the actual times of ECG recordings).  
12-lead ECG recordings will be made after the subjects have been resting in a supine position 
for at least 10 minutes. The subjects will avoid postural changes during the ECG recordings 
and clinical staff will ensure that subjects are awake during the ECG recording. 
At each time point, the ECG will be recorded in triplicate, to reduce variance and improve the 
precision of measurement. The triplicates will be performed at approximately 1-minute 
intervals. Each ECG recording (trace) will last 10 seconds. Repeat ECG will be performed 
until at least three 10-second ECG records per scheduled time-point meet the quality criteria 
set out in the SOM and the applicable SOP so to enable reading and analysing at least 5 
complexes per derivation. 


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All recorded ECG will be reviewed by a Research Physician and the review be documented in 
the CRF. With regards to the clinical assessment of QTc interval, QTcB will be assessed as 
this is automatically calculated by the equipment. If there is any indication of potential 
significant QTcB prolongation, QTcF will also be calculated and assessed by a Research 
Physician. If a subject shows an abnormal ECG, additional safety recordings (including the 
use of 5 or 12 lead Holter equipment) may be made and the abnormality be followed to 
resolution if required. Further details will be included in the SOM. 
 
12.3.2 Real Time Display (ECG Telemetry) 
A 12-lead real time ECG will be recorded as described in the Study Plan (Table 2 and Table 
3). ECG telemetry will be monitored by the Investigator or qualified member of clinical staff. 
The system will be managed according to local working practices. The ECG telemetry reports 
will be archived with study documents. 
 
12.3.3 24-hour Holter ECG 
Holter recording will be performed at screening as described in Table 2 and Table 3. If 12-
lead holter recording is taken on screening, each electronic Holter ECG file will be 
downloaded onto the GE Gatemed Holter Analysis system. This will allow the extraction of 
ten-second 12-lead ECG data files, which can be transferred onto the MUSE. All ECG files so 
acquired will then be analysed and over-read using the same process as for any other 12-lead 
ECG. 
 
12.4 Physical Examination, Height and Weight 
Physical examinations will be performed as detailed in the Study Plan (Table 2 and Table 3). 
A full physical examination includes an assessment of the following: eyes, ears, nose, throat, 
cardiovascular, respiratory, musculoskeletal, venous system, gastro-intestinal, lymphatic, 
dermatological and neurological system. 
A brief physical examination will be symptom oriented and will not include specific 
parameters of full physical examination.  
Height will be measured in centimetres and weight in kilograms. Measurements should be 
taken with subjects wearing light clothing and without shoes using calibrated scales for all 
measurements. BMI will be calculated from the height and weight. 
 
12.5 Pharmacokinetic Assessments 
For timing of individual samples refer to the Study Plan (Table 2 and Table 3). The date and 
time of collection will be recorded on the appropriate CRF. 
 
12.5.1 PK Blood Samples 
Venous blood samples for the determination of concentrations of LR12 (active ingredient of 
MOTREM) in plasma will be taken at the times presented in the Study Plan (Table 2 and 
Table 3). For blood volume see Section 12.7.  


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All sample handling procedures, including the time of each sample collection, the time of 
placement into frozen storage (at the end of the sample workup), and the date of transfer or 
shipment of the samples to the responsible analyst will be documented in detail in the SOM. 
The procedures and materials used, e.g. collection and storage tubes, were examined prior to 
any analytical measurements as part of the analytical method validation, to rule out any 
possible interference with the analyte. 
 
12.6 Immunogenicity 
The presence of anti-LR12 antibodies will be assessed according to the Study Plan (Table 2 
and Table 3). A blood sample will be collected for evaluation of potential immunogenicity 
evaluation from the appropriate vein for all healthy volunteers at the selected time-points. 
Sample analysis will be described in the SOM. Further details will be included in the SOM. 
 
12.7 Volume of Blood Sampling 
The total volume of blood that will be drawn from each subject in this study will be 
documented in the SOM and will not exceed 500 mL. 
 
13 ADVERSE EVENTS 
Safety will be determined by an evaluation of physical examination, vital signs, ECG 
parameters, laboratory tests and by the occurrence of AEs. 
Adverse event (AE) 
Any untoward medical occurrence in a patient or clinical study subject administered a 
medicinal product and which does not necessarily have a causal relationship with this 
treatment. Events occurring prior to the first administration are part of baseline information. 
An adverse event (AE) can therefore be any unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of an 
investigational medicinal product, whether or not considered related to the investigational 
medicinal product. 
 
Adverse reaction (AR)  
All untoward and unintended responses to an IMP related to any dose administered. 
All adverse events judged by either the reporting investigator or sponsor as having a 
reasonable suspected causal relationship to an investigational medicinal product are qualified 
as adverse reactions. The expression reasonable causal relationship means that there is 
evidence or argument to suggest a causal relationship. 
 
Multiple signs or symptoms   
If an AE consists of several signs or symptoms that can be represented by one single 
syndrome or diagnosis, the syndrome or diagnosis will be recorded in the CRF as the AE 
instead of the individual signs or symptoms.  


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Worsening 
Signs, symptoms, syndromes or diagnoses present before the first administration of the IMP 
will be considered as AEs if they worsen after the start of the IMP. 
 
AE rating 
The condition of the subjects will be monitored throughout the study. The investigator will 
collect the AEs reported spontaneously, observed, or elicited in response to a non-leading 
question (for example, "How have you been feeling since we last asked you?"). The 
investigator will record all AEs in the source records and the CRF. 
The assessment of intensity of an AE will be made using the following general categorical 
descriptors: 
Mild 
: Awareness of signs or symptoms, but no disruption of usual activity 
Moderate 
: Event sufficient to affect usual activity (disturbing) 
Severe 
: Inability to work or perform usual activities (unacceptable) 
The investigator should use clinical judgment in assessing the intensity of events not directly 
experienced by the subject (e.g., laboratory abnormalities). 
The assessment of intensity is outlined in section 8.3. 
The causal relationship of an AE to the IMP will be rated as follows: 
Unrelated 
Clearly and incontrovertibly due only to extraneous causes. 
Related 
There is a reasonable possibility that the IMP may have caused 
the AE, i.e. the relationship cannot be ruled out. It may include, 
for example, a temporal relationship, or a pharmacologically-
predicted event. Confounding factors, such as concomitant 
medications, a concurrent illness or relevant medical history, 
should also be considered. 
The action taken with the IMP for an AE will be rated as: product withdrawn, dose not 
changed, not applicable. AEs requiring therapy will be treated with recognised standards of 
medical care to protect the health and the well-being of the subject. 
 
The outcome of an AE will be rated as recovered, recovering, not recovered, recovered with 
sequelae, fatal or unknown. The investigator will follow up any AE until it is resolved or until 
the medical condition of the subject is stable. All relevant follow-up information will be 
collected. For AEs that are ongoing at the last visit, the investigator will make thorough 
efforts to document the outcome. 
 
13.1 Serious Adverse Events (SAE) and Suspected Unexpected Serious Adverse 
Reaction (SUSAR) 
13.1.1 Definitions 
Serious Adverse event 


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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 or incapacity, 
 Is a congenital anomaly or birth defect,  
 Is an important medical event. 
 
Death 
The death of a subject enrolled in a clinical study is per se not an event, but an outcome. Any 
AE resulting in a fatal outcome must be fully documented and reported, including situation 
for which the death occurred after treatment end, and regardless of the causality relationship 
between the death and the IMP. The cause of the death is usually the AE. If the cause cannot 
be determined, the case will be considered an unexplained death. 
Life-threatening 
Any AE that places the subject, in the view of the initial reporter (investigator), at immediate 
risk of death from the AE as it occurred, i.e. it does not include an AE that, had it occurred in 
a more severe form, might have caused death. 
Disability 
A substantial disruption of a person's ability to conduct normal life functions. 
Important medical event 
An important medical event that may not result in death, be life-threatening, or require 
hospitalisation may be considered as a SAE when, based upon appropriate medical 
judgement, it may jeopardise the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in the definition. The concept includes AEs which suggest 
a significant hazard, contraindication or precaution for use, occurrence of malignancy or 
development of drug dependency or drug abuse. 
Pregnancy 
Based on the limited reproduction toxicity information, healthy males only will be included. 
Suspected Unexpected Serious Adverse Reaction 
Suspected unexpected serious adverse reactions (SUSARs) are AEs which have a reasonable 
possibility to be related to an IMP and are both unexpected (i.e. the nature or severity is not 
expected from the information provided in the investigator’s Brochure) and serious. SUSARs 
are subject to expedited reporting to the national Competent Authority and Ethics Committee.  
 
13.1.2  Recording of Adverse Events and Follow-Up 
All (serious and non-serious) adverse events detected by the Investigator or delegates, or 
spontaneously notified by the subject at each visit/examination must be reported on the 
respective section of the CRF. 
The following information should be reported for each adverse event, whether or not it can be 
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 description of adverse event 
 date of onset/date of disappearance 
 characteristics of the event (seriousness, intensity) 
 actions taken (treatment required or dose adjustments must be reported in the CRF) 
 outcome 
 relationship with trial drug (causality assessment) and/or study participation 
 
All adverse events must be documented and followed up until the event is either resolved 
or a satisfactory explanation is found, or the investigator considers it medically 
justifiable to terminate the follow-up. 
Spontaneously reported SAEs will be collected until 30 days following the final study 
visit. 
SAEs experienced after this 30-day period will only be reported if the investigator 
suspects a causal relationship with the study drug.  
Adverse events (AEs) will be recorded in the CRF throughout the study from day of consent 
(screening visit) until the last follow up assessment.  
Any AEs that are unresolved at the subject's last AE assessment in the study (i.e. at the end of 
study visit) are to be followed up by the Investigator for as long as medically indicated. 
INOTREM SA retains the right to request additional information for any subject with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary. 
Findings and values related to physical examinations and measurements of ECG, vital signs, 
(tympanic temperature, blood pressure, and heart rate) and laboratory parameters will be 
defined as AEs if they are considered clinically relevant deteriorations compared with 
screening values, as judged by the PI. 
 
13.1.3 Reporting of serious adverse events  
If any SAE/SUSAR occurs, the investigator will take appropriate action immediately and will 
strive to identify the causes of the events. 
Any SAE/SUSAR will be notified by the Investigator to For Drug Consulting as soon as 
possible but not later than 24 hours by e-mail or fax to;  
E-mail: safety@fordrugconsulting.fr  
Phone: +33 (0) 1 46 55 27 11 
Fax : +33 (0) 1 47 46 18 48 
 
In addition, the investigator should contact the INOTREM SA Medical Officer. 
The initial report will be followed up by a full written report within three working days or five 
calendar days, whichever comes first unless no further information is available when the 
follow-up report will be provided as soon as possible when new information becomes 
available. Further follow-up reports will be provided as and when new information becomes 
available. Photocopies of results, consultant report(s), a summary of the outcome of the 
reaction and the Investigator's opinion of IMP relationship to the SAE/SUSAR will 
accompany the SAE form if and when available.  


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The Sponsor will also perform an evaluation of the seriousness, causality and expectedness of 
all SAEs. All SAEs judged by either the Investigator or the Sponsor as having a reasonable 
suspected causal relationship to an IMP (i.e. definitively, probably or possibly related) will 
qualify as serious adverse reactions. If the Sponsor disagrees with the Investigator’s causality 
assessment, both the opinion of the Investigator and the Sponsor are provided with the report. 
All SAEs will be included in the INOTREM SA pharmacovigilance database.  
SUSARs will be notified to the Competent Authority by For Drug Consulting and to the 
relevant REC within 7 (for fatal and life-threatening SUSARs) or 15 days (all other SUSARs).  
Annual safety reporting to the national Competent Authority and the Ethics Committee will 
be in agreement with ICH guideline E2F “Note for guidance on development safety update 
reports (DSUR)”. 
In addition, any other safety issue which may alter the current benefit–risk assessment of the 
IMP will be reported by the Sponsor (or delegate) on an expedited basis to Health Authorities, 
Ethics Committees and the Investigator.   
The detailed procedure of the SAE/SUSAR reporting will be described in a Safety 
Management Plan that will be finalised before the start of the study to exactly define the 
different tasks of the Investigator, the Sponsor and RPL (on behalf of the Sponsor) 
 
14 QUALITY ASSURANCE AND QUALITY CONTROL 
14.1 Quality Assurance and Quality Control 
A regulatory inspection of this study may be carried out by regulatory agencies. Such 
audits/inspections can occur at any time during or after completion of the study. If an audit or 
inspection occurs, the PI and RPL agree to allow the auditor/inspector direct access to all 
relevant documents and to allocate their time and the time of their staff to the 
auditor/inspector to discuss any findings or relevant issues.  
Quality Control (QC) procedures at the CPU will be implemented to ensure data recorded into 
the CRFs are accurate before CRFs are sent for data entry purposes. QC checks will be carried 
out on critical phases in the execution of the study. These control checks will be carried out 
according to the relevant SOPs. Records of these procedures will be documented and 
available for review. 
 
14.2 Monitoring 
All aspects of the study will be carefully monitored by the sponsor, or designee, for 
compliance with applicable government regulations with respect to Good Clinical Practice 
(GCP) and current standard operating procedures. 
The monitoring of this study will be performed by the Sponsor’s Monitor(s) or a designee in 
accordance with the principles of GCP as laid out in the International Conference on 
Harmonisation (ICH) “Good Clinical Practice: Consolidated Guideline”. 
The clinical monitor, as a representative of the Sponsor, has an obligation to follow the study 
closely. In doing so, the monitor will visit the Investigator and site periodically as well as 
maintain frequent telephone and letter contact. The monitor will maintain current personal 
knowledge of the study through observation, review of study records and source 


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documentation, and discussion of the conduct of the study with the Investigator and staff. 
Further details will be described in the SOM. 
 
15 STATISTICAL METHODS PLANNED AND DETERMINATION OF SAMPLE 
SIZE 
15.1 Statistical and Analytical Plans 
The analysis will be computed with SAS Version 9.4 (Copyright© 2013 by SAS Institute Inc., 
Cary, NC, USA). 
The statistical analysis plan will be agreed by the sponsor. 
Individual data listings will contain all available results. They will be presented by IMP 
(LR12 vs Placebo), dose group (Group 1-Group 8), subject number and time point if 
applicable.  
Descriptive statistics will be presented by IMP and time point.  
All relevant data will be summarised as follows: 
 Quantitative endpoints will be presented in terms of mean, standard deviation, median, 
Q1, Q3, extreme values, number of subjects and missing data. 
 Qualitative endpoints will be presented in terms of number and percentage of each 
modality and number of subjects and missing data. 
 
For quantitative endpoints, Student test for parametric tests or Wilcoxon test for non-
parametric tests will be used. 
For qualitative endpoints, Chi-square test for parametric tests or Fisher Exact test for non-
parametric tests will be used. 
 
15.1.1 Data Sets Analysed 
Randomised set will comprise all randomised subjects.  
Safety Set will include all randomised subjects who have taken the IMP, and who have at 
least one post-baseline assessment of safety, regardless any protocol deviations. 
Per Protocol Set will include only the subjects who complete the study according to the 
protocol. 
Subjects’ assignment in different sets will be performed during the pre-analysis review 
meeting. 
 
15.1.2 Demographic and other Baseline Characteristics 
Analysis will be performed on the Safety Set. 
Baseline characteristics such as demographic characteristics, subject’s habits, toxicology, and 
serology, will be listed and summarised using descriptive statistics already mentioned. 
Medical and surgical history, prior therapies will only be listed. 


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Previous medications will be coded according to the World Health Organization-Drug 
Reference List (WHO-DRUG dictionary version 2015-3) and will be listed. 
Individual safety data (clinical laboratory, vital signs, and ECG) measured before the first 
drug administration will be checked for validity of entrance criteria, and abnormalities will be 
documented. 
 
15.1.3 Safety analyses 
Adverse events: 
Adverse events are coded using the MedDRA dictionary version 18.1 or higher. They are 
classified by System Organ Class and Preferred Term. 
The number and percentage of subjects with at least one adverse event will be provided. 
Analysis of treatment-emergent adverse events (TEAE) 
Only TEAE will be summarised and described for the following criteria: 
 Number and percentages of subjects with at least one TEAE 
 Number and percentages of subjects with at least one severe TEAE 
 Number and percentages of subjects with at least one study treatment related TEAE  
 Number and percentages of subjects with at least one serious TEAE  
 Number and percentages of subjects with at least one TEAE leading to treatment 
withdrawal 
The maximum intensity encountered during the evaluation period will be checked. 
The number of TEAE of each category will also be provided by system organ class and 
preferred term. 
Analysis of deaths and other serious adverse events 
A listing of deaths will be provided. 
A summary table of the other serious adverse events should be provided. In case of low 
incidence of serious adverse events, only a listing will be done. 
 
Vital signs, ECG, physical examination and laboratory data: 
Vital signs (SBP, DBP, heart rate, T°), ECG, physical examination and laboratory data will be 
described at each visit/time. Changes from baseline will be described. Abnormal values will 
be identified in subject data listings. 
 
Concomitant and other treatments: 
Concomitant and other treatments are coded using the WHO-DRUG dictionary version 2014-
3. All treatments continued after the inclusion or appeared during the study will be 
summarised by Anatomical Therapeutic Class (ATC) and substance name. 
 
Anti- LR12 antibodies: 


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Anti- LR12 antibodies results (positive/negative) will be listed.  
 
15.2 Pharmacokinetics 
15.2.1 Evaluation of Pharmacokinetic Parameters  
Non-compartmental analysis will be used for estimation of pharmacokinetic parameters using 
the SAS software. Pharmacokinetic modelling may also be employed to assess potential time-
dependent pharmacokinetics. 
The following pharmacokinetic parameters will be calculated from measured plasma 
concentrations of LR12 for each subject and each treatment group: 
Cmax and tmax 
Cmax 
: Maximal plasma concentration 
tmax 
: Time at which the maximum plasma concentration occurs 
C0.25h 
: Concentration at the end of the loading infusion 
C8h 
: Concentration at the end of the maintenance infusion 
Css inf 
: Steady state concentration during the maintenance infusion 
Area under the curve (AUC) 
AUC(0-8h) 
(ng/ml.h) 
: Area under the plasma concentration-time curve from time 0 to time 8 h  
AUC(0-t) 
(ng/ml.h) 
: Area under the plasma concentration curve from administration to last observed 
concentration at time t measured by trapezoidal rules 
AUC(0-) 
(ng/ml.h) 
: Area under the plasma concentration-time curve from time 0 extrapolated to 
infinite time 
[AUC0- = AUC0-t + (Ct/z), where Ct = the observed concentration of drug for the 
last sample on the PK profile in which drug was detected, and z as defined below 
Plasma concentration half-life 
t1/2 (h) 
: Terminal elimination half-life. It will be calculated by application of the 
equation:  
t1/2 =ln2/z 
z (1/h) 
: Will be estimated by the linear regression of the logarithm of the terminal 
concentration as a function of time 
CL(L/h/kg) : Apparent systemic clearance  
 
 
Vd (L/kg) 
: Apparent volume of distribution (CL/z) 
 
Actual sampling times will be used for all calculations of the PK parameters. If there is any 
doubt in the actual time a sample was taken, then the scheduled time will be used. Special 


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consideration will be given to the estimation of z and corresponding t½ values. Values of z 
will be calculated from a minimum of three data points, wherever possible. Any values below 
the lower limit of quantification (LLOQ) of the assay before the tmax will be assumed to be 
zero. Values below the LLOQ which occur after the tmax will be ignored. 
 
15.2.2 Statistical Analysis on PK Parameters 
Serum concentrations will be listed and summarised by time point. The PK parameters will be 
listed for each subject and summarised for each treatment group using descriptive statistics (N 
- the number of subjects, arithmetic mean, SD - standard deviation, CV - coefficient of 
variation, geometric mean, median, minimum, maximum). 
Analysis of variance models will be applied to the dose normalised and logarithmically 
transformed pharmacokinetic parameters to investigate possible deviations from dose 
proportionality. 
 
15.3 Handling of Missing and Incomplete Data 
Unrecorded values will be treated as missing. The appropriateness of the method(s) for 
handling missing data will be reassessed at the data review prior to database lock. Depending 
on the extent of missing values, further investigation may be carried out into the sensitivity of 
the analysis results to the method(s) specified. 
 
15.4 Determination of Sample Size 
The sample size is based on experience from previous similar Phase I studies. No formal 
power calculation has been performed and mostly descriptive statistics will be used to 
summarise 
safety, 
pharmacokinetic 
and 
pharmacodynamics 
data. 
 
 
15.5 Interim Analysis 
One interim analysis of safety and PK data is planned, after the treatment phase (Day 2) of 
cohort 6 is complete. Details will be specified in a separate statistical analysis plan.” 
 
16 DATA MANAGEMENT  
Data Management will create the database under Oracle (V10.2.04 or higher) and the e-CRF 
entry screens using Clinsight Ennov Clinical © (V7 or higher) in compliance with the e-CRF 
design. 
The e-CRF application will be accessible by connecting on a dedicated and secure website 
using Clinsight Online module. Each user will connect by using personal identifier / 
password. 
The Data Manager will write the Data Handling Manual (DHM) which describes the various 
data management steps, the database structure (name and format of the items) and the 
annotated e-CRF, and the validation plan. 


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The investigator, sub-investigators or its designated representative will enter the data for each 
subject on the Ennov Clinical Online e-CRF application. The data will be extracted from the 
ORACLE database and formatted as SAS files (V9.4) using Ennov Clinical Export module.  
The Data Manager will program the consistency checks defined in the validation plan using 
Ennov Clinical Test module. These checks will result in the production of Electronic Data 
Clarification Forms (e-DCFs). The investigator, sub-investigator or its designated 
representative will directly answer to these e-DCFs on the e-CRF application.  
Adverse events will be coded using MedDRA dictionary, and concomitant treatment will be 
coded using WHO-DRUG dictionary version 2015-3 or higher. 
At the end of the validation process, the Data Manager will produce listings which describe 
all protocol deviations. The status of these deviations (minor or major) will be discussed 
during the pre-analysis review, and the analysis population will be defined. 
At the end of the data management process, the database will be frozen and the SAS files will 
be sent to INOTREM SA according to the Data transfer process. 
 
16.1 Case Report Forms 
The e-CRF will be available online, on a secure website (https://ecrf.novasco.fr/CSOnline/). 
Only the investigators, or the sub-investigators/designee, are authorised to entry data in the e-
CRF. They are identified using a login and a password as an electronic signature. At the 
beginning of the study, a login will be allocated to each site staff who will be asked to identify 
himself/herself by a personal password. 
The investigator, the sub-investigator or its designated representative will create a new e-CRF 
for each subject having signed the informed consent and randomised. Any additional 
information on data entry process will be included in the DHP. The investigator must check 
that all the data is accurate and correct. If any information is not applicable, missing (not 
determined) or unknown, the investigator will record "NA", "ND" or “UK” in the appropriate 
place. After a page/screen is completed, the investigator has to validate it (lock action). This 
action prevents from modification of the data after entry (data are “frozen”). 
If a data that has already been validated in the e-CRF has to be corrected, the initial value, the 
identity of the person who modify the data, the date and the reason of the modification are 
tracked in an audit trial file, linked to the e-CRF, not accessible/not modifiable to/by the 
investigators. When, the correction is done; the investigator has to validate it. 
Each opened case report form must be completed. After final verification by the monitor and 
resolution of possible queries, the data are definitively not modifiable by the investigator. 
 
17 SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES 
17.1 Sponsor’s Responsibilities 
In addition to the responsibilities described in the below sections the Sponsor is responsible to 
inform the PI of any safety update relating to the IMP. 
 


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17.1.1 GCP Compliance 
INOTREM SA and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their roles for this study in compliance with all applicable 
regulations and ICH GCP Guidelines. 
Visits to the Investigator site will be conducted by representatives of INOTREM SA to 
inspect study data, subjects’ medical records, and CRFs in accordance with current GCP and 
the respective local and national government regulations and guidelines. Records and data 
may additionally be reviewed by auditors or by competent authorities. 
 
17.1.2 Regulatory Approval  
INOTREM SA will ensure that Local Competent Authority requirements are met before the 
start of the study.  
 
17.1.3 Indemnity/Liability and Insurance  
INOTREM SA will adhere to the recommendations of the Association of British 
Pharmaceutical Industry (ABPI) Guidelines. A copy of the Indemnity document will be 
supplied to the Investigator before study initiation.  
INOTREM SA will ensure that suitable insurance cover is in place prior to the start of the 
study. An insurance certificate and a statement of insurance will be supplied to RPL. 
 
17.1.4 Protocol Management  
All protocols and amendments will be prepared by INOTREM SA and/or RPL. If it becomes 
necessary to issue a protocol amendment during the course of the study, INOTREM SA will 
notify the Investigator and collect documented Investigator Agreement to the amendment.  
 
17.1.5 End of Trial Notification  
INOTREM SA will submit an end of trial notification to the competent authority of the 
Member State within 90 days of the end of the trial in accordance with EU Directive 
2001/20/EC. The PI will be responsible for submitting these to the REC within 90 days of the 
end of the trial. 
For the purposes of this notification, the end of the trial will be defined as the last subject/last 
visit. 
 
17.1.6 Submission of Summary of Clinical Trial Report to Competent Authorities of 
Member States Concerned and Regulatory Approval  
All the relevant data and information will be reported in a study report prepared by 
INOTREM and submitted to the investigator for review comments and signature. The final 
study report will be used for the further development of the IMP and regulatory submissions. 
INOTREM SA will provide a summary of the clinical trial report within one year of the end 
of the complete trial to the competent authority of the Member State concerned as required by 


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the regulatory requirement and to comply with the Community guideline on Good Clinical 
Practice. 
 
17.2 Investigator’s Responsibilities 
17.2.1 GCP Compliance 
The Investigator must undertake to perform the study in accordance with ICH GCP 
Guidelines, EU Directive 2001/20/EC, and the applicable regulatory requirements.  
It is the Investigator’s responsibility to ensure that adequate time and appropriate resources 
are available at the study site prior to commitment to participate in this study. The 
Investigator should also be able to estimate or demonstrate a potential for recruiting the 
required number of suitable subjects within the agreed recruitment period. 
The Investigator will maintain a record of appropriately qualified persons to whom the 
Investigator has delegated significant trial-related tasks. An up-to-date copy of the curriculum 
vitae for the Investigator, Sub-investigator(s), and essential study staff will be provided to 
INOTREM SA (or designee) before starting the study. 
Agreement with the final Clinical Study Report will be documented by the dated signature of 
the PI, in compliance with Directive 75/318/EC, Directive 2001/83/EC, and ICH E3. 
 
17.2.2 Protocol Adherence and Investigator Agreement 
The PI and delegates must adhere to the CSP as detailed in this document. The PI will be 
responsible for enrolling only those subjects who have met CSP eligibility criteria. The PI will 
be required to sign an Investigator Agreement to confirm acceptance and willingness for 
themselves and delegates to comply with the CSP. 
 
17.2.3 Documentation and Retention of Records  
After completion of the study, all documents and data relating to the study will be kept in an 
orderly manner and securely by the PI in a secure file and/or electronically. The data will be 
available for inspection by INOTREM SA or their representatives. Essential documents must 
be retained for 2 years after the final marketing approval in an ICH region or at least 2 years 
have elapsed since the discontinuation of clinical development of MOTREM. The PI or 
delegate must contact INOTREM SA before destroying any study-related documentation and 
it is the responsibility of INOTREM SA to inform the investigative site of when these 
documents can be destroyed. In addition, all subject records and other source documentation 
will be kept for a longer period if required by the applicable regulatory requirements.  
 
17.3 Ethical Considerations 
This protocol complies with the principles of the World Medical Assembly (Helsinki 1964) 
and subsequent amendments (10). 
 


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17.3.1 Informed Consent  
The informed consent is a process by which a subject voluntarily confirms his/her willingness 
to participate in a clinical study. It is the responsibility of the PI or delegate to obtain written 
informed consent from subjects. All consent documentation must be in accordance with 
applicable regulations and GCP. Each subject is requested to sign the Informed Consent Form 
(ICF) after they have received and read the written subject information and received an 
explanation of what the study involves, including but not limited to: the objectives, potential 
benefits and risk, inconveniences, and the subject’s rights and responsibilities. Signed ICFs 
must remain on file and must be available for verification by Study Monitors at any time. 
Another signed original of the ICF must be given to the subject or the subject’s legally 
authorised representative. The PI or delegate will provide the Sponsor with a copy of the REC 
approved consent forms, and a copy of the REC written approval, prior to the start of the 
study.  
 
17.3.2 Research Ethics Committee (REC) Approval 
It is the responsibility of the PI to submit this CSP, the informed consent document (approved 
by INOTREM SA), relevant supporting information, and all types of subject recruitment 
information to the REC for review, and all must be approved prior to the start of subject 
screening. In addition, advertisements must be approved by the REC prior to use at the site. 
Prior to implementing changes in the study, INOTREM SA and the REC must also approve 
any substantial amendments to the CSP and corresponding updates to informed consent 
documents. For non-substantial protocol amendments (that do not require REC approval) and 
subsequent updates of the ICF all changes will be done in agreement with INOTREM SA and 
RPL. 
 
17.4 Confidentiality 
Data collected during this study may be used to support the development, registration, or 
marketing of medicinal product. INOTREM SA will control all data collected during the 
study, and will abide by the EU Directive on Data Privacy concerning the processing and use 
of subjects’ personal data. For the purpose of data privacy legislation, INOTREM SA will be 
the data controller. 
After subjects have consented to take part in the study, their medical records and the data 
collected during the study will be reviewed by INOTREM SA and/or its representatives. 
These records and data may, in addition, be reviewed by the following: independent auditors 
who validate the data on behalf of INOTREM SA; national or local regulatory authorities, and 
the REC which gave its approval for this study to proceed. 
Although subjects will be known by a unique number, their initials and date of birth will also 
be collected and used to assist INOTREM SA to verify the accuracy of the data, for example, 
that the results of study assessments are assigned to the correct subject. The results of this 
study containing the unique number, initials, date of birth, and relevant medical information 
including ethnicity may be recorded and transferred to and used in other countries throughout 
the world, which may not afford the same level of protection that applies within the EU. The 
purpose of any such transfer would be to support regulatory submissions made by INOTREM 
SA in such countries. 
 


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17.5 Publication Policy 
If the investigator wishes to publish or present the results of this study, the sponsor must be 
informed to in due time before the submission of any confidential information to an editorial 
board or scientific review committee. This will enable the sponsor to protect its proprietary 
information from disclosure to the public, and to provide comments based on information 
which may not yet be available to the investigator. 


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18 REFERENCES 
 
1.  
Bouchon A, Dietrich J, Colonna M. Cutting edge: inflammatory responses can be 
triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes. J 
Immunol. 2000 May 15;164(10):4991–5.  
 
2.  
Bouchon A, Facchetti F, Weigand MA, Colonna M. TREM-1 amplifies inflammation 
and is a crucial mediator of septic shock. Nature. 2001 Apr 26;410(6832):1103–7.  
 
3.  
Derive M, Massin F, Gibot S. Triggering receptor expressed on myeloid cells-1 as a 
new therapeutic target during inflammatory diseases. Self Nonself. 2010;1(3):225–30.  
 
4.  
Washington AV, Schubert RL, Quigley L, Disipio T, Feltz R, Cho EH, et al. A TREM 
family member, TLT-1, is found exclusively in the alpha-granules of megakaryocytes 
and platelets. Blood. 2004 Aug 15;104(4):1042–7.  
 
5.  
Xiao W, Mindrinos MN, Seok J, Cuschieri J, Cuenca AG, Gao H, et al. A genomic 
storm in critically injured humans. J Exp Med. 2011 Dec 19;208(13):2581–90.  
 
6.  
Washington AV, Gibot S, Acevedo I, Gattis J, Quigley L, Feltz R, et al. TREM-like 
transcript-1 protects against inflammation-associated hemorrhage by facilitating 
platelet aggregation in mice and humans. J Clin Invest. 2009 Jun;119(6):1489–501.  
 
7.  
Derive M, Bouazza Y, Sennoun N, Marchionni S, Quigley L, Washington V, et al. 
Soluble TREM-like transcript-1 regulates leukocyte activation and controls microbial 
sepsis. J Immunol. 2012;188(11):5585–92.  
 
8.  
Lorch U, Berelowitz K, Ozen C, Naseem A, Akuffo E, Taubel J. The practical 
application of adaptive study design in early phase clinical trials: a retrospective 
analysis of time savings. Eur J Clin Pharmacol. 2012;68(5):543–51.  
 
9.  
Parasrampuria DA, Benet LZ. Inclusion of placebos and blinding for ascending dose 
first-in-human studies and other underpowered phase 1 studies has not been justified 
and on balance is not useful. Basic Clin Pharmacol Toxicol. 2015;117(1):44–51.  
 
10.  
Association WM. WMA declaration of Helsinki: Ethical principles for medical 
research involving human subjects. [Internet]. 2013. Available from: 
http://www.wma.net/en/30publications/10policies/b3/ 
 
11.  
Emergency treatment of anaphylactic reactions - Guidelines for healthcare providers. 
Annotated with links to NICE guidance [Internet]. 2012. Available from: 
https://www.resus.org.uk/anaphylaxis/emergency-treatment-of-anaphylactic-reactions/ 


INOTREM SA. 
CONFIDENTIAL 
13 May 2016 
Protocol Ref: MOT-C-104 
Final Version 3.0 
Page 65 of 66 
 
19 APPENDICES 
19.1 UK Treatment Guideline for Anaphylaxis 
 
Source: Emergency treatment of anaphylactic reactions - Guidelines for healthcare providers. 
Annotated with links to NICE guidance July 2012 (11) 
 


INOTREM SA. 
CONFIDENTIAL 
13 May 2016 
Protocol Ref: MOT-C-104 
Final Version 3.0 
Page 66 of 66 
 
19.2 Acute Infusion Reactions Algorithm 
 
 


















Clinical Study Protocol Amendment [Non-substantial] 4 
Sponsor’s Reference: MOT-C-104  
RPL Study Code: C15030 
Date: 22 July 2016 
Page 1 of 7 
 
 
 
 
 
STUDY PROTOCOL 
 
Non-Substantial Amendment 4 
 
A Phase I, randomised, placebo controlled study to assess the safety, tolerability and 
pharmacokinetic profiles of ascending, single, intravenous doses of MOTREM (LR12) in 
healthy male subjects 
 
Investigational medicinal product: MOTREM (LR12) 
Development phase: Ia  
 
Version: 1.0  
Date: 22 July 2016 
 
 
Sponsor Study Code: 
CRO Study Code 
EudraCT Number 
MOT-C-104 
C15030 
2015-005654-35 
 
 
Sponsor 
INOTREM SA 
114 Rue La Boétie 
75008 Paris, France 
Sponsor’s Officer 
Jean-Jacques GARAUD, MD 
Chief Executive Officer 
114 Rue La Boétie 
75008 Paris, France 
Principal Investigator 
Dr Ulrike Lorch, MD FRCA FFPM  
Richmond Pharmacology Ltd. 
St George’s University of London 
Cranmer Terrace, Tooting 
London SW17 0RE, UK 
Study Site 
Richmond Pharmacology Ltd. 
Croydon University Hospital, Thornton Wing,  
530 London Road,  
Croydon, CR7 7YE, UK 
 
 
Information in this protocol is confidential and should not be disclosed, other than to 
those directly involved in the execution or the ethical/regulatory review of the study, 
without written authorisation from INOTREM SA or its affiliates. 






Clinical Study Protocol Amendment [Non-substantial] 4 
Sponsor’s Reference: MOT-C-104  
RPL Study Code: C15030 
Date: 22 July 2016 
Page 4 of 7 
 
 
Reason for Amendment: 
1. The purpose of this amendment is to adjust the maintenance dose increment between 
cohort 7 and cohort 8 to a factor of 2. The amendment describes the administration of a 
6 mg/kg/h maintenance dose to cohort 8 in line with Adaptive Feature number 1, limit VII, 
Adaptive Features 2 and 3 Limits I and III. 
The current approved protocol for the study MOT-C-104 (version 3.0 dated 13 May 2016) 
foresees an increment of 3 for the maintenance dose in all cohorts of Part B and progression 
to the maintenance dose of 9 mg/kg/h (over 7 hours and 45 minutes) in cohort 8.  
Since the dose of 9 mg/kg/h is not planned for therapeutic use and was only foreseen to 
document the safety of the product, a reduced maintenance dose of 6 mg/kg/h is considered 
sufficient for documenting the safety of the product in healthy volunteers considering the 
currently available data. The Safety Review Committee agreed to escalate to the cohort 8 
with an increment of 2 rather than 3 and thus give 6 mg/kg/h for 7 hours 45 minutes.  
These changes will not affect the volunteers’ safety. 
 
 


Clinical Study Protocol Amendment [Non-substantial] 4 
Sponsor’s Reference: MOT-C-104  
RPL Study Code: C15030 
Date: 22 July 2016 
Page 5 of 7 
 
 
Sections of the protocol affected: 
1. Section 5 Study Synopsis 
Old text 
Part B: 
Group 3: 0.5 mg/kg i.v. loading dose and 0.03 mg/kg/h maintenance dose i.v. over 7 hours and 
45 min; 
Group 4: 1 mg/kg i.v. loading dose and 0.1 mg/kg/h maintenance dose i.v. over 7 hours and 
45 min; 
Group 5: 2 mg/kg i.v. loading dose and 0.3 mg/kg/h maintenance dose i.v. over 7 hours and 
45 min; 
Group 6: 5 mg/kg i.v. loading dose and 1 mg/kg/h maintenance dose i.v. over 7 hours and 45 
min; 
Group 7: 5 mg/kg i.v. loading dose and 3 mg/kg/h maintenance dose i.v. over 7 hours and 45 
min; 
Group 8: 5 mg/kg i.v. loading dose and 9 mg/kg/h maintenance dose i.v. over 7 hours and 45 
min. 
Please refer to Table 1. 
Revised text (deleted text is shown as a strikethrough and inserted text is in bold and 
underlined) 
Part B: 
Group 3: 0.5 mg/kg i.v. loading dose and 0.03 mg/kg/h maintenance dose i.v. over 7 hours 
and 45 min; 
Group 4: 1 mg/kg i.v. loading dose and 0.1 mg/kg/h maintenance dose i.v. over 7 hours and 
45 min; 
Group 5: 2 mg/kg i.v. loading dose and 0.3 mg/kg/h maintenance dose i.v. over 7 hours and 
45 min; 
Group 6: 5 mg/kg i.v. loading dose and 1 mg/kg/h maintenance dose i.v. over 7 hours and 45 
min; 
Group 7: 5 mg/kg i.v. loading dose and 3 mg/kg/h maintenance dose i.v. over 7 hours and 45 
min; 
Group 8: 5 mg/kg i.v. loading dose and 9 6 mg/kg/h maintenance dose i.v. over 7 hours and 
45 min. 
Please refer to Table 1. 
 
2. Section 10.1.1 Doses and Treatment Regimen 
Old text 
Single doses of MOTREM (LR12) or matching placebo are planned to be administered i.v. as 
detailed in Table 11. 


Clinical Study Protocol Amendment [Non-substantial] 4 
Sponsor’s Reference: MOT-C-104  
RPL Study Code: C15030 
Date: 22 July 2016 
Page 6 of 7 
 
Table 11. Daily dose of IMP (MOTREM or matching placebo) for each dose group. 
Dose group 
 
i.v.  
loading dose  
T = 15’ 
Maintenance i.v. dose  
(mg/kg/h) 
T = 7h45’ 
Number of 
subjects 
Group 1 
1 mg 
- 
N = 1 
 
- 
 
Group 2 
10 mg 
- 
N = 1 
 
- 
 
Group 3 
0.5 mg/kg 
0.03 mg/kg/h 
N = 3 
Placebo 
Placebo 
N = 1 
Group 4 
1 mg/kg 
0.1 mg/kg/h 
N = 3 
Placebo 
Placebo 
N = 1 
Group 5 
2 mg/kg 
0.3 mg/kg/h 
N = 3 
Placebo 
Placebo 
N = 1 
Group 6 
5 mg/kg 
1 mg/kg/h 
N = 3 
Placebo 
Placebo 
N = 1 
Group 7 
5 mg/kg 
3 mg/kg/h 
N = 3 
Placebo 
Placebo 
N = 1 
Group 8 
5 mg/kg 
9 mg/kg/h 
N = 3 
Placebo 
Placebo 
N = 1 
 
Revised text (deleted text is shown as a strikethrough and inserted text is in bold and 
underlined) 
Single doses of MOTREM (LR12) or matching placebo are planned to be administered i.v. as 
detailed in Table 11. 
Table 11. Daily dose of IMP (MOTREM or matching placebo) for each dose group. 
Dose group 
 
i.v.  
loading dose  
T = 15’ 
Maintenance i.v. dose  
(mg/kg/h) 
T = 7h45’ 
Number of 
subjects 
Group 1 
1 mg 
- 
N = 1 
 
- 
 
Group 2 
10 mg 
- 
N = 1 
 
- 
 
Group 3 
0.5 mg/kg 
0.03 mg/kg/h 
N = 3 
Placebo 
Placebo 
N = 1 
Group 4 
1 mg/kg 
0.1 mg/kg/h 
N = 3 
Placebo 
Placebo 
N = 1 
Group 5 
2 mg/kg 
0.3 mg/kg/h 
N = 3 
Placebo 
Placebo 
N = 1 
Group 6 
5 mg/kg 
1 mg/kg/h 
N = 3 
Placebo 
Placebo 
N = 1 
Group 7 
5 mg/kg 
3 mg/kg/h 
N = 3 
Placebo 
Placebo 
N = 1 
Group 8 
5 mg/kg 
69 mg/kg/h 
N = 3 
Placebo 
Placebo 
N = 1 
 
 
 


Clinical Study Protocol Amendment [Non-substantial] 4 
Sponsor’s Reference: MOT-C-104  
RPL Study Code: C15030 
Date: 22 July 2016 
Page 7 of 7 
 
 
Inotrem SA considers this amendment to be non-substantial as it applies the protocol approved 
adaptive features and their limits. 
 
Persons who initiated the Amendment 
Inotrem SA and Richmond Pharmacology Ltd 
 
Sponsor: 
INOTREM SA, 114 Rue La Boétie, 75008 Paris, France 
 
Centres affected by the Amendment: 
Richmond Pharmacology Ltd, UK