Clinical trial NCT03610334
Conditions: Healthy Volunteers
Keywords: First-In-Human
Sponsor: InFlectis BioScience
Start date: 2018-06-21; Completion date: 2019-12-16
Enrollment: 72 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is the first study of single and multiple doses of IFB-088 in human subjects. The current study is designed to assess in the first part, the safety, tolerability, plasma and urine pharmacokinetics (PK) of single oral doses of IFB-088 in healthy subjects (Single Ascending Doses - SAD) and in a second part safety, tolerability, plasma and urine pharmacokinetics (PK) of multiple oral doses of IFB-088 in healthy subjects (Multiple Ascending Doses - MAD)

Detailed description:
Randomized, double blind, placebo controlled study of single ascending doses (SAD) and multiple ascending doses (MAD).

The SAD part consists of 6 cohorts of 8 healthy young male subjects, each receiving a single oral dose of IFB-088 or placebo (6 verum and 2 placebo). In each cohort, 2 subjects (1 verum and 1 placebo) will be dosed first. If the safety and tolerability results are acceptable, the 6 remaining subjects will be dosed by 2 successive groups of 3 subjects, with an adequate period between the 2 groups to detect the occurrence of any reaction or adverse events, namely at least 48H for the first cohort and at least 36H for the following cohorts. Indeed, in the first cohort (2.5 mg IFB-088 base), dosing will be in the morning only. From the second cohort, the planned daily dose will be divided into 2 doses separated by an interval of 12 hours (1 dose in the morning fasting and 1 dose in the evening 2 hours before dinner).

The MAD part consists of 3 cohorts of 8 healthy young male subjects, each receiving an oral dose divided into two doses of IFB-088 or placebo (6 verum and 2 placebo) for 14 days. In each cohort, the 2 first subjects will be dosed on Day 1 (one on active treatment and one on placebo). The 6 remaining subjects will be dosed by 2 successive groups of maximum 3 subjects with an adequate period between the groups to observe for any reaction and adverse events. This period will be of at least 36H, corresponding to at least 5-fold the half-life of the drug (based on results obtained during the SAD part) when steady state will be achieved. In each MAD cohort, the total daily dose will be divided into 2 doses separated by an interval of 12 hours.

Arms: arm 1: Cohort 1: A single daily dose of 2.5mg IFB-088 in oral capsule, is administered with 250 ml of water at room temperature, in the morning around 8:00am, in one intake arm 2: Cohort 1: A single daily dose of 2.5mg placebo in oral capsule, is administered with 250 ml of water at room temperature, in the morning around 8:00am, in one intake arm 3: Cohort 2: A single daily dose of 5.0mg IFB-088 in oral capsule, divided in two doses of 2.5mg are administered with 250 ml of water at room temperature, seperated by an interval of 12h, in the morning around 8:00am, and in the evening around 8:00pm arm 4: Cohort 2: A single daily dose of 5.0mg placebo in oral capsule, divided in two doses of 2.5mg are administered with 250 ml of water at room temperature, seperated by an interval of 12h, in the morning around 8:00am, and in the evening around 8:00pm arm 5: Cohort 3: A single daily dose of 10.0mg IFB-088 in oral capsule, divided in two doses of 5.0mg are administered with 250 ml of water at room temperature, seperated by an interval of 12h, in the morning around 8:00am, and in the evening around 8:00pm arm 6: Cohort 3: A single daily dose of 10.0mg Placebo in oral capsule, divided in two doses of 5.0mg are administered with 250 ml of water at room temperature, seperated by an interval of 12h, in the morning around 8:00am, and in the evening around 8:00pm arm 7: Cohort 4: A single daily dose of 20.0mg IFB-088 in oral capsule, divided in two doses of 10.0mg are administered with 250 ml of water at room temperature, seperated by an interval of 12h, in the morning around 8:00am, and in the evening around 8:00pm arm 8: Cohort 4: A single daily dose of 20.0mg Placebo in oral capsule, divided in two doses of 10.0mg are administered with 250 ml of water at room temperature, seperated by an interval of 12h, in the morning around 8:00am, and in the evening around 8:00pm arm 9: Cohort 5: A single daily dose of 40.0mg IFB-088 in oral capsule, divided in two doses of 20.0mg are administered with 250 ml of water at room temperature, seperated by an interval of 12h, in the morning around 8:00am, and in the evening around 8:00pm arm 10: Cohort 5: A single daily dose of 40.0mg Placebo in oral capsule, divided in two doses of 20.0mg are administered with 250 ml of water at room temperature, seperated by an interval of 12h, in the morning around 8:00am, and in the evening around 8:00pm arm 11: Cohort 6: A single daily dose of 60.0mg IFB-088 in oral capsule, divided in two doses of 30.0mg are administered with 250 ml of water at room temperature, seperated by an interval of 12h, in the morning around 8:00am, and in the evening around 8:00pm arm 12: Cohort 6: A single daily dose of 60.0mg Placebo in oral capsule, divided in two doses of 30.0mg are administered with 250 ml of water at room temperature, seperated by an interval of 12h, in the morning around 8:00am, and in the evening around 8:00pm arm 13: Cohort 7: subject taking 15.0mg of IFB-088 in oral capsule divided into 2 doses of 7.5mg administered with 250ml of water at room temperature, seperated by an interval of 12h, in the morning around 8:00am, an in the evening around 8:00pm, for 14 days. arm 14: Cohort 7: subject taking 15.0mg of placebo in oral capsule divided into 2 doses of 7.5mg administered with 250ml of water at room temperature, seperated by an interval of 12h, in the morning around 8:00am, an in the evening around 8:00pm, for 14 days. arm 15: Cohort 8: subject taking 30.0mg of IFB-088 in oral capsule divided into 2 doses of 15.0mg administered with 250ml of water at room temperature, seperated by an interval of 12h, in the morning around 8:00am, an in the evening around 8:00pm, for 14 days. arm 16: Cohort 8: subject taking 30.0mg of Placebo in oral capsule divided into 2 doses of 15.0mg administered with 250ml of water at room temperature, seperated by an interval of 12h, in the morning around 8:00am, an in the evening around 8:00pm, for 14 days. arm 17: Cohort 9: subject taking 50.0mg of IFB-088 in oral capsule divided into 2 doses of 25.0mg administered with 250ml of water at room temperature, seperated by an interval of 12h, in the morning around 8:00am, an in the evening around 8:00pm, for 14 days. arm 18: Cohort 9: subject taking 50.0mg of Placebo in oral capsule divided into 2 doses of 25.0mg administered with 250ml of water at room temperature, seperated by an interval of 12h, in the morning around 8:00am, an in the evening around 8:00pm, for 14 days.
Interventions: intervention 1: IFB-088 (2.5-60.0mg) oral capsule intervention 2: Placebo (2.5-60.mg) oral capsule intervention 3: IFB-088 (15.0-50.0mg) oral capsule intervention 4: Placebo oral (15.0-50.0mg) capsule
Intervention descriptions: intervention 1: SAD phase: IFB-088 will be administered during 1 day, in one (2.5mg) or 2 (5.0-60.0mg) intakes separated by an interval of 12 hours intervention 2: SAD phase: placebo (microcrystalline cellulosis) will be administered during 1 day, in one (2.5mg) or 2 (5.0-60.0mg) intakes separated by an interval of 12 hours intervention 3: MAD phase: multiple doses of IFB-088 (15.0-50.0mg) will be administered daily during 14 days, in two intakes, separated by an interval of 12 hours. intervention 4: MAD phase: multiple doses of placebo (microcrystalline cellulosis, 15.0-50.0mg) will be administered daily during 14 days, in two intakes, separated by an interval of 12 hours.

Protocol documents:
Prot_SAP_000.pdf: 
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TITLE PAGE 
Title: 
A double-blind, randomized, placebo-controlled, combined single 
and multiple ascending dose study to investigate the safety, 
tolerability and pharmacokinetic profile of IFB-088, in healthy 
volunteers 
Compound Number: 
 
Effective Date: 
 
 
EudraCT number: 2018-000443-29 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This confidential information about an investigational product is provided for the 
exclusive use of investigators of this product and is subject to recall at any time.  The 
information in this document may not be disclosed unless federal or state law or 
regulations require such disclosure.  Subject to the foregoing, this information may be 
disclosed only to those persons involved in the study who have a need to know, with the 
obligation not to further disseminate this information.   
 
 
 
 


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SPONSOR SIGNATORY: 
 
 
 
 
Date 
 
SPONSOR/MEDICAL MONITOR INFORMATION PAGE 
Medical Monitor and Sponsor Contact Information: 
Role 
Name 
Day 
Time 
Phone 
Number 
After-hours 
Phone/Cell 
Number 
Fax Number 
Address/email 
Chief 
Executive 
Officer 
Philippe 
GUEDAT 
 
+3325125200
7 
- 
+3324020497
3 
InFlectis 
BioScience 
Halle 13 - Bio 
Ouest Ile de Nantes 
21 rue La Noue 
Bras de Fer  
44200 NANTES 
Chief 
Medical 
Officer 
and 
medical 
Monitor 
Anne 
VISBECQ 
 
+3363063202
0 
+3363063202
0 
- 
annevisbecq@inflect
isbioscience.com 
Sponsor Legal Registered Address: 
InFlectis BioScience 
21 rue La Noue Bras de Fer 
44200 NANTES 
France 


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 INVESTIGATOR PROTOCOL AGREEMENT PAGE 
• 
I confirm agreement to conduct the study in compliance with the protocol. 
• 
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described clinical study. 
• 
I agree to ensure that all associates, colleagues and employees assisting in the conduct 
of the study are informed about their obligations. Mechanisms are in place to ensure 
that site staff receives the appropriate information throughout the study. 
 
SAD 
 
MAD 
Investigator Name: 
Dr Yves Donazzolo 
Investigator Address: 
Eurofins Optimed 
1 rue des Essarts 
38610 Gières, France 
Investigator Phone Number: 
+ 33 438 372 747 
 
 
Investigator Signature 
 
 
Date 
 
 
 


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TABLE OF CONTENTS 
SYNOPSIS .......................................................................................................................... 9 
LIST OF ABBREVIATIONS ........................................................................................... 16 
1. INTRODUCTION ...................................................................................................... 19 
 
Background ............................................................................................................. 19 
1.1.
 
Targeting PPP1R15A in CMT .................................................................. 20 
1.1.1.
 
IFB-088 ................................................................................................... 20 
1.1.2.
 
Non-clinical data ................................................................... 21 
1.1.2.1.
 
Rationale ................................................................................................................. 22 
1.2.
 
Study Rationale ........................................................................................ 22 
1.2.1.
 
Dose Rationale ......................................................................................... 23 
1.2.2.
 
Calculation of Safety Coverage ............................................. 23 
1.2.2.1.
 
Determination of the maximum recommended start dose in 
1.2.2.2.
human volunteers ............................................................... 25 
 
Determination of the maximal tested dose in human .............. 25 
1.2.2.3.
 
Rationale for Study population ................................................................. 34 
1.2.3.
 
Summary of Risk Management ................................................................................ 34 
1.3.
 
Cardiovascular Monitoring ....................................................................... 34 
1.3.1.
 
Drug-induced renal crystals ...................................................................... 34 
1.3.2.
 
Liver monitoring ...................................................................................... 35 
1.3.3.
2. OBJECTIVES AND ENDPOINTS............................................................................ 36 
 
Primary objectives ................................................................................................... 36 
2.1.
 
Secondary objectives ............................................................................................... 36 
2.2.
 
Exploratory objectives ............................................................................................. 36 
2.3.
3. INVESTIGATIONAL PLAN .................................................................................... 37 
 
Study Design ........................................................................................................... 37 
3.1.
 
Overview SAD study design .................................................................... 37 
3.1.1.
 
Overview MAD study design ................................................................... 38 
3.1.2.
 
Study endpoints ....................................................................................................... 39 
3.2.
 
Safety endpoints ....................................................................................... 39 
3.2.1.
 
Pharmacokinetic end points ...................................................................... 40 
3.2.2.
 
Biomarker assessment (exploratory) ......................................................... 40 
3.2.3.
 
Discussion of the Design ......................................................................................... 40 
3.3.
 
Dose Adjustment/Stopping Criteria ......................................................................... 41 
3.4.


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Data Package Requirements for Dose Escalation Committee Meetings ..... 42 
3.4.1.
 
Dose Adjustment/Stopping Pharmacokinetic Criteria ............................... 42 
3.4.2.
 
Stopping Safety Criteria ........................................................................... 43 
3.4.3.
 
Liver Chemistry Stopping Criteria ......................................... 43 
3.4.3.1.
 
Renal disorders ..................................................................... 44 
3.4.3.2.
 
QTc Withdrawal Criteria ....................................................... 44 
3.4.3.3.
 
Vital Sign Withdrawal Criteria .............................................. 45 
3.4.3.4.
 
Flow-Chart: Time and events ................................................................................... 46 
3.5.
 
SAD part Cohort 1 ................................................................................... 46 
3.5.1.
 
SAD part: from Cohort 2 .......................................................................... 47 
3.5.2.
 
MAD part ................................................................................................ 48 
3.5.3.
4. STUDY POPULATION............................................................................................. 49 
 
Number of Subjects ................................................................................................. 49 
4.1.
 
Eligibility Criteria ................................................................................................... 49 
4.2.
 
Inclusion Criteria ..................................................................................... 49 
4.2.1.
 
Non selection and non-inclusion Criteria .................................................. 50 
4.2.2.
 
Screen and Baseline Failures ................................................................................... 51 
4.3.
5. STUDY TREATMENT ............................................................................................. 52 
 
Blinding and emergency code-break procedure ........................................................ 52 
5.1.
 
Investigational Medicinal products description (active and placebo product) ............ 52 
5.2.
 
Manufacturing, Packaging and Labeling .................................................................. 53 
5.3.
 
Manufacturing of Study Drug at the Site .................................................. 53 
5.3.1.
 
Packaging and Labeling ........................................................................... 53 
5.3.2.
 
Randomization, storage, dispensation and accountability ......................................... 53 
5.4.
 
Randomization ......................................................................................... 53 
5.4.1.
 
Dispensing ............................................................................................... 54 
5.4.2.
 
Storage..................................................................................................... 54 
5.4.3.
 
Study Drug Accountability ....................................................................... 54 
5.4.4.
 
Assessment of Compliance ....................................................................... 54 
5.4.5.
 
Treatment of Study Treatment Overdose .................................................................. 55 
5.5.
 
Concomitant Medications and Non-Drug Therapies ................................................. 55 
5.6.
 
Permitted Medications ............................................................................. 55 
5.6.1.
 
Prohibited Medications and Non-Drug Therapies ..................................... 55 
5.6.2.
6. STUDY ASSESSMENTS AND PROCEDURES ..................................................... 55 


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Demographic/Medical History Assessments ............................................................ 56 
6.1.
 
Safety ...................................................................................................................... 56 
6.2.
 
Pharmacokinetics .................................................................................................... 58 
6.3.
 
Blood Sample Collection .......................................................................... 58 
6.3.1.
 
Urine Sample Collection .......................................................................... 59 
6.3.2.
 
Sample Analysis ...................................................................................... 59 
6.3.3.
 
Exploratory Marker(s) ............................................................................................. 59 
6.4.
 
Investigational schedule........................................................................................... 60 
6.5.
 
Screening visit ......................................................................................... 60 
6.5.1.
 
Admission Visit (D-1, one day prior to dosing) ........................................ 60 
6.5.2.
 
SAD ......................................................................................................... 61 
6.5.3.
 
Dosing Day (D1)................................................................... 61 
6.5.3.1.
 
Day 2 (D2) ............................................................................ 62 
6.5.3.2.
 
Follow-up / End of study visit (7 to 14 days post dose) .......... 62 
6.5.3.3.
 
MAD ....................................................................................................... 63 
6.5.4.
 
Dosing Day (D1)................................................................... 63 
6.5.4.1.
 
Day 2 .................................................................................... 63 
6.5.4.2.
 
Day 3 to Day 13 .................................................................... 64 
6.5.4.3.
 
Day 14 .................................................................................. 64 
6.5.4.4.
 
Day 15 to Day 17 .................................................................. 65 
6.5.4.5.
 
Follow-up / End of study visit (7 to 14 days post last dose).... 65 
6.5.4.6.
 
Lifestyle And/or Dietary Restrictions ....................................................................... 66 
6.6.
 
Contraception Requirements .................................................................... 66 
6.6.1.
 
Meals and Dietary Restrictions ................................................................. 66 
6.6.2.
 
Caffeine, Alcohol ..................................................................................... 66 
6.6.3.
 
Activity .................................................................................................... 67 
6.6.4.
 
Total volume of blood collected............................................................................... 67 
6.7.
 
SAD part: Collection schedule and Blood volume .................................... 67 
6.7.1.
 
MAD part: Collection schedule and Blood Volume .................................. 67 
6.7.2.
7. COMPLETION OR EARLY WITHDRAWAL OF SUBJECTS .............................. 69 
 
Subject Completion ................................................................................................. 69 
7.1.
 
Subject Withdrawal Criteria .................................................................................... 69 
7.2.
 
Subject Withdrawal Procedures ............................................................................... 69 
7.3.
8. ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAE) .............. 69 
 
Definitions of Adverse Events ................................................................................. 70 
8.1.


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Definition of Serious Adverse Events ...................................................................... 71 
8.2.
 
Expected and unexpected adverse events ................................................................. 72 
8.3.
 
Method of Detecting AEs and SAEs ........................................................................ 72 
8.4.
 
Recording of AEs and SAEs .................................................................................... 73 
8.5.
 
Evaluating AEs and SAEs ....................................................................................... 73 
8.6.
 
Assessment of Intensity ............................................................................ 73 
8.6.1.
 
Assessment of Causality ........................................................................... 73 
8.6.2.
 
Follow-up of AEs and SAEs .................................................................................... 74 
8.7.
 
Prompt Reporting of SAEs to the sponsor ................................................................ 74 
8.8.
 
Pregnancy ............................................................................................................... 75 
8.9.
 
Liver chemistry Follow-up procedures ................................................................... 75 
8.10.
9. DATA MANAGEMENT AND STATISTICAL CONSIDERATIONS ................... 77 
 
Data management .................................................................................................... 77 
9.1.
 
Data collection ......................................................................................... 77 
9.1.1.
 
External Data ........................................................................................... 77 
9.1.2.
 
Data validation ......................................................................................... 77 
9.1.3.
 
Data coding .............................................................................................. 78 
9.1.4.
 
Data Review meeting ............................................................................... 78 
9.1.5.
 
Sample Size Considerations ..................................................................................... 78 
9.2.
 
Data Analysis Considerations .................................................................................. 78 
9.3.
 
Description of data sets ............................................................................ 78 
9.3.1.
 
Hypothesis and statistics .......................................................................... 79 
9.3.2.
 
Interim Analysis and/or schedule of analyses ............................................ 79 
9.3.3.
 
Handling of dropouts and missing data ..................................................... 79 
9.3.4.
 
Demographic and baseline characteristics ................................................. 80 
9.3.5.
 
Study drug and concomitant therapy ......................................................... 80 
9.3.6.
 
Safety Analyses ....................................................................................... 80 
9.3.7.
 
Criteria ................................................................................. 80 
9.3.7.1.
 
Methodology ........................................................................ 81 
9.3.7.2.
 
Pharmacokinetic Analyses ........................................................................ 81 
9.3.8.
10. STUDY CONDUCT CONSIDERATIONS .............................................................. 82 
 
Regulatory and Ethical Considerations, Including the Informed Consent Process ... 82 
10.1.
 
Ethics Committee opinion ...................................................................... 82 
10.1.1.
 
ANSM authorisation .............................................................................. 82 
10.1.2.
 
Protocol Amendments ............................................................................ 82 
10.1.3.


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Regulatory requirements and ethical considerations ................................ 82 
10.1.4.
 
Subject confidentiality ............................................................................ 83 
10.1.5.
 
Urgent Safety Measures ......................................................................... 84 
10.1.6.
 
Quality Assurance and Quality Control .................................................................. 84 
10.2.
 
Monitoring ............................................................................................. 84 
10.2.1.
 
Audit/Inspection ..................................................................................... 84 
10.2.2.
 
Study and Site Closure ........................................................................... 85 
10.2.3.
 
Records Retention .................................................................................. 85 
10.2.4.
 
Report and Publication .......................................................................................... 85 
10.3.
 
Report .................................................................................................... 85 
10.3.1.
 
Publications ........................................................................................... 85 
10.3.2.
11. REFERENCES ........................................................................................................... 86 
12. APPENDICES............................................................................................................ 87 
 
Appendix 1: Liver Safety Algorithms .................................................................... 87 
12.1.
 
Appendix 2: Stopping rules.................................................................................... 88 
12.2.
 
 
 


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SYNOPSIS 
Name 
of 
Sponsor: 
InFlectis 
BioScience 
Protocol ID 
or Number  
P188 
Name of Investigational product: 
IFB-088 Oral capsule 
Name of active ingredients: 
IFB-088 
Title of Study  
A double-blind, randomized, placebo-controlled, combined single and multiple 
ascending dose study to investigate the safety, tolerability and pharmacokinetic profile 
of IFB-088, in healthy volunteers 
Principal Investigators 
SAD: Dr C. Audebert 
Study center  
CIC-CPCET Hôpital de la Timone- Assistance 
Publique des Hôpitaux de Marseille  
MAD: Dr Y. Donazzolo 
Eurofins Optimed 
1 rue des Essarts 
38610 Gières 
Phase of development  
Phase I 
Rationale 
This is the first study of single and multiple doses of IFB-088 in human subjects. The 
current study is designed to assess in the first part, the safety, tolerability, plasma and 
urine pharmacokinetics (PK) of single oral doses of IFB-088 in healthy subjects (SAD) 
and in a second part safety, tolerability, plasma and urine pharmacokinetics (PK) of 
multiple oral doses of IFB-088 in healthy subjects (MAD) 
Objectives 
Primary 
To investigate the safety and tolerability of IFB-088 after single and multiple oral doses 
in healthy volunteers 
Secondary 
To investigate the pharmacokinetics of IFB-088 after single and multiple oral doses in 
healthy volunteers 
Study Design 
Randomized, double blind, placebo controlled study of single ascending doses (SAD) 
and multiple ascending doses (MAD) 
The SAD part consists of 6 cohorts of 8 healthy young male subjects, each receiving a 
single oral dose of IFB-088 or placebo (6 verum and 2 placebo). In each cohort, 2 
subjects (1 verum and 1 placebo) will be dosed first. If the safety and tolerability 
results are acceptable, the 6 remaining subjects will be dosed by 2 successive groups of 
3 subjects, with an adequate period between the 2 groups to detect the occurrence of 
any reaction or adverse events, namely at least 48H for the first cohort and at least 36H 
for the following cohorts. Indeed, in the first cohort (2.5 mg IFB-088 base), dosing will 
be in the morning only. From the second cohort, the planned daily dose will be divided 
into 2 doses separated by an interval of 12 hours (1 dose in the morning fasting and 1 
dose in the evening 2 hours before dinner). 
The MAD part consists of 3 cohorts of 8 healthy young male subjects, each receiving 
an oral dose divided into two doses of IFB-088 or placebo (6 verum and 2 placebo) for 
14 days. In each cohort, the 2 first subjects will be dosed on Day 1 (one on active 
treatment and one on placebo). The 6 remaining subjects will be dosed by 2 successive 
groups of maximum 3 subjects with an adequate period between the groups to observe 
for any reaction and adverse events. This period will be of at least 36H, corresponding 
to at least 5-fold the half-life of the drug (based on results obtained during the SAD 
part) when steady state will be achieved. In each MAD cohort, the total daily dose will 
be divided into 2 doses separated by an interval of 12 hours. 


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Number of subjects  
Seventy-two (72) healthy young subjects (48 in the SAD part and 24 in the MAD part) 
Test product, dose and 
mode of administration  
 
Name 
Pharmaceutical 
Form 
Unit dose strength 
Mode of 
administration 
IFB-088 
Capsules 
2.5 to 30 mg 
Oral 
Placebo 
Capsules 
NA 
Oral 
SAD 
Cohort 1: A single dose of 2.5 mg IFB-088 oral capsule (n=6) or matching placebo 
(n=2) on Dl 
Cohort 2: A single daily dose of 5 mg of IFB-088 oral capsule (n=6) or matching 
placebo (n=2) divided into 2 doses of 2.5 mg separated by an interval of 12 hours on 
D1. 
Cohort 3: A single daily dose of 10 mg IFB-088 oral capsule (n=6) or matching 
placebo (n=2) divided into 2 doses of 5 mg separated by an interval of 12 hours on Dl 
Cohort 4: A single daily dose of 20 mg IFB-088 oral capsule (n=6) or matching 
placebo (n=2) divided into 2 doses of 10 mg separated by an interval of 12 hours on Dl 
Cohort 5: A single daily dose of 40 mg IFB-088 oral capsule (n=6) or matching 
placebo (n=2) divided into 2 doses of 20 mg separated by an interval of 12 hours on Dl 
Cohort 6: A single daily dose of 60 mg IFB-088 oral capsule (n=6) or matching 
placebo (n=2) divided into 2 doses of 30 mg separated by an interval of 12 hours on Dl 
Escalation to the next higher dose and any dose adjustments of the next dose levels will 
be based on safety and tolerability results of the previously administered dose and PK 
data of the previous dose cohorts. There will be a 2-fold increase from the first dose 
level (2.5 mg) to the second dose level. The dose levels of the following groups will be 
increased by 2-fold from the previous dose level from cohort 3 to cohort 5 and 1.5-fold 
from cohort 5 to the last cohort. 
MAD 
Cohort 1: A daily dose of 15 mg of IFB-088 oral capsule (n=6) or matching placebo 
(n=2), divided into 2 doses of 7.5 mg, separated by an interval of 12 hours from D1 to 
D14 
Cohort 2: A daily dose of 30 mg of IFB-088 oral capsule (n=6) or matching placebo 
(n=2), divided into 2 doses of 15 mg, separated by an interval of 12 hours from D1 to 
D14 
 Cohort 3: A daily dose of 50 mg of IFB-088 oral capsule (n=6) or matching placebo 
(n=2), divided into 2 doses of 25 mg, separated by an interval of 12 hours from D1 to 
D14 
Escalation to the next higher dose and any dose adjustments of the next dose levels will 
be based on safety, tolerability and PK results of the previously administered dose. 
Inclusion criteria  
Subjects must satisfy all of the following inclusion criteria: 
1. Healthy male 18 to 40 years of age inclusive, Caucasian. 
2. Healthy as determined by a responsible and experienced physician, based on a 
medical evaluation including medical history, physical examination, laboratory 
tests, vital signs and ECG.  
3. AST, ALT, alkaline phosphatase and bilirubin ≤ 1.5xULN (isolated bilirubin 
>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). 
4. ECG (12 leads) normal (120<PR<200ms; QRS<120ms; QTcF<450ms) and/or 
without clinically relevant impairments as judged by investigator. 


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5. Non-smoker or user of not more than tobacco- or nicotine-containing products ≤ 5 
cigarettes a day.  
6. Negative screen for alcohol and drugs of abuse at screening and admission. 
7. No history of psychiatric disorders assessed by a clinical psychological evaluation 
and the Mini International Neuropsychiatric Interview (MINI). 
8. Body mass index (BMI) between 19 and 27 kg/m² inclusive.  
9. Subject with female partners of child bearing potential must agree to use one of 
the contraception methods listed in Section 6.6.1 (Contraception requirements). 
This criterion must be followed from the time of the first dose of study 
medication until the follow up visit (for female partners) and with an additional 
period of 90 days (for subjects themselves). 
10. Willing and able to understand and sign an approved Informed Consent Form. 
11. Able to understand the protocol and to come to the visits. 
12. Who is, in the judgement of the investigator likely to be compliant during the 
study. 
13. Subject registered in the VRB file (volontaires se prêtant à des recherches 
impliquant la personne humaine). 
14. Covered by Health Insurance System and / or in compliance with the 
recommendations of National Law in force relating to biomedical research. 
Exclusion criteria  
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply: 
1. History of asthma, anaphylaxis or anaphylactoid reactions, severe allergic 
responses. 
2. History of relevant atopy or drug hypersensitivity. 
3. Known allergy to any component of IFB-088 oral capsule or its placebo (HPMC 
or cellulose microcrystalline). 
4. History of major medical, psychiatric illness or surgery which, in the judgment of 
the investigator, puts them ‘at risk’ or is likely to modify their handling of the 
study drug. 
5. Acute or chronic systemic disease or disorder (respiratory, gastrointestinal, renal, 
hepatic, haematological, lymphatic, neurological, cardiovascular, psychiatric, 
musculoskeletal, genitourinary, immunological, dermatological, endocrine). 
6. Impaired renal function defined by a creatinine clearance < 90 mL/min  calculated 
using the Cockcroft-Gault equation (according the FDA Guidance for Industry: 
Pharmacokinetics in patients with Impaired Renal Function, March 2010). 
7. History of nephritic colic and/or renal calculi. 
8. History of drug abuse and/or regular use of tobacco- or nicotine-containing 
products > 5/day within three months of the study.  
9. History of alcohol consumption exceeding, (on average 21 drinks/week for men) 
within 6 months of the first dose of study medication. 
10. Drinking excessive amounts of tea, coffee, chocolate and/or beverage containing 
caffeine (> 4 cups / day). 
11. Vital signs with a clinically significant abnormality at screening. 
12. ECG with a clinically significant abnormality at screening. 
13. Laboratory test values outside the clinically acceptable ‘normal range’ for healthy 
volunteers at screening. 
14. Positive HIV, Hepatitis B or Hepatitis C at screening. 
15. Positive urine drug test or positive breath alcohol test at screening or at admission 
to the clinical unit. 
16. Any medication (including St John’s Wort) within 14 days before administration, 
or within 5 times the elimination half-life of that drug, whichever is the longest 
(except paracetamol). 
17. Treatment with an investigational drug within 30 days or 5 half-lives (whichever 
is longer) prior to screening. 
18. Unable to refrain from consumption of grapefruit or grapefruit juice within 7 days 
prior to the first dose of study medication. 


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19. Unwillingness to abstain from sexual intercourse with pregnant or lactating 
women or to use a condom and spermicide and another form of contraception 
(e.g., IUD, birth control pills taken by female partner, diaphragm with spermicide) 
if engaging in sexual intercourse with a woman who could become pregnant until 
discharge from the study and during 90 additional days. 
20. Subjects unlikely to co-operate in the study, and/or poor compliance anticipated 
by the investigator. 
21. Subject being in the exclusion period of a previous trial. 
22. Subject having exceeded the earnings for the last 12 months, including the 
indemnities for the present study. 
23. Subject who could not be contacted in case of emergency. 
24. Subject refusing to give written informed consent. 
25. Subject who has received blood or plasma derivatives in the year preceding the 
study. 
26. Subject who has given blood within the past 3 months or has planned to give 
blood or sperm within the 90 days following the study. 
27. Subject who has forfeited their freedom by administrative or legal award, or who 
is under guardianship or under limited judicial protection. 
Concomitant medications 
and study restrictions 
Subjects must abstain from taking prescription or non-prescription drugs (including 
vitamins and dietary or herbal supplements), within 14 days or 5 half-lives 
(whichever is longer) prior to the first dose of study medication until completion of 
the follow-up visit. Occasional use of paracetamol at doses up to 2 grams/day will be 
permitted at the principal investigator’s discretion. 
Subjects will abstain from alcohol-, caffeine- or xanthine-containing beverages (e.g. 
coffee, tea, cola drinks, chocolate) for 24 hours prior to the start of dosing until 
collection of the final PK sample during each session. Subjects will abstain from 
grapefruit or grapefruit-containing products for 7 days prior to the first dosing until 
follow-up visit and from strenuous exercise for 48 hours prior to each blood 
collection for clinical laboratory tests. 
Procedures 
Screening 
Subjects will be screened for eligibility between D-21 and D-2 before the first study 
drug administration. Written informed consent will be obtained before any study 
procedure. The screening will consist of: medical history, full physical examination 
(inc1uding height and body weight), vital signs (supine and standing systolic and 
diastolic blood pressure, pulse rate and tympanic body temperature), 12-lead ECG, 
haematology, coagulation, plasma biochemistry and urinalysis tests, viral serology 
testing (hepatitis B antigen, Hepatitis C antibodies, Anti-HIV1 and Anti HIV2 
antibodies), drugs of abuse and alcohol screen, psychological interview and review 
of the eligibility criteria. 
The results of screening must be known to the investigator prior to the subject's 
admission. 
Admission 
Subjects will be admitted to the clinical unit one day prior to dosing (D-1) to 
undergo the following assessments: 
• Medical history and physical examination update, 
• Vital signs measurement (inc1uding tympanic body temperature), 
• 12-lead ECG, 
• Laboratory evaluation (haematology, coagulation, biochemistry, urinalysis), 
• Urine drug screen, 
• Alcohol breath test, 
• AE monitoring, 


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• Review of concomitant medications, 
• Verification of the eligibility criteria, 
• Randomization to the treatment group after check of all criteria. 
The results of admission assessments must be known by the investigator prior to the 
subjects dosing. 
Hospitalization period 
♦ 
SAD 
Subjects will be required to stay in the unit for up to 2 nights for the treatment period 
from Day-1 to Day 2. Subjects will be dosed on Day 1 and will be discharged after 
completion of all assessments and with medical authorization at Day 2, 32 hours 
after first dosing. 
♦ 
MAD 
Subjects will be required to attend the unit on the day (Day -1) prior to the first dose 
and to stay in the unit for 17 days. Subjects will be dosed from Day 1 to Day 14 and 
will be discharged after completion of all assessments and with medical 
authorization at Day 17. 
Follow-up (FU) 
Subjects will be required to return to the unit for a follow-up visit between 7 days 
and 14 days after last dosing or early discontinuation, for safety assessments: 
physical examination; vital signs (supine and standing systolic and diastolic blood 
pressure, pulse rate and tympanic body temperature), 12-lead ECG, haematology, 
coagulation, plasma biochemistry and urinalysis tests. 
Evaluation criteria  
Safety assessments 
♦ 
SAD 
• Adverse events (AEs): throughout the study period i.e. from screening to follow-up 
visit 
• Full physical examination at screening, discharge and FU and physical 
examination update at Day-1 and throughout the study on medical indication at the 
discretion of the investigator 
• Supine and standing vital signs: on D-1; Dl at pre-dose (in triplicate), and 0.5, 1, 2, 
3, 4, 6, 8, 12, 24 and 32h post dose; FU 
• Tympanic body temperature: on D-1; D1 pre-dose; and 1.5, 12, 24 and 32h post 
dose; FU 
• ECG on D-l; Dl at pre-dose (in triplicate) and 1, 2, 4, 8, 12, 24 and 32h post dose; 
FU 
• Laboratory evaluation: haematology, coagulation and biochemistry on D-1, D2 
24h post dose and FU; urinalysis on D-l; Dl at pre-dose and 12h, 24h and 32h post 
dose; FU 
• Vigilance (Bond and Lader VAS) on D1 pre-dose and 1.5, 12 and 32h post dose 
♦ 
MAD 
• Adverse events (AEs): throughout the all study period i.e. from screening to 
follow-up visit 
• Full physical examination at screening, discharge and FU and physical 
examination update at Day-1, D3, D6, D10 and D13 before morning dose and 
throughout the study on medical indication at the discretion of the investigator;  
• Supine and standing vital signs: on D-1; Dl at pre-dose (in triplicate), and 0.5, 1, 2, 
3, 4, 6, 8, 12 post first dose; D2 24h post first dose; every morning pre dose from 
D3 to D17; FU 


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• Tympanic body temperature: on D-1; D1 pre-dose, 1.5 and 12h post first dose; on 
D2, D4, D6, D8, D10 and D12 every morning before dosing; on D14 at pre dose, 
and 1.5, 12h post dose; on D17 before discharge; FU 
• ECG on D-l; Dl at pre-dose (in triplicate) and 1, 2, 4, 8, 12h post first dose; D3, 
D6, D10 and D13 in the morning before dosing and D17 at discharge; FU 
• Laboratory evaluation: haematology, coagulation and biochemistry on D-1, D3, 
D6, D10 and D13 in the morning before dosing and D17 at discharge; FU; 
urinalysis on D-l; Dl at pre-dose, D3, D6, D10 and D13 in the morning before 
dosing and D17 at discharge; FU 
• Vigilance (Bond and Lader VAS) on D1 pre-dose and 1.5, 12h post dose; on D14 
pre dose and 1.5, 12h post dose 
Pharmacokinetic Assessments in blood 
♦ 
SAD 
First cohort (dosing in the morning): blood sampling for PK of IFB-088 and its 
metabolite at pre-dose and 0.16, 0.33, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 12, 24 and 32h 
post dose 
From Cohort 2 (daily dose separated in 2 administrations with a 12-hour interval):  
blood sampling for PK of IFB-088 and its metabolite at pre-dose and 0.33, 0.66, 1, 2, 3, 
4, 5, 12, 12.25, 12.5, 13, 14, 16, 18, 24 and 32h post morning dose 
♦ 
MAD 
Blood sampling for PK of IFB-088 and its metabolite at D1and D14 pre-dose and 0.5, 
1, 2, 3, 4, 6, 8, 10, 12, 13, 14, 17, 19 and 21h post morning dose; D2 24h post first dose 
just before the morning administration; D7 pre dose, 1h and 2 h post dose, D15 at 24, 
30, 36 and 42h post D14 morning dose; D16 at 48h and 60h post D14 morning dose 
Pharmacokinetic Assessments in urine 
♦ 
SAD 
Urine sampling for PK of IFB-088 and its metabolite IFB-139:  
Cohort 1: pre-dose and 0-4, 4-8, 8-16, 16-32 h post-dose intervals. 
From Cohort 2:  pre-dose and 0-4, 4-8, 8-12, 12-24, 24-32h post-dose intervals 
♦ 
MAD 
Urine sampling for PK of IFB-088 and its metabolite: on D1 and D14: at pre-dose and 
0-4, 4-12, 12-24 h post first dose; D6 at pre-dose, 0-4 and 4-12h; D15 at 24-36 and D16 
at 36-48h post D14 morning dose 
Biomarker assessments (exploratory)  
There is currently no validated specific biomarker. So subjects will be asked to donate 
blood samples that could be used as healthy controls for research purposes in patients. 
A specific part in the informed consent will be signed. 
This assessment will be performed only for SAD part. 
♦ 
SAD 
Samples will be drawn at specific time points: Pre-dose, 1.5h and 24h post dose 
• One sample (3 ml) on heparin lithium tube for PBMC extraction 
• One sample (2.5ml) on PAXgene tube for RNA extraction 
Samples will be stored in the CRB (Centre de Ressources Biologiques) at -150°C for 5 
years after final database freeze and then destroyed.  
 


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♦ 
MAD  
Sampling for biomarkers will not be performed during the MAD part. 
Statistical methods  
Data entry and statistical analysis will be performed under the responsibility of the 
CIC-CPCET Pharmacometrics unit. 
The statistical software SAS® version 9.4 (SAS Institute Inc. Cary NC USA) will be 
used in statistical analysis. 
Safety parameters 
Laboratory results, vital signs measurements (blood pressure, heart rate, tympanic 
temperature), ECG parameters and VAS scores will be summarized using appropriate 
descriptive statistics. The incidence of all AEs and treatment-emergent AEs will be 
described by MedDRA® 21.0 or the latest available version at the study completion 
date (preferred term and system organ class). 
PK parameters  
The following parameters for IFB–088 and IFB-139 will be derived, where 
appropriate: 
Plasma 
• Maximum observed plasma concentration (Cmax), 
• Time of occurrence of Cmax (Tmax), 
• Terminal elimination rate constant (Kel), 
• Terminal half-life (t1/2), 
• Area under plasma concentration-time curve from hour 0 to last sample with 
measurable plasma concentrations (AUClast), 
• Area under plasma concentration-time curve from hour 0 to infinity (AUC0-∞), 
• Apparent volume of distribution (Vd/F), 
• Apparent body clearance (CL/F), 
• Last measurable plasma concentration (Clast), 
• Time to reach last measurable plasma concentration (Tlast) 
• Concentration at the end of a dosing interval before the next dose administration 
(Ctrough), 
Urine 
• Maximum observed urine concentration (CmaxU), 
• Time of occurrence of Cmax (tmaxU), 
• Area under urine concentration-time curve from hour 0 to last sample with 
measurable urine concentrations (AUClast), 
• Area under urine concentration-time curve from hour 0 to infinity (AUC0-∞), 
• Renal clearance (CLr), 
• Total amount excreted in urine (Ae), 
• Percent of drug recovered in urine (Ae %dose). 
Pharmacokinetic modelling will be performed using a non-linear mixed effects model 
with NONMEM software (ICON Development Solutions v7.4). Data will be analysed 
using a first order conditional estimation method. The R software (www.r-project.org, 
v3.2.2) will be used for goodness-of-fit diagnostics and graphical displays.  
Descriptive statistics and graphs will be performed for plasma and urine 
concentrations and PK parameters.  


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ABBREVIATIONS  
AE 
Adverse Event 
ALT 
Alanine aminotransferase (SGPT) 
ANOVA 
Analysis of Variance 
AST 
Aspartate aminotransferase (SGOT) 
ATF4 
Activating transcription factor 4 
AUC 
Area under concentration-time curve 
AUC(0-∞) 
Area under the concentration-time curve from time zero (pre-dose) 
extrapolated to infinite time 
AUC(last) 
Area under the concentration-time curve from time zero (pre-dose) to last time 
of quantifiable concentration within a subject across all treatments 
AUC(0-24) 
Area under the concentration-time curve from time zero (pre-dose) to 24 hour  
BID 
Twice a day 
BMI 
Body mass index 
BP 
Blood pressure 
CI 
Confidence Interval 
CL/F 
Apparent clearance following oral dosing 
Cmax 
Maximum observed concentration  
CMT 
Charcot Marie Tooth 
Ct 
Last observed quantifiable concentration 
CPK 
Creatine phosphokinase 
CRF 
Case Report Form 
CV 
Coefficient of variance 
DBP 
Diastolic blood pressure 
DEC 
Dose Escalation Committee 
DMP 
Data Management Plan 
DNA 
Desoxyribonucleic acid 
ECG 
Electrocardiogram 
EMA 
European Medicine Agency 
ER 
Endoplasmic Reticulum 
FDA 
Food and Drug Administration 
FIH 
First in human 
GCP 
Good Clinical Practice 


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GFR 
Glomerular Filtration Rate 
GGT 
Gamma glutamyltransferase 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
HBsAg 
Hepatitis B surface antigen 
HIV 
Human Immunodeficiency Virus 
h 
Hour(s) 
HED 
Human Equivalent Dose 
hERG 
Human Ether-à-go-go-Related Gene 
HNPP 
Hereditary neuropathy with liability to pressure palsies 
HR 
Heart rate 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IC50 
Half maximal inhibitory concentration 
IgM 
Immunoglobulin M 
IMP 
Investigational Medicine Product 
IMPD 
Investigational Medicine Product Dossier 
INR 
International Normalized Ratio 
IUD 
Intrauterine device 
Kg 
Kilogram 
L 
Liter 
LDH 
Lactate Deshydrogenase 
µg 
Microgram 
µL 
Microliter 
MAD 
Multiple Ascending Dose 
MPZ 
Myelin Protein Zero 
MPZS63del 
Transgenic myelin protein zero S63del mouse model 
MPZR98C/+ 
Heterozygous myelin protein zero R98C knock-in mouse model 
MRSD 
Maximum Recommended Starting Dose 
MTD 
Maximal Tolerated Dose 
NOAEL 
No Observed Adverse Effect Level 


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PK 
Pharmacokinetic 
PMP22 
Peripheral myelin protein 22 
PP1 
Protein Phosphatase 1 
PP/PPP1R15A 
Stress-induced holophosphatase complex 
PPP1R15A 
Protein phosphatase 1 regulatory subunit 15A 
PPP1R15B 
Protein phosphatase 1 regulatory subunit 15B 
QoL 
Quality of Life 
QTcB 
QT duration corrected for heart rate by Bazett’s formula 
QTcF 
QT duration corrected for heart rate by Fridericia’s formula 
RBC 
Red blood cells 
RNA 
Ribonucleic acid 
SAD 
Single ascending dose 
SAE 
Serious adverse event(s) 
SAP 
Statistical Analysis Plan 
SID 
Once a day 
SPM 
Study Procedures Manual 
TEAE 
Treatment-emergent adverse event 
Tlast 
Time to reach last measurable plasma concentration 
t½ 
Terminal phase half-life 
Tmax 
Time of occurrence of Cmax 
ULN 
Upper limit of normal 
UPR 
Unfolded Protein Response 
VAS 
Visual Analogic Scale 
WBC 
White blood cells 
WT 
Wild Type 
 
 
 


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1. 
INTRODUCTION 
 
Background  
1.1.
The unfolded protein response (UPR) is a stress response of the endoplasmic reticulum (ER) to 
a disturbance in protein folding and homeostasis (Hetz et al, 2013), observed in many diseases, 
including 
cancer, 
diabetes, 
autoimmune 
conditions, 
liver 
disorders, 
obesity, 
and 
neurodegenerative disorders. When this adaptive mechanism is insufficient to handle the 
unfolded protein load, cells undergo apoptosis. By targeting components of this signaling 
response, it may become possible to reverse their toxic effects and so to treat a wide range of 
neurodegenerative disorders (Charcot-Marie-Tooth, Amyotrophic Lateral Sclerosis, Multiple 
Sclerosis…) (Roussel et al, 2013). 
Charcot-Marie -Tooth (CMT), a group of rare inherited peripheral neuropathies, is one of the 
most common degenerative neurological disorders (mean prevalence: 1/2500). It is 
characterized by progressive development of symptoms, the main ones being symmetric distal 
limb weakness, atrophy, foot deformity, musculoskeletal and neuropathic pain, loss of dexterity, 
fatigue, and sensory loss (Pareyson et al, 2009). Quality of life (QoL) is highly compromised as 
patients encounter muscle atrophy and thus difficulties in carrying out fine motor skills (El-
Abassi et al, 2014). CMT is thus a debilitating disease which, while qualified as rare, still 
presents a “high” prevalence rate for an orphan condition. CMT1A subtype is by far the most 
common form of CMT (prevalence 1:5000). It is a demyelinating neuropathy associated with an 
autosomal dominant 1.4 Mb duplication on chromosome 17p11.2 that includes the peripheral 
myelin protein 22 gene (PMP22) expressed predominantly in the compact myelin of Schwann 
cells (SC). 
Preclinical and clinical studies strongly suggest that the duplication of PMP22 gene is 
responsible for CMT1A. Correct stoichiometry of PMP22 is required to maintain compact 
myelin integrity; too much PMP22 (i.e. duplication) causes CMT1A; too little (PMP22 gene 
deletion) causes hereditary neuropathy with liability to pressure palsies (HNPP). PMP22 protein 
folds with low efficiency under normal conditions (Sanders et al., 2001) and nearly 80% of the 
newly synthetized protein is rapidly degraded. In response to PMP22 overexpression in 
CMT1A, excessive PMP22 polypeptides accumulate in cytosolic aggregates and are targeted to 
degradation by the ubiquitin proteasome system (Fortun et al 2006). Autophagic and lysosomal 
components as well as heat shock proteins (HSPs) are recruited to ubiquitin positive PMP22 
aggregates, likely reflecting an attempt by the cells to clear them through alternate pathways. 
Evidences suggest that PMP22 overexpression in SC, leads to the activation of UPR as 
accredited by the expression of PPP1R15A in the sciatic nerve of CMT1A transgenic rats (N. 
Callizot, P. Miniou & P. Guédat, Presentation at the 6th International Consortium Meeting of 
CMT and related neuropathy, September 2016, Italy).  
This process likely contributes to SC dysfunction, peripheral nerve demyelination, and 
secondary axonal damages which are the major cause of weakness in CMT1A (van Paassen et 
al, 2014). SC which are involved in axonal support, survival and protection of neurons, and the 
formation of myelin sheath of the peripheral nervous system (PNS), acquire a persistent 
differentiation defect in CMT1A. As a result, SC lose their differentiated molecular markers and 
structural features leading to re-expression of more immature molecular markers, such as Neural 
Cell Adhesion Molecule (NCAM) (Klein et al. 2014) and c-Jun (Hanemann et al. 1996; Hutton 
et al. 2011; Sociali et al. 2016) and the proliferation of immature non-myelinating SC ensues.  


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The last decade has seen the first CMT clinical trials, however there is still no cure for CMT and 
no effective treatment to reverse or slow the underlying disease process (Micallef et al. 2009, 
Gess, et al. 2015). While several drugs are under examination, there are only few ongoing 
clinical trials (PXT3003 [combination of baclofen, naltrexone, and sorbitol], and ulipristal). 
 
 
Targeting PPP1R15A in CMT 
1.1.1.
Myelin-forming cells such as Schwann cells in peripheral nervous system which synthetize a 
large amount of myelin proteins and lipids are particularly susceptible to endoplasmic reticulum 
quality control failure. Activation of ER stress/UPR have been involved in several myelin 
disorders, such as CMT neuropathies (Pennuto et al., 2008, Neuron; Saporta at al., 2012, Brain; 
Okamoto et al., 2013, Hum Mol Genet, D’Antonio et al., 2009, J. Neurosci. Res.). Indeed, the 
translation arm of the UPR has been shown to be activated and PPP1R15A expression level 
increased in sciatic nerve from MPZS63del mice model of CMT1B (Pennuto et al., 2008, 
Neuron, D’Antonio et al., 2013, JEM). Activation of UPR response has also been described in 
the MPZR98C mice CMT1B model (Saporta et al., 2012, Brain). In defective nerve tissues of a 
transgenic rat model over-expressing PMP22 gene that closely mimics autosomal dominant 
CMT1A (Sereda et al., 1996) PPP1R15A protein expression has been detected in CMT1A 
sciatic nerve samples from 110 days old rats. In contrast PPP1R15A expression was detected in 
none of the analysed WT samples. In addition, the expression of the transcription factor ATF-4 
which regulates PPP1R15A expression is detected exclusively in the CMT1A samples analysed 
(Unpublished data - InFlectis Bioscience, Neurosys - IIS2017001/IIS2016001).  
In the context of these pathologies, restoring protein homeostasis by prolongating protein 
translation attenuation by a selective inhibitor of PPP1R15A activity might provide a therapeutic 
strategy to cure and or limit CMT pathology evolution.  
 
 
IFB-088 
1.1.2.
The first validated selective inhibitor of PPP1R15A is Guanabenz (2-(2,6-dichlorobenzylidene)-
hydrazinecarboximidamide) (Tsaytler et al. Science 2011), an alpha-2 adrenergic receptor 
agonist that was used as an antihypertensive drug for decades under the trademark Wytensin. 
The hypotensive activity of Guanabenz limits its potential use in CMT.  
A medicinal chemistry research program using Selective Optimization of Side Activity (SOSA) 
strategy (Wermuth CG, Drug Discovery Today 2006) was launched to identify selective 
inhibitors of PPP1R15A without alpha-2 adrenergic activity. 
IFB-088 (2-(2-chlorobenzylidene) hydrazinecarboximidamide acetate), a close chemical 
derivative of Guanabenz (GBZ), selective inhibitor of PPP1R15A correcting protein misfolding 
defects, devoid of alpha-2 adrenergic activity, was identified from this program. 
InFlectis BioScience’s drug candidate, IFB-088, a first-in-class, orally available, would be the 
first treatment ever targeting the UPR in the frame of neurological diseases (Charcot- Marie-
Tooth disease type 1A and type 1B - CMT1A and CMT1B). 


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IFB-088 mechanism of action in CMT is validated and published (Das et al. 2015; 6th 
International Consortium Meeting of CMT and related neuropathy September 2016, Italy). The 
implementation of a series of in vitro and in vivo CMT1 (types A & B) studies demonstrate that 
IFB-088 is a promising potential therapeutic agent for CMT patients. 
An Orphan drug designation was granted to IFB-088 for the treatment of CMT, by the FDA 
(USA, 10 September 2015) and by the EMA (EU, 14 December 2015). 
 
 
Non-clinical data 
1.1.2.1.
Full details on nonclinical data are provided in the Investigator’s Brochure. Nonclinical studies 
have been performed in accordance with ICH guidance, and Good Laboratory Practices. 
 
1.1.2.1.1.  Pharmacology 
In vitro pharmacology studies demonstrated that the selective PPP1R15A inhibition by IFB-088 
prolongs protein translation attenuation, delays and attenuates the activation of the stress 
response pathway in stressed cells only, thereby restoring proteostasis and improving stressed 
cells survival. The absence of effect under non-stressed conditions has also been confirmed.  
Therapeutic IFB-088 efficacy has been demonstrated in different CMT1 animal models: 
decreased PMP22 protein expression in sciatic nerves and improvement of the motor deficits 
and sensory performances in CMT1A rats, improvement of myelination in ex vivo dorsal root 
ganglia cultures of CMT1B models, improvement of motor deficits and increased myelin 
thickness in CMT1B MPZS63del mouse model.  
 
Potential off target effects reported with IFB-088 as well as a moderate hERG channel blocker 
effect are observed in IC50 ranges which are not expected to be reached in humans. The 
moderate effect on the hERG channel was identified in vitro whereas the in vivo telemetry 
conducted in dogs confirmed that IFB-088 has no effect on dog cardiovascular function. Finally, 
three in vivo safety pharmacology studies conducted in rats and dogs demonstrated that IFB-088 
has no effect on CNS, respiratory and cardiovascular functions up to 9 mg/kg/day when 
administered once or twice daily.  
 
1.1.2.1.2. Pharmacokinetics and metabolism 
Several pharmacokinetic studies were conducted in mice, rats and dogs. IFB-088 is absorbed 
after single oral administration in Sprague Dawley rats with an oral bioavailability of 15%. The 
pharmacokinetic and the tissue distribution profile of IFB-088 in Sprague Dawley rats indicate 
that IFB-088 reach the CMT target organ (sciatic nerve). In rats, PK was found to be non-linear 
based on AUC values, and different between males and females. In dogs, no relevant difference 
was seen in the exposure between the sexes, and the exposures (AUC0-24) increased 
proportionally within the dose and remained similar on day 28, after repeated dosing, compared 
to day 1 (single dose). An in vitro study on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, 
CYP2D6 and CYP3A4 did not evidence potential for IFB-88 to inhibit CYP450. No major 


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differences were observed regarding metabolism profile in human hepatocytes and other animal 
species especially dog and rat hepatocytes models.  
 
1.1.2.1.3. Toxicology 
The safety of IFB-088 was evaluated in CD1 mice, Sprague Dawley rats and Beagle dogs. 
Preliminary toxicity studies emphasized renal findings after 10 days of daily administration 
from 10 mg/kg in rats and for daily administration of 6 mg/kg for 14 days in dogs (minimal to 
slight tubule vacuolation in the kidneys). In rats, in a 28-day toxicity study, daily administration 
of 9 mg/kg was also considered as adverse mainly due to renal and hematologic findings. The 
No Observed Adverse Effect Level (NOAEL) was established at 3 mg/kg/day or 1.5 mg/kg/BID 
in Sprague Dawley rats. In Beagle dogs, twice daily administration of 4.5 mg/kg (9 mg/kg/day) 
for 28 days was well tolerated (NOAEL in this species) without any renal findings, suggesting 
that when administered twice daily IFB-088 is better tolerated than when daily administered. 
 
In vitro genotoxicity studies conducted with IFB-088 showed a weak mutagenic effect in non-
mammalian and mammalian cell systems at the maximum. Following equivocal or positive in 
vitro genotoxicity results, an in vivo genotoxicity study was performed in rats to ward off a 
genotoxic risk for human; in Sprague Dawley rats after 3 days daily administration up to 
20 mg/kg, the in vivo micronucleus test in bone marrow tissue combined to an in vivo Comet 
assay on liver tissue indicate that IFB-088 had no genotoxic activity in vivo. More information 
on genotoxicity is available in the expert report provided in appendix of the IMPD. 
 
 
Rationale 
1.2.
 
Study Rationale 
1.2.1.
IFB-088 is intended to be developed for the treatment of Charcot-Marie-Tooth disease and also 
other degenerative pathologies resulting from the accumulation of misfolded proteins. IFB-088 
has not been previously administered in human subjects.   
The current First-In-Human (FIH) study (Phase 1) aims at examining the safety, tolerability, 
plasma pharmacokinetics (PK) of single doses and repeated doses of IFB-088 in healthy 
volunteers. This Phase 1 study is designed to support future clinical developments of IFB-088 in 
CMTs and other degenerative pathologies, such as Multiple Sclerosis, Amyotrophic Lateral 
Sclerosis, Oculo-Pharyngeal Muscular Dystrophy and Retinitis Pigmentosa for which preclinical 
efficacy in animal models has been obtained.  
The current study will include 2 sequential parts. 
The first part of the current study will examine the safety, tolerability, plasma and urine 
pharmacokinetics (PK), of single doses of IFB-088 in healthy subjects (SAD). 
The second part of this study will examine the safety, tolerability, plasma and urine 
pharmacokinetics (PK), of multiple doses of IFB-088 in healthy subjects (MAD). 
 


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Dose Rationale for the SAD part 
1.2.2.
The dose selection of IFB-088 is based on the No Observed Adverse Effect Level (NOAEL) in 
animals as per the principles laid down in the Guideline on strategies to identify and mitigate 
risks for first-in human clinical trials with IMPs (EMEA/CHMP/SWP/28367/07 Rev.1) and the 
anticipated pharmacokinetic and pharmacodynamic response in humans, using available 
preclinical biology, toxicology, and pharmacokinetic data from mice, rats, and dogs.  
This range of selected doses has the double objective 1) to ensure the safety of subjects 
participating in the study and 2) to cover the doses at which this New Chemical Entity is 
expected to exert a beneficial effect in patients affected with CMT as well as in the above-
mentioned degenerative diseases.   
 
Calculation of Safety Coverage  
1.2.2.1.
Toxicology studies in rodent (mice, rat) and non-rodent animal species (dog) were conducted to 
assess IFB-088 safety (see section 4.3.3 & 4.3.4 of Investigator’s Brochure):  
- 
Non GLP toxicology studies in CD1 mice, Sprague Dawley rats and Beagle dogs;  
- 
GLP repeated dose toxicity studies in Sprague Dawley rats and Beagle dogs at doses up 
to 9 mg/kg/day for up to 28 days. Observations and pharmacokinetic parameters are 
summarized in Table 1. 
 
 


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Table 1: Summary of results from toxicology studies up to 28 days in rats and dogs 
 
Study
Regimen
Main findings
sexe
Plasma 
Tmax
Cmax 
(ng/ml)
AUCt 
(ng/ml*h)
AUC0-24 
(ng/ml*h)
Repeated 
administration
10 days
P.O.: 5 mg/kg SID
No clinical signs were reported and pathological changes or 
renal microscopic examination (tubular basophilia and 
dilatation) were considered as non-adverse
Female 
& Male
N.D.
N.D.
N.D.
N.D.
Repeated 
administration
10 days
P.O.: 10 mg/kg SID
10 mg/kg administered daily for days was considered as adverse 
due to: 
-thin appearance, hunched posture, ptyalism and renal 
impairment in both genders
Female 
& Male
N.D.
N.D.
N.D.
N.D.
44288 TSC 
14-day 
toxicology 
non-GLP 
study in 
Beagle Dogs
Repeated 
administration
14 days
P.O.: 6 mg/kg SID
Dose was clinically well tolerated in dogs (MTD), but:
- increased liver enzymes activity (in the female dog)
- increased thrombocytes count were considered as adverse
- microscopy, histologically, both dogs had minimal to slight 
tubule vacuolation in the kidneys. In the female, this adverse 
renal effect was associated with microscopic renal findings (i.e. 
tubular degeneration/necrosis and tubule dilation)
Female 
& Male
N.D.
N.D.
N.D.
N.D.
Female
1h
0.37
ND
ND
Male
ND
ND
ND
ND
Female
1h
1.02
ND
ND
Male
1h
0,36
ND
ND
Female T1: 30min
T2: 2h
T1: 5.64
T2: 7.98
4.49
Male
T1: 30min
T2: 2h
T1: 5.64
T2: 7.98
4.48
Female T1: 30min
T2: 2h
T1: 5.64
T2: 7.98
9.54
Male
T1: 30min
T2: 2h
T1: 5.64
T2: 7.98
3.76
Female
1h
3.76
8.54
12.55
Male
1h
2.33
4.53
6.46
Female
1h
4.73
8.71
11.49
Male
1h
1.85
4.38
6.63
Female
1h
20.58
44.17
63.49
Male
1h
6.30
22.38
38.66
Female
30min
10.38
38.84
60.99
Male
3h
6.80
31.27
65.79
Female T1: 30min
T2: 2h
T1: 5.64
T2: 7.98
30.9
Male
T1: 30min
T2: 2h
T1: 3.70
T2: 8.77
34.5
Female T1: 30min
T2: 2h
T1: 5.77
T2: 5.51
37.0
Male
T1: 30min
T2: 2h
T1: 3.98
T2: 3.81
64.3
Female T1: 30min
T2: 2h
T1: 13.57
T2: 11.25
89.4
Male
T1: 30min
T2: 2h
T1: 13.26
T2: 12.97
94.1
Female T1: 30min
T2: 2h
T1: 16.78
T2: 16.26
119
Male
T1: 30min
T2: 2h
T1: 17.38
T2: 10.78
90.4
Female
T1: 3h
T2: 2h
T1: 26.82
T2: 39.29
297
Male
T1: 3h
T2: 2h
T1: 39.60
T2: 74.88
472
Female
T1: 3h
T2: 2h
T1: 29.62
T2: 49.11
391
Male
T1: 30min
T2: 2h
T1: 34.70
T2: 48.20
338
44287 TSR 
10-day 
toxicology 
non-GLP 
study in 
Sprague 
Dawley Rats
Repeated 
administration
28 days P.O.: 1 mg/kg 
SID
Repeated 
administration
28 days P.O.: 1.5 
mg/kg BID
No adverse effect
No adverse effect
44289 TSR
28-day 
toxicology 
GLP study in 
Sprague 
Dawley Rats
Repeated 
administration
28 days P.O.: 3 mg/kg 
SID
NOAEL
Repeated 
administration
28 days P.O.: 9 mg/kg 
SID
9 mg/kg administered daily for 4 weeks was considered as 
adverse due to: 
- Higher leucocyte counts and fibrinogen levels, higher urea, 
creatinine calcium and inorganic phosphorus concentrations
- Adverse microscopic findings in kidneys and non-adverse 
findings were noted in the liver and bone marrow (males only)
- Ongoing but incomplete recovery seen in kidneys and liver in 
microscopic samples of this group.
No adverse effect
No adverse effect
Repeated 
administration
28 days P.O.: 0.5 
mg/kg BID (6h 
between the 2 
treatments)
Repeated 
administration
28 days P.O.: 1.5 
mg/kg BID (6h 
between the 2 
treatments)
44290 TSC 
28-day 
toxicology 
GLP study in 
Beagle dogs
NOAEL
Highest tested dose
Repeated 
administration
28 days P.O.: 4.5 
mg/kg BID (6h 
between the 2 oral 
treatments)


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A non-GLP toxicity study in rats showed renal toxicity after repeated (10 days) oral 
administration at ≥10 mg/kg once a day (study 44287 TSR). In the 28-day GLP toxicity study in 
rats, the administration of 9 mg/kg once daily led to adverse effects, notably renal and 
haematology abnormal findings. Thus, the NOAEL was established at 3 mg/kg/day, 
administered in one or two doses in Sprague Dawley rats (study 44289 TSR). 
 
In the 14-day non-GLP toxicity study in dogs, the 6 mg/kg/day dose administered once daily 
was well tolerated clinically but females had adverse microscopic tubular degeneration/necrosis 
in the kidneys. The once daily dose of 6 mg/kg is considered to be the Maximum Tolerated 
Dose for a 2-week treatment period (study 44288 TSC). In the 28-day GLP toxicity study in 
dogs (study 44290 TSC), twice daily administration up to 9 mg/kg/day (i.e. 4.5 mg/kg/BID) was 
well tolerated without any renal toxicity or other findings suggesting that, for a given dose, 
twice daily administration is better tolerated than once daily administration, due to the 
minimisation of Cmax, while AUC remains similar. Therefore, in the present clinical study, it is 
planned to administer IFB-088 twice daily starting from cohort 2, to reduce the Cmax exposure. 
The NOAEL in Beagle dogs was established at 4.5 mg/kg administrated twice a day 
(9 mg/kg/day). 
 
 
Determination of the maximum recommended start dose in human volunteers 
1.2.2.2.
The dose of 2.5 mg per day was selected as the maximum recommended start dose for the 
present clinical trial, based on the following considerations: 
1. 
According to the applicable guidelines on dose selection for first in human trials 
(paragraph 7.2 of EMEA/CHMP/SWP/28367/07 Rev. 1 and FDA guidance 2005 - 
Guidance for Industry Estimating the Maximum Safe Starting Dose in Initial Clinical 
Trials for Therapeutics in Adult Healthy Volunteers), the calculation of the maximum 
recommended start dose (MRSD) is based on the no observed adverse effect level 
(NOAEL) converted into a human equivalent dose (HED) from which a safety factor is 
applied to derive the MRSD. As suggested by the above guidelines, the rat species was 
selected, both in terms of toxicology (most sensitive species) and in terms of 
pharmacology (species used for some animal models).  
2. 
The NOAEL in this species being 3mg/kg/day, the 6.2 division factor should be applied to 
convert animal dose to HED (FDA Guidance 2005), it translates into 0.484 mg/kg in 
humans, that corresponds to a daily dose of 29 mg for a human weighing 60 kg. A safety 
factor of 10 (FDA Guidance 2005) is then applied to calculate the MRSD, which is thus 
estimated at 2.90 mg. 
 
Determination of the maximal tested dose in human 
1.2.2.3.
Assessment of the target dose based on efficacy data in rodents 
IFB-088’s biological target PPP1R15A is present only in defective cells. PPP1R15A protein 
being conformation sensitive and part of a protein complex, there is no validated in vitro assays 
available to evaluate IFB-088 efficacy. Therefore, the efficacy of IFB-088 was evaluated in vivo 
in different validated rodent models (transgenic mouse and rat models). A non-exhaustive list of 
animal efficacy studies is presented in Table 2. 


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Table 2: Summary of in vivo pharmacology studies for IFB-088 in several animal models 
Therapeutic 
indication 
Animal model
(targeted organ) 
Tested doses 
Efficacy 
Remarks 
Charcot-Marie-
Tooth-1A 
PMP22 
transgenic 
rat 
(Sciatic nerve tissue) 
P.O.: 0.76 mg/kg 
SID 
Very 
weak 
and 
partial 
First partial effect observed
Report CMT1A-REPORT-NC-2017-01 
P.O.: 2.29 mg/kg 
SID 
Good
Report CMT1A-REPORT-NC-2017-01
Charcot-Marie-
Tooth-1B 
MPZ-S63del 
transgenic mouse  
(Sciatic nerve tissue) 
P.O.:  1 mg/kg BID 
(2 mg/kg/day) 
Good
Das et al. Science 2015
Amyotrophic 
Lateral Sclerosis 
SOD1-G93A 
transgenic mouse 
(Brain tissue) 
P.O.:  1 mg/kg BID 
(2 mg/kg/day) 
Partial
Das et al. Science 2015
P.O.:  5 mg/kg SID
Good
Multiple Sclerosis 
mouse 
immunized 
with 
CFA 
and 
MOG35–55 
to 
induce chronic EAE 
(Brain tissue) 
I.P.: 4 mg/kg SID 
only female 
Good, 
but not 
maximal 
Prosecution of US patent application 
N°14/773,088 to USPTO 
Declaration of Dr Brian Popko 
(University of Chicago) dated 
January 3, 2017 under 37 C.F.R § 
1.131  
Exhibit D (IFB-088 is named Sephin1) 
I.P.: 8 mg/kg SID
only female 
Good 
P.O.: Oral administration 
I.P.: intraperitoneal administration 
SID: once a day administration 
BID: twice a day administration 
 
IFB-088 was administered by the oral route in the CMT1A, CMT1B and ALS animal models 
but by intra peritoneal (IP) route in the MS mouse model.  
The lowest daily dose administered per os resulting in a weak and partial efficacy in the 
CMT1A transgenic rat model was 0.76mg/kg. Applying the allometric conversion mentioned 
above, this corresponds to 7.35 mg in humans (assuming a conversion factor of 6.2 and based 
on a Human body weight of 60 kg).  
IFB-088 administered by IP route in female MS mouse model showed optimal efficacy at the 
dose of 8 mg/kg/day, the highest tested in the study (Table 2). To convert this dose into a per os 
dose, pharmacokinetic data were generated following IP and oral administration of IFB-088 at 
4mg/kg and 8mg/kg (studies PSN 11-233 and 17-672 Table 3). The following results were 
obtained. (Of note, in mice the pharmacokinetics are similar in females and males) (Table 3). 
- 
Oral administration of 10 mg/kg gives an AUCtoral of 215.9 ng/ml.h in male mice 
- 
IP administration of 4mg/kg gives an AUCtIP of 105 ng/ml.h in female mice 
- 
IP administration of 8 mg/kg gives an AUCtIP of 337 ng/ml.h in female mice 
Based on the results, a population pharmacokinetics model was developed for the IP route 
(NONMEM v7.3 Software), allowing the estimation of pharmacokinetic parameters (Clearance 
(CL), central volume of distribution (Vc)) and inter- and intra-individual variability in mice and 
the simulation of AUCtIP.  


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Simulations were performed using this population pharmacokinetic model to predict the 
pharmacokinetic response in a typical mouse, after once daily IP administration of various IFB-
088 doses. Parameter estimates (CLIP and AUCtIP) and their reported variability were used to 
simulate time-concentration curves in 1000 mice. 
For IP administration of 10 mg/kg, the AUCtIP,predicted was estimated at 443.3 ng/ml.h. 
The ratio of AUCtIP, predicted/AUCtoral = 443.3/215.9 = 2.05 for the single dose of 10 mg/kg 
(AUCtoral was the result of pharmacokinetics study (study PSN 11-233), a non-compartmental 
analysis that does not take account the variability). 
The IP administration of 8 mg/kg gives an AUCtIP,predicted of 354.7 ng/ml.h and CLIP,predicted of 
0.676 L/h. 
Therefore, based on these results we can predict the oral dose to get the corresponding AUCtIP 
of 8mg/kg:  
Doseoral,predicted = 2.05 (AUCtIP x CLIP) = 0.492 mg, corresponding to 16.41 mg/kg 
Taking into account the allometric conversion of animal doses to HED, the corresponding 
highest efficient dose in Human is 80.1 mg (16.41 (highest efficient dose in mice) / 12.3 
(allometric factor for mouse) x 60 (body weight in kg for human)). 
Based on this extrapolation, the maximal dose daily administered to cover all kind of therapeutic 
indications listed above is 80.1 mg in human (corresponding AUC of 111.14 ng/ml.h).  
 
Therefore, the range of Pharmacologically Active Dose (PAD) is estimated to be comprised 
between 7.35 mg and 80.1 mg in humans (Table 2).  
To add additional safety, we propose to not exceed 75% of this highest value 80.1 x 75% = 
60 mg, the maximal dose planned to be administered in humans is therefore 60 mg. 
 


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Table 3: Summary of pharmacokinetic studies in different species 
 
 
Estimation of the safety of the target dose of 60 mg in Humans 
Based on toxicity and pharmacokinetic studies in rats and dogs, population pharmacokinetics 
models were developed (NONMEM v7.3 software). These population pharmacokinetics models 
allow to assess pharmacokinetic parameters ((apparent clearance (CL/F) and apparent central 
volume of distribution (Vc/F)) in rats and dogs. 
A first population pharmacokinetics model was developed with rats’ data to assess 
pharmacokinetic parameters in rats and a second population pharmacokinetics model was 
developed with dogs’ data to assess pharmacokinetic parameters in dogs (Results and validation 
of models were presented in the report IFB-088preclinicmodeling v270717.pdf).  
Then, a third population pharmacokinetics model was developed with all the data (rats’ and 
dogs’ data). This third model is an interspecies population pharmacokinetics model that was 
used to assess pharmacokinetic parameters in rats and dogs and to compare these results with 
the two previous developed models (Results and validation of model were presented in the 
report IFB-088preclinicmodeling v270717.pdf). This interspecies population pharmacokinetics 
model was also used to predict pharmacokinetic parameters in humans. Estimated and predicted 
pharmacokinetics parameters are summarized in Table 4. 
 
 
 
 
Study N°
Species
sexe
Regimen
Study 
status
sampling time
Plasma 
Tmax
Cmax 
(ng/ml)
AUCt 
(ng/ml*h)
PSN 11-232
Single I.V.: 2 mg/mg
2min, 15min, 30min, 
1h, 3h, 6h, 8h, 24h
2min
143.55
79.23
PSN 11-233
Single P.O.: 10 mg/kg
15min, 30min, 1h, 2h, 
3h, 6h, 8h, 24h
15min
132.67
215.9
Male
10min
127.98
128.5
Female
10min
87.1
105.7
Male
10min
380.7
363.8
Female
10min
380.0
337.3
12-640
Sprague 
Dawley 
Rat
Male 
Single P.O.: 10 mg/kg
Non-GLP 10min, 30min, 1h, 2h, 
4h, 6h, 8h, 24h
10min
46.4
34.23
Repeated administration 7 
days P.O.: 1.15 mg/kg SID
2h
4.32
ND
Repeated administration 7 
days P.O.: 1.15 mg/kg BID
2h
2.03
ND
Repeated administration 7 
days P.O.: 2.29 mg/kg SID
2h
3.89
19.89
Repeated administration 7 
days P.O.: 7.66 mg/kg SID
2h
9.01
43.02
16-326
Sprague 
Dawley 
Rat
Male 
Single P.O.: 2.29 mg/kg
Non-GLP 10min, 30min, 1h, 2h, 
4h, 6h, 8h, 24h
10min
17.35
12.52
17-672
10min, 30min, 1h, 2h, 
4h, 6h, 8h, 24h
Sprague 
Dawley 
Rat
Non-GLP
Single .I.P: 4mg/kg
Single I.P.: 8mg/kg
Mouse 
C57BL/J6
15-035A
Male 
Non-GLP
after last 
administration: 2h, 4h, 
8h, 24h
Discovery
Mouse 
CD1
Male


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Table 4: Estimated PK parameters in rats and dogs and predicted PK parameters in humans, 
using the NONMEM v7.3 Software 
  
Rat 
Dog 
Human*(60kg) 
CL/F (L/h/kg) 
145.2 
19.2 
9.7 (9.6 – 9.9) 
Vc/F (L/kg) 
389.9 
44.5 
20.9 (20.4 – 21.3) 
*Pharmacokinetic parameters derived from bootstrap analysis (95%CI) 
 
Simulations were performed using this interspecies population pharmacokinetic model to predict 
the pharmacokinetic response in a standard 60 kg individual, after once and twice daily 
administrations of various IFB-088 doses over 14 days. Concentration-time profiles were 
simulated for 1000 typical 60kg humans. Cmax and AUC0-24h were simulated for 1000 rats 
(effective dose and NOAEL dose in rats), 1000 dogs (NOAEL rat dose and NOAEL dog dose) 
and 1000 typical 60kg humans to determine Cmax and AUC0-24h safety coverage. 
The maximum clinical dose was determined from dog data as the pharmacokinetic is not linear 
in rats with differences between sexes. Based on these elements and the Guidance for Industry 
M3(R2) FDA. The maximum clinical dose should not be higher than half of the AUC at the 
highest dose tested in dogs not showing toxicity (considered as NOAEL).   
The mean AUC at the highest dose not showing toxicity in dogs (4.5mg/kg twice daily) is 
376.46 ng/ml.h-1 (Table 1). Therefore, half of the AUC is 188.23 ng/ml.h, which corresponds to 
a dose of 135.79 mg in a human being weighing 60kg. 
According to the model, the corresponding AUC for a 60 mg daily dose in humans is 83.15 
ng/ml.hr, which is far below 188.23 ng/ml.h (Table 5). 
Data on Cmax are consistent with those on AUC. The half of the Cmax in dogs receiving 4.5 mg/kg 
twice daily is 23.77 ng/ml while the Cmax in humans receiving a total daily dose of 60 mg is 
10.57 ng/ml. Thus, the target dose of 60 mg/day (30 mg BID) can be considered as safe in 
humans. 
 
Table 5: Predicted mean plasma Cmax and AUC(0-inf) in humans following first day dosing of 
IFB-088 and associated safety coverage 
Daily 
dose 
(mg) 
Daily 
administered 
doses  
(n x mg) 
Escalating 
dose ratio 
Expected 
Human 
Cmax 
(ng/ml) 
Expected 
Human 
AUC (0-inf) 
(ng/ml.hr) 
Cmax safety 
coverage % of 
corresponding 
maximal Cmax 
in human 
AUC safety 
coverage 
% of AUC in 
dog 
2.5 
1 x 2.5 
 
0.84 
3.69 
3.5% 
0.98% 
5 
2 x 2.5 
2 
0.88 
6.93 
3.7% 
1.84% 
10 
2 x 5 
2 
1.76 
15.32 
7.4% 
4.07% 
20 
2 x 10 
2 
3.52 
27.72 
14.8% 
7.36% 
40 
2 x 20 
2 
7.04 
55.44 
29.6% 
14.73% 
60 
2 x 30 
1.5 
10.57 
83.15 
44.47% 
22.09% 
 


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The escalating dose levels (Table 5) were chosen to not exceed an escalating ratio of 2 except 
for the last dose level with a smaller ratio of 1.5. 
It might be worth noting that the antihypertensive drug Guanabenz, a structural analogue of 
IFB-088 (with only one atom difference), displays a similar biological activity on PPP1R15A 
(Tsaytler et al., Science 2011; Das et al., Science 2015) and similar pharmacokinetic profile in 
Sprague Dawley rats (plasma, brain, retina and sciatic nerve – Report 16-326). Guanabenz is 
still marketed in certain countries (including Japan) at doses up to 64 mg/day as 32mg/day BID. 
Criteria to stop escalating dose: 
The dose escalation will be stopped if in a given volunteer: 
- 
The AUC is higher than 111.14 ng/ml.h (simulated AUC for the highest efficient dose in 
Human and which is lower than the half of AUC in dogs at the NOEL) 
- 
The Cmax reaches 23.77 ng/ml.h (half of the Cmax in dogs at the NOAEL).  
The maximum recommended starting dose (MRSD) for IFB-088 in adult healthy volunteers was 
evaluated at 2.90 mg/day in Humans. 
The maximal daily dose to be administered in Humans to cover the different envisioned 
therapeutic indications was evaluated at 80 mg/day. Therefore, in order ensure optimal safety, 
the dose ranges selected are:  
- 
2.5 mg/day for the first therapeutic dose;  
- 
60 mg/day given as 2 administrations of 30 mg for the highest therapeutic dose. 
 
 
Dose Rationale for the MAD part 
1.2.3.
 
Update on Safety coverage 
1.2.3.1.
Additional toxicology studies have been conducted in rodent (rat) and non-rodent (dog) animal 
species to further assess IFB-088 safety (see sections 4.3.1 & 4.3.4 of Investigator’s Brochure): 
- 
GLP repeated dose toxicity studies in Sprague Dawley rats and Beagle dogs at doses up 
to 12 mg/kg/day for 13 weeks. Observations and pharmacokinetic parameters of IFB-088 
and its major metabolite (IFB-139) are summarized in Table 6. 


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Table 6: Summary of results from the GLP 13-week toxicology studies in rats and dogs 
 
 
In the 13-week GLP toxicity study in rats, the administration of IFB-088 at dose levels ≥ 
6 mg/kg/day (i.e. 3 mg/kg BID) led to adverse effects similar to those observed in the 28-day 
study, i.e. renal and haematology abnormal findings. Thus, the NOAEL remained at 3 
mg/kg/day, administered in one (studies 44289 TSR – 28-day treatment) or two doses in 
Sprague Dawley rats (studies 46232 TCR – 13-week treatment). 
In the 13-week GLP toxicity study in dogs (study IFB088-13W-DOGS), the administration of 
IFB-088 up to 12 mg/kg/day (i.e. 6 mg/kg BID) was well tolerated without any renal toxicity or 
other findings. 
Study
Regimen
Main findings
analyte
Day of 
admin.
sexe
Plasma 
Tmax
Cmax 
(ng/ml)
AUCt 
(ng/ml*h)
Female
T1: 30min
1.69
8.07
Male
T1: 30min
0.79
5.86
Female
T1: 30min
1.63
8.86
Male
T1: 10min
0.50
3.79
Female
T1: 3h
1.20
7.85
Male
T1: 7h
0.98
7.04
Female
T1: 9h
0.93
9.43
Male
T1: 7h
1.56
8.98
Female
T1: 30min
2.95
26.4
Male
T1: 30min
2.01
13.4
Female
T1: 30min
2.73
29.9
Male
T1: 10min
2.94
23.6
Female
T1: 7h
1.20
15.1
Male
T1: 3h
4.67
36.6
Female
T1: 9h
2.96
36.6
Male
T1: 9h
13.7
99.1
Female
T1: 30min
12.9
64.5
Male
T1: 30min
5.50
58.0
Female
T1: 30min
9.42
72.5
Male
T1: 3h
5.90
113
Female
T1: 30min
5.18
71.2
Male
T1: 3h
3.19
149
Female
T1: 9h
9.92
123
Male
T1: 13h
35.3
628
Female
T1: 30min
9.3
102.7
Male
T1: 30min
12.0
105.1
Female
T1: 30min
13.4
78.8
Male
T1: 30min
17.0
93.4
Female
T1: 8h
1.20
10.0
Male
T1: 3h
2.2
25.5
Female
T1: 30min
3.7
20.9
Male
T1: 8h
3.1
28.8
Female
T1: 3h
16.2
182.9
Male
T1: 3h
17.4
188.8
Female
T1: 3h
21.4
198.9
Male
T1: 3h
20.0
197.4
Female
T1: 8h
2.5
37.4
Male
T1: 8h
4.6
56.5
Female
T1: 6h
7.8
61.2
Male
T1: 12h
5.1
69.0
Female
T1: 3h
41.2
467.6
Male
T1: 3h
51.2
650.0
Female
T1: 30min
84.8
517.0
Male
T1: na
78.6
759.8
Female
T1: 8h
7.5
102.7
Male
T1: 8h
6.7
110.6
Female
T1: 30min
21.8
158.6
Male
T1: 12h
20.9
225.4
Major 
metabolite 
IFB-139
1
90
Repeated 
administration
13 weeks P.O.: 6 
mg/kg BID (6h 
between the 2 
treatments)
12 mg/kg/day
NOAEL
IFB-088
1
90
Major 
metabolite 
IFB-139
1
90
1
90
IFB088-13W-
DOGS 
13-week 
toxicology 
GLP study in 
Beagle Dogs
Repeated 
administration
13 weeks P.O.: 1.5 
mg/kg BID (6h 
between the 2 
treatments)
3 mg/kg/day
No adverse effect
IFB-088
1
90
Major 
metabolite 
IFB-139
1
90
Repeated 
administration
13 week P.O.: 3 
mg/kg BID (6h 
between the 2 
treatments)
6 mg/kg/day
No adverse effect
IFB-088
1
90
90
1
90
1
90
1
90
1
90
1
46232 TSR
13-week 
toxicology 
GLP study in 
Sprague 
Dawley Rats
IFB-088
Major 
metabolite 
IFB-139
Repeated 
administration
13 weeks P.O.: 1.5 
mg/kg BID (6h 
between the 2 
treatments)
3 mg/kg/day
Repeated 
administration
13 week P.O.: 3 
mg/kg BID (6h 
between the 2 
treatments)
6 mg/kg/day
Repeated 
administration
13 weeks P.O.: 6 
mg/kg BID (6h 
between the 2 
treatments)
12 mg/kg/day
NOAEL
At 6 mg/kg/day administered as 3 mg/kg BID for 13 weeks was 
considered as adverse due to: 
- 2 out of 10 males presented enlarged kidneys, with irregular 
colour and/or surface; these changes correlated with the 
presence of crystal nephropathy at microscopic examination.
- One female presented non-adverse, reversible, minimal bile 
duct hyperplasia.
There were no other remarkable, test item-related signs at 6 
mg/kg/day
12 mg/kg/day administered as 6 mg/kg BID for 13 weeks was 
considered as adverse due to: 
- crystal nephropathy in the kidneys was the main 
histopathological finding. This observation was adverse and not 
reversible after the 4-week treatment-free period. 
- In addition to deaths (males) and effects on body weight, the 
high-dose level of 12 mg/kg/day produced numerous other 
treatment-related findings, and it could be concluded that most 
of them were limited to this dose level. Most of the findings 
recorded at the high-dose were not reversible after a 4-week 
recovery period.
IFB-088
Major 
metabolite 
IFB-139
IFB-088
Major 
metabolite 
IFB-139


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The NOAEL in Beagle dogs increased and was established at 12 mg/kg administrated in two 
doses (6 mg/kg BID). 
After 13 weeks of IFB-088 treatment, the maximal exposures (AUCt) at the NOAEL in Beagle 
Dogs were 517.0 and 759.8 ng/ml.h with Cmax of 84.8 and 78.6 ng/ml in females and males 
respectively. At the NOAEL, IFB-139 the major metabolite has an AUCt of 158.6 and 225.4 
ng/ml.h with Cmax of 21.8 and 20.9 ng/ml in females and males respectively (IFB-139 is an 
inactive metabolite). 
 
 
Determination of the maximal tested dose in the Multiple Ascending Dose part of 
1.2.3.2.
the study 
This Phase 1 study was initially designed to support future clinical developments of IFB-088 in 
CMT and other degenerative pathologies, such as Multiple Sclerosis, Amyotrophic Lateral 
Sclerosis, Oculo-Pharyngeal Muscular Dystrophy and Retinitis Pigmentosa for which preclinical 
efficacy in animal models has been obtained. 
Based on the extrapolation presented in paragraph 1.2.2.3, the maximal daily exposure to cover 
all targeted therapeutic indications was estimated at 111.14 ng/ml.h (simulated AUC in human 
for the highest efficient dose in animals). According to the interspecies population 
pharmacokinetics model, the simulated AUC0-24 for a 60 mg daily dose (2x30 mg/day) in 
humans was 83.15 ng/ml.h. Pharmacokinetic results of the SAD show an AUC0-24h of 51.41 +/- 
20.45 ng/ml.h, which is less than half of the maximal daily exposure expected to cover all 
targeted therapeutic indications (111.14 ng/ml.h). As initial targeted exposures will not be met 
in this study, the company made the strategic decision to focus only on the treatment of Charcot-
Marie-Tooth disease, in which exposures required in animals for efficacy are lower. 
Based on the optimal doses to treat CMT in animal models (Table 2, paragraph 1.2.2.3), the 
targeted exposure for optimal efficacy in CMT patients will be in the range of 19.89 – 43.18 
ng/ml.h (targeted AUC0-inf), corresponding to a Cmax for 2 administrations per day between 2.5 
and 3.89 ng/ml (Table 7). 
Table 7: Estimated exposure for optimal efficacy in CMT patients 
Targeted 
therapeutic 
indication 
Animal model 
Optimal doses 
for efficacy in 
animals 
Extrapolated 
Cmax expected in 
humans 
Extrapolated 
AUCt expected 
in humans 
Charcot-Marie-
Tooth 1A 
PMP22 
transgenic rats 
2.29 mg/kg once 
a day 
3.89 ng/mL 
19.89 ng/ml.h(1) 
Charcot-Marie-
Tooth 1A 
MPZS63Del 
transgenic mice 
1 mg/kg twice a 
day 
2.5 ng/ml 
43 ng/ml.h(2) 
(1) Data from study report 15-035A 
(2) Data extrapolated from study report PSN 11-233, based on pharmacokinetics data of CD1 mice administered 
with single dose of IFB-088 10 mg/kg per os (Table 2, paragraph 1.2.2.3). At 10 mg/kg, AUCt was 215.9 ng/ml.h. 
Taking into account that IFB-088 AUCt is dose-proportional at these dose levels, estimated AUCt of 2x1mg/kg/day 
is 43 ng/ml.h (= 2 x 215.9/10). 
 


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Pharmacokinetics results of the single day of IFB-088 in healthy subjects (SAD) are quite 
similar to those observed in animal studies and population pharmacokinetics model based on 
preclinical data (rats and dogs) is considered satisfactory with a 30-40% margin of error to 
predict SAD results. Indeed, as observed in preclinical studies, IFB-088 pharmacokinetics is 
characterized by an important volume of distribution, suggesting that IFB-088 rapidly 
disappears from the blood compartment. Moreover, following two administrations of IFB-088 
separated by an interval of 12 hours, there is no accumulation of IFB-088 at T24h after the first 
daily administration. Concerning pharmacokinetics-dose linearity, increases in IFB-088 Cmax 
and AUC0-24h are dose-proportional between 20 and 60 mg daily. As expected, IFB-139 the 
inactive major metabolite of IFB-088 is present in a similar range as observed in preclinical 
studies. 
Based on results obtained in different CMT animal models, the exposure (AUC0-24h) for optimal 
efficacy is estimated between 19.89 and 43.18 ng/ml.h and Cmax for 2 administrations per day in 
the range of 2.5 to 3.89 ng/ml (Table 7). According to the pharmacokinetics results from the 
SAD in healthy volunteers, the three following doses of 15, 30 and 50 mg daily cover to the 
range of optimal efficacy (exposure between 12.82 and 42.62 ng/ml.h, Cmax between 1.20 and 
3.77 ng/ml). The escalating ratio is 2 between the low and middle doses and 1.66 between the 
middle and high doses. To conclude, the maximal ascending dose will be 50 mg daily (2 x 25 
mg) according to the preclinical population pharmacokinetics model and the preliminary 
pharmacokinetics results of the single day. 
Table 8: Predicted mean plasma Cmax and AUC(0-inf) in humans following 14-day dosing of IFB-
088 and associated safety coverage 
Daily 
dose 
(mg) 
Daily 
administered 
doses  
(n x mg) 
Escalating 
dose ratio 
Expected 
Human 
Cmax 
(ng/ml)(1) 
Expected 
Human 
AUC (0-inf) 
(ng.hr/ml)(1) 
Cmax safety 
coverage % 
of Cmax in 
dogs(2) 
AUC safety 
coverage 
% of AUC in 
dogs(2) 
15 
2 x 7.5 
- 
1.20 
12.82 
1.5% 
2.5% 
30 
2 x15 
2 
2.26 
25.57 
2.9% 
4.9% 
50 
2 x 25 
1.67 
3.77  
42.62 
4.9% 
8.2% 
Stopping criteria 
23.77 
111.14 
30.2% 
21.5% 
(1) Data are extrapolated from pharmacokinetics results of the SAD observed at a daily dose of 60mg (30mg BID), 
taking into account that IFB-088 Cmax and AUC are dose-proportional at these dose levels. 
(2) Safety coverage is calculated based on Cmax and AUCt at NOAEL for the sex with the lowest Cmax and the lowest 
AUCt 
Criteria for dose modifications or stopping dose escalation: 
The criteria to modify planned doses or stop dose escalation will be the same as the ones used 
for single ascending dose escalation, as NOAEL in Sprague Dawley rats is maintained and 
NOAEL in Beagle dogs increased following the results of the 13-week GLP toxicity study, i.e. 
- 
AUC > 111.14 ng/ml.h, and 
- 
Cmax > 23.77 ng/ml. 
 
 
Based on the SAD exposure in humans and on the additional toxicity studies performed in 
animals, the daily doses for the multiple ascending dose to be administered in Humans to cover 


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the envisioned therapeutic indications (Charcot-Marie-Tooth) and to ensure maximum safety 
are:  
- 
15 mg/day given as 2 administrations of 7.5 mg in the first cohort;  
- 
30 mg/day given as 2 administrations of 15 mg in the second cohort; 
- 
50 mg/day given as 2 administrations of 25 mg in the third cohort. 
 
 
Rationale for Study population 
1.2.4.
As is usual in first-in-man studies, the population to be included is healthy young males between 
18 and 40 years old (inclusive) at screening. The selection of healthy subjects is justified on the 
basis that PK, safety, and tolerability, can be investigated accurately in this population. 
In this population, the study can be performed under standardized conditions, reducing the 
influence of confounding factors. 
No medical benefit for the subjects can be expected beyond the thorough medical check-up that 
each subject will receive prior to treatment and at the end of the study. The potential risks 
associated with IFB-088 are not known, as this product has not yet been tested in humans.  
The study protocol is designed to ensure a careful observation and medical management in order 
to minimize any associated risk in this study. 
The participation of healthy subjects in this study is justified with regard to the expected benefit 
for the target population that will receive this therapy after registration of the compound. 
 
 
Summary of Risk Management 
1.3.
 
Cardiovascular Monitoring 
1.3.1.
Since IFB-088 is devoid of alpha-2 adrenergic activity, a potent reduction in blood pressure is 
not expected with IFB-088. In addition, even if in vitro, in a HERK study IFB-088 was 
classified as a potential moderate HERK channel inhibitor, IFB-088 at 1, 3 or 9 mg/kg/day (0.5, 
1.5, 4.5mg/kg/administration) had no effect on heart rate, systolic, diastolic and mean arterial 
blood pressure, ECG parameters or body temperature in conscious male beagle dogs and no 
treatment-related arrhythmias were observed at any of the dose-levels administered in dog (see 
Investigator Brochure section 4.1.3.2 and section 4.1.3.5). Nevertheless, as usual in a first in 
man study a particular attention will be focused on cardiovascular monitoring. Vital signs 
(systolic and diastolic blood pressure, heart rate) will be closely monitored at regular intervals 
post dosing, both in supine and standing position and ECG parameters will be controlled at 
regular intervals post-dosing. 
 
 
Drug-induced renal crystals 
1.3.2.
Preliminary toxicity studies pointed out renal findings after 10 or 14 days once a day 
administration from 10 mg/kg in dogs and rats. In particular, intratubular crystals were observed 


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at the upper dose tested. IFB-088 was localized in the crystals observed in each kidney from 
each treated animal whereas IFB-139 metabolite was distributed in the entire kidney tissue with 
the most intense signals localized in the crystals. 
In Beagle dogs, twice daily administration for 28 days was well tolerated up to 9mg/kg 
(NOAEL in this species) without any renal findings suggesting that when administered twice 
daily IFB-088 is better tolerated than when daily administered. 
A twice-daily administration is thus proposed from cohort 2 and an appropriate monitoring plan 
will be set up with a regular check of renal function parameters (creatinine, urea, estimated 
Glomerular Filtration Rate and urinary dosage of Beta2 microglobulin, proteins and creatinine), 
volume of diuresis and urinary parameters by dipstick (pH, hematuria). An increased excretion 
of beta2microglobulin in the urine is a sensitive indicator of proximal tubular dysfunction 
(Ostermann M., Joannidis M (2016). 
A minimal intake of at least 2L of water post dosing will be mandatory to ensure a sufficient 
hydration (250 mL with study drug, then 500 mL between dosing and T4H, 1000 mL between 
T4H and T12H and 500 ml between T12H and T24H). 
 
 
Liver monitoring  
1.3.3.
Hepatic enzymes are systematically recorded in phase 1 trials but, considering that at the highest 
dose tested in the 28-day GLP study in rats (9 mg/kg/day SID), an increase of liver enzymes was 
observed, and that there is a known important hepatic first pass effect for guanabenz, a strategy 
will be implemented according the FDA guidance (Drug-Induced Liver Injury: Premarketing 
Clinical Evaluation) to initiate close observation immediately upon detection and confirmation 
of early signals of possible impairment of liver function (See Section 3.4.3.1 and 8.10). 
 
 
 


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2. 
OBJECTIVES AND ENDPOINTS 
 
Primary objectives 
2.1.
End Points 
To 
investigate 
the 
safety 
and 
tolerability after single and multiple 
oral doses of IFB-088 in healthy 
volunteers  
- Adverse events 
- Laboratory parameters (haematology, chemistry, 
urinalysis)  
- 12-lead ECG parameters 
- Vital signs (supine and standing systolic and 
diastolic blood pressure, pulse rate, tympanic 
temperature) 
- Vigilance (Bond and Lader scale)  
 
Secondary objectives 
2.2.
End Points 
To investigate the pharmacokinetics 
after single and multiple oral doses 
of IFB-088 and its metabolite in 
healthy volunteers 
- Plasma 
- Peak plasma concentration (Cmax) 
- Time of peak plasma concentration (tmax)  
- Area under the plasma concentration-time curve 
from time-zero to last sample with measurable 
concentration 
(AUClast) 
and 
from 
time 
0 
extrapolated to infinity (AUC0-∞) 
- Terminal half-life (t½)  
- Apparent total body clearance (CL/F)  
- Urine 
- Maximum observed concentration (Cmax) 
- Time of occurrence of CmaxU (tmaxU) 
- Area under concentration-time curve from time-
zero to last sample with measurable concentration 
(AUClast) and from time 0 to infinity (AUC0-∞) 
- Renal clearance 
- Total amount excreted in urine (Ae) 
- Concentration at the end of a dosing interval before 
the next dose (Ctrough) 
 
Exploratory objectives 
2.3.
End Points 
To explore UPR related biomarkers 
- Blood samples 
 
 
 


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3. 
INVESTIGATIONAL PLAN 
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those specified in 
the Time and Events Table, are essential and required for study conduct. 
 
Study Design 
3.1.
This is a double blind, randomized, placebo-controlled combined SAD and MAD study. 
 
Overview SAD study design 
3.1.1.
This part of the study will be conducted according to a randomized, double blind, placebo 
controlled, single oral ascending dose design in 6 independent cohorts of 8 healthy male 
subjects. If a subject is withdrawn from this study part, the subject may be replaced as necessary 
with another subject assigned to the same treatment with respect to active and placebo doses at 
the discretion of the sponsor’s team in consultation with the investigator.  
Each potential subject will undergo: 
• 
A Screening visit prior to initiation of any study-specific procedures:  
o It can take place up to 21 days before the first dosing session, 
o Informed consent will be obtained prior to any procedure with an assessment of 
inclusion and exclusion criteria. 
• 
A Treatment Phase: 
o Subjects will be required to join the unit on the day prior to dosing (Day -1) and 
will be required to stay in the unit for up to 2 nights for the treatment period. 
Subjects will be dosed on Day 1. A continuous monitoring of adverse events, 
regular check of vital signs, ECG and diuresis will be set up. PK blood samples 
and urine samples will be taken for up to 32 h post-morning dose.  
o Vigilance will be assessed at regular intervals by Visual Analogic Scales (VAS) 
from pre-dose to discharge (Bond Lader).  
o Safety parameters particularly vital signs, in the opinion of the investigator, must 
have returned to baseline values prior to discharge. Duration of both subject stay 
and PK sampling may be subject to changes, depending on emerging safety and 
PK results. 
• 
A Follow-up visit: 
o Subjects will be required to return to the unit for a follow-up visit 7 to 14 days 
after dosing.  
Cohort features: 
• It is anticipated that 6 cohorts of 8 subjects will be studied.   
• In each cohort, 6 subjects will receive active treatment and 2 will receive placebo.  
 
IFB-088 dosing  
• The planned doses of IFB-088 are 2.5 mg, 5, 10, 20, 40 and 60 mg administered as oral 
capsule.  


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• The maximum daily predefined dose will be 60 mg. 
• The planned dosing schedule may be adjusted to allow administration of intermediate 
doses if dose-limiting toxicity becomes evident at any dose level or to obtain additional 
safety, tolerability, or PK data. 
• In the first group of each cohort, two (2) subjects will be dosed on Day 1 (one on active 
treatment and one on placebo). The 6 remaining subjects will be dosed by successive 
groups of 3 subjects, with an adequate period between groups to observe for any reaction 
and adverse events (at least 36 hours between last assessment of the subjects and dosing 
of the following). 
• In the first cohort (2.5 mg), dosing will be in the morning under fasting state (see Section 
6.6.2)  
• From the second cohort, the planned daily dose will be divided into 2 doses separated by 
an interval of 12 hours (1 dose in the morning fasting and 1 dose in the evening 2 hours 
before dinner) (See paragraph 1.2.2.1). 
 
• A dose escalation committee (DEC) comprised of members from the sponsor’s team and 
the investigator’s team, will be convened prior to the start of each subsequent dosing 
session to interpret the clinical safety, tolerability, laboratory, and PK exposure, and 
make a decision to proceed to the next higher dose. 
 
• Data gathered from previous cohort will be available prior to dosing the next cohort in 
order to carefully monitor each dose level. 
 
 
Overview MAD study design 
3.1.2.
This part of the study will be conducted according to a randomized, double-blind, placebo 
controlled, multiple oral ascending dose design in 3 independent cohorts of 8 healthy male 
subjects. 
Each potential subject will undergo: 
• 
A Screening visit prior to initiation of any study-specific procedures:  
o This can take place up to 21 days before the first dosing session, 
o Informed consent will be obtained prior to any procedure with an assessment of 
inclusion and exclusion criteria 
• 
A Treatment Phase: 
o Subjects will be required to join the unit on the day (Day -1) prior to the first dose 
and will be required to stay in the unit for 17 days for the treatment period. 
Subjects will be dosed from Day 1 to Day 14. A continuous monitoring of adverse 
events, regular check of vital signs, ECG and diuresis will be set up and serial PK 
blood and urine samples will be collected.  
o Vigilance will be assessed at regular intervals by Visual Analogic Scales (VAS) 
from pre-dose to discharge (Bond Lader).  
• 
A Follow-up visit: 


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o Subjects will be required to return to the unit for a follow-up visit 7 to 14 days 
after last dosing.  
 
Cohort features: 
• It is anticipated that 3 cohorts of 8 subjects each will be studied.   
• In each dosing session, 6 subjects will receive active treatment and 2 will receive 
placebo.  
 
IFB-088 dosing  
• The planned doses are 15 mg per day (2 x 7.5 mg at 12-hour interval) in cohort 1, 30 mg 
per day (2 x 15 mg at 12-hour interval) in cohort 2 and 50 mg per day (2 x 25 mg at 12-
hour interval) in cohort 3.  
• The maximum predefined dose will be 60 mg daily (30 mg twice). 
• The planned dosing schedule may be adjusted to allow administration of intermediate 
doses if dose-limiting toxicity becomes evident at any dose level or to obtain additional 
safety, tolerability, PK data. 
• In the first group of each cohort, two (2) subjects will be dosed on Day 1 (one on active 
treatment and one on placebo). The 6 remaining subjects will be dosed by successive 
groups of maximum 3 subjects, with an adequate period between dosing to observe for 
any reaction and adverse events (i.e. at least 36 hours between last assessment of the 
subjects and dosing of the following, corresponding to at least 5 fold the half-life of the 
drug according to PK results obtained in the SAD part). This period could be modified 
on the basis of safety and PK results. 
• A dose escalation committee (DEC) comprised of members from the sponsor’s team and 
the investigator’s team, will be convened prior to the start of each subsequent dosing 
session to interpret the clinical safety, tolerability, laboratory, and PK exposure, and 
make a decision to proceed to the next higher dose. 
 
Data will be available prior to dosing the next cohort in order to carefully monitor each dose 
level. 
 
 
Study endpoints 
3.2.
 
Safety endpoints 
3.2.1.
Safety and tolerability parameters evaluated during this study are: 
• Clinical safety: adverse event information, prior and concomitant medications, physical 
examination (including body weight), vital signs, 12-lead ECGs, vigilance (Bond and 
Lader VAS) 
• Laboratory safety assessments: standard hematology, biochemistry analyses, urinalysis, 
serology, alcohol breath test, urine drug screen. 


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Pharmacokinetic end points  
3.2.2.
The following parameters for IFB-088 and IFB-139 will be derived, where appropriate: 
 
Plasma:  
• Maximum observed plasma concentration (Cmax), 
• Time of occurrence of Cmax (tmax), 
• Terminal elimination rate constant (Kel), 
• Terminal half-life (t1/2.), 
• Area under plasma concentration-time curve from hour 0 to last sample with measurable 
plasma concentrations (AUClast), 
• Area under plasma concentration-time curve from hour 0 to infinity (AUC0-∞), 
• Apparent volume of distribution (Vd/F), 
• Apparent total body clearance (CL/F), 
• Last measurable plasma concentration (Clast), 
• Time to reach last measurable plasma concentration (Tlast), 
• Concentration at the end of a dosing interval before the next dose administration 
(Ctrough), 
Urine: 
• Maximum observed urine concentration (CmaxU), 
• Time of occurrence of Cmax (tmaxU), 
• Area under urine concentration-time curve from hour 0 to last sample with measurable 
urine concentrations (AUClast), 
• Area under urine concentration-time curve from hour 0 to infinity (AUC0-∞), 
• Renal clearance (CLr), 
• Total amount excreted in urine (Ae), 
• Percent of drug recovered in urine (Ae %dose). 
Additional parameters could be calculated if deemed necessary. 
 
 
Biomarker assessment (exploratory)  
3.2.3.
There is no biological UPR biomarker identified in fluids in healthy subjects. 
With the subject’s consent, blood samples will be collected during this SAD part of the study 
and may be used as healthy controls for the purpose of research of UPR biomarkers in patients’ 
populations. 
 
 
Discussion of the Design 
3.3.
The selected designs for the 2 parts of this study are as follows: 
The SAD part consists of 6 cohorts of 8 healthy young male subjects, each receiving a single 
oral dose of IFB-088 or placebo (6 verum and 2 placebo) administered daily in the morning 
(cohort 1) or divided into 2 doses, 12h apart (cohort 2 to 6).  


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In each cohort, 2 subjects (1 verum and 1 placebo) are to be dosed first; if the safety and 
tolerability results are acceptable after at least 36 hours (48 hours for cohort 1), two groups of 3 
subjects will be dosed at least 36 hours apart (48 hours for cohort 1). 
The MAD part consists of 3 cohorts of 8 healthy young male subjects, each receiving an oral 
dose of IFB-088 or placebo (6 verum and 2 placebo) daily for 14 days.  
In each cohort, 2 subjects (1 verum and 1 placebo) are to be dosed first and after an adequate 
period of time to observe for any reaction or adverse event (at least 36h), and if the safety and 
tolerability results are acceptable, a maximum of 3 subjects will be dosed then a maximum of 3 
subjects after at least 24 hours. The 36-hour interval between the administration for the first 2 
subjects in a cohort and the remaining subjects have been specified according to the available 
safety and PK data obtained in the SAD part of the study.  
 
These designs are well-established for first-in-man studies and appropriate to assess the 
preliminary safety and tolerability of new drug candidate. 
For the SAD part, the sample size of 8 subjects per dose level (6 verum and 2 placebo) is 
deemed adequate for this type of study (Buoen C et al 2003). 
For the MAD part, there will be 8 healthy young subjects per dose level (6 verum and 2 
placebo). This number is deemed adequate for the objectives of this study part (Buoen C et al 
2003). 
 
During this study, safety parameters will be closely followed by regular measurements, to 
enable a detection of any changes as early as possible and to be able to stop dosing before 
occurrence of major deleterious effect.  
The follow-up observation for the end of study visit will take into account the results of 
previously available PK parameters (especially for the potential occurrence of delayed AEs) and 
could be changed if necessary for safety reasons. 
The use of placebo as a control is necessary to provide reliable scientific evidence of safety and 
tolerability and to ensure a reliable evaluation of the tested drug. 
A double-blind design is used in conjunction with a placebo control to prevent a potential bias 
generated by the knowledge of the administered test drug. 
The sequential ascending dose design will be used for a safe determination of the maximal 
exposure in human. 
This study design is in line with the current regulatory guidance and appropriate to reach the 
objectives of the study. (Guideline on strategies to identify and mitigate risks for first-in-human 
and early clinical trials with investigational medicinal products - EMEA/CHMP/SWP/28367/07 
Rev. 1 20 July 2017). 
 
 
Dose Adjustment/Stopping Criteria 
3.4.
In the SAD part, a starting dose of 2.5 mg of IFB-088 administered as oral capsule was judged 
to be safe for a first-in-human administration. Escalation to the next higher dose and any dose 


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adjustments of the next dose levels will be based on safety and tolerability results and available 
PK data of the previously administered dose group. 
In the tentative dosing scheduled, there will be a 2-fold increase from the first dose level (2.5 
mg) to the second dose level. The dose levels of the following groups will be increased by 2-
fold from the previous dose level, until the dose level of 40 mg, and then 1.5-fold between the 2 
last dose levels. The planned dosing schedule may be adjusted to allow administration of 
intermediate doses. 
In the MAD part, the planned doses are 15 mg per day (2 x 7.5 mg at 12-hour interval) in cohort 
1, 30 mg per day (2 x 15 mg at 12-hour interval) in cohort 2 and 50 mg per day (2 x 25 mg at 
12-hour interval) in cohort 3. 
The decision to proceed to the next dose level of IFB-088, will be made by the Dose Escalation 
Committee based on safety, tolerability and preliminary PK data obtained at the prior dose level.  
Dose escalation will stop at doses, which are predicted on the basis of ongoing PK projections, 
to correspond to concentrations greater than the PK stopping limits (Section 3.4.2).  
 
 
Data Package Requirements for Dose Escalation Committee Meetings 
3.4.1.
Dataset from a dosing session including IFB-088 plasma concentrations from the previous 
dose(s)/cohort(s) and safety data including AEs, vital signs, ECG (12-lead) and laboratory 
parameters up to at least 32 hours post last dose will be available prior to dosing the next group. 
The DEC, comprised of the Investigator, the Pharmacologist of the clinical center, the 
statistician, a representative of the Pharmacovigilance platform, and a Sponsor’s representative, 
will be convened prior to the start of each subsequent dosing session to interpret the clinical 
safety, tolerability, laboratory data and PK exposure, and make a decision to proceed to the next 
higher dose. Additional advisors could be invited as required. 
A DEC charter will be provided to the members before the start of the study. 
The DEC may unblind the treatment assignment for any subject with an SAE or for any 
treatment group after reasonable justification (e.g. subjects experiencing grade 3 events or 
findings) (Sibille et al, 2010).  
The DEC will make a recommendation to proceed to the next higher dose as per protocol, or to 
modify the next dose or to stop the trial. 
At the end of each meeting, the DEC will document in writing the decision that has been taken. 
 
 
Dose Adjustment/Stopping Pharmacokinetic Criteria  
3.4.2.
As pharmacokinetic is not linear in rats with significant differences between males and females, 
and is linear without sex differences in dogs, dog rather than rat data have been used to modelize 
human pharmacokinetics. 
Dosing will be stopped if the observed AUC(0-inf), at a given dose level in any subject, is 
> 111.14 ng/ml.h-1 (simulated AUC for the highest efficient dose in Human, lower than the half 
AUC in dogs at the NOAEL) or if the observed Cmax is > 23.77 ng/ml which corresponds to the 
half of the Cmax at the NOAEL in dog. 


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If the predicted upper limit of 95% CI of AUC(0-inf) at the next dose level is > 111.14 ng/ml.h-1 
or of Cmax is > 23.77 ng/ml, the next dose level may be decreased, or a decision could be made 
not to dose further.   
 
 
Stopping Safety Criteria  
3.4.3.
The dose should not be escalated further if one of the circumstances listed below occurs in 
subjects within the same cohort, unless it is obvious that the occurrence is not related to the 
administration of the treatment: 
• 
Occurrence of a Serious Adverse Event considered at least possibly related to the IMP 
administration in one subject (See Section 8.3). In that case, study has to be immediately 
interrupted.  
• 
Possibly drug related severe AE in 2 subjects in the same cohort, independent of within or 
not within the same system-organ-class (EMA Guidelines on strategies to identify and 
mitigate risks for first-in-human and early clinical trials with investigational medicinal 
products) 
• 
Clinically significant drug-related laboratory abnormalities of the same character in 2 or 
more subjects e.g. 
- 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST)> 5 times the 
upper limit of normal (5 ULN) (Grade 3), 
- 
Creatinine > 120 µmol/L (1.2 ULN) (Grade 1) 
(FDA’s Guidance on Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials; Sibille et al 2010). 
Moreover, the occurrence of moderate adverse reactions within the same system-organ-class in 
more than one subject, and/or clinically significant changes from baseline measurements will be 
considered as a safety signal and will have to lead to increase caution and a closer assessment of 
safety parameters in the other subjects. In such a case, data from all subjects would be to be 
reviewed. 
 
 
Liver Chemistry Stopping Criteria 
3.4.3.1.
Liver chemistry threshold stopping criteria have been designed to ensure subject safety and to 
evaluate liver event etiology (in alignment with the FDA premarketing clinical liver safety 
guidance).   
Study treatment will be stopped for a subject if the following liver chemistry stopping criteria 
is met:  
• 
ALT or AST ≥ 3xULN 
Refer to Section 8.10, Liver Chemistry Follow-up Procedures, for details of the required 
assessments if a subject meets the above criteria. 
 


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Triglycerides Stopping Criteria 
3.4.3.2.
Several subjects experienced hypertriglyceridemia during the SAD part of the study. All cases 
were below the threshold of 5.6 mmol/L (i.e. 5 g/L), above which hypertriglyceridemia is 
considered clinically significant (European Atherosclerosis Society, European Society of 
Cardiology, French Society of Endocrinology) and no correlation or possible dose relationship 
was established. Moreover, some subjects with hypertriglyceridemia were in the placebo groups. 
Nevertheless, a stopping criterion for triglycerides has been added in the MAD part of the study:  
Study treatment will be stopped for a subject if the following criterion is met:  
• 
Serum triglycerides ≥ 5.6 mmol/L and the subject is receiving IFB-088 
Study treatment will be stopped for the whole cohort and the dose will not be escalated, if 
the following criterion is met:  
• 
Serum triglycerides ≥ 5.6 mmol/L in 2 subjects receiving IFB-088. 
Next cohort could be administered a lower dose intermediate between the previous cohort 
and the present cohort. 
 
 
Renal disorders  
3.4.3.3.
The dose should not be escalated further if one of the circumstances listed below occurs in 2 
or more subjects within the same cohort: 
• 
Creatinine > 120 µmol/L (1.2 ULN) (Grade 1)  
• 
Or a change from baseline ≥30µmol/L within 24 h 
• 
Or a change from baseline ≥ 50% within one week  
(KDIGO definition Ostermann and Joannidis, 2016) 
• 
Hematuria > 2+, verified by cytologic exam, on 2 samples and considered at least possibly 
related to the IMP 
• 
Urinary ratio Beta 2 microglobulin/ creatinine ≥ 2N 
One subject that will meet one of these criteria above will be withdrawn from the study. 
 
 
QTc Withdrawal Criteria 
3.4.3.4.
A subject that meets the criteria below will be withdrawn from the study. The QT correction 
formula used to determine discontinuation should be the same throughout the study. 
• 
QTcB and QTcF > 500 msec, OR 
• 
Change from baseline: QTc >60 msec 
Withdrawal decisions are to be based on an average QTc value of triplicate ECGs. If an ECG 
demonstrates a prolonged QT interval, obtain 2 more ECGs over a brief period, and then use the 
averaged QTc values of the 3 ECGs to determine whether the subject should be discontinued 
from the study. 


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The dose should not be escalated further if 2 or more subjects present a prolonged QT 
interval as defined above. 
 
 
Vital Sign Withdrawal Criteria  
3.4.3.5.
The dose should not be escalated further if 2 or more subjects, within a dose-level, receiving 
IFB-088 experience a grade 3 vital signs (heart rate and/or blood pressure) adverse event that 
are deemed possible or probably related to study drug by the investigator. 
The grading for adverse events is based on FDA’s Guidance on Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials: 
 
Vital Signs* 
Grade 3 
Tachycardia (beats per minute) 
> 130 
Bradycardia -  beats per minute** 
< 45 
Hypertension (systolic) - mm Hg 
> 155 
Hypertension (diastolic) – mm Hg 
> 100 
Hypotension (systolic) – mm Hg 
< 80 
*Assuming supine position, at least 5 min at rest conditions, not sleeping subjects, measurements on the 
same arm and several concordant results 
**When resting heart rate is between 60-100 beats per minutes. Use clinical judgment when 
characterizing bradycardia among some healthy subject populations, for example, conditioned athletes. 
 
Stopping rules for an individual subject, for the dose escalation and within a cohort are summarized in 
Appendix 2. 
 


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Flow-Chart: Time and events  
3.5.
 
SAD part Cohort 1 
3.5.1.
 
Follow-up
Day 7 to Day 
14
Pre-dose
0 h
0.16h 0.33h 0.5 h
0,75h
1 h
1,5h
2 h
2,5h
3h
4h
5h
6h
8h
12h
24h
32h
(7 to 14 days 
post-last 
dose)
Informed Consent
X
Demographics
X
Medical / drug and alcohol 
history
X
Psychological interview
X
Full Physical Exam
X
X
X
HIV, Hepatitis B & C 
serologies
X
Vital signs (SBP, DBP, HR)1
X
X
X2
X
X
X
X
X
X
X
X
X
X
X
Tympanic temperature
X
X
X
X
X
X
X
X
Urine Drug abuse & Breath 
Alcohol
X
X
Hematology/Coagulation/Bio
chemistry
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
Eligibility criteria
X
X
Admission to Unit
X
Brief Physical Exam
X
12-lead ECG
X
X
X3
X
X
X
X
X
X
X
X
Randomization
X
Study treatment dosing4
X
Vigilance assessment
X
X
X
X
Plasma PK Sampling
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood sampling for 
exploratory biomarkers
X
X
X
Urine PK Sampling5
X
Adverse Event Review
X
X
Concomitant Medication 
Review
X
X
Discharge
X
1         SBP, DBP and HR in supine and standing position
2         SBP, DBP and HR in triplicate with an interval of 10-30 minutes between each measurement
3         ECG in triplicate with an interval of 10-30 minutes between each measurement
4         In the first cohort one single dose fasting in the morning
5         Urine sampling for PK of IFB-088 and metabolites: pre-dose and 0-4, 4-8, 8-16, 16-32
Procedures
Screening 
(D-21 to 
Day -2)
Day -1
Day 1
Day 2
Study days 


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SAD part: from Cohort 2 
3.5.2.
 
Follow-up
Day 7 to Day 
14
Pre-dose
0 h
0,33h 0,5h
0.66h
1 h
1,5h
2 h
3h
4h
5h
6h
8h
12h
12,25h 12,5 h
13h
14h
16h
18h
24h
32h
(7 to 14 days 
post-last dose)
Informed Consent
X
Demographics
X
Medical / drug and alcohol history
X
Psychological interview
X
Full Physical Exam
X
X
X
HIV, Hepatitis B & C serologies
X
Vital signs (SBP, DBP, HR)1
X
X
X2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Tympanic temperature
X
X
X
X
X
X
X
X
Urine Drug abuse & Breath Alcohol
X
X
Hematology/Coagulation/Biochemistry
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
Eligibility criteria
X
X
Admission to Unit
X
Brief Physical Exam
X
12-lead ECG
X
X
X3
X
X
X
X
X
X
X
X
Randomization
X
Study treatment dosing4
X
X6
Vigilance assessment
X
X
X
X
Plasma PK Sampling
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood sampling for exploratory 
biomarkers
X
X
X
Urine PK Sampling5
X
Adverse Event Review
X
X
Concomitant Medication Review
X
X
Discharge
X
1         SBP, DBP and HR in supine and standing position
2         SBP, DBP and HR in triplicate with an interval of 10-30 minutes between each measurement
3         ECG in triplicate with an interval of 10-30 minutes between each measurement
4       From the cohort 2 the total dose is separaeted in two intakes with an interval of 12 hours
5         Urine sampling for PK of IFB-088 and metabolites: pre-dose and 0-4, 4-8, 8-12, 12-24 and 24-32
6        Evening dosing after PK sampling
Procedures
Screening 
(D-21 to 
Day -2)
Day -1
Study days 
Day 1
Day 2


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MAD part 
3.5.3.
  
Screening
(up to 21 days 
prior to Day 1)
Informed Consent
X
Demographics
X
Medical/drug &Alcohol history
X
Clinical psychological evaluation and 
MINI
X
Full Physical Exam
X
X
X
X
X
X
X
HIV, Hepatitis B, Hepatitis C serologies
X
Vital signs (SBP, DBP, HR)1
X
X
X2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Tympanic temperature3
X
X
X
X
X
X
X
X
X
X
X
X
Urine Drug abuse&Breath Alcohol
X
X
Hematology/Coagulation/ Biochemistry
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
Eligibility criteria
X
X
Admission to Unit
X
Brief Physical Exam
X
X
X
X
X
12-lead ECG
X
X
X4
X
X
X
X
X
X
Randomization
X
Study treatment dosing5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vigilance (VAS)10
X
X
Plasma PK Sampling
X6
X7
X8
X6
X7
X7
Urine PK Sampling
X9
X
X9
X9
X9
X9
Adverse Event Review
X
X
Concomitant Medication Review
X
X
Discharge
X
Procedures
Day -1
Day 1
Day 2
Day 3
Day 15 Day 16 Day 17
Follow up 7 to 
14 days post 
last dose
Day 11 Day 12 Day 13 Day 14
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 4
1         SBP, DBP and HR in supine and standing position, Day 2 : 24h post first dose, from Day 3 to Day 14 : every morning pre dose , from Day 15 to Day 17 : in the morning 
2         Pre dose : SBP, DBP and HR in triplicate with an interval of 10-30 minutes between each measurement and then 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 12h post first dose
3      On Day -1; on Day 1 and Day 14: pre dose, T1.5h and T12h post first dose; on Day 2, Day 4, Day 6, Day 8, Day 10 and Day 12 every morning pre dose; on Day 17 before discharge; FU
4         Pre dose: ECG in triplicate with an interval of 10-30 minutes between each measurement then 1h, 2h, 4h 8h and 12h after first dose
5         Dosing twice daily, two intakes being seperated by a 12-hour interval
10       Assessment of vigilance: Day 1 and Day 14: pre dose, 1.5h and 12h post morning dose
6         Plasma sampling: Day 1 and Day 14: pre dose, then 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 10h, 12h (just before evening dose), 13h and 14h post morning dose.  Reference time is the time of the morning dose
7         Plasma sampling: Day 2: 17h, 19h, 21h and 24h post Day 1 first dose, and just before the morning administration; Day 15 : 17h, 19h, 21h, 24h, 30h, 36h and 42h; Day 16: 48h and 60h post Day 14 morning dose
8      Plasma sampling: Day 7 pre dose, then 1h and 2h post morning dose
9         Urine sampling for PK of IFB-088 and metabolites: Day 1 and Day 14: pre-dose and 0-4h, 4-12h, 12-24h post morning dose; Day 6: pre dose, 0-4h, 4-12h; Day15: 24-36h, Day 16: 36-48h post D14 morning dose


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4. 
STUDY POPULATION 
 
Number of Subjects 
4.1.
A sufficient number of subjects will be enrolled so that 8 subjects will complete dosing and 
critical assessments for each of the cohorts. Six cohorts are planned in the SAD part (48 
subjects) and 3 cohorts in the MAD part (24 subjects). 
If a subject is withdrawn from the study, the subject may be replaced as necessary with 
another subject assigned to the same treatment with respect to active and placebo doses at 
the discretion of the sponsor’s team in consultation with the investigator. 
Subjects will be recruited from the clinical unit’s database and via advertisements through 
mailing lists or announcement. The advertisement will be submitted to the Ethics 
Committee. 
Inclusion of the same subjects in the 2 successive parts of the study (SAD then MAD) is 
possible, provided that the subjects have not met any discontinuation criteria during the 
first part, that they are not in the exclusion period (i.e. one month for SAD) and that they do 
not exceed the earnings for the last 12 months (EMA Guidelines on strategies to identify 
and mitigate risks for first-in-human and early clinical trials with investigational medicinal 
products Paragraph 8.2.5). 
 
 
Eligibility Criteria 
4.2.
 
Inclusion Criteria 
4.2.1.
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply: 
1. Healthy male 18 to 40 years of age, inclusive, Caucasian. 
2. Healthy as determined by a responsible and experienced physician, based on a medical 
evaluation including medical history, physical examination, laboratory tests, vital signs 
and ECG. A subject with a clinically significant abnormality or laboratory parameters 
significantly outside the reference range for the population being studied may be 
included only if according to the investigator’s opinion, the finding is unlikely to 
introduce additional risk factors and will not interfere with the study procedures. 
3. AST, ALT, alkaline phosphatase and bilirubin ≤ 1.5xULN (isolated bilirubin 
>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). 
4. ECG (12 leads) normal (120<PR<200 ms; QRS<120ms; QTcF<450ms) and/or without 
clinically relevant impairments as judged by investigator. 
5. Non-smoker, or user of tobacco- or nicotine-containing products ≤ 5/day.  
6. Negative screen for alcohol and drugs of abuse at screening and admission. 
7. No history of psychiatric disorders assessed by a clinical psychological evaluation and 
the Mini International Neuropsychiatric Interview (MINI). 


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8. Body mass index (BMI) between 19 and 27 kg/m2 inclusive where: 
BMI = 
weight in kg 
(height in meters)2 
9. Subject with female partners of child-bearing potential must agree to use one of the 
contraception methods listed in Section 6.6.1 (Contraception requirements). This 
criterion must be followed from the time of the first dose of study medication until the 
follow up visit (for female partners) and with an additional period of 90 days (for 
subjects themselves). 
10. Willing and able to understand and sign an approved Informed Consent Form. 
11. Able to understand the protocol and to come to the visits. 
12. Who is, in the judgement of the investigator likely to be compliant during the study. 
13. Subject registered in the VRB file (volontaires se prêtant à des recherches impliquant la 
personne humaine). 
14. Covered by Health Insurance System and / or in compliance with the recommendations 
of National Law in force relating to biomedical research. 
 
 
Non-selection and non-inclusion Criteria 
4.2.2.
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply: 
1. History of asthma, anaphylaxis or anaphylactoid reactions, severe allergic responses. 
2. History of relevant atopy or drug hypersensitivity. 
3. Known allergy to any component of IFB-088 oral capsule or its placebo (HPMC or 
cellulose microcrystalline). 
4. History of major medical, psychiatric illness or surgery which, in the judgment of the 
investigator, puts them ‘at risk’ or is likely to modify their handling of the study drug. 
5. Acute or chronic systemic disease or disorder (respiratory, gastrointestinal, renal, 
hepatic, 
hematological, 
lymphatic, 
neurological, 
cardiovascular, 
psychiatric, 
musculoskeletal, genitourinary, immunological, dermatological, endocrine).  
6. Impaired renal function defined by a creatinine clearance < 90 mL/min calculated using 
the Cockcroft-Gault equation (FDA Guidance for Industry: Pharmacokinetics in 
patients with Impaired Renal Function, March 2010). 
7. History of nephritic colic and/or renal calculi. 
8. History of drug abuse and/or regular use of tobacco- or nicotine-containing products > 
5/day within three months of the study.  
9. History of alcohol consumption exceeding, (on average 21 drinks/week for men) within 
6 months of the first dose of study medication. 


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10. Drinking excessive amounts of tea, coffee, chocolate and/or beverage containing 
caffeine (> 4 cups / day). 
11. Vital signs with a clinically significant abnormality at screening. 
12. ECG with a clinically significant abnormality at screening. 
13. Laboratory test values outside the clinically acceptable ‘normal range’ for healthy 
volunteers at screening. 
14. Positive HIV, Hepatitis B or Hepatitis C at screening. 
15. Positive urine drug test or positive breath alcohol test at screening or at admission to the 
clinical unit. 
16. Any medication (including St John’s Wort) within 14 days before administration, or 
within 5 times the elimination half-life of that drug, whichever is the longest (except 
paracetamol). 
17. Treatment with an investigational drug within 30 days or 5 half-lives (whichever is 
longer) prior to dosing. 
18. Unable to refrain from consumption of grapefruit and grapefruit juice within 7 days 
prior to the first dose of study medication. 
19. Unwillingness to abstain from sexual intercourse with pregnant or lactating women or 
to use a condom and spermicide and another form of contraception (e.g., IUD, birth 
control pills taken by female partner, diaphragm with spermicide) if engaging in sexual 
intercourse with a woman who could become pregnant until discharge from the study 
and during 90 additional days. 
20. Subjects unlikely to co-operate in the study, and/or poor compliance anticipated by the 
investigator. 
21. Subject being in the exclusion period of a previous trial. 
22. Subject having exceeded the earnings for the last 12 months, including the indemnities 
for the present study. 
23. Subject who could not be contacted in case of emergency. 
24. Subject refusing to give written informed consent. 
25. Subject who has received blood or plasma derivatives in the year preceding the study. 
26. Subject who has given blood within the past 3 months or have planned to give blood or 
sperm within the 90 days following the study. 
27. Subject who has forfeited their freedom by administrative or legal award, or who is 
under guardianship or under limited judicial protection. 
 
 
Screen and Baseline Failures 
4.3.
Data for screen and baseline failures will be collected in source documentation at the site. 
These data will be filled in the eCRF but will not be fully exported in the clinical database. 


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Only the following data will be exported and transmitted to the sponsor: reason of 
withdrawal, acknowledgement of consent obtainment and inclusion / non-selection / non-
inclusion criteria. 
5. 
STUDY TREATMENT  
 
Blinding and emergency code-break procedure 
5.1.
This will be a double-blind study. 
One copy of the randomization list will be provided to the unblinded pharmacist for preparation 
of the treatment. 
One set of the sealed code break envelopes will be provided to the investigational site, one 
for the DEC if needed, one set to the Pharmacy and one to Stragen Services, the CRO in 
charge of SAE processing. 
The DEC will be authorized to un-blind for subjects experiencing grade 3 events or 
findings to help the dose escalation process (Sibille et al 2010). 
 
The investigator or treating physician may unblind a subject’s treatment assignment only in 
the case of an emergency, when knowledge of the study treatment is essential for the 
appropriate clinical management or welfare of the subject.  
Whenever possible, the investigator will first discuss options with the sponsor before 
unblinding the subject’s treatment assignment. If this is impractical, the investigator must 
notify the sponsor as soon as possible. 
The documentation must include the name of the individual breaking the blind, the date on 
which the blind was broken, and a description of the event that led to the unblinding. The 
investigator must also indicate in source documents and in the CRF that the blind was 
broken and provide the date, time, and reason for breaking the blind.  
 
 
Investigational Medicinal products description (active and placebo 
5.2.
product)  
The active investigational product IFB-088 is formulated as an oral capsule dosage form. 
During the clinical study, the Investigational Medicinal Product (IMP) will be 
manufactured as unit doses ranging from a low strength of 2.5 mg dose to a high strength 
30 mg dose.  
The Placebo for IFB-088 Capsule will be manufactured as unit doses ranging from 2.5 mg 
fill weight to 30 mg fill weight with a placebo excipient i.e. Cellulose microcrystalline. The 
capsule used for the placebo formulation will thus be identical to that used for the active 
formulation. 
 
The composition of the 2.5 mg to 30 mg anticipated capsule strength and matching placebo 
are presented in Table 9.  
 


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Table 9: Composition of the 2.5 mg to 30 mg IFB-088 capsule strength and matching placebo 
Product name 
Pharmaceutical 
Form 
Unit dose 
strength 
Mode of 
administration 
Dosing 
instructions 
IFB-088 oral 
capsule  
Size 5 white 
opaque capsules 
2.5 mg to 30 mg 
Oral 
Study medication 
will be 
administered by 
the study 
personnel during 
each dosing day 
with 250 ml of 
water at room 
temperature 
Placebo oral 
capsule 
Size 5 white 
opaque capsules 
2.5 mg to 30 mg 
Oral 
 
 
Manufacturing, Packaging and Labeling 
5.3.
 
Manufacturing of Study Drug at the Site 
5.3.1.
The IMPs (IFB-088 oral capsules and matching placebo capsules) will be manufactured by 
the Pôle Pharmacie, Assistance Publique-Hôpitaux de Marseille, which has the 
authorization for experimental drug preparation.  
 
 
Packaging and Labeling 
5.3.2.
The IMPs will be packed and labeled according to GMP for medicinal products and all 
applicable regulatory requirements at the Pôle Pharmacie, Assistance Publique-Hôpitaux de 
Marseille. The IMPs will be packed into 50 mL white high-density polyethylene (HDPE) 
bottle with HDPE screw caps. Bottle filling depend on the cohort of the study. The number 
of capsules per bottle may vary depending on the dose and the phase of the clinical study.  
The trial medication will be labelled according to the regulations set in Annex 13 to the 
Current Edition of the GMP Guideline.  
Packaging of all the investigational products will allow blinded administration. 
 
 
Randomization, storage, dispensation and accountability  
5.4.
 
Randomization  
5.4.1.
Randomization lists will be generated by Amatsi prior to the start of the study, using the 
website randomization.com, and validated by the QC team. A randomisation list will be 
generated for each part of the study (SAD, MAD), based on a 2-block size design by 
cohort. The first blocks will contain two units with a ratio of 1:1, the second block will 
contain six units, 1 placebo and 5 verum. 


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Dispensing 
5.4.2.
The study drugs will be dispensed to the investigating site by the pharmacist of the clinical 
site after regular prescription by the investigator or delegated medical physician and 
administered under investigator/medical supervision. Only subjects enrolled in the study 
may receive study treatment. 
 
 
Storage 
5.4.3.
Study drug will be stored in a locked area, accessible only to appropriate study personnel in 
the pharmacy in accordance with the storage conditions defined on the IMP labels. Storage 
temperature will be followed by an automated reporting system.  
The pharmacist on study site will be responsible for the correct storage and handling of the 
IMPs. 
 
 
Study Drug Accountability 
5.4.4.
An accurate and current accounting of the dispensing and return of study drug for each 
subject will be maintained on an on-going basis by the Pharmacy. 
The responsible person(s) in the Pharmacy will document the amount of study treatment 
produced and the amount dispensed to subjects.  
All unused IMPs must be returned in the original containers. Non-used, returned study drug 
and empty IMP containers may be destroyed after the Pharmacist and the monitor have 
performed accountability and the Sponsor has confirmed in writing that destruction can be 
done.  
Each time a dose is dispensed to a subject, the following information should be recorded: 
the protocol and cohort, the subject's study number, the daily dose prescribed, the number 
of capsules dispensed, the batch number, and the signature of the pharmacist dispensing the 
drugs.  
As the monitor of the study must remain blinded of study treatment, a final drug 
accountability review and reconciliation will be completed at the completion or termination 
of the study, and any discrepancies must be investigated and their resolution documented. 
 
 
Assessment of Compliance 
5.4.5.
All IMP doses will be administered in the clinical unit under the direct supervision of the 
Investigator or his designee. 
After administration of IMP, a hand check and a mouth check will be performed to verify 
that the subject has swallowed the dose. 
Drug administration information will be recorded in the source documents and in the drug 
accountability form. 


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Treatment of Study Treatment Overdose 
5.5.
An overdose is defined as any dose of IFB-088 greater than that specified in the 
randomization code for that subject.  
In such a case, the investigator will use symptomatic treatment to treat any overdose, 
depending on the signs and symptoms. 
 
 
Concomitant Medications and Non-Drug Therapies 
5.6.
 
Permitted Medications 
5.6.1.
Occasional use of paracetamol at doses of ≤ 2 grams/day will be permitted at the principal 
investigator’s discretion. Other concomitant medication may be considered on a case-by-
case basis by the investigator and the sponsor, and use should be restricted to 4 hours after 
dosing if possible. 
All concomitant medications taken during the study will be recorded in the CRF with drug 
name, dates of administration, the dosage and the reason of the prescription.  
 
 
Prohibited Medications and Non-Drug Therapies 
5.6.2.
Subjects must abstain from taking prescription or non-prescription drugs (including 
vitamins and dietary or herbal supplements), within 14 days or 5 half-lives (whichever is 
longer) prior to the first dose of study medication until completion of the follow-up visit, 
unless in the opinion of the Investigator and sponsor the medication will not interfere with 
the study. 
 
6. 
STUDY ASSESSMENTS AND PROCEDURES 
This section lists the parameters of each planned study assessment. The exact timing of 
each assessment is listed in the Time and Events Tables (Section 3.5). Detailed procedures 
for obtaining each assessment are provided below.  
Whenever vital signs, 12-lead ECGs and blood draws are scheduled for the same nominal 
time, the assessments should occur in the following order: 12-lead ECG, vital signs, blood 
draws. The timing of the assessments should allow the blood draw to occur at the exact 
nominal time.  
The timing and number of planned study assessments and procedures may be altered during 
the course of the study based on newly available data (e.g. to obtain data closer to the time 
of peak plasma concentrations) to ensure appropriate monitoring. Additional safety tests 
(such as vital signs, physical exams, and clinical laboratory tests (up to a maximum of 
approximately 500 mL of blood from the subject within a 30-day period)) may also be 
obtained during the course of the study based on newly available data, to ensure appropriate 
safety monitoring.  


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The Ethics Committee will be informed of any safety issues that require alteration of the 
safety monitoring scheme. 
The actual date and time should be recorded for all procedures and the Investigator should 
make every effort to perform procedures at the scheduled nominal dates and times. 
 
 
Demographic/Medical History Assessments 
6.1.
Demographic data will include date of birth, height in centimeters, and body weight in 
kilograms. 
Medical/medication/alcohol and drug abuse histories will be assessed as related to the 
eligibility criteria listed in Section 4.2 as well as life habits (tobacco, tea, coffee, chocolate 
and/or beverage containing caffeine). 
 
 
Safety 
6.2.
Planned timepoints for all safety assessments are listed in the Time and Events Table 
(Section 3.5). Additional time points for safety tests (such as vital signs, physical exams 
and laboratory safety tests) may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring. 
 
Physical Exam 
• 
A complete physical examination will include assessments of the head, eyes, ears, 
nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and 
spleen), lymph nodes and extremities. Height and weight will also be measured and 
recorded. 
• 
A brief physical examination will include assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen). 
• 
Physical examination can also be performed throughout the study on medical 
indication at the discretion of the investigator. 
• 
A clinical psychological evaluation will be conducted at screening 
Examinations will be performed by the Investigator or his designee. 
 
Vigilance 
Vigilance will be assessed at regular intervals by a Visual Analogic Scale, namely the 
Bond-Lader VAS of Mood and Alertness: this questionnaire of 16 analogue scales derives 
3 factors that assess change in Self-rated Alertness, Self-rated Calmness and Self-rated 
Contentment. 
 
Vital Signs 


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• 
Vital sign measurements will include tympanic temperature, systolic (SBP) and 
diastolic blood pressure (DBP), pulse rate (HR) in supine and standing positions. The 
subject should be allowed to relax at least 5 minutes before taking the first BP in 
supine position. Standing BP and pulse rate will be measured at both 1 and 3 min of 
standing. 
• 
At baseline in Day 1 pre-dose, vital sign measurements (except tympanic temperature) 
will be conducted in triplicate (with an interval of approximately 10 - 30 minutes 
between each record). The average value of each parameter will be considered as 
baseline value. 
• 
Tympanic temperature, SBP, DBP and HR will be checked post dose at specified time 
points (see Flow-Chart Time and Events Section 3.5.). 
• 
If possible, BP measurements will be taken from the same arm (opposite to the arm 
that is used for blood sampling) by an automated BP monitor using the oscillometric 
method (e.g. Dinamap). Normal ranges for vital signs parameters will be according to 
the CPCET’s standard operating procedures (SOP). 
• 
In the case of an out-of-range value, measurements will be repeated immediately to 
confirm the change and the investigator or designee will be informed: 
SBP  
> 150 mm Hg or < 100 mm Hg 
DBP  
> 90 mm Hg or < 45 mm Hg 
HR  
> 100 bpm or < 45 bpm 
 
Electrocardiogram (ECG) 
• 
12-lead ECGs will be obtained at each time point during the study using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and 
QTc intervals. Subjects must rest in the supine position for at least 5 minutes before 
recording. The ECG may be recorded during the period of rest required before the 
measurements of supine BP and pulse. A qualified physician will review the ECGs 
promptly and any clinically important finding will be recorded on the appropriate CRF. 
• 
At baseline in Day 1 pre-dose, ECG recordings will be conducted in triplicate (with an 
interval of approximately 10 - 30 minutes). The average value of each parameter will 
be considered as baseline value. 
• 
ECG recordings will be performed post dose at specified time points (see Flow-Chart 
Time and Events). 
• 
Parameters:  
- 
Measured parameters: HR, PR, QRS duration, QRS axis, QT; 
- 
Derived parameters: two corrections of the QT interval will be investigated: 
Fridericia's correction (QTcF) and Bazett's correction (QTcB); 
- 
Observations and comments on the quality of trace, on normality or abnormality. 
• 
Refer to Section 3.4.3.3 for QTc withdrawal criteria and additional QTc readings that 
may be necessary.  
 


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Clinical Laboratory Assessments 
The following parameters will be determined: 
 
• 
Hematology: 
Red blood cell (RBC) count, hemoglobin, hematocrit, white blood cell (WBC) count with 
differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils), platelets, 
reticulocyte count. 
• 
Coagulation: 
Activated partial thromboplastin time (APTT), international normalized ratio (INR). 
• 
Biochemistry: 
Sodium, potassium, chloride, calcium, total bilirubin, alanine aminotransferase (ASAT), 
aspartate aminotransferase (ALAT), gamma-glutamyl transferase (GGT), alkaline 
phosphatases, total protein, albumin, urea, uric acid, bicarbonate, creatine phosphokinase 
(CPK), creatinine, glycaemia, lactate dehydrogenase (LDH), total cholesterol, HDL and 
LDL cholesterol, triglycerides. 
• 
Urinalysis: 
Specific gravity, pH, glucose, protein, blood, nitrites, leucocytes and ketones by dipstick, 
cytobacteriological exam (if abnormal results on dipstick); beta 2 microglobulin (B2M), 
proteinuria and creatinuria on urinary sample 
• 
Other screening tests: 
Hepatitis B antigen (HBs Ag), Hepatitis C antibodies (Anti-HCV Ab), Anti-HIV1 and Anti 
HIV2 antibodies (only at screening) 
• 
Alcohol breath test.  
• 
Drug screen (amphetamines, cocaine, opiates, cannabinoids and benzodiazepines). 
 
All clinically significant abnormal laboratory test values identified after IMP administration 
will be reported as an adverse event and had to be controlled until the return to normal or 
baseline. If laboratory values do not return to normal or baseline within a reasonable 
period, the etiology should be identified  
Laboratory tests will be performed in local labs of the hospital for the SAD part, and by the 
Groupe Oriade (Mr Bernard CADOUX, 83 Avenue Gabriel Péri, 38400 St Martin d’Hères) 
for the MAD part. 
 
 
Pharmacokinetics 
6.3.
 
Blood Sample Collection 
6.3.1.
Venous blood samples (8 mL) for the determination of plasma concentrations of IFB-088 
and its metabolite IFB139 will be drawn by direct venipuncture or via an intravenous 


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catheter into heparin - lithium Vacutainer polyethylene tubes during the SAD and MAD 
parts of the study at the time points indicated in Section 3.5, Time and Events Table.  
The actual date and time of each blood sample collection will be recorded.  
Details of PK blood sample processing, storage and shipping procedures will be provided 
in a Laboratory Procedures Manual (LPM) provided by the sponsor. 
 
 
Urine Sample Collection 
6.3.2.
Urine samples for pharmacokinetic analysis of IFB-088 and its metabolite will be collected 
at the time points listed in Section 3.5, Time and Events Table.  
Urine will be collected in containers (adapted to the collected urine volume) at the 
designated time points in the SAD and MAD parts of the study. The total volume collected 
by period will be recorded in the CRF. After homogenization, 3 aliquots of 5 ml of the 
resulting urine will be transferred into polypropylene tubes and stored at -80°C until 
required for analysis. 
Sufficient hydration (at least 2L/day) will be provided and the diuresis will be carefully 
monitored. 
Details of PK urine sample collection, processing, storage and shipping procedures are 
provided in a LPM provided by the sponsor. 
 
 
Sample Analysis 
6.3.3.
Plasma and urine samples analysis will be performed under the management of ADME 
Bioanalyses (Eurofins) after completion of each cohort.  
Concentrations of IFB-088 and its metabolite will be determined in plasma and urine 
samples using the currently approved analytical methodology.  
The bioanalytical and pharmacokinetic parts of this study will be described in details in a 
EUROFINS ADME BIOANALYSES protocol. 
IFB-088 and its metabolite will be analyzed in plasma and urine samples using the 
PKH/MOA/982, PKH/MOA/983 and PKH/MOA/1137 bioanalytical methods which will 
be previously validated at EUROFINS ADME BIOANALYSES according to Bioanalytical 
Method Validation EMA July 2011 and Bioanalytical Method Validation FDA draft 
September 2013. 
 
 
Exploratory Marker(s)  
6.4.
There is currently no validated specific biomarker. 
So, in the SAD part of the study, healthy subjects will be asked to donate blood samples 
that could be used for research purposes as healthy controls in future studies conducted in 
patients. A specific part in the informed consent will be signed. 
Two samples will be drawn: 


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• One sample (3 ml) on heparin lithium tube for PBMC extraction 
• One sample (2.5 mL) on PAXgene tube for RNA extraction 
Times of sampling are summarized on the Flow-Charts of SAD in Section 3.5. 
Samples will be stored at -150°C for 5 years after final database freeze and then destroyed. 
Blood samples for the analysis of biomarkers will be stored in the CRB (Centre de 
Ressources biologiques). 
No blood sampling for exploratory biomarkers will be performed during the MAD part of 
the study. 
 
 
Investigational schedule 
6.5.
See Section 3.5, Time and Events Table 
 
Screening visit 
6.5.1.
The screening visit will include the following: 
• Signature and date of an ICF before any study specific screening procedures, 
• Verification of the eligibility criteria, 
• Medical history, 
• Weight (kg) and height (cm), BMI,  
• Physical examination and clinical psychological evaluation and MINI, 
• Vital signs measurement (Systolic and diastolic blood pressure, heart rate in supine 
and standing position, tympanic body temperature), 
• 12-lead ECG, 
• Laboratory evaluation (hematology, coagulation, biochemistry and urinalysis), 
• Viral serology testing [hepatitis B antigen (HBs Ag), Hepatitis C antibodies (Anti-
HCV Ab), Anti-HIV1 and Anti HIV2 antibodies],  
• Urine drug of abuse screening,  
• Alcohol breath test. 
 
 
Admission Visit (D-1, one day prior to dosing) 
6.5.2.
Subjects will be admitted to the unit one day prior to dosing and will undergo the following 
investigations: 
• Medical history update, 
• Physical examination update, 
• Vital signs measurement (inc1uding tympanic body temperature), 
• 12-lead ECG, 


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• Laboratory evaluation (hematology, coagulation, biochemistry, urinalysis), 
• Urine drug screen, 
• Alcohol breath test, 
• AE monitoring, 
• Review of concomitant medications, 
• Verification of the eligibility criteria, 
 
 
SAD 
6.5.3.
 
Dosing Day (D1) 
6.5.3.1.
The study drug will be administered after an overnight fast of at least 8 hours. 
Subjects will have the following procedures performed at pre-dose: 
• Verification of the eligibility criteria, 
• Randomization to the group treatment (verum or placebo) after check of all criteria, 
• Vital signs in triplicate except tympanic temperature, 
• 12-lead ECG in triplicate, 
• PK blood sampling, 
• PK urine sampling, 
• Blood sampling for exploratory assessment of biomarkers, 
• AE monitoring, 
• Vigilance assessment. 
In the first cohort, the planned dose (2.5 mg) will be administered in the morning in a single 
intake. 
From the second cohort, the total dose planned in the cohort will be administered in 2 
intakes separated by a 12-hour interval, the first intake in the morning at around 8:00 am 
and the second one at around 8:00 pm in the evening. 
The intake hour (H0) on Dl (morning dose) will be the reference time for implementing the 
following procedures at several time-points (see Flow chart Section 3.5.1 and 3.5.2) 
• Vital signs (inc1uding tympanic body temperature), 
• 12-lead ECG, 
• Diuresis monitoring, 
• PK blood sampling, 
• PK urine sampling, 
• Blood sampling for exploratory assessment of biomarkers, 


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• AE monitoring, 
• Vigilance assessment. 
In cohort 1, meals will be served at H4 and H14 post-dose. 
From the cohort 2, meals will be served at H4 (around 12:00 a.m) and at H14 post first 
dose, 2 hours after the second administration in the evening (around 10:00 p.m). 
 
 
Day 2 (D2) 
6.5.3.2.
The following procedures will be performed at H24 and H32 post first dose (see Flow chart 
Section 3.5.1 and 3.5.2): 
• Vital signs (inc1uding tympanic body temperature) (H24 post-dose and H32 post 
dose), 
• Physical examination update at H32 post dose, 
• 12-lead ECG, 
• PK blood sampling (H24 post-dose and H32 post dose), 
• PK urine sampling, 
• Blood sampling for exploratory assessment of biomarkers, 
• Laboratory evaluation (hematology, biochemistry, urinalysis) at H24 post dose  
• Urinalysis only at H32 post dose, 
• Vigilance assessment at H32 post dose,  
• AE monitoring. 
A breakfast will be offered after the H24 post-dose sampling has been drawn. 
After medical authorization, the subject will be discharged after assessment of evaluations 
planned at H32 post first dose. 
The subject will be asked to return for a follow-up visit, scheduled 7 to 14 days post dose. 
 
 
Follow-up / End of study visit (7 to 14 days post dose) 
6.5.3.3.
The following procedures will be performed  
• Vital signs measurement (inc1uding tympanic body temperature), 
• Physical examination update, 
• 12-lead ECG, 
• Laboratory evaluation (hematology, coagulation, biochemistry and urinalysis), 
• AE monitoring, 
• Review of concomitant medications. 


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MAD 
6.5.4.
See Flow-Chart Section 3.5.3 
 
 
Dosing Day (D1) 
6.5.4.1.
The first administration of the study drug will be done after an overnight fast of at least 8 
hours. 
Subjects will have the following procedures performed at pre-dose: 
• Verification of the eligibility criteria, 
• Vital signs in triplicate except tympanic temperature, 
• 12-lead ECG in triplicate, 
• PK blood sampling, 
• PK urine sampling (baseline), 
• AE monitoring, 
• Vigilance assessment. 
The daily dose planned in each cohort will be administered in 2 intakes separated by a 12-
hour interval, the first intake in the morning at 8:00 am and the second one at 8:00 pm in 
the evening. 
The intake hour (H0) on Day l morning will be the reference time for implementing the 
following procedures at several time-points (see Flow chart Section 3.5.3): 
• Vital signs (inc1uding tympanic body temperature), 
• 12-lead ECG, 
• Diuresis monitoring, 
• PK blood sampling at several time points, 
• PK urine sampling, 
• AE monitoring, 
• Vigilance assessment at pre-dose, 1.5h post first dose and 12h post first dose before 
evening dose. 
All assessments planned at 12h post first dose will be performed before the evening dose. 
 
 
Day 2  
6.5.4.2.
The following procedures will be performed at several time points: 
• Study treatment dosing in 2 daily administrations separated by an interval of 12 
hours, 


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• Vital signs (inc1uding tympanic body temperature) before morning dose, 
• Diuresis monitoring, 
• PK blood sampling (17h, 19h, 21h and 24h post first dose of Day 1, just before the 
Day 2 morning dose), 
• PK urine sampling (end of collection interval T12-T24h of Day 1), 
• AE monitoring. 
 
 
Day 3 to Day 13  
6.5.4.3.
The following procedures will be performed at several time points: 
• Study treatment dosing in 2 daily administrations separated by an interval of 12 
hours, 
• Vital signs every morning before dosing, 
• Tympanic body temperature in the morning before dosing on Day 4, Day 6, Day 8, 
Day 10 and Day12,  
• 12-lead ECG on Day 3, Day 6, Day 10 and Day 13, 
• Diuresis monitoring on Day 6, 
• Safety laboratory tests (hematology, coagulation, biochemistry) in fasting state, at 
Day 3, Day 6, Day 10 and Day 13, 
• Urinalysis on Day 3, Day 6, Day 10 and Day 13, 
• PK blood sampling in the morning at Day 7 pre-dose, then 1h and 2h post morning 
dose, 
• PK urine sampling on Day 6: pre dose, 0-4h and 4-12h, 
• AE monitoring. 
 
 
Day 14 
6.5.4.4.
The following procedures will be performed at several time points (see Flow chart Section 
3.5.3): 
• Study treatment dosing in 2 daily administrations separated by an interval of 12 
hours, 
• Vital signs (inc1uding tympanic body temperature) in the morning pre-dose, 
• Diuresis monitoring, 
• PK blood sampling, 
• PK urine sampling, 
• AE monitoring, 


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• Vigilance assessment at pre-dose, 1.5h post first dose and 12h post morning dose. 
 
 
Day 15 to Day 17 
6.5.4.5.
The following procedures will be performed: 
• Full physical exam at Day 17 before discharge, 
• Vital signs every morning, 
• Tympanic body temperature at Day 17, 
• Safety laboratory tests (hematology, coagulation, biochemistry) in fasting state at 
Day 17, 
• Urinalysis on Day 17, 
• 12-lead ECG on Day 17, 
• Diuresis monitoring on Day 15 and Day 16, 
• PK blood sampling on Day 15 (17h, 19h, 21h, 24h, 30h, 36h and 42h post Day 14 
morning dose) and on Day 16 (48h and 60h post Day 14 morning dose),  
• PK urine sampling on Day 15 (end of collection of T12-24h and T24-36h post Day 
14 morning dose) and on Day 16 (T36-48h post Day 14 morning dose), 
• AE monitoring, 
• Discharge after assessment of scheduled evaluations and medical authorization. 
The subject will be asked to return for a follow-up visit, scheduled 7 to 14 days post last 
dose. 
 
 
Follow-up / End of study visit (7 to 14 days post last dose) 
6.5.4.6.
The following procedures will be performed  
• Vital signs measurement (inc1uding tympanic body temperature) 
• Full physical examination, 
• 12-lead ECG, 
• Laboratory evaluation (hematology, coagulation, biochemistry and urinalysis), 
• AE monitoring, 
• Review of concomitant medications. 
 


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Lifestyle And/or Dietary Restrictions 
6.6.
 
Contraception Requirements 
6.6.1.
Subjects with female partners of child-bearing potential must use condom while the female 
partner must use a highly effective contraceptive, such as IUD, birth control pills or 
diaphragm with spermicide, after the first dose of study treatment and until the end of study 
visit (for female partners) and during an additional 90 days period (for subjects 
themselves).  
 
 
Meals and Dietary Restrictions  
6.6.2.
The first dose of the study drug in the morning will be done in the fasting state. Subjects 
will be required to fast from all food and drink with the exception of water for 8 hours prior 
to study drug administration. Water is permitted and may be consumed ad libitum post-
dosing with a minimal intake of 2L/day to assure a sufficient diuresis, distributed as 
follows: 500 mL between dosing and T4H, 1000 mL between T4H and T12H and 500 mL 
between T12H and T24H. 
Moreover, subjects will be asked on Day-1: 
• 
To ensure sufficient hydration (around 2L over the 24-hour period) with a normal salt 
intake, 
• 
To refrain from any fruit juice and sparkling water, 
• 
These recommendations will be maintained during the hospitalization period. 
In the SAD part, a standard lunch will be provided approximately 4 hours post-dosing. 
Dinner will be served 14 hours post morning dose (2 hours after the evening administration 
and after completion of assessments scheduled at this time from Cohort 2).  
In the MAD part, a breakfast will be provided 2 hours post-morning dose, standard lunch 5 
hours post-morning dose, a snack 9 hours post-morning dose and a dinner will be served 2 
hours post-evening dose. Therfore, breakfast will be served at 10 AM, lunch at 1 PM, snack 
at 5 PM and dinner at 10 PM  
Subjects will be requested to abstain from consumption of grapefruit or grapefruit-
containing products) for 7 days prior to first dosing and until the follow up visit. 
 
 
Caffeine, Alcohol 
6.6.3.
During each dosing session, subjects will abstain from alcohol and xanthine-containing 
beverages (e.g. coffee, tea, cola drinks, chocolate) for 24 hours prior to the start of dosing 
until collection of the final pharmacokinetic sample during each session.  
 


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Activity 
6.6.4.
Subjects will abstain from strenuous exercise for 48 hours prior to each blood collection for 
clinical laboratory tests. Subjects may participate in light recreational activities during 
studies (e.g., watch television, read). 
 
 
Total volume of blood collected 
6.7.
Blood samples will be obtained according to the following schedule: 
 
SAD part: Collection schedule and Blood volume  
6.7.1.
 Screening Visit (D-21 to D-2) 
Biochemistry, Hematology, Coagulation, Serologies (5+2+4+8.5 mL) 
Total =19.5 mL 
 
 Admission Visits D-l 
Biochemistry, Hematology, Coagulation (5+2+4 mL) 
Total = 11 mL 
 
 Dosing Visit Dl 
PK samples: 14 samples (14 x 8 mL) 
Exploratory biomarkers samples: 2 samples ([3+2.5 mL] x 2) 
Total = 123 mL  
 
 D2 
PK samples: 2 samples (Cohort 1) (2 x 8 mL), 3 samples (Cohorts 2 to 6) (3 x 8 mL) 
Exploratory biomarkers samples 1 sample (3+2.5 mL) 
Biochemistry, Hematology, Coagulation (5+2+4 mL) 
Total = 32.5 mL (Cohort 1), 40.5 mL (From Cohort 2 to 6) 
 
 Follow up visit 
Biochemistry, Hematology, Coagulation (5+2+4 mL)  
Total = 11 mL 
 
Total on the overall duration of the study: 197 mL (Cohort 1) and 205 mL (Cohorts 
2 to 6) 
 
 
MAD part: Collection schedule and Blood Volume  
6.7.2.
 Screening Visit (D-21 to D-1) 
Biochemistry, Hematology, Coagulation, Serologies (9+2+2.7+5 mL) 
Total =18.7 mL 
 
 Admission Visits D-l 
Biochemistry, Hematology, Coagulation (5.5+2+2.7 mL) 
Total = 10.2 mL 
 


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 Dosing Visit Dl 
PK samples: 12 samples (12 x 8 mL) 
Total = 96 mL  
 
 Dosing Visit D2 
PK samples: 4 samples (4 x 8 mL) 
Total = 32 mL 
 
 Dosing Visit D3 
Biochemistry, Hematology, Coagulation (5.5+2+2.7 mL)  
Total = 10.2 mL 
 
 Dosing Visit D6 
Biochemistry, Hematology, Coagulation (5.5+2+2.7 mL)  
Total = 10.2 mL 
 
 Dosing Visit D7 
PK samples: 3 samples (3 x 8 mL) 
Total = 24 mL 
 
 Dosing Visit D10 
Biochemistry, Hematology, Coagulation (5.5+2+2.7 mL)  
Total = 10.2 mL 
 
 Dosing Visit D13 
Biochemistry, Hematology, Coagulation (5.5+2+2.7 mL)  
Total = 10.2 mL 
 
 Dosing Visit Dl4 
PK samples: 12 samples (12 x 8 mL) 
Total = 96 mL  
 
 Dosing Visit D15 
PK samples: 7 samples (7 x 8 mL) 
Total = 56 mL 
 
 Dosing Visit D16 
PK samples: 2 sample (2 x 8 mL) 
Total = 16 mL 
 
 Dosing Visit D17 
Biochemistry, Hematology, Coagulation (5.5+2+2.7 mL)  
Total = 10.2 mL 
 
 Follow up visit 
Biochemistry, Hematology, Coagulation (5.5+2+2.7 mL)  
Total = 10.2 mL 
 


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Total on the overall duration of the study: 410.1 mL  
 
7. 
COMPLETION OR EARLY WITHDRAWAL OF SUBJECTS 
 
Subject Completion 
7.1.
A completed subject is one who has completed all phases of the study including the follow-
up visit. 
The end of the study is defined as the last subject’s last visit. 
 
 
Subject Withdrawal Criteria 
7.2.
Refer to Section 3.4 for dose adjustment/stopping criteria based on safety and PK criteria. 
A subject may withdraw from study treatment at any time at his own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral or 
administrative reasons. 
 
 
Subject Withdrawal Procedures 
7.3.
In the event a randomized subject is withdrawn from the study for any reason, the 
Investigator should make every effort to perform a final study visit 7 to 14 days after last 
administration of investigational product and complete the assessments and procedures 
outlined in the Time & Events Table for ‘Follow Up’.  
Subjects who withdraw due to an AE(s) must have the AE followed as indicated in Follow-
Up of AEs/SAEs. 
Subjects who withdraw may be replaced at the discretion of the sponsor’s team in 
consultation with the investigator. 
 
8. 
ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAE) 
The investigator or site staff is responsible for detecting, documenting and reporting events 
that meet the definition of an AE or SAE. 
AEs will be collected from the signature of Informed Consent and until the follow-up visit.  
This period will be extended on all on-going AEs after the last visit until all AEs are finally 
resolved. 
SAEs will be collected over the same time period as stated above for AEs.  
There is no time limit on the collection of SAEs that are considered related to study drug. 
Nevertheless and by default, the collection of SAE is primarily set as 1 month after the end 
of study participation. If the Investigator detects an SAE in a study subject after the end of 
the period of observation, and considers the event possibly related to prior study treatment 


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or procedures, he must contact the sponsor to determine how the SAE should be 
documented and reported. 
 
 
Definitions of Adverse Events and New Facts 
8.1.
 Definition of an Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of a medicinal product.   
Events meeting the definition of an AE include: 
• 
Any abnormal laboratory test results (hematology, coagulation, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., ECGs, vital signs measurements), 
including those that worsen from baseline, and felt to be clinically significant in the 
medical and scientific judgment of the investigator. 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study treatment administration even though 
it may have been present prior to the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent; this should be reported regardless of sequelae). 
 
 Treatment Emergent Adverse Event and Repetition of Adverse Event 
• 
A treatment-emergent AE is any AE that occurs after dosing, or that was present prior 
to dosing but is exacerbated after dosing. 
• 
AE occurring after subject enrolment (ICF signature) but prior to first study drug 
administration will be recorded as a non-treatment emergent adverse event (NTEAE). 
• 
A clinically relevant worsening of an AE (e.g., relevant change in severity, 
seriousness) must result in a new entry. The original entry remains unresolved and is 
given an end date reflecting the date of the worsening and a comment must be entered 
stating that the AE is continuing with a changed severity/seriousness (e.g., "continues 
as event name with onset date and new severity/seriousness"). The onset date of the 
new entry is also the date of worsening. 
 Events that do not meet the definition of an AE include: 


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• 
Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that 
leads to the procedure is an AE. 
• 
Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
 
 Definition of New Facts 
A New Fact is defined as an incident, experience, or outcome that generally will warrant 
consideration of changes to the protocol or consent in order to protect the safety, welfare, or 
rights of participants. A New Fact may warrant corrective actions. Examples of corrective 
actions or changes that might need to be considered include:  
• 
Modification of inclusion or exclusion criteria to mitigate the newly identified risks  
• 
Implementation of additional safety monitoring procedures 
• 
Suspension of enrollment of new participants or halting of study procedures for 
enrolled participants  
• 
Modification of informed consent documents to include a description of newly 
recognized risks  
• 
Provision of additional information about newly recognized risks to previously 
enrolled participants. 
The sponsor informs immediately the competent authorities of those new events and the 
measures taken and ensure that the Ethics Committee is notified at the same time (France: 
ANSM, CPP, ARS). 
 
 
Definition of Serious Adverse Events 
8.2.
 General definitions 
A SAE or Serious Adverse Drug Reaction (ADR) is any untoward medical occurrence that 
at any dose: 
• 
Results in death 
• 
Is life-threatening (refers to immediate risk of death as the event occurred) 
• 
Requires inpatient hospitalization or prolongation of an existing hospitalization  
• 
Results in a persistent or significant disability or incapacity (defined as a substantial 
disruption in a person's ability to conduct normal life functions) 
• 
Is a congenital anomaly or birth defect 
Additionally, important medical events may be considered SAEs when, based on 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. Examples of 


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such events inc1ude allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse. 
NOTE: In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
out-patient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
 
 
Expected and unexpected adverse events 
8.3.
As this is a first-in-man (FIM) study, no AEs are defined as expected in humans. 
Potential adverse reactions were identified from findings in the non-clinical toxicity studies 
and are mentioned in the Section 1.3 “Summary of Risk Management”. 
According to the French legislation and to the directives of the Health Authority (ANSM: 
“Obligations de déclarations immediates du promoteur” Mai 2017), in a FIM study, a 
serious adverse drug reaction is considered as a New Fact and New Facts identified by the 
Investigator are to be notified without delay to the sponsor.  
In case of New Facts, the administrations of the IMP will be withheld for all subjects, 
emergency measures will be implemented. The Authorities (ANSM, CPP and ARS) will be 
notified without delay by the sponsor’s representative. 
In the event of a suspension of the trial, before restarting, the subjects will have to be 
informed and, when needed, to sign a new ICF approved after amendment of the study. 
 
 
Method of Detecting AEs and SAEs 
8.4.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about AE 
occurrence. Appropriate questions include: 
• 
“How are you feeling?” 
• 
“Have you had any (other) medical problems since your last visit/contact?” 
• 
“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?”  
Subjects will be provided with a study card containing important information on the study 
particularly contact of the study staff (investigator) and an emergency phone number to be 
contacted 24/24 with a physician of the clinical center on duty. 
 


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Recording of AEs and SAEs 
8.5.
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) relative to 
the event. The investigator will then record all relevant information regarding an AE/SAE 
in the appropriate pages in the CRF.  
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms. 
The following will also be specified: 
• Other actions (none, medication required, tests required, hospitalization required or 
prolonged, treatment unblinded, other-specify) 
• Outcome and date of outcome according to the following definitions: 
o Recovered/resolved 
o Recovering/resolving 
o Not recovered/not resolved 
o Recovered with sequelae/resolved with sequelae 
o Fatal 
o Unknown 
• Seriousness: yes or no (criteria for SAE see above) 
 
 
Evaluating AEs and SAEs 
8.6.
 
Assessment of Intensity 
8.6.1.
The investigator will make an assessment of intensity for each AE and SAE reported during 
the study and will assign it to one of the following categories: 
 Mild: An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities (Grade 1). 
 Moderate: An event that is sufficiently discomforting to interfere with normal 
everyday activities, no treatment except paracetamol (Grade 2). 
 Severe: An event that prevents normal everyday activities or requires treatment 
(Grade 3). 
 
An AE that is assessed as severe will not be confused with an SAE. Severity is a category 
utilized for rating the intensity of an event; and both AEs and SAEs can be assessed as 
severe.  
 
 
Assessment of Causality 
8.6.2.
The investigator has to assess the relationship between study treatment and the occurrence 
of each AE/SAE.  
The relationship of an AE to the IMP is based on all available information at the time of the 
completion of the CRF and is graded as follows: 


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• Not related: a reaction for which sufficient information exists to indicate that the 
etiology is unrelated to the study drug; the subject did not receive the study 
medication or the temporal sequence of the AE onset relative to administration of 
the study medication is not reasonable or the event is c1early related to other factors 
(subject' s clinical state, therapeutic intervention or concomitant therapy). 
 
• Unlikely: Does not follow a reasonable temporal sequence from administration of 
the IMP, or is most likely related to another etiology than the trial drug such as the 
patient’s clinical state, environmental factors or other therapies. 
 
• Possibly: a clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the drug but which could also be explained by 
concurrent disease or other drugs or chemicals. 
 
• Probably: a clinical event including laboratory test abnormality, with a reasonable 
time sequence to administration of the drug, unlikely to be attributed to concurrent 
disease or other drugs and which follows a clinically reasonable response on 
withdrawal (de-challenge). 
 
• Definitely: a reaction that follows a reasonable temporal sequence from 
administration of the drug, or in which the drug level has been established in body 
fluids or tissues, that follows a known or expected response pattern to the suspected 
drug, and that is confirmed by improvement on stopping or reducing the dosage of 
the drug, and reappearance of the reaction on repeated exposure (re-challenge if 
applicable). 
 
 
Follow-up of AEs and SAEs 
8.7.
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts. All AEs and SAEs will be followed until resolution. 
 
 
Prompt Reporting of SAEs to the sponsor 
8.8.
Once the investigator determines that an event meets the protocol definition of an SAE, the 
SAE will be reported to the sponsor without delay, within 24h.  
Any follow-up information on a previously reported SAE will also be reported to the 
sponsor within 24 hours. 
The SAE form must be completed and faxed [Fax number +33 478425571] or emailed 
[email: InFlectisPV@stragen.fr] to Stragen Services. Stragen Services acknowledges the 
receipt of the SAE information by email to the investigational site within one working day. 
In the absence of email acknowledging the receipt or in case of issue in sending the fax or 
email, the investigator shall contact Stragen Services by any means for ensuring the receipt 
of SAE information at the earliest opportunity. 


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The initial report must be as complete as possible, including details of the Serious Adverse 
Event, and most importantly an assessment of the causal relationship between the SAE and 
the study medication. Information not available at the time of the initial report (e.g., end 
date of the Serious Adverse Event or laboratory values received after the report) must be 
documented on a follow-up “SAE report form”. 
The SAE report form and the instructions on completion are provided in the investigator’s 
study file.  
 
 
Pregnancy 
8.9.
Because the effect of the study drug on sperm is unknown, pregnancies in partners of male 
subjects included in the study will be reported by the study-site personnel within 24 hours 
of their knowledge of the event using the SAE form. 
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae 
in the infant will be required. For this purpose, follow-up requests will be initiated by 
Stragen Services, at the end of each trimester of the pregnancy and at least until delivery, 
using a specific Pregnancy Form. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, and ectopic pregnancy) are considered SAEs and must be reported 
using the Serious Adverse Event Form. 
 
 
Liver chemistry Follow-up procedures 
8.10.
Refer to the diagram in Appendix 1 for a visual presentation of the procedures listed 
below. 
The procedures listed below are to be followed if a subject meets the liver chemistry 
stopping criteria defined in Section 3.4.3.1: 
• 
Immediately withdraw the subject from study treatment.  
• 
Notify the medical monitor of the sponsor within 24 hours of learning of the 
abnormality to confirm the subject’s study treatment cessation and follow-up. 
• 
Complete the “Safety Follow-Up Procedures” listed below. 
• 
If the event also meets the criteria of an SAE (see Section 8.2), all remaining subjects 
of the cohort will be informed immediately, and the IMP administration immediately 
stopped. The sponsor will be notified without any delay. The SAE form will be 
completed with the relevant details. 
Safety Follow-Up Procedures for subjects with ALT ≥ 3xULN: 
• 
Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values. 
Safety Follow-Up Procedures for subjects with ALT ≥3xULN and total bilirubin 
≥2xULN (>35% direct bilirubin); or ALT ≥ 3xULN and INR > 1.5: 


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• 
This event is considered an SAE (see Section 8.2). Serum bilirubin fractionation 
should be performed if testing is available. If fractionation is unavailable, urinary 
bilirubin is to be measured via dipstick (a measurement of direct bilirubin, which 
would suggest liver injury). 
• 
All remaining subjects of the cohort will be informed immediately and the IMP 
administration immediately stopped. The sponsor will be notified without any delay. 
• 
Make every reasonable attempt to have subjects return to the clinic within 24 hours for 
repeat liver chemistries, additional testing, and close monitoring (with specialist or 
hepatology consultation recommended). 
• 
Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values. 
In addition, for all subjects with ALT ≥ 3xULN, every attempt must be made to also 
obtain the following: 
• Viral hepatitis serology including: 
- 
Hepatitis A IgM antibody. 
- 
Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM).  
- 
Hepatitis C RNA.  
- 
Cytomegalovirus IgM antibody. 
- 
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing). 
- 
Hepatitis E IgM antibody. 
• Blood sample for pharmacokinetic (PK) analysis. Record the date/time of the PK blood 
sample draw and the date/time of the dose of study treatment prior to blood sample 
draw on the source documents and the CRF. 
• Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH). 
• Fractionate bilirubin, if total bilirubin ≥ 2xULN. 
• Assess eosinophilia. 
• Record the appearance or worsening of clinical symptoms of hepatitis (fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash or eosinophilia) on the 
AE CRF. 
• Record use of concomitant medications, on the appropriate pages of the CRF. 
The following are required for subjects with ALT ≥ 3xULN and bilirubin ≥ 2xULN (>35% 
direct) but are optional for other abnormal liver chemistries: 
• Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney 
microsomal antibodies. 
• Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to 
evaluate liver disease. 
 


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9. 
DATA MANAGEMENT AND STATISTICAL CONSIDERATIONS 
 
Data management 
9.1.
CIC-CPCET Pharmacometry unit will be responsible for activities associated with the data 
management of this study. This will include setting up a relevant database and data transfer 
mechanisms, along with appropriate validation of data and resolution of queries. Data 
generated within this clinical study will be handled according to the relevant SOPs of the 
data management and biostatistics unit.  
A detailed Data Management Plan (DMP) will be established before the study initiation. 
 
 
Data collection 
9.1.1.
All the results will be recorded in an electronic CRF for each subject. Designated study site 
staff will enter data required by the protocol into CRFs.   
All data obtained in this study should be source-documented. The appropriate study site 
staff will record all data on source documents immediately. If any form of printout is 
available, each copy of such printouts should be dated, signed by the investigator and 
attached to the subject’s file. 
It is the responsibility of the investigator to ensure that CRFs are kept up to date so that 
they always contain the latest observations on the subjects enrolled. Corrections to CRFs 
will be made directly into the CRF by the investigator or an authorised staff member. For 
any correction made, user’s identification, date and reason(s) for the change will be 
reported in the audit trail. 
All supportive documentation in addition to the CRF, such as laboratory results, ECG 
traces must be clearly identified with the study code, the subject’s number and initials. Any 
personal information, including the subject's name, must be removed or rendered illegible 
to preserve individual confidentiality. 
 
 
External Data 
9.1.2.
External data will concern PK data (Excel files provided by laboratory and by PK 
modeling). A data transfer protocol will be validated, and the data will be directly imported 
into the study database. 
 
 
Data validation 
9.1.3.
Consistency checks will be implemented according to the DMP. If inconsistencies are 
detected, queries will be generated using eCRF queries and all queries will be documented 
in an audit file. 
 


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Data coding 
9.1.4.
Adverse events (AEs) and medical histories will be coded according to the Medical 
Dictionary for Regulatory Activities (MedDRA 21.0 or the latest available version at the 
study completion date). Concomitant medications will be coded according to the ATC 
codes. 
 
 
Data Review meeting 
9.1.5.
A Data Review meeting will be organized before locking the database at the end of each 
study part (i.e. end of SAD and end of MAD). Reconciliation of pharmacovigilance 
database and study database will be done before each meeting.  
The study database will be locked in SAS export format. Formatted database will be 
transferred for statistical analysis. 
A data management report will document all steps at the end of the study. 
 
 
Sample Size Considerations 
9.2.
No formal sample size calculation has been performed (no formal hypothesis will be tested). 
The sample size is based on empirical considerations and on the literature.  
Nevertheless, a sample size of 6 subjects receiving an active drug provides a chance of 26% 
to observe at least one adverse event, with a true adverse event rate estimated to 5%. This 
level of predictability is deemed adequate for this FTIH study.   
No sample size re-estimation will be planned. 
 
 
Data Analysis Considerations 
9.3.
Statistical analysis will be performed by the Pharmacometrics unit of the Clinical 
Pharmacology department.  
Complete details of the planned statistical analyses will be provided in the Statistical 
Analysis Plan (SAP).  
Patients’ characteristics and safety data will be analyzed using SAS® software version 9.4 
(SAS Institute Inc., Cary, NC, USA). 
Pharmacokinetic data will be analyzed using NONMEM ICON Development Solutions 
v7.4) and R software (www.r-project.org, v3.2.2). 
 
 
Description of data sets 
9.3.1.
Several populations will be considered: 
The Included set will be defined as all included subjects. 
The Randomized set will be defined as all randomized subjects. 


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The Safety set will be defined as all included subjects having taken at least one dose of IMP. 
The PK set will be defined as all randomized subjects having taken at least one dose of IMP 
without protocol deviation affecting PK evaluation and with available PK data. 
The analysis sets will be validated during the final data review meeting. 
A summary of protocol deviations by treatment group and the corresponding listing by 
subject will be generated. 
 
 
Hypothesis and statistics 
9.3.2.
No formal statistical hypothesis will be tested. Safety data including but not limited to AEs, 
vital signs, ECGs, and laboratory safety tests will be descriptively summarized by doses. 
Estimation approach will be adopted to estimate both the between- and within-subject PK 
variability and to assess the dose proportionality following single dosing of IFB-088.  
Descriptive statistics will be supplied according to the nature of the criteria: 
- Quantitative variables: sample size, arithmetic mean, standard deviation (SD), median, 
minimum and maximum (with geometric mean and coefficient of variation (CV) for PK); 
- Qualitative variables: sample size, absolute and relative frequencies per class. 
 
 
Interim Analysis and/or schedule of analyses 
9.3.3.
No formal interim analysis is planned. During dose escalation phases, PK and safety data 
will be reviewed on an in-stream basis to inform the dose escalation decision.  
Statistical analyses will be performed after achievement of each cohort in order to provide 
ongoing safety, PK data so that the DEC can have access to all information they need to 
decide the dose escalation. A statistical report will be generated for each DEC meeting, the 
content will be detailed in the DEC charter. 
A final analysis will be done after SAD part and after MAD part, statistical results will be 
presented in the clinical study report. 
 
 
Handling of dropouts and missing data 
9.3.4.
Dropout subjects will not be analyzed for pharmacokinetics. 
No repositioning of visits will be done. 
If not otherwise stated: 
- 
Missing data other than baseline values will not be replaced. 
- 
Baseline for safety parameters will be defined as the last available parameter value 
before and closest to the first dosing. 
 


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Demographic and baseline characteristics 
9.3.5.
The following analysis will be performed on the Randomized set. 
The subjects' demographic and baseline characteristics will be summarized by treatment 
group and listed by subject. 
Tables by treatment group with the number of subjects having at least one medical or 
surgical history and the corresponding listing by subject will be edited; by system organ 
class and preferred term, if relevant (MedDRA). Tables by treatment group with the 
number of subjects having at least one previous treatment and concomitant treatment and 
the corresponding listing by subject will be prepared.  
Baseline safety parameters: 
Individual safety data (clinical laboratory, vital signs, ECG and physical examination) 
measured before the first drug administration will be checked for validity of entrance 
criteria, and abnormalities will be documented. Abnormal physical findings at baseline will 
be listed. Individual abnormalities before dosing will be flagged in data listings and 
presented along with post-dose measurements in the statistical appendices.  
 
 
Study drug and concomitant therapy 
9.3.6.
Drug dispensing information and details of drug dosing (actual treatment received, actual 
dose received, date and time of drug intake) for each subject will be listed by treatment 
group. 
Subjects who received concomitant treatments along with the study drug will be listed by 
treatment group and subject. If relevant, concomitant medications will also be summarized 
by anatomic class and therapeutic class (ATC drug dictionary) for each treatment group and 
overall subjects, presenting the frequency of subjects (n) taking a given medication and the 
number of occurrence of each medication. 
 
 
Safety Analyses 
9.3.7.
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively according to standard international guidelines. 
 
Criteria 
9.3.7.1.
• 
Adverse events 
• 
Vital signs: supine and standing systolic and diastolic blood pressure, pulse rate, 
tympanic temperature 
• 
Standard 12-lead ECG 
• 
Laboratory parameters: hematology, coagulation, biochemistry, urinalysis 
• 
Physical examination 
• 
Vigilance (Bond and Lader VAS) 


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Methodology 
9.3.7.2.
Laboratory data (hematology, biochemistry, coagulation and urinalysis), vital signs, 
vigilance VAS and ECG parameters, (raw data and changes from baseline) will be 
described. 
In addition, vital signs, ECG and laboratory data could be compared to potentially clinically 
significant range (PCSA) to be specified in the SAP. 
All these parameters will be listed by subject and assessment time. Data that is out of 
normal ranges will be flagged as well clinical significance. 
Adverse events (AEs) will be coded according to the Medical Dictionary for Regulatory 
Activities (MedDRA version 21.0). They will be classified into pre-defined standard 
categories according to chronological criteria: 
• 
Pre-treatment AEs are defined as AEs that occurred or worsened (or become serious) 
prior to the first study drug administration. 
• 
The treatment-emergent AEs (TEAEs) are defined as AEs that occurred or worsened 
(or become serious) during an exposure of study drug. 
The number of subjects with at least one adverse event and number of AEs for each 
treatment group will be summarized by categories, and if relevant detailed by system organ 
class and preferred term. 
All safety analyses will be based on the TEAEs using the safety set. Pre-treatment AEs will 
be listed by subject in statistical appendices.  
TEAEs will be summarized by treatment group: 
• 
The number and percentage of subjects with at least one TEAE overall, any severe 
TEAE, any serious TEAE, and any TEAE leading to treatment discontinuation. 
• 
The number and percentage of subjects with at least one TEAE by system-organ class 
and preferred term. 
• 
The number of occurrences of TEAE by system-organ class and preferred term. 
Subjects presenting TEAEs will be listed, sorted by, treatment, system organ class, and 
preferred term. 
Serious adverse events will be listed, sorted by treatment and subject. 
 
 
Pharmacokinetic Analyses  
9.3.8.
A non-compartmental analysis to calculate pharmacokinetic parameters of IFB-088 and 
IFB-139 in plasma and urine (described in §3.2.2) will be performed by the 
Pharmacometrics Unit.  
Plasma concentrations of IFB-088 will be used to estimate pharmacokinetics parameters in 
human and compare to estimated pharmacokinetics parameters from inter-species model. 
Pharmacokinetic modeling will be performed using a non-linear mixed effects model with 


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NONMEM software (ICON Development Solutions v7.4). Data will be analysed using a 
first order conditional estimation method. The R software (www.r-project.org, v3.2.2) will 
be used for goodness-of-fit diagnostics and graphical displays. 
Pharmacokinetics data of SAD will be analyzed using a population pharmacokinetic 
modeling approach to develop a pharmacokinetic model in human. This new 
pharmacokinetic model will be used to estimate pharmacokinetic parameters and variability 
in human and simulate new dosing schemes (with AUC and Cmax information) to help 
choosing the doses for MAD. 
Pharmacokinetic modeling will be performed by the Pharmacometrics Unit. 
Pharmacokinetic data will be listed and presented in graphical and/or tabular form as 
appropriate to the data, and will be summarized descriptively.  
 
10. 
STUDY CONDUCT CONSIDERATIONS 
 
Regulatory and Ethical Considerations, Including the Informed 
10.1.
Consent Process 
 
Ethics Committee opinion 
10.1.1.
It is the responsibility of the Sponsor to seek and obtain the favorable opinion of the CPP 
(Independent Ethics Committee).  
The present trial will not be initiated until this favorable opinion is obtained. 
 
 
ANSM authorisation 
10.1.2.
It is the responsibility of the Sponsor to seek and obtain the authorization from ANSM 
(Agence Nationale de Sécurité du Médicament) for conducting the trial.  
The present trial will not be initiated until the ANSM authorization is received. 
 
 
Protocol Amendments 
10.1.3.
Any significant change (substantial modification) in the study requires a protocol 
amendment sent to ANSM and/or CPP. The investigator must not make any changes to the 
study without regulatory authorities and sponsor approval except when necessary to 
eliminate apparent immediate hazards to the subjects. 
 
 
Regulatory requirements and ethical considerations 
10.1.4.
In compliance with French law, according the articles R1121-10 to R1121-15 of the Public 
Health Code (Code de Santé Publique), an approval as a site for Phase 1 biomedical 
research was granted to the clinical unit by the regional Agency of Health (ARS) (Renewal 
numbers N° 2017-02 for CIC-CPCET, N°2017-8358 for Eurofins|Optimed) 


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The study will be conducted in accordance with all applicable regulatory requirements and 
in accordance with ICH Good Clinical Practice (GCP E6 R2), all applicable subject privacy 
requirements, and the guiding principles of the Declaration of Helsinki (last amendment 
2013).  
Written informed consent must be obtained from each subject prior to participation in the 
study. Two Inform Consent forms will be prepared, one for the SAD part and one for the 
MAD part. The form for the MAD, updated before implementation of this part, with the 
safety and PK results collected during the SAD part and with the MAD planned dose 
levels, will be submitted to the CPP. 
Subjects will be informed by an investigator of all pertinent aspects of the trial: the purpose 
of the study, the study drug, the trial procedures to be followed, including all invasive 
procedures, its possible risks and restrictions, the duration of subject’s participation, and the 
fee that they will receive. Each subject must be informed that participation in the study is 
voluntary and that he may withdraw from the study at any time, that records identifying the 
subjects will be kept in confidential manner, except for the trial monitor and the regulatory 
authorities which will be granted direct access to medical records for verification of data 
and study procedures, and that data collected on CRFs during the study will be documented 
in an pseudonymous fashion. An information sheet will be given to each subject. The 
language used in the oral and written information about the trial and written informed 
consent form, should be easily understandable to the subject. 
Before informed consent may be obtained, the investigator should provide the subject 
ample time and opportunity to inquire about details of the trial and to decide whether or not 
to participate in the trial. The subject should carefully read before signing and dating the 
informed consent form. The informed consent form must be signed and personally dated by 
both the subject and the investigator. A copy of the signed document should be given to the 
subject. A copy will be kept for 15 years by the investigator (the second copy given to the 
subject). 
Whenever important new information becomes available that may be relevant to the 
subject's consent, the written subject information sheet and any other written information 
provided to subjects will be revised by the sponsor and be submitted again to the Ethics 
committee for review and approval. The approved, revised information will be provided to 
each subject in the trial for signing and dating. The Investigator will explain the changes to 
the previous version. 
 
 
Subject confidentiality  
10.1.5.
All personal data collected and processed for the purposes of this study should be managed 
by the Investigator and his/her staff with adequate precautions to ensure confidentiality of 
those data, and in accordance with the Health Insurance Portability and Accountability Act 
applicable to French national laws and regulations on personal data protection and the 
General Data Protection Regulation nᵒ 2016/679. 
Monitors, auditors, and other authorized agents of the sponsor and/or its designee, the 
ethics committee approving this research, and ANSM, as well as those of any other 
applicable agency, will be granted direct access to the study subjects’ original medical 
records for verification of clinical study procedures and/or data, without violating the 


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confidentiality of the subjects to the extent permitted by the law and regulations. In any 
presentations of the results of this study or in publications, the subjects’ identity will remain 
confidential. 
 
 
Urgent Safety Measures 
10.1.6.
If an event occurs that is related to the conduct of the study or the development of the study 
treatment, and this new event is likely to affect the safety of subjects, the sponsor and the 
investigator will take appropriate urgent safety measures to protect subjects against any 
immediate hazard. See paragraph 8.3. 
 
Quality Assurance and Quality Control  
10.2.
 
Monitoring 
10.2.1.
The study will be monitored by the CRO Qualissima. 
In accordance with GCP, the monitor, representative of the sponsor will monitor the study 
and site activities to verify that the: 
• 
Data are authentic, accurate, and complete. 
• 
Safety and rights of subjects are being protected. 
• 
Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements. 
The monitor will check that the CRFs have been correctly completed, with comparison of 
source documents and check that AEs have been documented. 
Source data must be available at the study site to document the existence of the research 
subjects and to substantiate the integrity of study data collected. Source data must include 
the original documents relating to the study, as well as the medical treatment and medical 
history of the subject. 
The investigator agrees to allow the monitor direct access to all relevant documents. 
This study will be monitored at regular intervals, by mutual agreement of the investigator 
and the monitor. 
 
 
Audit/Inspection 
10.2.2.
The Sponsor or its representative may conduct audits at the investigative site, before, during or 
after the study. The Regulatory Authorities may also carry out an inspection at any time. In 
this case, the Investigator must inform the Sponsor as soon as he receives the notification of 
inspection. 
The investigator must allow the auditor(s) and inspector(s) to: 
• 
Inspect the site, facilities and material used for the study, 
• 
Meet the members of the team involved in the study, 


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• 
Have direct access to study data and source documents, 
• 
Consult all relevant documents  
 
 
Study and Site Closure 
10.2.3.
Upon completion or premature discontinuation of the study, the monitor will conduct site 
closure activities with the investigator or site staff, as appropriate, in accordance with 
applicable regulations and GCP. 
In addition, the sponsor reserves the right to temporarily suspend or prematurely 
discontinue this study at any time for reasons including, but not limited to, safety or ethical 
issues or severe non-compliance.  
 
 
Records Retention 
10.2.4.
Following closure of the study, the investigator must maintain all site study records and 
investigator file, in a safe and secure location. The records must be maintained to allow 
easy and timely retrieval, when needed (e.g., audit or inspection), and, whenever feasible, 
to allow any subsequent review of data in conjunction with assessment of the facility, 
supporting systems, and staff.  
To comply with all applicable regulatory requirements, the minimum retention time will be 
not less than 15 years. 
 
 
Report and Publication 
10.3.
 
Report 
10.3.1.
The results of the study will be reported in a Clinical Study Report. This report will be 
prepared by the investigational site according to the guidance ICH E3 “Structure and 
Content of Clinical Study Report”. 
 
 
Publications 
10.3.2.
The sponsor must review and approve any results of the study or abstracts for professional 
meetings prepared by the Investigator(s). Published data must not compromise the 
objectives of the study.  
 
 
 


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11. 
REFERENCES 
1. Buoen C, Holm S, Thomsen MS. (2003) Evaluation of the cohort size in phase 1 dose 
escalation trials based on laboratory data. J Clin Pharmacol. May;43(5):470-6. 
 
2. EMA (2017) Guidelines on strategies to identify and mitigate risks for first-in-human 
and early clinical trials with investigational medicinal products 
 
3. Ostermann M., Joannidis M.(2016) Acute kidney injury 2016: diagnosis and diagnostic 
workup. Critical care 20:299 
 
4. Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, 
Baker R, Dunbar GC. (1998) The Mini-International Neuropsychiatric Interview 
(M.I.N.I.): the development and validation of a structured diagnostic psychiatric 
interview for DSM-IV and ICD-10. Clin Psychiatry.;59 Suppl 20:22-33;quiz 34-57. 
 
5. Sibille M., Patat A., Caplain H., Donazzolo Y (2010). A safety grading scale to support 
dose escalation and define stopping rules for healthy subject firts-entry-into-man studies. 
Br J Clin Pharmacol 70:3, 736-748 
 
6. U.S. Food and Drug Administration. (2005). Guidance for Industry: Estimating the 
Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutic in Adult Healthy 
Volunteers. 
 
7. U.S. Food and Drug Administration. (2007) Guidance on Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials 
 
8. U.S. Food and Drug Administration (2010) Guidance for Industry: Pharmacokinetics in 
patients with Impaired Renal Function 
 
9. U.S. Food and Drug Administration (2009) Drug-Induced Liver Injury: Premarketing 
Clinical Evaluation 
 
 
10. U.S. Food and Drug Administration (1995) Guidance for Industry: Structure and 
Content of Clinical Study Reports (ICH E3) 
 
 
 


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12. 
APPENDICES 
 
Appendix 1: Liver Safety Algorithms 
12.1.
 
 
 
 
 
 
 
ALT or AST ≥3ULN? 
Bilirubin≥ 2xULN
(>35% direct) or
INR > 1.5 (if 
measured
No
No
Yes
Yes
Continue investigational medicinal product (IMP)
 
 
 
 
 
  
 
  
  
 
  
 
 

 
) 
  
 
 
 
 
  
  
 
  
Instruct subject to stop the IMP 
Notify the sponsor within 24 hours 
Check liver chemistries weekly until resolved 
Perform liver follow up assessments (serology, PK sample) 
Withdraw subject from study after complete liver chemistry 
monitoring 
Instruct subject to stop the IMP 
Notify the sponsor and arrange clinical follow-up within 24 hours 
Perform liver follow up assessments (serology, PK sample) 
Report as SAE 
Check liver chemistries twice weekly until resolved 
Consultation with hepatologist recommended 
Withdraw subject from study after complete liver chemistry 
monitoring 


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Appendix 2: Stopping rules 
12.2.
 
Stopping rules 
Individual subject 
Within a cohort/dose 
escalation 
ALT or AST ≥ 3 x ULN 
1 subject 
 
ALT or AST > 5 x ULN 
 
2 subjects 
Triglycerides ≥ 5.6 mmol/L 
1 subject 
2 subjects 
Creat > 1,2 x ULN or 
Increase in serum creat by ≥ 30 µmol/L within 24h or 
Increase in serum creat to ≥ 1,5 x baseline within 7 days 
1 subject 
2 subjects 
β2 microglobuline ≥ 2 x ULN 
1 subject 
2 subjects 
Hematuria > 2+ on dipstick verified by cytologic exam, on 
2 samples and considered at least possibly related to the 
IMP 
1 subject 
2 subjects 
QTcB and QTcF > 500 msec or 
Change from baseline: QTc  > 60 msec 
1 subject 
2 subjects 
HR < 45 or HR > 130 bpm* 
1 subject 
2 subjects 
SBP < 80 or SBP > 155 mmHg 
1 subject 
2 subjects 
DBP > 100 mmHg 
1 subject 
2 subjects 
Occurrence of a Serious Adverse Event considered at least 
possibly related to the IMP administration 
1 subject 
1 subject 
Possibly drug related severe AEs in the same cohort, 
independent of within or not within the same system-organ 
 
2 subjects 
Clinically significant drug-related laboratory abnormalities 
of the same character  
 
2 subjects 
AUC(0-inf) > 111.14 ng/ml.h-1 or  
Cmax > 23.77 ng/ml 
 
1 subject (only for 
dose escalation) 
* When resting heart rate is between 60-100 beats per minutes. Use clinical judgment when 
characterizing bradycardia among some healthy subject populations, for example, conditioned 
athletes.