A Phase I Clinical Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of Single Doses of 4P004 Versus Placebo Injected in the Target Knee of Patients With Grade 2 to 4 Osteoarthritis on the Kellgren and Lawrence Severity Index
Phase: PHASE1
Conditions: Knee Osteoarthritis
Sponsor: 4Moving Biotech

 
 
 
 
 
 
 
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A Phase I Clinical Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of 
Single Ascending Doses of 4P-004 Versus Placebo Injected in the Target Knee Joint 
of Patients with Grade 2 to 4 Osteoarthritis on the Kellgren and Lawrence Severity 
Index. 
 
Protocol Name:  
 
LASARE 
Compound:   
 
LIRAGLUTIDE 
Sponsor Name:  
 
4Moving Biotech 
Legal Registered Address:  Campus de l’Institut Pasteur de Lille 
1 rue du Professeur Calmette, 59 000 Lille (France) 
Protocol code number:  
4MB-LAS-P 
Scientific Coordinator: 
Professor Francis BERENBAUM 
Study CRO:   
 
ARTIALIS SA. 
EudraCT: 
 
 
2022-000703-12 
EU CT: 
 
 
2022-500271-31-00 
 
Date : 
17-July-2023  
 
 
 
Version 
Date 
Author 
Summary of Changes 
1.0 
28/04/22 
O. FLEUROT 
 
1.1 
09/06/22 
O. FLEUROT 
Addition of one stopping rule and 
modification of data protection section 
2.0 
09/05/2023 
O. FLEUROT 
Modification of V1 window 
Addition of window for serology tests 
Modification of T0-15 window changed to 
T0-4h window 
Addition of ECG window at T12 
Modification of laboratory detail regarding 
PK analysis 
Typo of WBC unit 
Modification of I16 inclusion criteria 
Modification of E10 exclusion criteria 
Change in unit of hypoglycemia 
3.0 
17/07/2023 
O. FLEUROT 
Change in dose to be received by cohort 4: 
according to the blinded clinical safety 
review in cohort 3 the Sponsor considered 
that the MTD may have been reached and 
wants to test a lower dose (below cohort 3 
dose). The dose of 6 mg (or 4.5 mg) will not 
be tested. 

 
 
 
 
 
 
 
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The cohort 4 will receive either 4P004 2 mg 
or placebo. 
 
 
 

 
 
 
 
 
 
 
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INTERVENTIONAL RESEARCH PROTOCOL 
RELATING TO A MEDICINAL PRODUCT FOR HUMAN USE 
PROTOCOL SIGNATURE PAGE 
 
Title: A Phase I Clinical Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of Single Ascending Doses of 
4P-004 Versus Placebo Injected in the Target Knee Joint of Patients with Grade 2 to 4 Osteoarthritis on the Kellgren 
and Lawrence Severity Index (LASARE) 
 
Version   
 
 N° 3.0 of 17/07/2023 
Protocol code number :  
4MB-LAS-P 
EudraCT number:   
2022-000703-12 
EU CT:  
 
2022-500271-31-00 
 
The study will be carried out in accordance with the protocol, with current good practices and with statutory and 
regulatory requirements. 
 
Name of Local Principal Investigator: 
Address: 
 
I have read the protocol and agree that the study will be conducted in compliance with the protocol and in accordance 
with the principles of the current version of the Declaration of Helsinki (Recommendations guiding Medical Doctors in 
Biomedical Research Involving Human Patients). The conduct of the study will be in accordance with the Notes for 
Guidance on Good Clinical Practice (CPMP/ICH/135/95). 
I acknowledge that I am responsible for the 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 at my 
site are informed about their obligations. Mechanisms are in place to ensure that site staff receive the appropriate 
information throughout the study. 
 
Date:  
 
 
  
 
 
Local Principal Investigator’s Signature: 
 
 
4Moving Biotech, Sponsor 
Professor Francis BERENBAUM 
CEO & CMO 
Address : Campus de l’Institut Pasteur de Lille-1, rue du Professeur Calmette, 59000 Lille, France 
Date:  
 
 
 
 
 
Signature:  
 

 
 
 
 
 
 
 
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Table of content 
1 STUDY SUMMARY ...................................................................................................................... 8 
1.1 Synopsis ..................................................................................................................................... 8 
1.2 Study flowcharts ..................................................................................................................... 10 
1.2.1 Whole study flowchart ...................................................................................................... 10 
1.2.2 Visit 2 (randomization): D1-D2 study flowchart (24h hospitalization) ............................ 11 
1.2.3 Global study scheme ......................................................................................................... 12 
2 INTRODUCTION ........................................................................................................................ 13 
2.1 Background ............................................................................................................................ 13 
2.2 Rationale ................................................................................................................................. 15 
2.3 Risk / Benefit Assessment ...................................................................................................... 16 
3 OBJECTIVES AND ENDPOINTS ............................................................................................. 17 
3.1 Objectives ................................................................................................................................ 17 
3.1.1 Primary objectives ............................................................................................................. 17 
3.1.2 Secondary objective .......................................................................................................... 17 
3.1.3 Exploratory objectives ....................................................................................................... 17 
3.2 Endpoints ................................................................................................................................ 18 
3.2.1 Primary endpoints ............................................................................................................. 18 
3.2.2 Secondary endpoint ........................................................................................................... 18 
3.2.3 Exploratory endpoints ....................................................................................................... 18 
4 STUDY DESIGN AND DESCRIPTION .................................................................................... 18 
4.1 Overall design ......................................................................................................................... 18 
4.2 Scientific rationale for study design ..................................................................................... 19 
4.3 Justification for route of administration .............................................................................. 19 
4.4 Justification for dose .............................................................................................................. 20 
4.5 End of study definition .......................................................................................................... 20 
4.6 Early study termination ........................................................................................................ 20 
4.6.1 Clinical criteria for early study termination ...................................................................... 21 
4.6.2 Criteria for premature termination or suspension of investigational sites......................... 22 
5 STUDY POPULATION ............................................................................................................... 22 
5.1 Inclusion criteria .................................................................................................................... 22 
5.2 Exclusion criteria ................................................................................................................... 22 
5.3 Screen failures ........................................................................................................................ 23 
6 STUDY INTERVENTION .......................................................................................................... 24 
6.1 Study intervention administered .......................................................................................... 24 

 
 
 
 
 
 
 
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6.1.1 Liraglutide ......................................................................................................................... 24 
6.1.2 Placebo .............................................................................................................................. 24 
6.2 Preparation / Handling / Storage /Accountability .............................................................. 24 
6.2.1 IMP preparation, administration and handlings ................................................................ 24 
6.2.2 IA injection ........................................................................................................................ 24 
6.3 Measures to minimize bias: randomization and blinding .................................................. 25 
6.4 Changes in IMP cohort dosing.............................................................................................. 26 
6.5 Concomitant therapy ............................................................................................................. 26 
7 DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL .............................................................................................................................. 26 
7.1 Discontinuation of study intervention .................................................................................. 26 
7.2 Participant discontinuation / Withdrawal from the study ................................................. 26 
7.3 Lost to follow up ..................................................................................................................... 27 
8 STUDY ASSESSMENTS AND PROCEDURES ....................................................................... 27 
8.1 Safety assessments .................................................................................................................. 28 
8.1.1 Physical examination ......................................................................................................... 28 
8.1.2 Vital signs .......................................................................................................................... 28 
8.1.3 Electrocardiograms ............................................................................................................ 28 
8.1.4 Clinical safety laboratory assessment ............................................................................... 28 
8.1.5 Local safety ....................................................................................................................... 29 
8.1.6 Target knee pain ................................................................................................................ 29 
8.2 Adverse events and serious adverse events .......................................................................... 29 
8.2.1 Time period and frequency for collecting AE, AESI and SAE ........................................ 30 
8.2.2 Method of detecting AEs and SAEs .................................................................................. 30 
8.2.3 Follow-up of AEs and SAEs ............................................................................................. 30 
8.2.4 Regulatory reporting requirements for SAEs .................................................................... 30 
8.2.5 Pregnancy .......................................................................................................................... 31 
8.2.6 Adverse event of special interest (AESI) .......................................................................... 31 
8.3 Treatment of overdose ........................................................................................................... 31 
8.4 Pharmacokinetics ................................................................................................................... 32 
8.4.1 Pharmacokinetic sample collection ................................................................................... 32 
8.4.2 Bioanalytical methods ....................................................................................................... 32 
8.4.3 Pharmacokinetic parameters.............................................................................................. 32 
8.5 Visits requirements ................................................................................................................ 32 
8.5.1 Screening visit, D-7 (D-14 to D-4) .................................................................................... 32 
8.5.2 Inclusion visit, D1, full day hospitalization ...................................................................... 33 

 
 
 
 
 
 
 
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8.5.3 Hospital discharge, D2 ...................................................................................................... 33 
8.5.4 Phone call (Virtual visit), D4 ± 1d .................................................................................... 34 
8.5.5 Follow-up visit, D8 ± 2d ................................................................................................... 34 
8.5.6 EoS visit: Phone call (Virtual visit), D29 ± 2d ................................................................. 34 
8.6 Participant compensation ...................................................................................................... 35 
9 DATA MANAGEMENT .............................................................................................................. 35 
9.1 Data Capture .......................................................................................................................... 35 
9.2 Access Rights .......................................................................................................................... 35 
9.3 Audit Trail .............................................................................................................................. 35 
9.4 Data Sources ........................................................................................................................... 35 
9.4.1 Investigator’s site data ....................................................................................................... 35 
9.4.2 Participant reported outcome............................................................................................. 36 
9.5 Data Validation ...................................................................................................................... 36 
9.6 Coding ..................................................................................................................................... 36 
9.7 Data Lock ................................................................................................................................ 36 
10 STATISTICAL METHODS ...................................................................................................... 36 
10.1 Statistical and analytical plans ........................................................................................... 36 
10.1.1 Analysis sets .................................................................................................................... 36 
10.1.2 Analysis of demographics and other baseline characteristics ......................................... 37 
10.1.3 Pharmacokinetic analysis ................................................................................................ 37 
10.1.4 Safety analysis ................................................................................................................. 37 
10.1.5 Surrogate efficacy markers analysis ................................................................................ 38 
10.2 Sample size determination .................................................................................................. 38 
11 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........ 39 
11.1 Appendix 1: Regulatory, ethical, and study oversight considerations ............................ 39 
11.1.1 Regulatory and ethical consideration .............................................................................. 39 
11.1.2 Financial disclosure ......................................................................................................... 40 
11.1.3 Informed Consent Process ............................................................................................... 40 
11.1.4 Data protection ................................................................................................................ 40 
11.1.5 Data and Safety Monitoring Board ................................................................................. 42 
11.1.6 Data quality assurance ..................................................................................................... 42 
11.1.7 Source documents ........................................................................................................... 43 
11.1.8 Study and site start and closure ....................................................................................... 43 
10.1.9 Publication policy ............................................................................................................ 44 
11.2 Appendix 2: Clinical safety laboratory tests ..................................................................... 44 
11.3 Appendix 3: Adverse events Definitions, Recording and Reporting ............................... 45 

 
 
 
 
 
 
 
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11.3.1 Definition of AE .............................................................................................................. 45 
11.3.2 Definition of SAE ............................................................................................................ 46 
11.3.3 Definition of SUSAR ...................................................................................................... 47 
11.3.4 Recording and follow-up of AE and/or SAE .................................................................. 47 
11.3.5 Reporting of SAEs, and Other Reportable Safety Events to the Medical monitor ......... 50 
11.4 Appendix 4: Contraceptive guidance and collection of pregnancy information ............ 50 
11.4.1 Definitions ....................................................................................................................... 50 
11.4.2 Contraceptive guidance ................................................................................................... 51 
11.4.3 Collection of pregnancy information .............................................................................. 52 
11.5 Appendix 5: Exploratory tests ............................................................................................ 53 
11.6 Appendix 6: Abbreviations ................................................................................................. 53 
11.7 Appendix 7: References ....................................................................................................... 56 
 
 
 

 
 
 
 
 
 
 
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1 STUDY SUMMARY 
 1.1 Synopsis 
Protocol title 
A Phase I Clinical Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of Single 
Ascending Doses of 4P-004 Versus Placebo Injected in the Target Knee Joint of Patients with Grade 
2 to 4 Osteoarthritis on the Kellgren and Lawrence Severity Index (KL 2-4). 
Short title 
Safety, tolerability and pharmacokinetics of intra-articular (IA) single ascending dose of 4P-004 in 
patient with Kellgren and Lawrence grade 2 to 4 osteoarthritic (OA) knee. 
Acronym 
LASARE : safety, tolerabiLity, and phArmacokinetics of Single Ascending doses of 4P-004 versus 
placebo injected in the taRget knee joint of patients with grade 2 to 4 ostEoarthritic (OA) knee. 
Objectives  
Primary objectives  
• To characterize safety and tolerability of single IA administration of 4P-004 at escalating 
doses (0.3, 1.0, 3.0 mg) in participants with knee OA.   
• To determine the maximum tolerated dose (MTD) defined by occurrence of Dose Limiting 
Toxicities (DLTs) 
Secondary objective 
• To characterize the plasma PK of liraglutide when administered as single IA doses at 
escalating dose levels in participants with knee OA. 
Exploratory Objectives 
• Collection of biological fluids (blood, urine) 
Endpoints 
Primary Endpoints  
• Number of Adverse Events (AEs), serious AEs (SAEs) (Common Terminology Criteria 
Adverse Events [CTC-AE]) including target knee pain, and tenderness, erythema, swelling, 
local pain at injection site. 
• Vital signs, ECG: Mean change, number of PCSA (Potentially Clinically Significant 
Abnormality), Percentage of participants with PCSA. 
• Laboratory changes (RBC, WBC, ALT, AST, glycemia, amylasemia, creatinin clearance): 
Mean changes number of PCSA, Percentage of participants with PCSA. 
Secondary Endpoint 
• Plasma concentration of liraglutide following a single IA injection. PK samples: pre-injection 
(T0-4h) and 2, 4, 8, 12, 16 and 24-hours post injection. 
Exploratory endpoints 
Serum and Urine OA-related biomarkers (exploratory proteomic research of 4P-004 efficacy-
related biomarkers). 
Overall design 

 
 
 
 
 
 
 
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This phase I study is a multicenter, randomized, double-blind, placebo-controlled study to assess the 
safety and tolerability of single ascending dose of IA 4P-004 at 0.3, 1.0, 3.0  mg in participants,  
• Between 18 and 80 years of age, 
• with target knee OA stage KL 2-4 
A total of 32 participants will be enrolled in 4 cohorts, in each cohort participants will receive either 
4P-004 or placebo (6:2).  
Description of Sites/Facilities Enrolling Participants 
Three investigational sites will participate. 
Participants will be recruited via investigator’s patient register or via advertising. 
Description of study intervention  
4P-004 at 0.3, 1.0, 3.0 and 2.0 mg or placebo IA injection  
Data and Safety Monitoring Board (DSMB) 
The DSMB will be composed of 2 independent physicians specialized, one in rheumatology and 
one in diabetology.  
After each dose level completion (and at any time if needed), a DSMB evaluation based on a safety 
data analysis is intended by the sponsor before moving forward to the next higher dose level (or to 
randomize the next participant).  
Study Duration 
The total duration of the study is approximately 7 months  
Participant Duration 
The total duration of the study will be around 5 to 6 weeks for each participant: 
• Screening between 4 to 14 days before treatment (D-14 to D-4) 
• Treatment period of 1 day (D1) 
• Follow-up period of 28 days  
 
 

 
 
 
 
 
 
 
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1.2 Study flowcharts 
1.2.1 Whole study flowchart 
 
Study Period 
SCR 
RDZ 
FU  
 
EoS 
Study  Day (D) 
D-7 
D-14/D-4 
D1* 
D2 
D4 ±1d 
D8** ±2d 
D29 ±2d 
Visit (V)/ Phone Call (PC) 
Number 
V1 
V2 
PC1 
V3 
PC2 
Informed consent 
x 
  
 
  
  
  
Incl/excl criteria 
x 
x 
 
  
  
  
ECG 
x 
x 
 
  
  
  
Target knee X Ray*** 
x 
 
 
 
 
 
Medical history 
x 
x 
 
  
  
  
Prior & conc medication 
x 
x 
x 
x 
x 
x 
Demographics 
x 
  
 
  
  
  
Body Weight 
x 
 x 
 
  
 x 
 
Hospitalization 
 
    <---------> 
 
 
 
Inclusion 
  
x 
 
  
  
  
Randomization 
  
x 
 
  
  
  
Diary distribution 
x 
 
 
 
 
 
Diary Verification 
 
x 
x 
x 
x 
x 
Study treatment 
  
  
 
  
  
  
Knee IA injection 
  
x 
 
  
  
  
Safety assessment 
  
  
 
  
  
  
Physical Exam 
x 
x 
x 
  
x 
  
Vital Signs 
x 
x 
x 
  
x 
  
AEs / SAEs / AESI 
 
x 
x 
x 
x 
x 
Target knee pain 
x 
x 
x 
x 
x 
x 
Local reaction 
 
x 
x 
 
 
 
Blood PK  
  
x 
x 
  
  
  
Clinical safety laboratory tests 
 
 
 
 
 
 
SARS-CoV-2 Rapid Antigen Test 
 
(x) 
 
 
 
 
Hematology 
x 
  
 
  
x 
  
Chemistry / Serology 
x 
  
 
  
x 
  
Glycemia / Glucose meter  
x 
x 
 
  
x 
  
Urine Pregnancy test 
  
x 
 
  
  
  
Exploratory analyses 
  
  
 
  
  
  
Blood Sample 
 
x 
x 
 
x 
 
Urine Sample 
 
x 
x 
  
x 
  
 EoS: end-of-study, FU: follow-up, RDZ: randomization, SCR: screening  
 
 
*D1 is a full day hospital (approximately 24 hours), the participant is discharged on D2. 
**D8 Visit: to be performed at any time (before D8) in case of premature study discontinuation. 
***Target knee X Ray: to be done locally before D1, but not necessary if performed within the 6 
previous months. 
 

 
 
 
 
 
 
 
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Clinical safety laboratory tests: 
• Results of SARS-CoV-2 Rapid Antigen Test should be negative on D1 before definitive 
inclusion and randomization in the study (test to be performed if required according to 
standard practice on site), 
• Urine Pregnancy test for WOCBP should be negative on D1 before definitive inclusion and 
randomization in the study, 
• Results of RBC, Hemoglobin, WBC, Platelets, AST, ALT, Amylasemia, creatinine clearance 
should be obtained before D1 (sampling within 14 days before D1), 
• Tests for Human Immunodeficiency Virus (HIV), hepatitis B virus [Hepatitis B surface 
Antigen (HBsAg)] and hepatitis C virus [Hepatitis C virus antibodies (HCV-Ab)] can be based 
on participant-reported medical history, available medical records, and the most recently 
available laboratory results for the participant (tests performed within the previous 12 
months). 
 
 
1.2.2 Visit 2 (randomization): D1-D2 study flowchart (24h hospitalization) 
 
D1 / D2 
T0 - 4h* 
T0 
1h 
2h 
3h 
4h 
5h 
6h 
8h 
10h 
12h 
16h 
24h 
Urine Pregnancy Test 
x 
 
 
 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 Rapid Antigen Test 
(x) 
 
 
 
 
 
 
 
 
 
 
 
 
Definitive inclusion 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization** 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
Bodyweight 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Veinous line 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
IMP IA injection 
 
x 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
x 
 
x 
x 
 
x 
 
 
x 
 
x 
 
x 
ECG 
x 
 
 
 
 
 
 
 
 
 
x*** 
 
 
AEs / SAEs / AESI 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Target knee pain  
x 
    x 
x 
x 
x 
x 
x 
 
 
 
 
x 
Local reaction  
 
   
x 
x 
x 
x 
x 
 
 
 
 
 
x 
Glycemia 
x 
 
 
x 
 
x 
 
 
x 
 
x 
x 
 
Blood glucose meter 
x 
  
x 
 
 
 
 
x 
 
x 
 
 
x 
Blood PK sample 
x 
 
 
x 
 
x 
 
 
x 
 
x 
x 
x 
Blood sample 
x 
 
 
 
 
 
 
 
x 
 
 
 
x 
Urine Sample 
x 
 
 
 
 
 
 
 
x 
 
 
 
x 
 
*For practical reasons, all procedures planned before T0 (time of administration) can be done 
within 4 hours before T0.  
**Randomization will be done before T0once results of the SARS-CoV-2 test (if required 
according to standard practice on site) and urine pregnancy test (if necessary) are available. 
All assessments after T0 must be carried out ± 10 minutes compared to the theoretical time. 
*** A time window of ± 2 hours for the ECG planned at T0 +12 is allowed  
AEs / SAEs / AESI reporting is continuous during the hospitalization 
 

 
 
 
 
 
 
 
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1.2.3 Global study scheme 
 
 

 
 
 
 
 
 
 
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2 INTRODUCTION 
2.1 Background 
Osteoarthritis (OA) has been defined as “a disorder involving movable joints characterized by cell 
stress and extracellular matrix degradation initiated by micro- and macro-injury that activates 
maladaptive repair responses including pro-inflammatory pathways of innate immunity. The disease 
manifests first as a molecular derangement (abnormal joint tissue metabolism) followed by anatomic, 
and/or physiologic derangements (characterized by cartilage degradation, bone remodeling, 
osteophyte formation, joint inflammation and loss of normal joint function), that can culminate in 
illness.” (OARSI). The disease occurs when the dynamic equilibrium between the breakdown and 
repair of joint tissues becomes unbalanced, often in a situation where the mechanical loads applied 
exceed those that can be tolerated by the joint tissues. 
OA is characterized by progressive cartilage loss, subchondral bone-remodeling, osteophyte 
formation and synovial inflammation, with resultant joint pain and increasing disability. OA can 
affect single and/or multiple peripheral joints such as knee, hip, and hand. 
Globally prevalent cases of osteoarthritis increased (and disability induced by OA) by more than 
110% in almost 30 years with 517 million of affected people (GBD et al., 2020; Long et al., 2022). 
The current therapeutic arsenal of OA aims at alleviating pain and minimizing loss of physical 
function. To date, there is no structural-modifying drug to slow or revert the disease. More precisely, 
standard therapy is patient personalized and includes changes in lifestyle (nutrition, exercise, weight 
loss, physical therapy) and symptom-modifying medications (paracetamol, topical and/or oral non-
steroidal anti-inflammatory drugs (NSAIDs), opioid analgesics, IA injections of corticosteroids, and 
hyaluronic acid although there is no consensus to consider the latter a standard therapy. Prosthetic 
replacement surgery is performed when OA symptoms are advanced, and pain is unmanageable. 
Liraglutide is a biotechnology-derived peptide for which the mechanism of action relies on the 
glucagon-like peptide GLP-1 receptor (GLP-1 receptor or GLP-1R) thanks to its GLP-1 analogue 
structure. GLP-1R is involved in the control of blood sugar level by enhancing insulin secretion. 
Liraglutide was originally studied as an agent that stimulates insulin release from pancreatic beta cells 
following oral nutrient ingestion, or postprandially, as well as an agent slowing stomach emptying 
with an impact on body weight management. These biological activities are the basis of the clinical 
indications claimed for the marketed product Victoza® (SmPC provided in IB, Appendix I), 
Saxenda® and Xultophy® (in association with insulin degludec) currently authorized in more than 
50 countries including the EU, USA, UK, Canada, Australia. 
Considering the following: 
(i) 
Recent studies reporting the impact of the GLP-1 – GLP-1R axis stimulation in 
chondrocytes (Que et al., 2019; Meurot et al., 2022) and macrophages (Shiraishi et al., 
2012), 
(ii) 
The key roles of chondrocytes and macrophages in the formation and progression of 
osteoarthritis, 
(iii) 
The current therapeutic arsenal of osteoarthritis aims at alleviating pain and minimizing 
loss of physical function without disease modifying action,  

 
 
 
 
 
 
 
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the sponsor has investigated the potential of liraglutide to treat OA. Indeed, chondrocytes and 
macrophages play a crucial role in the progression of OA in patients and acting in concert on these 
two cell types could prove beneficial as a curative treatment for OA. 
Unlike the approved conditions of Victoza® as detailed in the SmPC (i.e., daily subcutaneous bolus 
administration of maximum 1.8 mg), the investigational medicinal product (IMP) 4P-004 is intended 
to be administered by IA injection once.  
4P-004 is intended to prevent OA associated physiopathological degeneration (“Prevent structural 
damage” as per CPMP/EWP/784/97 Rev. 1 “Guideline on clinical investigation of medicinal products 
used in the treatment of osteoarthritis”).  
In the current Investigator’s Brochure (IB), all IMP-related non-clinical and clinical data supporting 
the safety and efficacy of the following items are provided: 
• The new route of administration, 
• The dose regimen, 
• The indication in OA. 
 
PK Data 
In human, after a single subcutaneous (SC) administration (current authorized route of administration) 
liraglutide is well absorbed from the injection site. Overall bioavailability following SC 
administration is estimated to be 55% in human. The distribution volume is low and close to plasma 
volume, which indicates that a high fraction of liraglutide is circulating in plasma. Liraglutide is 
extensively bound to plasma protein (>98%). 
The mean clearance following subcutaneous administration of a single dose liraglutide is 
approximately 1.2 l/h with an elimination half-life of approximately 13 hours. 
Renal impairment 
No dose adjustment is required for patients with mild or moderate renal impairment. There is no 
therapeutic experience in patients with end-stage renal disease, and Victoza is therefore not 
recommended for use in these patients. 
Hepatic impairment 
No dose adjustment is recommended for patients with mild or moderate hepatic impairment. Victoza 
is not recommended for use in patients with severe hepatic impairment. 
Interaction Data 
In vitro, liraglutide has shown very low potential to be involved in pharmacokinetic interactions with 
other active substances related to cytochrome P450 and plasma protein binding. 
The small delay of gastric emptying with liraglutide may influence absorption of concomitantly 
administered oral medicinal products. Interaction studies did not show any clinically relevant delay 
of absorption and therefore no dose adjustment is required. 
 
Safety pharmacology 
Safety pharmacology studies were performed in rats and dogs to evaluate any adverse effects on the 
central nervous system (CNS), the respiratory system, or the cardiovascular system during initial 
marketing authorization. A transient and mild increase in glycemia was observed in male and female 

 
 
 
 
 
 
 
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rats following anesthesia and IA administration of 300 μg of 4P-004 that was resolved at 24h. This 
transient and reversible effect on blood glucose was not observed after IA knee joints administration 
of 0.9 mg of 4P-004 in Beagle dogs. 
 
2.2 Rationale 
OA is a slowly degenerative disease that affects the whole joint with impact on the articular cartilage, 
subchondral bone and the synovial membrane. Identified risks factors for OA include age, sex, 
obesity, traumatic injuries (post-traumatic OA) and cardiometabolic factors. Dysregulation in 
glucose, lipid metabolism as well as overall low-grade inflammation are common phenotypes found 
in OA and metabolic disease, which prompted scientists to suggest that OA was not only a age-related 
degenerative disease but also a proper component of the metabolic syndrome (metabolic OA) 
(Kornaat et al.,2009;  Courties, et al., 2017).  
Glucagon-like peptide-1 (GLP-1) belongs to the incretin family, a group of hormones with glucose-
dependent insulin secretion activity. Notably Glucagon-Like Peptide 1(GLP-1) analogues such as 
liraglutide have been developed and used in humans since 2009 for the treatment of type 2 diabetes 
mellitus. In recent years, numerous studies have detailed the anti-inflammatory impact of GLP-1 in 
numerous organs and diseases (Nauck, 2016; Li et al., 2017). Thus, GLP-1 analogues could also 
prove beneficial for OA treatments.   
The non-clinical studies (in vitro and in vivo) in the literature or conducted by the sponsor with 
liraglutide provide a mechanistic basis for its primary pharmacological effect for the target indication 
in OA, whereby liraglutide with its anti-inflammatory, anti-catabolic and anabolic activities acts in 
concert on the synovial membrane inflammation and the articular cartilage to alleviate OA-related 
symptoms and structure damages. 
GLP-1 binds to the Glucagon-like-peptide-1 receptor (GLP-1 receptor or GLP-1R). In cartilage, GLP-
1 receptor is expressed in OA human chondrocytes (Meurot et al., 2022), and the agonist activity of 
liraglutide on this receptor increases rat chondrocytes viability through increased resistance against 
cell-stress and apoptosis (Chen et al., 2018). Furthermore, liraglutide dose-dependently decreases the 
secretion and gene expression of metalloproteinases (MMP-3, MMP-13) and aggrecanases 
(ADAMTS-4, ADAMTS-5), while increasing the gene expression of Sox9, a transcription factor 
crucial for chondrocytes differentiation, collagen 2 and aggrecan, thus liraglutide possesses anti-
catabolic activity and anabolic activities in murine chondrocytes (Meurot et al., 2022). In the 
destabilization of medial meniscus (DMM) model, a surgically induced OA model in rat, repeated IA 
injections of liraglutide 60µg for 6 weeks decreases proteoglycan loss resulting in significantly less 
cartilage degeneration width model of OA (sponsor, see IB), the benefits of liraglutide on cartilage 
structure is also confirmed in the literature (Chen et al., 2018). 
Liraglutide presents strong anti-inflammatory activity and decreases in a dose-dependent manner the 
secretion of NO, PGE2, IL-6 by murine macrophages and chondrocytes in vitro (with an average 
IC50 value of 50 nM). In the monoiodoacetate (MIA) rat model of inflammatory OA and pain, a 
single IA administration of liraglutide dose-dependently decreases pain during von Frey test 
(mechanically induced pain assessment), with a long-lasting effect of 4 weeks (sponsor). 
Furthermore, in the MIA-induced OA mouse, single administration of Liraglutide decreases 

 
 
 
 
 
 
 
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mechanically induced pain as well as synovial membrane inflammation score (liraglutide 
20 µg, p = 0.0099, compared to vehicle-treated group) (Meurot et al., 2022).  
Additionally, it has been demonstrated that liraglutide GLP-1R agonist does not exhibit cytotoxic 
effects on chondrocytes, prevents from interleukin-mediated cytotoxicity (Chen et al, 2018) and 
shows an anti-inflammatory activity through the PKA/CREB pathway activation (Que et al, 2019).  
 
Pharmacokinetic exploration of liraglutide distribution demonstrates that subcutaneous 
administration does not allow liraglutide passage within synovial fluid of animals while intra-articular 
administration would provide a synovial exposition. In addition, IA administration of liraglutide leads 
to systemic level comparable with those observed upon subcutaneous administration. Thus, the intra-
articular route of administration is necessary to obtain a local action on OA tissues. 
Therefore, and in contrast with the current standard of care in OA, these mechanisms of action allow 
to prevent structural damages during the evolution of the disease (cartilage protection) and alleviate 
symptoms with a long-lasting analgesic effect. Thus, IA administration of 4P-004 is expected to act 
as a disease-modifying OA drug (DMOAD) upon IA administration. 
 
2.3 Risk / Benefit Assessment 
The safety profile of 4P-004 is well known when administered subcutaneously (for long-term use) 
but no human data is available regarding the safety profile after IA injection.  
As part of its preclinical data package, the sponsor intends to rely on previously published and 
assessed data of liraglutide containing authorized medicinal products (Victoza®, Saxenda®) to 
address systemic safety and toxicology of liraglutide. PK studies performed in dogs have shown very 
reproducibly that there is no more liraglutide after 24h in the articulation after IA injection in the 
knee-joint (see IB). A GLP extended single dose toxicity study of knee IA administration 4P-004 has 
been performed in rats. The product was well tolerated, no adverse signs of toxicity were observed 
up to the higher tested dose of 300 µg, which was determined as the No Observed Adverse Effect 
Level (NOAEL) dose of the study. Detailed presentation of the GLP-Toxicity study is available in 
the current IB. 
Liraglutide adverse events 
The most frequently reported adverse reactions during clinical trials were gastrointestinal disorders 
(repeated subcutaneous administration):  
• nausea and diarrhea were very common (≥1/10),  
• vomiting, constipation, abdominal pain, and dyspepsia were common (≥1/100 to <1/10). 
Headache and nasopharyngitis were also common. 
Hypoglycemia was common, and very common when liraglutide is used in combination with a 
sulfonylurea in patients with type 2 diabetes mellitus (Victoza®). 
In clinical trials in overweight or obese patients without type 2 diabetes mellitus treated with 
Saxenda®, no severe hypoglycemic events (requiring third party assistance) were reported. Symptoms 
of hypoglycemic events were reported by 1.6 % of patients treated with Saxenda® and 1.1% of 

 
 
 
 
 
 
 
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patients treated with placebo; however, these events were not confirmed by blood glucose 
measurements. The majority of events were mild. 
Allergic reactions including urticaria, rash and pruritus have been reported from marketed use of 
liraglutide. Few cases of anaphylactic reactions with additional symptoms such as hypotension, 
palpitations, dyspnea, and oedema have been reported with marketed use of Victoza. Few cases 
(0.05%) of angioedema have been reported during all long-term clinical trials with Victoza. 
Liraglutide overdose 
From clinical trials and marketed use, overdoses have been reported of up to 40 times (72 mg) the 
recommended maintenance dose (Nakanishi et al., 2012). Events reported included severe nausea, 
vomiting, diarrhea and severe hypoglycemia. 
In the event of overdose, appropriate supportive treatment should be initiated according to the 
participant’s clinical signs and symptoms. The participant should be observed for clinical signs of 
dehydration and blood glucose should be monitored. 
Additional details regarding risks for participants in this clinical study may be found in the SmPC/IB 
and informed consent documents. 
 
Blind review by the Sponsor of ongoing clinical safety data in Cohort 3 (as of 17 July 2023):  
After blinded review of clinical safety data in cohort 3 (dose = 3mg), the Sponsor decided that, taking 
into consideration the benefit/risk for patients and the potential issues of performing a future double-
blind  study, the Maximum Tolerated Dose may have been reached based on adverse event “nausea” 
for 5 participants and “vomiting” for 4 of them. Consequently, the Sponsor decided to test an 
intermediate dose of 2 mg in cohort 4 to obtain clinical safety information with this dose. Higher 4P-
004 doses than 3 mg will not be tested in this study. 
 
3 OBJECTIVES AND ENDPOINTS 
3.1 Objectives 
3.1.1 Primary objectives 
• To characterize safety and tolerability of single IA administration of 4P-004 at escalating 
doses (0.3, 1.0, 3.0 mg) in participants with knee OA grade 2 to 4 osteoarthritis (OA) on the 
Kellgren and Lawrence severity index (KL 2-4)  
• To determine the maximum tolerated dose (MTD) defined by occurrence of Dose Limiting 
Toxicities (DLTs) in participants with knee OA KL 2-4. 
3.1.2 Secondary objective 
• To characterize the plasma PK of liraglutide when administered as single IA doses at 
escalating dose levels in participants with knee OA KL 2-4. 
3.1.3 Exploratory objectives 
• Collection of biological fluids (blood, urine). 
 

 
 
 
 
 
 
 
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3.2 Endpoints 
3.2.1 Primary endpoints 
• Number of Adverse events (AEs), serious AEs (SAEs) (Common Terminology Criteria 
Adverse Events [CTC-AE]) from ICF signature to D29, including target knee pain and 
tenderness, erythema, swelling, local pain at injection site. 
• Vital signs from D-7 to D8, ECG from D-7 to D1: Mean change, number of Potentially 
Clinically Significant Abnormality (PCSA), Percentage of participants with PCSA 
• Laboratory changes (Red Blood Cells (RBC), White Blood Cells (WBC), Hemoglobin (Hb), 
platelets, alanine transaminase (ALT), aspartate transaminase (AST), glycemia, amylasemia, 
creatinin clearance) from D-7 to D8: Mean changes number of PCSA, Percentage of 
participants with PCSA. 
3.2.2 Secondary endpoint 
• Plasma concentration of liraglutide following a single IA injection. PK samples: D1 pre-
injection (T0-4h) and 2, 4, 8, 12, 16 and 24 hours post injection.  
Plasma concentrations will be performed by Nuvisan GmbH (Am Feld 32, 
85567 Grafing, Allemagne)  . 
3.2.3 Exploratory endpoints 
• Serum and urine OA-related biomarkers (exploratory proteomic research of 4P-004 efficacy-
related biomarkers) at D1 (T0-4h, T0+8h), D2 (T0+24h) and D8. 
Human blood serum and urine samples will be collected and shipped to AO Research Institute 
Davos for liquid biomarker identification. 
 
4 STUDY DESIGN AND DESCRIPTION 
4.1 Overall design 
Phase I study for IA injection, double-blind, placebo-controlled, randomized, multicenter, single 
ascending dose is designed to assess the safety, tolerability and pharmacokinetic of 4P-004 in 
participants with target knee OA KL 2-4. 
Participants will be enrolled in 4 cohorts; in each cohort participants will receive either 4P-004 or 
placebo (6:2). 4P-004 dose will increase with cohort 1 to 4.  
For the highest dose cohort (3mg), a sentinel dosing will be implemented (see section 4.2).  
Recruitment of participants 
Participants will be recruited via investigators’ patient registry or via advertising. More information 
is provided in Patient Recruitment Procedure. 
A Screening visit at D-7 (D-14 to D-4) will be performed at study site and if the participant still agrees 
to participate in the study after the investigator has answered all his/her questions, the participant will 
sign the informed consent form. This visit should take place around 7 days before the randomization 
day (D-14 to D-4). During this visit, the eligibility of the participant will be evaluated. 

 
 
 
 
 
 
 
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The Randomization visit (Day 1 to Day 2) will be performed at study site and the participant will be 
randomized in the study after review of inclusion & exclusion criteria. The participant will be 
hospitalized for 24 hours. The IMP IA injection will be performed by the investigator after a veinous 
infusion line has been set up (see Investigator & Pharmacy manuals and sections 1.2 and 6.2.2). 
Participant will be monitored during the 24-hour hospitalization and will be discharge on D2. 
The Follow-up visit at D4 (±1 day) will be a virtual visit by phone call unless abnormal, clinically 
significant findings are observed upon discharge or at the investigator’s discretion (participants 
should then be brought back to the clinic for re-evaluation). 
The Follow-up visit at D8 (±2 days) will be a face-to-face visit. Participant will be asked to fill in a 
diary and a NRS questionnaire up to Day 29 to record any AE (in particular pain in the target knee) 
and analgesic medication taken.  
The End of Study (EoS) visit at D29 (±2 days) will be a virtual visit by phone call unless abnormal, 
clinically significant findings are observed upon discharge or at the investigator’s discretion 
(participants should then be brought back to the clinic for re-evaluation). Participant will be asked to 
send back to the Investigator the diary and the NRS questionnaire 
An independent Data and Safety Monitoring Board (DSMB) will be set up for this study (see DSMB 
Charter) and will review safety data during the study. The DSMB will be composed of 2 physicians 
specialized, one in rheumatology and one in diabetology. 
Members will review the safety data in sessions on a regular basis during the study, and at any time 
if any SAE at least possibly related to liraglutide or safety issue occurs (see section 11.1.5 and DSMB 
Charter). 
 
4.2 Scientific rationale for study design 
This phase 1 study is randomized, double-blinded, and placebo-controlled in order to avoid subjective 
bias in the assessment of the safety and tolerability of 4P-004.  
To mitigate risks associated with 4P-004, first IA injection in human, hypoglycemic properties and 
other potential risks based on preclinical and clinical data: 
• Participants are enrolled in 4 cohorts with IMP dose increasing from cohort 1 to 3; 
• Study-specific eligibility criteria have been added to the standard criteria to ensure that 
participants at increased risk of hypoglycemia are excluded (see section 5.2); 
• A DSMB is set up; 
• Two sentinel participants are included for the highest tested dose (3.0 mg), all data up to D8 
evaluation (including lab safety but not PK data) of these sentinel participants will be 
reviewed by the DSMB before randomization of the next participant;  
• In case of any potential MTD occurring in participant receiving 3.0 mg dose, an intermediate 
dose of 2.0 mg will be tested. Similar rule of follow-up will be applied to this cohort. 
 
4.3 Justification for route of administration 
Pharmacokinetic studies have been performed with liraglutide in dogs (Study report 4P004-027-PK 
see IB). This study demonstrates that:  

 
 
 
 
 
 
 
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• subcutaneous administration (authorized route of administration) of liraglutide does not allow 
diffusion into the synovial fluid, 
• upon IA administration, liraglutide exhibit similar systemic blood exposure as upon 
subcutaneous administration. 
Thus, to expose the diseased tissue, local IA administration is necessary. 
 
4.4 Justification for dose  
As part of this phase I trial, four different dose levels of 4P-004 will be investigated: 0.3 mg, 1.0 mg, 
2.0 mg and 3.0 mg. These dose levels have been selected considering the results of pharmacological 
data (efficacy) and toxicological data (safety) (see IB for detailed justification on dose selection).  
Dose 1 (starting dose; 0.3 mg): 
0.3 mg is the human starting dose considered for the clinical trial. 0.3 mg is the Minimum anticipated 
biological level dose (MABEL). It is assumed that both safety and potential clinical benefit for the 
patient are ensured with this first dose of 0.3 mg, which is in line with EMEA/CHMP/SWP/28367/07 
Rev. 1 considerations. 
Dose 2 (1.0 mg): 
One milligram in human is around the effective dose leading to an optimal analgesia effect of 4P-004 
in induced osteoarthritis rat model following human equivalent dose (HED) conversion. 
Dose 3 (3.0 mg): 
Three milligrams correspond to the maximum daily dose of liraglutide as specified in the SmpC of 
the approved medicinal product Saxenda® for the treatment of obesity (subcutaneous route). This 
dose is intended to establish a comparison between subcutaneous and IA routes with respect to safety 
and tolerability (see Saxenda® EPAR). Sentinel participants will be included for this dose-cohort 
during the clinical study. 
Three milligrams correspond to the highest intended dose to be administered during the clinical trial.  
Sentinel participants will be included for this dose-cohort during the trial. If any potential MTD 
occurs in patient receiving 4P-004, 3.0 mg, established by the investigator as at least possibly related 
to the IMP, administration of this dose will be stopped, and an intermediate dose of 2.0 mg will be 
tested.  
 
4.5 End of study definition  
The overall study ends when the last participant completes the last study-related contact, withdraws 
consent, or is lost to follow-up (i.e., the participant is unable to be contacted by the investigator). 
 
4.6 Early study termination 
The study will be completed as planned unless one or more of the following criteria are satisfied that 
require temporary suspension or early termination of the study. 

 
 
 
 
 
 
 
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The clinical study may be terminated early if new information or other evaluation regarding the safety 
or efficacy of the study drug that indicates a significant change in the known risk/benefit profile for 
the drug, such that the risk is no longer acceptable for participants participating in the study. 
 
4.6.1 Clinical criteria for early study termination 
It is agreed that for reasonable cause, either the investigator or the Sponsor may terminate this study, 
provided a written notice is submitted at a reasonable time in advance of intended termination; if by 
the investigator notice is to be submitted to the sponsor and if by the Sponsor, notice will be provided 
to each investigator. 
Stopping rules  
The study will be immediately suspended, and no additional IMP administered pending review and 
discussion of all appropriate study data by the DSMB if 1 or more participants develop any of the 
following adverse events deemed to be possibly, probably, or definitely related to the IMP by the 
Investigator and/or Medical Monitor, based upon close temporal relationship or other factors: 
• Severe local reaction within 7 days after injection 
• Clinical manifestations of hypoglycemia  
• Severe gastro-intestinal adverse event  
• Potentially clinically significant ECG abnormalities. 
• Any serious adverse event considered reasonably related to the IMP (SAR) by the Principal 
Investigator. 
 
The study will not be restarted until all parties have agreed to the course of action to be taken and the 
EC has been notified. 
Dose limiting toxicity (DLT) describes side effects of a drug that are serious enough to prevent an 
increase in dose or level of that treatment. 
When more than 1 DLT occurs in a dosing cohort, dose escalation must be stopped and this dose level 
will be identified as the non-tolerated dose. 
DLT is based on: 
• Expert‘s opinion 
• Any related SAE 
In this study, with liraglutide, DLT will be established if any of the following occurs: 
• Anaphylaxis (angioedema, hypotension, shock, bronchospasm, hypoxia, or respiratory 
distress),  
• Hypoglycemia (blood glucose level ≤ 2.5 mmol/L) within 2 days after injection, 
• Amylasemia ≥ 3ULN within 7 days after injection, 
• Serious gastro-intestinal adverse event within 7 days after injection. 
 

 
 
 
 
 
 
 
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4.6.2 Criteria for premature termination or suspension of investigational sites 
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure adequate 
performance of the study, or as otherwise permitted by the contractual agreement. 
Discontinuation of specific sites or of the study as a whole are handled as part of section 11.1.8. 
 
5 STUDY POPULATION 
5.1 Inclusion criteria  
I1. Participants who have the capacity to give informed consent and who are willing to comply 
with all study related procedures and assessments (consent via legally authorized 
representative will not be accepted), 
I2. Ambulatory participants, agreeing a 24-hour hospitalization, 
I3. Participants between 18 and 80 years of age, 
I4. Female participant of childbearing potential (WOCBP), must use contraceptive consistent 
with local regulations regarding the methods of contraception for those participating in 
clinical studies (see section 11.4) for at least 5 days following IMP injection, and must have 
a negative urine pregnancy test done within 24h before randomization,  
I5. Male participants (whose partners are of childbearing potential) must consent to use 
methods of contraception consistent with local regulations regarding the methods of 
contraception for those participating in clinical studies (see section 11.4), for at least 90 days 
following IMP injection, 
I6. Participants with knee osteoarthritis, KL 2-4 of their target knee (defined at screening as 
the knee with greater pain based on the participant’s evaluation and the investigator’s 
clinical judgment), 
I7. X-ray of the target knee within 6 months (if not, to be performed before randomization), 
I8. ECG within normal range, 
I9. WBC (white blood cell count) > 3500/µL, 
I10. Hemoglobin > 12 g/dL, 
I11. Platelets > 100,000/ µL, 
I12. Creatinine clearance (CrCl) > 60 mL/min, 
I13. Glycemia within normal range, 
I14. AST, ALT < 1.5 upper limit of normal (ULN), 
I15. Amylasemia < 1ULN, 
I16. Negative tests for COVID-19 (if required by the standard practice on site), HIV, HbsAg 
and hepatitis C Ab (Determination of HIV and hepatitis status can be based on participant-
reported medical history, available medical records, and the most recently available laboratory 
results for the participant [tests performed within the previous 12 months]). 
5.2 Exclusion criteria  
E1. Breastfeeding women, 

 
 
 
 
 
 
 
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E2. Treatment with systemic glucocorticoids greater than 10 mg prednisone or the equivalent 
per day within 4 weeks prior to screening, 
E3. Any treatment with glucosamine or chondroitin sulfate in the previous 3 months, 
E4. Any glucagon-like peptide 1 analogue hormones, 
E5. Anticoagulant treatment (current or within the last 10 days), 
E6. Treatment of the target knee with any IA injection (steroids, hyaluronic acid derivatives, 
PRP ….) within 3 months, 
E7. Knee surgery (of the target knee) performed within the previous 12 months or planned 
within the next 6 months, 
E8. Any partial knee replacement of the target knee, 
E9. Any known active infections or increased predisposition for the development of infections 
E10. Clinical signs and symptoms of active joint crystal disease, or any inflammatory joint 
disease, 
E11. Diabetes type I or II, 
E12. Congestive Heart Failure stage III or IV of NYHA classification, 
E13. Inflammatory bowel disease, 
E14. Any other chronic condition that has not been well controlled for a minimum of 3 
months, 
E15. History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin or in-situ cervical cancer) within the last 5 years, 
E16. Any condition, including laboratory findings, that in the opinion of the investigator 
constitutes a risk or contraindication for participation in the study or that could interfere with 
the study objectives, conduct or evaluation, (for example, any abnormal reaction to previous 
IA injection), 
E17. Hypersensitivity to the active substance liraglutide or to any of the excipients: Disodium 
phosphate dihydrate, Propylene glycol, Phenol, 
E18. Participation in an interventional clinical research trial within 12 weeks prior. 
 
5.3 Screen failures  
Screen failures are defined as participants who consent to participate in the clinical study but are not 
subsequently randomly assigned to the IMP. A minimal set of screen failure information is required 
to ensure transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure reasons, eligibility criteria, and 
any SAEs. 
Participant numbers assigned to subjects who fail screening should not be reused. If a participant fails 
screening but is later successfully rescreened (Individuals who are defined as screen failures may be 
rescreened once), the data for the participant will be entered as if these were 2 separate participants.  
Therefore, the data should be entered as follows: 
• The screen failure data should be entered as a screen failure participant. 

 
 
 
 
 
 
 
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• Rescreened participant should be assigned a new participant number and treated as a stand-
alone participant. 
6 STUDY INTERVENTION 
6.1 Study intervention administered 
A complete description of the IMP and its proper handling will be provided in the Pharmacy manual 
available to the clinical site. 
6.1.1 Liraglutide 
Liraglutide will be provided at 6 mg per mL in a clear and colourless or almost colourless, isotonic 
solution, pH=8.15. Solution also contains disodium phosphate dihydrate, propylene glycol, phenol 
and water. 
6.1.2 Placebo 
NaCl 0.9% sterile solution will be used as placebo. 
NaCl 0.9% solution is commonly used in biological research. 
 
6.2 Preparation / Handling / Storage /Accountability 
A complete description of the Investigational Medicinal Product (IMP) preparation, handling, storage 
and accountability will be provided in the Pharmacy manual available to the clinical site. 
The product should be stored in a refrigerator (2°C–8°C), away from the freezer compartment. It 
should not be freeze. Sites are requested to maintain a temperature log according to their SOP to 
ensure storage temperature remains within acceptable limits. 
The pharmacist who will be responsible for IMP preparation in an unblinded condition will be 
responsible for IMP accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records).  
The used pen will be kept by the Pharmacist in a secure location up to the full documented 
reconciliations performed with the Sponsor at the end of the study. The Pharmacist should wait for 
the written approval form from the Sponsor before proceeding to their destruction. Any annotation 
on the box containing the pen should be considered as source documents until the time of pen 
destruction. 
 
6.2.1 IMP preparation, administration and handlings 
Dilution will be made according to the dose to get a total volume of 2 mL to be injected 
intraarticularly. Details are provided in the Pharmacy manual.  
 
6.2.2 IA injection 
The IMP will be administered by IA injection. A complete and detailed description can be found in 
the Investigator manual. It is recommended, but not mandatory, to do the IA injection with 
ultrasound guide. 
Use of local anesthetic agent (lidocaine or other) or X-ray contrast agent are not allowed to avoid 
any interference with the IMP. 

 
 
 
 
 
 
 
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The skin is cleansed and sterilized.  
The sterile needle 0.8 x 50mm (type Becton Dickinson Microlance™ 3 Aiguilles 21G 2RB green is 
inserted in the knee IA joint space.  
The injection itself (with a second syringe prepared with 2mL of IMP, see Investigator manual) is 
possibly preceded by an aspiration phase of the synovial fluid, if any, to  
- 
i) free the knee from the tension linked to the excess volume of synovial fluid in the knee,  
- 
ii) make laboratory assessment of the synovial fluid as per standard practice. 
 
6.3 Measures to minimize bias: randomization and blinding 
All consented participants will be given a unique screening number that will be used to identify the 
participant for all procedures. Screening numbers must not be re-used for different participants. 
Participants can be rescreened once. 
Randomization 
Randomization will be performed using a pre-established randomization list. This list will be 
generated by a statistician for the IMPs (4P-004 or placebo) based on study design (sequential 
randomization according to the dose escalation and sentinel patients). 
The randomization will be requested by the site at visit 2 (on D1) after eligibility confirmation. 
Participants will be assigned their treatment according to the randomization schedule in the order in 
which they are randomized into the study. 
Product code lists (4P-004 or placebo) will be generated and managed by the unblinded responsible 
person delegated by the sponsor. 
The unblinded responsible person will communicate the result of the randomization (arm 4P-004 or 
placebo) and the associated product code to the pharmacy of PI site. 
Except for the unblinded pharmacist who will prepare the IMP, the Investigator and the whole study 
team will remain blinded for the study IMP. 
Complete instructions will be provided to the site in the randomization and code break procedure. 
In case a participant needs to be replaced, the replacement participant should receive the same 
treatment that the participant being replaced would have received. The unblinded responsible person 
will attribute the replacement code to the next patient. 
Unblinding 
In case of an emergency, the Investigator has the sole responsibility for determining if the unblinding 
of a participant’s intervention assignment is warranted (e.g., in case of an AE, the code must only be 
broken in circumstances when the knowledge of the IMP is required for treating the participant). 
Participant safety must always be the first consideration when making such a decision. If the 
Investigator decides that the unblinding is warranted, the Investigator should make every effort to 
contact the Sponsor prior to unblinding a participant’s intervention assignment, unless this could 
delay emergency treatment of the participant. Code breaking can be performed at any time by using 
the sealed envelope handled by the Investigator. If a participant’s intervention assignment is 
unblinded, the Sponsor must be notified immediately and maximum 24 hours after breaking the blind 
(details are given in the code break procedure). The date, time of the day, and reason that the blind 

 
 
 
 
 
 
 
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was broken must be recorded in the source documentation and electronic case report form (eCRF), 
as applicable. If the code is broken by the Investigator, the participant must be withdrawn from the 
study treatment. 
Methods of blinding 
This is a double-blind study but the Pharmacist who will prepare the IMP material to be injected will 
not be blinded. Only the Pharmacist who has not any contact with the participant will be unblinded. 
The DSMB will have access to unblinded data if deemed necessary by the DSMB. No unblinding 
information will be shared by the DSMB with the study team excepted the unblinded responsible 
person who will provide tables for the DSMB open/closed sessions. Details about the distribution of 
unblinding data to the DSMB while protecting the blind are described in the DSMB charter. 
 
6.4 Changes in IMP cohort dosing 
If any potential MTD occurs in participant receiving 4P-004, 3.0 mg, established by the investigator as at least possibly 
related to the IMP, administration of this dose will be stopped, and an intermediate dose of 2.0 mg will be tested. 
6.5 Concomitant therapy 
Any medication (including over-the-counter or prescription medicines, vitamins, and/or herbal 
supplements) that the participant is receiving at the time of randomization or receives during the study 
must be recorded along with: 
• Reason for use, 
• Dates of administration including start and end dates, 
• Dosage information including dose and frequency. 
Oral analgesics (paracetamol, non-Steroidal anti-inflammatory drug [NSAID], tramadol, opioids) or 
topical NSAID if needed are allowed during the study, all treatments taken for pain relief will be 
recorded in the eCRF (via participant’s diary). 
Other treatments not listed in exclusion criteria initiated before the study start can be pursued during 
the whole study and will be recorded in the CRF. 
 
7 DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL 
7.1 Discontinuation of study intervention 
NA 
7.2 Participant discontinuation / Withdrawal from the study 
A participant may withdraw from the study at any time at his/her own request or may withdraw at 
any time at the discretion of the Investigator for safety, behavioral, compliance, or administrative 
reasons. In these situations, if possible, the D8 visit should be performed if discontinuation is before. 
Clarification should be made with the participant if  
• he/she does not want to come back to next scheduled or  

 
 
 
 
 
 
 
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• he/she does not want anymore his/her data to be analyzed for the purpose of the study  
The Investigator should make every effort to perform the EoS Visit. 
All study withdrawals should be recorded by the Investigator in the appropriate screens of the eCRF 
and in the participant’s medical records. In the medical record, at least the date of the withdrawal and 
the reason should be documented. 
In addition, a participant may withdraw his/her consent to stop participating in the study. If the 
participant withdraws consent for disclosure of future information, the Sponsor may retain and 
continue to use any data collected before such a withdrawal of consent. If a participant withdraws 
from the study, he/she may request destruction of any samples taken and not tested (e.g., archival 
samples for future use), and the Investigator must document this in the site study records. The site 
should document any case of withdrawal of consent. 
Should participant withdraw from the study between D1 and D8, or at any later time, participants 
replacement will be evaluated on a case-by-case basis. 
 
7.3 Lost to follow up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether the participant wishes to and/or should continue in the study. 
• Before a participant is deemed lost to follow up, the Investigator or designee must make every 
effort to regain contact with the participant (where possible, several telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the participant’s medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
The Statistical Analysis Plan (SAP) will specify how these participants lost to follow-up for their 
primary endpoints will be considered. 
 
8 STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the Study Flowcharts (section 1.2).  
Adherence to the study design requirements, including those specified in the Study Flowchart is 
essential and required for study conduct. 
All Screening evaluations must be completed and reviewed to confirm that potential participants meet 
all eligibility criteria. The Investigator will maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for screening failure, as applicable. 

 
 
 
 
 
 
 
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Procedures conducted as part of the participant’s routine clinical management and obtained before 
signing of the informed consent form (ICF) may be utilized for screening purposes provided the 
procedures met the protocol-specified criteria and were performed within the time frame defined in 
the Study Flowchart and/or in inclusion or exclusion criteria (see sections 1.2, 5.1, 5.2). 
The maximum amount of blood collected from each participant over the duration of the study, 
including any extra assessments that may be required, will not exceed 100 mL(the exact assessment 
specific volumes are described in section 11.2) within approximately 14 days. Repeated or 
unscheduled samples may be taken for safety reasons or for technical issues with the samples. 
 
8.1 Safety assessments 
Planned time points for all safety assessments are provided in the Study Flowchart. 
8.1.1 Physical examination 
A physical examination will be conducted at screening, D1, D2 and D8 visits. A symptom-based 
physical examination will include organ systems, which are deemed, at the discretion of the 
Investigator, necessary to be evaluated. 
Height (at screening only) and weight will also be measured at screening, D1 and D8 and recorded 
(Body mass index will be calculated automatically).  
8.1.2 Vital signs 
Vital signs will be measured at screening and D1, D2 and D8 as outlined in the Study flowcharts (see 
Section 1.2). They will be measured in a sitting position after 5 minutes of rest and will include 
systolic and diastolic blood pressure, and pulse. Blood pressure and pulse measurements will be 
assessed with a completely automated device. Manual techniques will be used only if an automated 
device is not available. 
8.1.3 Electrocardiograms 
Three 12-lead ECG will be obtained at screening and D1 as outlined in the Study flowcharts (see 
section 1.2). 
Electrocardiogram parameters will be based upon the automatic reading of the device. These ECG 
parameters and morphology need to be reviewed by the Investigator. If the device does not provide 
automatic reading, then the ECG parameters will need to be determined and interpreted by the 
Investigator. 
8.1.4 Clinical safety laboratory assessment 
See section 11.2 for the list of clinical safety laboratory tests to be performed and section 1.2 (Study 
flowcharts) for the timing and frequency. 
• The Investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the Investigator to be more severe than expected for the participant’s condition. 

 
 
 
 
 
 
 
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• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 4 weeks after the last dose of IMP should be repeated until 
the values return to normal or baseline or are no longer considered clinically significant by 
the Investigator or Medical Monitor. 
✓ If such values do not return to normal/baseline within a period of time judged reasonable 
by the Investigator, the etiology should be identified, and the Sponsor notified. 
✓ All protocol-required laboratory assessments, as defined in section 11.2, must be 
conducted in accordance with the Laboratory manual and the Study flowcharts (see 
section 1.2). 
• If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the Investigator (e.g., SAE, AE, or dose modification), then the results 
must be recorded in the eCRF.  
8.1.5 Local safety 
The evaluation of IA injection site reaction following IMP administration will be performed by the 
Investigator or designees as outlined in section 1.2.2. Findings at the site of injection such as, but not 
limited to tenderness, erythema, and swelling, will be recorded in the eCRF in 3 different grades 
(mild/moderate/severe).  
8.1.6 Target knee pain 
The participants will also assess target knee pain using a numerical rating scale (NRS), 11 points (0-
10) to assess pain of the target knee as outlined in section 1.2: 
• At screening (as a mean of the previous 2 days) 
• At D1:  T0-4h as - a mean of the previous 2 days and - currently and every hour after T0 up 
to T0+6h  
• At D2 before hospital discharge: assessment from IA injection to hospital discharge 
• From D3 to D8 Visit: daily, assessment from the previous 24 hours 
• From D15 to D29:  weekly assessment based on pain during the previous 2 days.  
A pre-paid and pre-printed envelope will be given to the participant on D8 visit for mailing these 
records to the Investigator. 
 
8.2 Adverse events and serious adverse events 
All AEs will be coded and graded according to the Division of AIDS, table for grading the severity 
of Adult and Pediatric Adverse Events (DAIDS, Corrected Version 2.1 July 2017). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following up 
AEs that are serious, considered related to the IMP or study procedures, or that caused the participant 
to discontinue the study. 
The definitions of an AE, SAE and suspected unexpected serious adverse reactions (SUSAR), as well 
as the method of recording, evaluating, and assessing causality of AE and SAE and the procedures 

 
 
 
 
 
 
 
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for completing and transmitting AE, SAE, SUSAR and other reportable safety event reports can be 
found in Appendix 3. 
The investigator and any designees are responsible for detecting, documenting, and reporting events 
that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AEs, SAEs, and other reportable safety events for 
outcome according to Section 8.2.3. 
The investigator, who is a qualified physician, will assess events that meet the definition of an AE or 
SAE as well as other reportable safety events with respect to seriousness, intensity/toxicity and 
causality. 
8.2.1 Time period and frequency for collecting AE, AESI and SAE 
All AEs and SAEs will be collected from the signing of the ICF until the end of study at the time 
points specified in the study flowcharts (section 1.2). 
All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours of learning event, as indicated in section 11.3. 
The Investigator will submit any updated SAE data to the Sponsor or designee within 24 hours of it 
being available. 
8.2.2 Method of detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the procedures 
for completing and transmitting SAE reports are provided in section 11.3. 
8.2.3 Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each participant at 
subsequent visits/contacts. At the prespecified study end date, all SAEs will be followed until 
resolution, stabilization, the event is otherwise explained, or the participant is lost to follow-up. 
Further information on follow-up procedures is provided in section 11.3. 
8.2.4 Regulatory reporting requirements for SAEs 
• Prompt notification by the Investigator to the Sponsor or designee of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, Independent Ethics Committees (IEC), and 
Investigators. 
• Adverse events that are considered expected will be specified in the reference safety 
information (see IB). 
• SUSARs are reported to regulatory authorities, Investigators, and IECs as follows: 
o For SUSARs that are life-threatening or result in death, reporting is no later than 7 
days after first knowledge by the Sponsor, with all relevant follow-up information 
subsequently reported within an additional 8 days. 

 
 
 
 
 
 
 
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o For SUSARs, other than those that are life-threatening or result in death, reporting is 
no later than 15 days after first knowledge by the Sponsor. 
• An Investigator who receives an Investigator safety report describing a SAE, SUSAR, or any 
other specific safety information (e.g., summary or listing of SAEs) from the Sponsor will 
review and then file it along with the IB and will notify the IEC, if appropriate according to 
local requirements. It is the responsibility of the Sponsor to assess whether an event meets the 
criteria for a SUSAR, and therefore, is expedited to regulatory authorities. 
8.2.5 Pregnancy 
If a pregnancy is reported, the Investigator should inform the Sponsor or designee within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in section 11.4. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.2.6 Adverse event of special interest (AESI) 
An AESI is an AE (serious or nonserious) of scientific and medical concern specific to the Sponsor’s 
product or program, for which ongoing monitoring and immediate notification by the Investigator to 
the Sponsor or designee is required.  
All reported AESIs will be reviewed by an independent DSMB.  
For AESIs, the Sponsor is to be informed immediately (i.e., within 24 hours), as per SAE notification 
guidelines described in section 11.3, even if a seriousness criterion is not met, using the corresponding 
pages of the case report form (to be sent) or screens in the eCRF: 
• Pregnancy of a female participant entered in a study as well as pregnancy occurring in a female 
partner of a male participant entered in a study with IMP. It will be qualified as an SAE only 
if it fulfills one of the seriousness criteria (see section 11.3). Follow-up of the pregnancy in a 
female participant or in a female partner of a male participant is mandatory until the outcome 
has been determined (see section 11.4). 
• Symptomatic overdose (serious or non-serious) with IMP. Any adverse event(s) associated 
with (“results from”) an overdose of IMP will be reported as a serious adverse event, even if 
no other seriousness criteria are met. 
Other project specific AESI: 
• Anaphylaxis, 
• Severe IMP injection site reactions (severe tenderness, erythema, swelling…), 
• Hypoglycemia, 
• Severe Gastro-intestinal disorder. 
8.3 Treatment of overdose 
All doses upper than the planned dose will be considered as an overdose. If needed, the participant 
should be observed for clinical signs of dehydration and blood glucose should be monitored. 
In the event of an overdose, the Investigator/treating physician should: 
• Contact the Monitor (CRA) immediately. 

 
 
 
 
 
 
 
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• Closely monitor the participant for any AE/SAE and laboratory abnormalities at least for 7 
days. Special attention should be paid to glycemia levels in the 24 hours, 
• Document appropriately in the eCRF. 
8.4 Pharmacokinetics 
8.4.1 Pharmacokinetic sample collection 
Blood samples (one 3 mL sample per scheduled time) will be collected for the determination of 
concentrations of 4P-004 as planned in the study flowcharts (section 1.2). The actual time of sample 
collection will be recorded on the source document and eCRF. 
Instructions for collecting, processing, and shipping of samples are provided in the laboratory manual. 
 
8.4.2 Bioanalytical methods 
The analyses will be performed by high performance liquid chromatography (HPLC) coupled with 
mass spectrometry (MS) and ultraviolet-visible spectroscopy (UV). 
The development and validation of the analytical method as well as the dosing of PK samples will 
be performed by Nuvisan GmbH (Am Feld 32, 85567 Grafing, Germany)  in accordance with the 
company’s standard operating procedures and following international guidelines.  
 
8.4.3 Pharmacokinetic parameters 
The following PK parameters will be calculated from measured plasma concentrations for each 
participant: 
Maximum observed concentration (Cmax) 
Time of maximum observed concentration (Tmax) 
Area under the curve (AUC0-t)  
Half-life (T1/2) 
 
8.5 Visits requirements 
8.5.1 Screening visit, D-7 (D-14 to D-4) 
The screening visit can be performed 4 to 14 days before the IMP administration. 
During this visit the Investigator will: 
• explain and answer all questions the participant has, 
• if the participant agrees, obtain the written informed consent, 
• review all inclusion / exclusion criteria, demographics, medical history and medication 
history, 
• notify all pain killer medication taken in the past month, 
• do a physical examination, including vital signs, weight and height, 
• do an ECG, 
• ask the participant to rate his/her pain of the target knee pain (as a mean of the previous 2 
days) with the NRS 
• take blood samples for clinical safety lab, 

 
 
 
 
 
 
 
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• give the participant diary to collect medical events and treatments taken up to next visit,  
• give the appointment for the inclusion visit (day of IMP administration) with 24-hour 
hospitalization and other follow-up visits. 
8.5.2 Inclusion visit, D1, full day hospitalization 
During this visit (24 hours hospitalization), the Investigator will: 
• review inclusion / exclusion criteria, concomitant medication (from screening), 
• do physical exams, ECGs, measure vital signs as per D1-D2 Study Flowchart (section 1.2.2), 
• record any AE since screening, 
• put a veinous line, 
• remind the participant to fill in the NRS (before any study intervention on D1) for assessing 
target knee pain in the previous 2 days and during the hospitalization as outlined in section 
1.2.2, 
• randomize the participant (performed by the pharmacist) 
• take blood / urine samples for glycemia, PK and OA-related biomarkers samples as per D1-
D2 Study Flowchart (section 1.2.2), 
• do the IA injection (modalities given in section 6.2.2 and in the Investigator manual) of the 
IMP extemporaneously prepared in a vial by the pharmacist (procedure for preparation is 
detailed in the Pharmacy manual), 
• record AEs as per D1-D2 Study Flowchart (section 1.2.2), 
• monitor the participant during the coming 24 hours: 
o on local reaction as per D1-D2 Study Flowchart (section 1.2.2) 
o on blood sugar level (veinous / capillary measures):  
▪ after IMP injection, glycemia will be systematically monitored (capillary 
measures via glucose meter and/or veinous measures) as per D1-D2 Study 
Flowchart (section 1.2.2), 
▪ when planned measurement indicates glycemia is ≤ 70 mg/dL without clinical 
symptom repeat the test each 30 min up to obtaining threshold value >70 
mg/dL, 
▪ at any time if occurrence of one or more symptoms of hypoglycemia (common 
presenting symptoms include nausea, confusion, tremor, sweating, 
palpitations, or hunger), sugar will be given to the participant and a blood 
glycemia test should be immediately performed and closely monitored. 
8.5.3 Hospital discharge, D2 
Before participant discharge from the hospital, the investigator or delegate will 
• perform a physical exam and record vital signs, 
• remind the participant   
o to assess target knee pain [NRS] (based on the previous 24 hours) on a daily basis 
from D3 to the next visit date (D8), 

 
 
 
 
 
 
 
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o to fill in the diary from D2 (after hospital discharge) up to the next visit (D8) to self-
report adverse events and pain killer medication,   
• give appointment for a virtual visit (phone call) at D4 ± 1d and for a face-to-face visit on D8 
± 2 days. 
No specific physical limitation is recommended from the day after the injection. 
In case of safety concerns after hospital discharge, the participant will be asked to call the investigator 
/ to return to the hospital for an unscheduled safety control visit according to the investigator 
judgement. 
8.5.4 Phone call (Virtual visit), D4 ± 1d 
At D4 (±1 day), follow-up -unless abnormal, clinically significant findings are observed upon 
discharge or at the investigator’s discretion (participants should then be brought back to the clinic for 
re-evaluation) will be a virtual visit by phone. 
During this phone call, the Investigator or delegate will: 
• review the diary with the participant, 
• record adverse events if any, 
• remind the participant  
o to assess target knee pain (NRS) on a daily basis up to the next visit  
o to self-report adverse events and pain killer medication up to the next visit, 
• confirm the appointment for D8 visit. 
In case of safety concerns, the participant will be asked to return to the hospital for a safety control 
visit. 
8.5.5 Follow-up visit, D8 ± 2d 
During this visit, the Investigator or delegate will: 
• review the diary with the participant, 
• record adverse events if any, 
• take a blood sample for routine tests and OA exploratory biomarkers, 
• take a urine sample for exploratory biomarkers, 
• remind the participant   
o to assess target knee pain [NRS] (based on the previous 48 hours) at D15, D22 and 
D29, 
o to fill in the diary for the 3 coming weeks (up to D29) to self-report adverse events 
and pain killer medication 
• give the participant a pre-paid and pre-printed envelope for mailing back the diaries and the 
NRS questionnaire to the Investigator after the D29 phone call (end of study visit/virtual visit). 
8.5.6 EoS visit: Phone call (Virtual visit), D29 ± 2d 
The Investigator or delegate call the participant by phone and will ensure that the participant 
completed the diary (AE, target knee pain, pain killer intake, concomitant medications) and will 
remind the participant to send the diary and the NRS questionnaire as planned. 

 
 
 
 
 
 
 
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The investigator will also inquire for any ongoing AEs or SAEs, worsening of AEs or SAEs, or 
development of new AEs or SAEs. 
In case of safety concerns, the participant will be asked to return to the hospital for a safety control 
visit. 
 
8.6 Participant compensation 
For the purpose of the study, the participant will have to go 3 times to the investigational site including 
a day of hospitalization (day of study drug administration) for around 24 hours, during which several 
blood samples for PK study will be drawn. Details of compensation given to the participant are 
provided in the ICF. 
 
9 DATA MANAGEMENT 
The sponsor or designated representative (e.g., contract research organization) will perform the data 
management activities in accordance with the data management plan (DMP). The DMP will outline 
the systems and procedures to be used in the study. 
 
9.1 Data Capture 
Data will be entered from the source document in an electronic CRF (eCRF, web database) by the 
Investigator or his/her designee. At the end of the study, each eCRF must be signed electronically by 
the Investigator. 
 
9.2 Access Rights 
Designated personnel (Sponsor, Investigator or designee) will be provided with a personal username 
and password to access the eCRF database. This username/password pair may be used by a single 
individual only; passwords must not be shared with any other person. 
 
9.3 Audit Trail 
The EDC systems developed for this study comply with the Good Clinical Practices (GCP) predicate 
rule requirements, laws and regulations (General Data Protection Regulation - GDPR) and allows an 
audit of actions performed by users. Thus, all data modifications will be documented in an audit trail 
file. After the last verification, the relevant data will be locked into the database. The system is also 
compliant with the e-signature laws (particularly the Title 21 CFR Part 11 of the Code of Federal 
Regulations); in that saving the data is equivalent to a handwritten signature. 
 
9.4 Data Sources 
For this study, the following data sources are identified:  
9.4.1 Investigator’s site data 
These data will be directly entered into eCRF by the Investigator or his/her designee. The exhaustive 
list of clinical data collected at each visit will be described in the Source Data Verification List. This 
form will be completed and approved by the Investigator or his/her designee during Initiation visit. 

 
 
 
 
 
 
 
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9.4.2 Participant reported outcome 
These data are reported by the participant himself and will be entered in the eCRF. This section 
describes the questionnaires, note book that will be used in this study and how data will be managed 
(entered in eCRF or filled as paper source document). 
Data to be entered in eCRF: 
• NRS Questionnaire, 
• Diary, including AEs/SAEs and concomitant treatments reported by the participant. 
 
9.5 Data Validation 
All data entered into the eCRF will be validated by the DM. All computerized edit checks 
programmed to validate the data, at least on primary outcome data are described in the Data 
Validation Plan document, written by the DM. 
Data discrepancies will trigger automatic queries, directly displayed on the screen when data entered 
are saved. If necessary, manual queries will be sent to the Investigator for clarification. All these 
discrepancies/queries have to be answered or confirmed by the site. 
 
9.6 Coding 
 
TYPE OF DATA 
DATASET 
DICTIONARY 
Adverse Events 
AE 
MedDRA, most up-to-date version  
Serious Adverse Events 
SAE 
MedDRA, most up-to-date version 
Medical History 
MH 
MedDRA, most up-to-date version 
Concomitant Medications 
CM 
ATC/DDD Index, most up-to-date 
version 
 
9.7 Data Lock 
Clinical database will be locked after review, query resolution, signatures of the eCRF and 
determination that clinical database is ready for analysis. 
Once the Trial is finished and database is locked, the DM should follow the database unlock/relock 
process to document any further change. 
 
10 STATISTICAL METHODS 
10.1 Statistical and analytical plans 
A statistical analysis plan (SAP) will be prepared and finalized prior to database lock. This document 
will provide further details regarding the definition of analysis variables and analysis methodology to 
address all study objectives. 
10.1.1 Analysis sets 
Safety set 
The safety analysis set will consist of all participants who are enrolled and received 1 dose of study 
drug. Participants in this analysis set will be used for demographic, baseline characteristics, and safety 
summaries. 

 
 
 
 
 
 
 
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PK Set 
The PK set will consist of all participants who receive study drug and have at least 1 measurable 
plasma concentration.  
Blood samples for placebo will not be analyzed by the bioanalytical laboratory except for 2 samples 
per participant receiving placebo, 1 predose and the other around the expected time at which Cmax 
occurred (as emerging from the actual measurement of the samples of the first dose group) to ensure 
from a safety perspective that no additional participants could have been on active treatment. 
10.1.2 Analysis of demographics and other baseline characteristics 
Descriptive statistics (N, mean, SD, median, minimum, and maximum) will be generated for 
continuous demographic variables and baseline characteristics variables (age, height, weight, and 
BMI) for pooled placebo, each 4P-004 dose level, 4P-004 overall and overall total. The number and 
percentage of participants in each class of the categorical demographic variables and baseline 
characteristics variables (sex, ethnicity, and race) will be tabulated for pooled placebo group, each 
4P-004 dose level, 4P-004 overall and overall total. Pooled placebo corresponds to participants 
receiving placebo in the 4 pooled cohorts.   
Demographic variables will be summarized overall for participants who are screened, but not enrolled 
in the study. Individual demographic characteristics, date of informed consent, and reason for screen 
failure will be listed. 
10.1.3 Pharmacokinetic analysis 
Concentrations in plasma 
The plasma concentration of 4P-004 will be summarized by dose level over each scheduled sampling 
time using descriptive statistics. Individual plasma concentration data vs time will be presented in a 
data listing. 
PK parameters 
Descriptive statistics (N, arithmetic mean, SD, median, minimum, maximum and percent coefficient 
of variation [%CV]) will be used to summarize the plasma PK parameters for 4P-004 by, dose level.  
10.1.4 Safety analysis 
The safety evaluation will be based upon the review of the individual values (clinically significant 
abnormalities), descriptive statistics (summary tables, figures) and, if needed, on statistical analysis 
(appropriate estimations, confidence intervals). No statistical significance tests will be performed on 
safety data. 
Potentially clinically significant abnormality (PCSA) values are defined as abnormal values 
considered medically important by the Sponsor, according to predefined criteria/thresholds based on 
literature reviews and defined by the Sponsor for clinical laboratory tests, vital signs, and ECG 
parameters. 
All safety data will be presented in listings and will be summarized by placebo, each 4P-004 dose 
level, 4P-004 overall, and overall total.  
 
AEs 

 
 
 
 
 
 
 
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All AEs will be coded by system organ class (SOC) and preferred term (PT) using the Medical 
Dictionary for Regulatory Activities (MedDRA). Clinical judgment should be used to determine the 
severity of AEs as described in Section 11.3.4. 
TEAEs with onset occurring within 7 days (onset date – date of dose + 1 ≤ 7) after study drug 
administration will be listed and included in the summary tables. TEAEs will be summarized by SOC 
and PT. The following summary tables will be included in the report: summary of TEAEs and drug-
related AEs, relationship of AEs to study drug (related vs not-related), severity of AEs and related 
AEs. AEs leading to study drug discontinuation and SAEs will be listed. Data listings will be provided 
for all AEs including PTE, TEAEs, AEs leading to study drug discontinuation, and SAEs. 
Local tolerability 
The number (%) of participants with injection site reactions will be summarized overall and by 
maximum severity by treatment group. The incidence of AEs related to local tolerability findings will 
be summarized over time. 
Target knee pain 
Results of the NRS will be summarized by visit, maximum value with corresponding visit and will 
be presented per participant and treatment group.  
Clinical safety laboratory evaluation 
Individual results of laboratory tests from hematology, and chemistry that meet PCSA criteria to be 
defined in the SAP will be listed and summarized. Baseline, post-dose, and change from Baseline to 
post-dose laboratory data will be summarized. All clinical laboratory data will be listed. 
Vital signs 
Individual results of vital signs that meet PCSA criteria to be defined in the SAP will be listed and 
summarized. Observed values and changes from Baseline in vital sign measurements (systolic and 
diastolic blood pressure and heart rate,) will be summarized. All vital signs data will be provided in 
the data listings. 
 
ECG  
ECGs will be summarized by changes from baseline values at each dose level using descriptive 
statistics. 
10.1.5 Surrogate efficacy markers analysis 
These parameters are exploratory, and analysis will be described in the SAP. 
 
10.2 Sample size determination 
The sample size for this study of 8 participants in each cohort (6 active : 2 placebo) is considered to 
be sufficient for evaluation of safety, tolerability, and PK of each cohort. The sample size was not 
based on statistical power considerations. 
 

 
 
 
 
 
 
 
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11 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
11.1 Appendix 1: Regulatory, ethical, and study oversight considerations  
11.1.1 Regulatory and ethical consideration  
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki and the applicable amendments and Council for International Organizations of 
Medical Sciences (CIOMS) International Ethical Guidelines,  
• Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP) 
Guidelines, 
• Applicable laws and regulations (eg, data protection law as General Data Protection 
Regulation - GDPR). 
The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g advertisements) must 
be submitted to an IEC by the Investigator and reviewed and approved by the IEC before the study is 
initiated. 
Any amendments to the protocol will require IEC approval before implementation of changes made 
to the study design, except for changes necessary to eliminate an immediate hazard to study 
participants. 
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IEC annually or more frequently 
in accordance with the requirements, policies, and procedures established by the IEC. 
• Determining whether an incidental finding should be returned to a participant and, if it meets 
the appropriate criteria, to ensure the finding is returned (an incidental finding is a previously 
undiagnosed medical condition that is discovered unintentionally and is unrelated to the aims 
of the study for which the tests are being performed). The following should be considered 
when determining the return of an incidental finding:  
o The return of such information to the study participant (and/or his/her designated 
healthcare professional, if so, designated by the participant) is consistent with all 
applicable national, state, or regional laws and regulations in the country where the 
study is being conducted, and  
o The finding reveals a substantial risk of a serious health condition or has reproductive 
importance, AND has analytical validity, AND has clinical validity.  
• The participant in a clinical study has the right to opt out of being notified by the Investigator 
of such incidental findings. In the event that the participant has opted out of being notified 
and the finding has consequences for other individuals, e.g., the finding relates to a 
communicable disease, Investigators should seek independent ethical advice before 
determining next steps.  
o In case the participant has decided to opt out, the Investigator must record in the 
site medical files that she/he does not want to know about such findings. 

 
 
 
 
 
 
 
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• Notifying the IEC of SAEs or other significant safety findings as required by IEC procedures.  
• Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 Code of Federal Regulations (CFR), ICH guidelines, the IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local regulations. 
As applicable, according to Directive 2001/20/EC, the Sponsor will be responsible for obtaining 
approval from the Competent Authorities of the EU Member States and/or Ethics Committees, as 
appropriate, for any amendments to the clinical trial that are deemed as “substantial” (i.e., changes 
which are likely to have a significant impact on the safety or physical or mental integrity of the clinical 
trial participants or on the scientific value of the trial) prior to their implementation. 
11.1.2 Financial disclosure  
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial certification 
or disclosure statements to the appropriate regulatory authorities. Investigators are 1 year responsible 
for providing information on financial interests during the study and for after completion of the study. 
11.1.3 Informed Consent Process  
For the ICF and the optional future use of sample ICF, the following applies: 
• The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study, in language and terms they are able to understand.  
• Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IIEC or study center.  
• The medical record must include a statement that written informed consent was obtained 
before the participant was screened in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF.  
• Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study.  
• A copy of the signed and dated ICF(s) must be provided to the participant or the participant’s 
legally authorized representative. 
Participants who are rescreened are required to sign a new ICF. 
11.1.4 Data protection 
All personal data collected related to participants, Investigators, or any person involved in the study, 
which may be included in the Sponsor’s databases, shall be treated in compliance with all applicable 
laws and regulations including the GDPR. 
Data collected must be adequate, relevant and not excessive, in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective. 

 
 
 
 
 
 
 
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Participant race and ethnicity will be collected in this study because these data are required by 
regulatory agencies. 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information which would make the participant identifiable will not be transferred to 
the Sponsor. 
• The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant as described in the informed consent.  
• The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IEC members, and by inspectors from regulatory authorities. 
When archiving or processing personal data pertaining to the Investigator and/or to the participants, 
the Sponsor shall take all appropriate measures to safeguard and prevent access to this data by any 
unauthorized third party. To comply with the applicable rules on the protection of personal data, 
specifically regarding the implementation of the organizational and technical arrangements aiming 
to avoid unauthorised access, disclosure, dissemination, alteration or loss of information and 
processed personal data, the Sponsor has implemented and maintains the following measures: 
• restriction and monitoring of physical access to the offices and information processing 
facilities to employees, personnel and approved visitors; 
• ensuring appropriate and restricted user access relevant to the function and type of activity 
performed in relation to the clinical trial; implementing the pseudonymisation and 
encryption of personal data, as appropriate; 
• implementing the ability to ensure the ongoing confidentiality, integrity, availability and 
resilience of processing systems and services;  
• implementing network, application, database security by means of firewalls and 
antivirus/anti-malware; ensuring detection of malware purposed for unauthorized deletion, 
blocking, copying of information, disabling security measures and response to such attacks; 
• means to restore the availability and access to personal information in a timely manner in 
the event of a physical or technical incident;  
• logging of security events/incidents in information systems;  
• implementing procedures that cover reporting, analysis, monitoring and resolution of 
security incidents; 
• ensuring that information systems, computers and software involved in the performance of 
the services provided in the Study are backed up; 
• a process for regularly testing, assessing and evaluating the effectiveness of technical and 
organisational measures for ensuring the security of the processing;  
• implementing procedures to capture within reasonable time-manner any personal data 
breach occurred; Indeed, the Sponsor has put in place a functional process of reporting of 
any data breach occurring at Sponsor’s or its sub-contractor’s facilities and premises.  In 
case of the occurrence of any data breach, Sponsor will immediately apply relevant 
measures to mitigate the risks to data subjects as appropriate in relation to the specific 
context of the data breach, taking into account its source, underlying intentions, possibilities 
of recovery etc… Any data breach presenting risks to the rights and freedoms of data 

 
 
 
 
 
 
 
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subjects will be reported to the relevant supervisory data protection authority within 72 
hours of Sponsor becoming aware of the data breach. In addition, in case of occurrence of a 
high-risk breach, data subjects will be informed by the Sponsor (via clinical Study site). 
• implementing procedures and practices for securing destruction of paper documents 
containing personal data; 
• implementing business continuity procedures ensuring that the Sponsor can continue to 
provide services through operational interruption 
• All locations, personnel and information systems that are used to perform services for the 
Study will be covered; 
• Participant data are intended to be used for the whole drug development program from 
collection to reimbursement. 
11.1.5 Data and Safety Monitoring Board 
A DSMB will be charged with monitoring the safety of participants in this study. It will also be 
responsible for providing recommendations for protecting the safety and ensuring the welfare of these 
participants to the Sponsor during the study. Two independent physicians, one rheumatologist and 
one endocrinologist will be part of this board. 
The members of the DSMB must not be involved with the study in any other way (e.g., they cannot 
be study investigators) and must have no competing interests that could affect their roles with respect 
to the study. 
The DSMB responsibilities and the data review processes are fully described in the DSMB charter. 
In the above capacities, the DSMB is advisory to the Sponsor. The Sponsor is responsible for 
promptly reviewing and for taking into account in a timely manner the recommendations of the 
DSMB in terms of study continuation with or without alterations or of potential study termination. 
 
11.1.6 Data quality assurance  
• All participant data relating to the study will be recorded on printed or eCRF unless 
transmitted to the Sponsor or designee electronically (e.g laboratory data). The Investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the electronic case report form (eCRF). 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
• The Investigator must permit study-related monitoring, audits, IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
• The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data. The Sponsor assumes accountability for actions delegated to other 
individuals (e.g Contract Research Organizations). 
• Study monitors will perform ongoing source data verification (SDV) to confirm that data 
entered into the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 

 
 
 
 
 
 
 
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study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements. 
• Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the Investigator for 15 years after the signature of the final study report unless 
local regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the Sponsor. No records 
may be transferred to another location or party without written notification to the Sponsor. 
11.1.7 Source documents  
• Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
Investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available. 
• Definition of what constitutes source data can be found in the study reference manual. 
• If no monitoring visit can take place on site (due to the pandemic status) and where permitted, 
a remote Data Source Verification (SDV) can be done. 
 
11.1.8 Study and site start and closure 
The study start date is the date on which the clinical study will be open for recruitment of participants. 
The first act of recruitment is the first site open and will be the study start date. 
The Sponsor or designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study completion. 
A study site is considered closed when all required documents and study supplies have been collected 
and a study-site closure visit has been performed. 
• Note: in case of investigational site closure or complete regional or national lock-down due 
to a local epidemic or international pandemic, the study may be suspended regionally or 
nationally at the affected sites. Every effort will be made to continue the follow-up of already 
recruited participants as close to the SoE as possible. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination reasons for study termination by the 
Sponsor, as well as reasons for the early closure of a study site by the Sponsor or Investigator may 
include but are not limited to: 
• For study termination:  
o Information on the product leading to doubt regarding the benefit/risk ratio, 
o Discontinuation of further study intervention development. 
• For site termination: 

 
 
 
 
 
 
 
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o Failure of the Investigator to comply with the protocol, the requirements of the IEC or 
local health authorities, the Sponsor’s procedures, or GCP guidelines, 
o Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the Investigator, 
o Total number of participants included earlier than expected. 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs, the regulatory authorities, and any Contract Research Organization(s) used 
in the study of the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The Investigator shall promptly inform the participant and should assure appropriate 
participant therapy and/or follow-up. 
10.1.9 Publication policy 
The results of this study may be published or presented at scientific meetings. The Sponsor will 
comply with the requirements for publication of study results. In accordance with standard editorial 
and ethical practice, the Sponsor will generally support publication of multicenter studies only in their 
entirety and not as individual site data. In this case, a coordinating investigator will be designated by 
mutual agreement. 
If publication activity is not directed by the Sponsor, the investigator agrees to submit all manuscripts 
or abstracts to the Sponsor before submission. This allows the Sponsor to protect proprietary 
information and to provide comments. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
 
11.2 Appendix 2: Clinical safety laboratory tests 
The tests detailed in Table 1 will be performed by local laboratories 
Additionally, if laboratory results not specifically required by the study protocol are used to make 
either a study intervention decision or response evaluation, the results must be entered into the eCRF. 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in Section 5 of 
the protocol. 
Additional tests may be performed at any time during the study as determined necessary by the 
investigator or required by local regulations. 
The investigator (or medically qualified designee) must document their review of each laboratory 
safety report (e.g., hematology, chemistry, pregnancy). 
Table 1 - Protocol-required laboratory assessments 
Laboratory assessments  
 
Parameters 
Serology 
 
 
 
• HIV 
• HbsAg 
• Hepatitis C Ab 
Hematology   
 
 
• Red blood cell (RBC) count 
• Hemoglobin 

 
 
 
 
 
 
 
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• Hematocrit 
• Platelet count 
• White blood cell (WBC) count with differential: neutrophils, 
  
 lymphocytes, monocytes, eosinophils and basophils  
Clinical chemistry 
 
 
• Creatinine (including glomerular filtration rate calculation); 
• Serum electrolytes: potassium, chloride, sodium, calcium; 
• Liver function tests: aspartate aminotransferase (AST),  
   alanine aminotransferase (ALT); 
• Amylasemia  
• Glycemia  
Urinalysis Pregnancy test 
  
• β-human chorionic gonadotropin (HCG) for women of  
  
 childbearing potential (only at screening for WOCBP) 
Other test 
• Rapid Antigen test for SARS-CoV-2 (if required by standard 
   practice of site) 
Exploratory Research  
  
• Blood proteomics 
• Urine proteomics 
Table 2 Approximate Whole Blood Volume (mL) 
Study day 
Screening 
D1/D2 
D8 
Hematology 
4 
0 
4 
Chemistry 
4 
0 
4 
Glycemia 
2 
14 
2 
Serology 
7 
0 
0 
PK samples 
0 
35 
0 
Biomarkers 
0 
15 
5 
Total per visit 
17 
64 
15 
Total per participant 
 
 
96 mL 
 
On D1/D2 (as per Flowcharts in sections 1.2.1 & 1.2.2): 
• PK samples: 7 X 3 mL + 7 X 2 mL (discarded) 
• Glycemia: 9 X 2 mL 
• Biomarkers: 4 X 5 mL 
11.3 Appendix 3: Adverse events Definitions, Recording and Reporting 
11.3.1 Definition of AE 
AE definition (as per International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH) E6 (R2) Good Clinical Practice (GCP) 
Guidelines definition): 
• An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the study 
intervention. 

 
 
 
 
 
 
 
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• 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 study intervention. 
Events meeting the AE definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (e.g., ECG, radiological scans, vital signs measurements), including those 
that worsen in severity and/or frequency from baseline, considered 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 intervention administration even though it 
may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention 
or a concomitant medication. 
Events NOT meeting the AE definition 
• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• Situations in which 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. 
• 
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened. 
 
11.3.2 Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions are 
met. 
 
 

 
 
 
 
 
 
 
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An SAE is defined as any untoward medical occurrence that, at any dose, meets one of the following 
conditions: 
a. Results in death. 
b. Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically might 
have caused death, if it were more severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
Hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an 
elective procedure to treat a pre-existing condition that has not worsened is not an SAE.)  
d. Results in persistent or significant disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
This definition is not intended to include experiences of relatively minor medical significance such 
as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g 
sprained ankle) that may interfere with or prevent everyday life functions but do not constitute a 
substantial disruption. 
e. Congenital anomaly or birth defect in the offspring of a study participant. 
f. Other important medical events. 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is appropriate 
in other situations such as important medical events that may not be immediate life-threatening or 
result in death or hospitalization but may jeopardize the participant or may require medical or surgical 
intervention to prevent one of the other outcomes listed in the above definition. These events should 
usually be considered serious. 
11.3.3 Definition of SUSAR 
A Suspected Unexpected serious Adverse Reaction (SUSAR) is a serious adverse reaction for 
which the nature and severity is not consistent with the information set out in the reference Safety 
Information (see IB). 
11.3.4 Recording and follow-up of AE and/or SAE 
AE and SAE recording 
When an AE/SAE occurs, either spontaneously revealed by the patient or observed by the 
Investigator, and whether believed by the Investigator to be related or unrelated to the study drug, it 
is the responsibility of the Investigator to review all documentation (e.g., hospital progress notes, 
laboratory, and diagnostics reports) related to the event. 
• The Investigator will record all relevant AE/SAE information on the AE CRFs/worksheets at 
each examination. 
• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE eCRF page. 

 
 
 
 
 
 
 
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• There may be instances when copies of medical records for certain cases are requested by the 
Sponsor. In this case, all participant identifiers, with the exception of the participant number, 
will be blinded on the copies of the medical records before submission to the Sponsor. 
• 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 (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
• As far as possible, each AE/SAE is described by: duration (start and end dates), event 
verbatim, solicited/unsolicited, frequency (relationship to the study treatment), intensity 
grade, seriousness, action taken and outcome. 
Assessment of intensity  
The investigator will make an assessment of intensity for each AE and SAE (and other reportable 
safety event) by recording the grade according to the Table for Grading the Severity of Adult and 
Pediatric Adverse Events (NIH DAIDS version 2.1, 2017). Any AE which changes DAIDS grade 
over the course of a given episode will have each change of grade recorded on the AE 
CRFs/worksheets. 
• Grade 1 Mild event: Mild symptoms causing no or minimal interference with usual social and 
functional activities with intervention not indicated. 
• Grade 2 Moderate event: Moderate symptoms causing greater than minimal interference with 
usual social and functional activities with intervention indicated. 
• Grade 3 Severe event: Severe symptoms causing inability to perform usual social and 
functional activities with intervention or hospitalization indicated. 
• Grade 4 Potentially life-threatening event: Potentially life-threatening symptoms causing 
inability to perform basic self-care functions with intervention indicated to prevent permanent 
impairment, persistent disability, or death. 
• Grade 5 Death: Deaths related to an AE. 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described in 
the definition of an SAE, NOT when it is rated as severe. 
Assessment of causality 
The relationship of each AE to study intervention will be assessed using the following categories: 
• Related: An AE that follows a reasonable temporal sequence from administration of a drug 
(including the course after withdrawal of the drug), or for which possible involvement of the 
drug cannot be ruled out, although factors other than the drug, such as underlying diseases, 
complications, concomitant drugs and concurrent treatments, may also be responsible. 
• Not Related: An AE that does not follow a reasonable temporal sequence from administration 
of a drug and/or that can reasonably be explained by other factors, such as underlying diseases, 
complications, concomitant drugs and concurrent treatments. 
 

 
 
 
 
 
 
 
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Category 
Criteria 
Final reporting of relationship 
to study drug (interpretation used 
for regulatory reporting purpose) 
Definitely (must 
have all the 
mentioned criteria) 
• 
Follows a reasonable temporal sequence from 
administration of the drug 
• 
Cannot be reasonably explained by the known 
characteristics 
of 
the 
patient’s 
clinical 
state, 
environment or toxic factors, or other modes of therapy 
administered to the patient 
• 
Disappears or decreases on cessation or reduction in 
dose and recurs with re-exposure to drug (if re-
challenge occurs) 
• 
Follows a known pattern of response to the drug 
Related 
Probable  
(must have the first 
three) 
• 
Follows a reasonable temporal sequence from 
administration of the drug 
• 
Cannot be reasonably explained by the known 
characteristics 
of 
the 
patient’s 
clinical 
state, 
environment or toxic factors, or other modes of therapy 
administered to the patient 
• 
Disappears or decreases on cessation or reduction in 
dose  
• 
Follows a known patter of response to the drug 
• 
Reappears on re-challenge 
Possible 
(must have the first 
two) 
• 
Follows a reasonable temporal sequence from 
administration of the drug 
• 
May have been produced by the patient’s clinical state, 
environment or toxic factors, or other modes of therapy 
administered to the patient 
• 
Follows a known pattern of response to the suspected 
drug 
Unlikely 
(must have the first 
two) 
• 
Does not follow a reasonable temporal sequence from 
administration of the drug 
• 
May readily have been produced by the patient’s 
clinical state, environment or toxic factors, or other 
modes of therapy administered to the patient 
• 
Does not reappear or worsen when the drug is re-
administered 
 
 
 
Not related 
Unrelated  
• 
Is clearly and incontrovertibly due to extraneous causes 
(disease, environment, etc.) 
• 
Do not meet the criteria for drug relationship listed 
under Unlikely, Possible, Probable or Definitely 
 
 
Assessment of AE Outcome 
The investigator will assess the outcome of all unsolicited AEs (including SAEs) recorded during the 
study, as: 
• Resolved 
• Resolving 
• Not resolved 
• Resolved with sequelae 
• Fatal (for SAEs only) 
 

 
 
 
 
 
 
 
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Follow-up of AE and SAE 
• If information is not available at the time of the first report becomes available at a later date, 
the investigator should complete a follow-up SAE form or provide other written 
documentation and submit it to the monitor/Pharmacovigilance immediately within 24 hours 
of receipt. 
• All SAEs will be followed up until satisfactory resolution or until the Investigator deems the 
event to be chronic or the patient to be stable. 
 
11.3.5 Reporting of SAEs, and Other Reportable Safety Events to the Medical monitor 
• Any event considered to be serious should be recorded on the SAE reporting form. All SAEs, 
regardless of relationship, and pregnancies must be reported via eCRF within 24 hours of the 
Investigator becoming aware of the event. Other supporting documentation may be requested 
by the Sponsor and should be provided as soon as possible. 
• The primary mechanism for reporting an SAE to the medical monitor and pharmacovigilance 
will be the electronic data collection tool. 
o If the electronic system is unavailable, then the site will use the paper SAE form in 
order to report the event within 24 hours. 
o The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated data on 
a previously reported SAE after the electronic data collection tool has been taken off-line, 
then the site can report this information on a paper SAE form or to the Medical Monitor by 
phone. Contacts for SAE reporting can be found in the Investigator site file.  
• Following notification from the Investigator, Sponsor’s Monitor (or designee) will report 
events that are serious, unexpected and are considered to be causally related to the study 
products (SUSARs) to the competent authorities (CA) within the required timelines: fatal and 
life-threatening events within 7 calendar days and all other SAEs within 15 calendar days. 
• The Investigator (or designee) will be responsible for reporting the SUSAR to ethics 
committees. 
 
 
11.4 Appendix 4: Contraceptive guidance and collection of pregnancy information 
11.4.1 Definitions 
Woman of childbearing potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 

 
 
 
 
 
 
 
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If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP 
• Premenarchal 
• Premenopausal female with 1 of the following 
o Documented hysterectomy, 
o Documented bilateral salpingectomy, 
o Documented bilateral oophorectomy, 
For individuals with permanent infertility due to an alternate medical cause other than the above (e.g., 
Mullerian agenesis, androgen insensitivity), Investigator discretion should be applied to determining 
study entry. 
Note: Documentation can come from the site personnel’s: review of the participant’s medical records, 
medical examination, or medical history interview. 
• Postmenopausal female  
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. 
o A high follicle-stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception 
or hormonal replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with more than one FSH measurement (>ULN as defined 
by central laboratory readout) is required. 
Females on HRT and whose menopausal status is in doubt will be required to use one of the non-
estrogen hormonal highly effective contraception methods if they wish to continue their HRT during 
the study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status 
before study randomization. 
11.4.2 Contraceptive guidance 
Mandatory use of contraception must cover the study drug administration period plus 5 times the 
half-life of liraglutide (half-life around 13 hours) i.e. 5 days (in order to cover extreme values). 
Contraceptives allowed during the study includea: 
Highly Effective Methodsb That Have Low User Dependency 
• Implantable progestogen-only hormone contraception associated with inhibition of ovulationc  
• Intrauterine device (IUD)  
• Intrauterine hormone-releasing system (IUS)c  
• Bilateral tubal occlusion  
• Vasectomized partner 
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole 
sexual partner of the woman of childbearing potential and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. (Spermatogenesis cycle 
is approximately 90 days.) 
Highly Effective Methodsb That Are User Dependent 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation 

 
 
 
 
 
 
 
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- oral 
- intravaginal 
- transdermal 
- injectable 
• Progestogen-only hormone contraception associated with inhibition of ovulation  
- oral 
- injectable 
• Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.) 
 
a  Contraceptive use by men or women should be consistent with local regulations regarding the use 
of contraceptive methods for those participating in clinical studies. 
b  Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ 
from those when used consistently and correctly. 
c  If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable contraceptive methods are limited to those which inhibit ovulation as the primary mode 
of action. 
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal [coitus 
interruptus]), spermicides only, and lactational amenorrhea method (LAM) are not acceptable 
methods of contraception for this study. Male condom and female condom should not be used 
together (due to risk of failure with friction). 
11.4.3 Collection of pregnancy information  
Male participants with partners who become pregnant 
• The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This applies 
only to male participants who receive the investigational medicinal product. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The female 
partner will also be followed to determine the outcome of the pregnancy. 
• Information on the status of the mother and child will be forwarded to the Sponsor. Generally, 
the follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. Any 
termination of the pregnancy will be reported regardless of fetal status (presence or absence 
of anomalies) or indication for the procedure. 
• The Investigator should assess if there was any relationship between the outcome and the 
exposure to study drug. 
 
 

 
 
 
 
 
 
 
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Female participants who become pregnant 
• The Investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study. The initial information will be recorded on the 
appropriate form and submitted to the Sponsor within 24 hours of learning of a participant’s 
pregnancy. 
• The participant will be followed to determine the outcome of the pregnancy (i.e., healthy birth, 
spontaneous or voluntary abortion, presence or absence of any birth defects, congenital 
abnormality, or complications for the mother and/or newborn). The Investigator will collect 
follow-up information on the participant and the neonate, and the information will be 
forwarded to the Sponsor. Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date. Any termination of pregnancy will be reported, 
regardless of fetal status (presence or absence of anomalies) or indication for the procedure. 
• Any pregnancy complication or elective termination of a pregnancy for medical reasons will 
be reported as an AE or SAE. 
• A spontaneous abortion (occurring at <22 weeks gestational age) or still birth (occurring at 
>22 weeks gestational age) is always considered to be an SAE and will be reported as such. 
• Any post-study pregnancy related SAE considered reasonably related to the study intervention 
by the Investigator will be reported to the Sponsor as described in Section 8.3.4. While the 
Investigator is not obligated to actively seek this information in former study participants, he 
or she may learn of an SAE through spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study. 
• The Investigator should assess if there was any relationship between the outcome and the 
exposure to study drug. 
 
11.5 Appendix 5: Exploratory tests 
Exploratory tests will be described in a separate document. 
 
11.6 Appendix 6: Abbreviations  
ADAMTS: a disintegrin and metalloproteinase with thrombospondin motifs 
AE: adverse event 
AESI: adverse event of special interest 
ALT: alanine aminotransferase 
AST: aspartate aminotransferase 
ATC: anatomical therapeutic chemical 
AUC: area under the curve 
CA: competent authority 
CFR: Code of Federal Regulations 
CIOMS: Council for International Organizations of Medical Sciences 
CrCl: creatinine clearance 
Cmax: maximum concentration 

 
 
 
 
 
 
 
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CNS: central nervous system 
CONSORT: consolidated standards of reporting trials 
COVID-19: coronavirus infectious disease due to SARS-CoV-2 
CREB: cAMP response element binding protein 
CRF: case report form 
CSR: clinical study report 
CTC AE: common terminology for adverse events 
DDD: defined daily dose 
DMM: destabilization of the medial meniscus 
DMOAD; disease-modifying osteoarthritis drug  
DMP: Data management plan 
DSMB: data and safety monitoring board 
EC: ethics committee 
ECG: electrocardiogram 
eCRF: electronic case report form 
EMA: european medical agency 
EoS: End of Study 
EoT: End of Treatment 
FDA: food and drug administration 
FIM: first-in-man 
GCP: Good Clinical Practice 
GDPR: General Data Protection Regulation 
GLP: good laboratory practice 
GLP-1(R): glucagon-like peptide 1 (receptor) 
HBsAg: hepatitis B surface antigen 
HCG: human chorionic gonadotropin 
HCV-Ab: hepatitis C virus antibody 
HED: human equivalent dose 
HIV: human immunodeficiency virus 
hMSC: human mesenchymal stem cells  
HPLC: high performance liquid chromatography 
HRT: hormonal replacement therapy 
IB: investigator’s brochure 
ICF: informed consent form 
ICH: international council for harmonisation 
IA: intra-articular 
IC50: half maximal inhibitory concentration  
IEC: Independent Ethics Committee 
Ig: immunoglobulin 
IL-6: interleukin 6 
IMP: investigational medicinal product 
IV: intravenous(ly) 
KL: Kellgren and Lawrence classification 

 
 
 
 
 
 
 
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MABEL: minimum anticipated biological effect level  
MIA: mono-iodo-acetate 
MedDRA: medical dictionary for regulatory activities 
MMP: matrix metalloproteinase 
NO: nitric oxyde 
NOAEL: no observed adverse effect level 
NRS: numerical rating scale 
NSAID: nonsteroidal anti-inflammatory drug 
OA: osteoarthritis 
OARSI: osteoarthritis research society international 
PCSA: potentially clinically significant abnormality 
PD: pharmacodynamic(s) 
PGE2: prostaglandin 2 
PK: pharmacokinetic(s) 
PKA: protein kinase A 
SAE: serious adverse event 
SAP: statistical analysis plan 
SC: subcutaneous(ly) 
SD: standard deviation 
Sox9: SRY-Box Transcription Factor 9 
SUSAR: suspected unexpected serious adverse reaction 
t1/2: elimination half-life 
TEAE: treatment-emergent adverse event 
Tmax: time to maximum concentration 
ULN: upper limit of normal 
WOCBP: women of childbearing potential 
 

 
 
 
 
 
 
 
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11.7 Appendix 7: References 
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DZ, Wang XY. Glucagon-like peptide-1 receptor regulates endoplasmic reticulum stress-induced 
apoptosis and the associated inflammatory response in chondrocytes and the progression of 
osteoarthritis in rat. Cell Death Dis. 2018 Feb 12;9(2):212. https://doi.org/10.1038/s41419-017-0217-
y. 
Courties A, Sellam J, Berenbaum F. Metabolic syndrome-associated osteoarthritis. Curr Opin 
Rheumatol. 2017 Mar;29(2):214-222. DOI: 10.1097/BOR.0000000000000373. PMID: 28072592. 
GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 
countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 
2019. Lancet (London, England).  2020; 396(10258):1204-22.  https://doi.org/10.1016/S0140-
6736(20)30925-9. 
Kornaat PR, Sharma R, van der Geest RJ, Lamb HJ, Kloppenburg M, Hellio le Graverand MP, Bloem 
JL, Watt I. Positive association between increased popliteal artery vessel wall thickness and 
generalized osteoarthritis: is OA also part of the metabolic syndrome? Skeletal Radiol. 2009 
Dec;38(12):1147-51. DOI: 10.1007/s00256-009-0741-7.  Epub 2009 Jul 3. PMID: 19575196; 
PMCID: PMC2773838. 
Long H, Liu Q, Yin H, Wang K, Diao N, Zhang Y, Lin J, Guo A. Prevalence trends of site-specific 
osteoarthritis from 1990 to 2019: findings from the Global Burden of Disease. Arthritis & 
Rheumatology. https://doi.org/10.1002/art.42089. 
 
Meurot C, Martin C, Sudre L, Breton J, Bougault JC, Rattenbach R, Bismuth K, Jacques C & 
Berenbaum F. Liraglutide, a glucagon‑like peptide 1 receptor agonist, exerts analgesic, 
anti‑infammatory and anti‑degradative actions in osteoarthritis. Nature.com/scientific reports 
2022;12:1567 https://doi.org/10.1038/s41598-022-05323-7 
 
Nakanishi R, Hirose T, Tamura Y, Fujitani Y, Watada H. Attempted suicide with liraglutide overdose 
did not induce hypoglycemia. Diabetes Research and Clinical Practice 2013;99: e3-e4 PMID: 
23149376 https://doi.org/10.1016/j.diabres.2012.10.017. 
 
Que Q, Guo X, Zhan L, Chen S, Zhang Z, Ni X, Ye B, Wan S. The GLP-1 agonist, liraglutide, 
ameliorates inflammation through the activation of the PKA/CREB pathway in a rat model of knee 
osteoarthritis. J Inflamm (Lond). 2019 Jun 6;16:13.  doi: 10.1186/s12950-019-0218-y. 
 
Shiraishi D, Fujiwara Y, Komohara Y, Mizuta H, Takeya M. Glucagon-like peptide-1 (GLP-1) 
induces M2 polarization of human macrophages via STAT3 activation. Biochem Biophys Res 
Commun. 2012 Aug 24;425(2):304-8 doi: 10.1016/j.bbrc.2012.07.086.