Conditions: Osteonecrosis of the Femoral Head
Keywords: Osteonecrosis Femoral Head Hip Orthopedics Bone Musculoskeletal Disorders
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 68
Healthy volunteers: no

Brief summary:
Non-traumatic osteonecrosis is a painful disorder of the hip characterized by a necrosis of the osteomedullary tissue, which leads to subchondral bone collapse and joint destruction. Core decompression is currently the treatment of choice for early stage osteonecrosis of the femoral head. This method consists in decompressing the rigid intra-osseous chamber to promote revascularization, thus halting progression of the disease and stimulating repair. Still this treatment remains highly controversial, since the success rates of the first studies have not been repeated.

The exact pathology mechanisms involved in osteonecrosis have not yet be fully elucidated. Several hypotheses have been evoked, including fat embolism, trabecular bone microfractures, microvascular tamponade and, more recently, impaired bone and/or mesenchymal cells recruitment.

Three studies have indicated the potential clinical benefits of cell-based approaches for the treatment of osteonecrosis (Hernigou 1997, Hernigou \& Beaujean 2002, Gangji et al. 2004). This is on the basis of these observations that a proprietary population of autologous osteoblastic cells (PREOB®) has been developed.

This Phase 3 study aims at demonstrating the efficacy and safety of PREOB® in the treatment of early stage osteonecrosis of the femoral head. More specifically, the purpose of the study is to demonstrate that core decompression/PREOB® implantation into the necrotic lesion is superior to core decompression/placebo implantation in relieving hip symptoms and halting (or reverting) radiological progression of the disease.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Core decompression/PREOB® implantation intervention 2: Core decompression/placebo implantation
Intervention descriptions: intervention 1: All patients will undergo a core decompression under general anesthesia combined with the implantation of PREOB® into the necrotic lesion (single administration). intervention 2: All patients will undergo a core decompression under general anesthesia combined with the implantation of placebo into the necrotic lesion (single administration).

Protocol document:
Prot_SAP_000.pdf: 
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Clinical Study Protocol 
PREOB-ON3 
Protocol Number: 000001/BT 
EudraCT Number: 2009-012929-11 
NTC Number: 01529008 
 
 
 
 
Title 
Phase III, Pivotal, Multicentre, Randomised, Double-blind Controlled Study to Evaluate the 
Efficacy and Safety of Autologous Osteoblastic Cells (PREOB®) Implantation in Early Stage 
Non Traumatic Osteonecrosis of the Femoral Head 
 
 
 
 
 
Sponsor 
Bone Therapeutics S.A. 
Rue Auguste Piccard, 37 
B-6041 Gosselies, Belgium 
 
 
Sponsor’s Representative in the United States of America 
Bone Therapeutics USA Inc. 
10 Milk Street, Suite 1055 
Boston, MA 02108 
 
 
 
Good Clinical Practice (GCP) Statement 
This study will be performed in compliance with Good Clinical Practice (GCP), the 
Declaration of Helsinki (with amendments), and all applicable legislation and regulatory 
requirements. 


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PROTOCOL SPONSOR SIGNATORY APPROVAL  
 
Protocol Number: 000001/BT 
 
Title of the protocol:  
Phase III, pivotal, multicentre, randomised, double-blind controlled Study to evaluate the 
Efficacy and Safety of Autologous Osteoblastic Cells (PREOB®) Implantation in Early Stage 
Non Traumatic Osteonecrosis of the Femoral Head.  
 
Date of the protocol (Version 6.1): May 15, 2017 
 
 
Sponsor’s representative 
 
 
 
 
Guy Heynen, MD 
Chief Clinical and Regulatory Officer 
 
 
Name and Title 
 
Date 
Signature 
 


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INVESTIGATOR SIGNATURE AND AGREEMENT WITH THE PROTOCOL 
In accordance with all applicable legal and regulatory requirements, 
I, the undersigned, agree to conduct this study in compliance with this Protocol and to assume 
responsibility for the proper conduct of the study at this site. 
Agree that the clinical trial will be carried out in accordance with any and all applicable laws, 
regulations, guidance, guidelines, and principles regarding the: 
- 
Ethical principles for medical research involving human subjects 
- 
Good Clinical Practice as regards conduct of clinical trials and investigational medicinal 
products for human use 
- 
Clinical safety data management, notification, and reporting  
- 
Advanced Therapy Medicinal Products (According to EMA) 
- 
Sponsor Standard Operating Procedures (SOPs)  
Agree:  
- 
That my primary responsibility is to safeguard the rights and well-being of each patient 
participating in this study, and that the patient’s rights and well-being must take 
precedence over the goals and requirements of the study. 
- 
To ensure the confidentiality and protection of all information obtained from and about 
the participants. 
- 
To obtain the informed consent of the patients prior to their participation in the study 
and ensure that:  
* Verbal information, adapted to the patient, has been provided, avoiding direct or 
indirect coercion;  
* The patient has understood the study; 
* The patient information sheet and written consent form (approved version) has 
been provided; 
* The patient has been given a reasonable period of reflection (opportunity to inquire 
about details of the trial and to decide whether or not to participate in the trial). 
- 
To keep the written proof of the informed consent of the patients or their authorised 
legal representatives. 
- 
To ensure that no clinical samples are retained on site or elsewhere without the approval 
of the Sponsor and the express written informed consent of the patient. 


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- 
To perform no other biological assays on the clinical samples except those described in 
the protocol or its amendment(s). 
- 
To promptly report any unanticipated problems that involve any risk to patient in 
research covered under this agreement. 
- 
To ensure the transfer of the information and the data collected for the study (CRF) in a 
clear, legible way and in conformity with the source documents (patient file).   
- 
To ensure to have the necessary resources (e.g., qualified personnel and material 
resources) to successfully complete the study with regard to deadlines. 
I acknowledge 
- 
That I have been informed that certain Regulatory Authorities require the Sponsor to 
obtain and supply, as necessary, details about the Investigator’s ownership interest in 
the Sponsor or the investigational product, and more generally about his/her financial 
ties with the Sponsor. The Sponsor will use and disclose the information solely for the 
purpose of complying with regulatory requirements. 
 
Principal Investigator 
 
 
 
 
 
 
 
Name and Title 
 
Date 
Signature 
 


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TABLE OF CONTENTS 
1 
INTRODUCTION ............................................................................................................. 21 
 
Background of the Study .......................................................................................... 21 
1.1.1 Osteonecrosis of the Femoral Head ................................................................. 21 
1.1.2 Current Therapeutic Strategies for Osteonecrosis ........................................... 21 
1.1.3 Pathophysiological Mechanisms and Rationale for the Use of PREOB® in 
Osteonecrosis .............................................................................................................. 22 
 
Study Rationale ........................................................................................................ 26 
 
Risks and Benefit Assessment .................................................................................. 31 
2 
INVESTIGATIONAL PLAN ............................................................................................ 33 
 
Overall Study Design ............................................................................................... 33 
 
Main Study Objectives and Endpoints ..................................................................... 33 
2.2.1 Follow-up Period ............................................................................................. 33 
2.2.2 Long Term Follow-up ..................................................................................... 35 
2.2.3 Clinical Study Report ...................................................................................... 35 
 
Main Study Plan and Procedures .............................................................................. 36 
2.3.1 Patient Information and Informed Consent ..................................................... 36 
2.3.2 Inclusion and Exclusion Criteria ..................................................................... 37 
2.3.3 Randomisation ................................................................................................. 40 
2.3.4 Blinding ........................................................................................................... 41 
2.3.5 Bone Marrow Harvest and Blood Collection Procedures ............................... 41 
2.3.6 Core decompression and Implantation Procedures ......................................... 42 
2.3.7 Follow-up Period ............................................................................................. 42 
 
Long -Term Follow-up ............................................................................................. 42 
3 
DETAILED SCHEDULE OF VISITS AND PROCEDURES .......................................... 43 
 
Screening Period (Visit 1) ........................................................................................ 46 
 
Randomisation .......................................................................................................... 47 
 
(Sham) Bone Marrow Harvest and Blood Collection (Visit 2, Day -21) ................. 48 
 
Product Implantation (Visit 3, Day 0 and Day +1) .................................................. 49 
Follow-up Visits - up to Month 24 ........................................................................... 50


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3.5.1 Follow-up Visit 4 (Month 1 ± 1 week) and Visit 5 (Month 3 ± 2 weeks) ....... 50 
3.5.2 Follow-up Visit 6 (Month 6 ± 4 weeks) and Visit 7 (Month 12 ± 4 weeks) ... 51 
3.5.3 Follow-up Visit 8 (Month 18 ± 4 weeks) ........................................................ 51 
3.5.4 Follow-up Visit 9 (Month 24 ± 4 weeks) ........................................................ 52 
 
Long Term Follow-up (Months 36 and 48 ± 4 weeks)............................................. 52 
4 
DETAILED DESCRIPTION OF THE PROCEDURES AND INVESTIGATIONAL 
MEDICINAL PRODUCT ................................................................................................. 54 
 
Bone Marrow Harvest and Blood Collection Procedures (performed by the 
Independent Physician) ...................................................................................................... 54 
 
Core Decompression and Implantation Procedures.................................................. 55 
4.2.1 Control of the Investigational Medicinal Product Quality .............................. 55 
4.2.2 Core decompression/Investigational Medicinal Product implantation (PREOB® 
or Placebo)................................................................................................................... 56 
4.2.3 Peri-operative antibiotic therapy and other medications ................................. 57 
5 
INVESTIGATIONAL PRODUCT AND STARTING MATERIALS .............................. 58 
 
Investigational Medicinal Products .......................................................................... 58 
Investigational Medicinal Product Post-administration Sterility Testing................. 59
 
Tracking, Traceability, and Accountability of Investigational Medicinal Product .. 59 
6 
LABORATORY ASSESSMENT ...................................................................................... 61 
 
Blood for Laboratory Testing ................................................................................... 61 
 
Storage of collected Blood and exceeding Starting Materials .................................. 61 
 
Use of exceeding Bone Marrow, Peripheral Blood, and PREOB® product ............. 62 
7 
SAFETY: TOLERABILITY MEASUREMENTS AND ENDPOINTS ........................... 63 
 
Overview of Safety Parameters and Endpoints ........................................................ 63 
7.1.1 Vital Signs ....................................................................................................... 63 
7.1.2 Physical Examination ...................................................................................... 64 
7.1.3 Laboratory Safety Measurements .................................................................... 64 
 
Other Safety Measurements ..................................................................................... 65 
7.2.1 Women with childbearing potential ................................................................ 65 
7.2.2 Additional safety examinations and procedures .............................................. 65 


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8 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS .......................................... 66 
 
Definitions ................................................................................................................ 66 
 
Assessment of Adverse Events ................................................................................. 70 
8.2.1 Observation period for the occurrence of AEs and SAEs ............................... 71 
8.2.2 Summary of Possible Risks related to the Procedures .................................... 72 
8.2.3 Summary of Observed Adverse Events (AE) and Serious Adverse Events 
(SAE) possibly related to Study Treatment in Osteonecrosis ..................................... 73 
 
Management of Safety Issues ................................................................................... 73 
8.3.1 Safety Data Notification Reporting, and Monitoring ...................................... 73 
8.3.2 Annual Safety Reports – Development Safety Update reports (DSURs) ....... 77 
8.3.3 Safety Data Monitoring ................................................................................... 77 
8.3.4 Data Safety Monitoring Board ........................................................................ 77 
 
Procedure in Case of Pregnancy ............................................................................... 78 
 
Emergency Procedures ............................................................................................. 78 
8.5.1 Emergency Contact Procedure ........................................................................ 78 
8.5.2 Methods for Breaking the Blind ...................................................................... 79 
Long-Term Pharmacovigilance System ................................................................... 80
9 
PREMATURE REMOVAL FROM THE STUDY ........................................................... 81 
 
Reasons for Early Discontinuation ........................................................................... 81 
 
Procedure for Early Discontinuation ........................................................................ 82 
 
Replacement of Patients ........................................................................................... 82 
10 
STATISTICAL CONSIDERATIONS AND METHODS OF ANALYSIS ...................... 83 
 Collection and Derivation of Efficacy Assessments ............................................... 83 
10.1.1 Primary Efficacy Endpoint ............................................................................ 83 
10.1.2 Secondary Efficacy Endpoints ...................................................................... 84 
10.1.3 Exploratory Efficacy Endpoints .................................................................... 84 
 Collection and Derivation of Safety Assessments .................................................. 85 
 Statistical Considerations ........................................................................................ 85 
10.3.1 General Considerations ................................................................................. 85 
10.3.2 Statistical Hypotheses for the Primary Endpoint ........................................... 86 


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 Sample Size ............................................................................................................. 86 
 Analysis Sets ........................................................................................................... 88 
 Statistical Methods .................................................................................................. 88 
10.6.1 Primary Efficacy Endpoint Analyses ............................................................ 88 
10.6.2 Secondary Efficacy Endpoint Analyses ........................................................ 88 
10.6.3
Exploratory Efficacy Endpoint Analyses...................................................... 89
10.6.4 Safety Endpoint Analyses ............................................................................. 89 
 Interim Analysis ...................................................................................................... 90 
11 
STUDY MANAGEMENT ................................................................................................ 91 
 Monitoring .............................................................................................................. 91 
 Source Documents .................................................................................................. 92 
 Source Data Verification ......................................................................................... 93 
 Completion of Electronic Case Report Forms, Signing, and Filing ....................... 94 
 Data Management ................................................................................................... 95 
 Audits and Inspections ............................................................................................ 95 
 Access to Source Data ............................................................................................ 96 
Training of Staff...................................................................................................... 96
 Changes to the Protocol .......................................................................................... 96 
12 
ADMINISTRATIVE, LEGAL, AND ETHICAL ASPECTS ........................................... 98 
 Ethical Principles and Conduct of the Trial ............................................................ 98 
 Health Authorities and Independent Ethics Committees/Institutional Review Board
 
101 
 Patient Data Protection and Confidentiality.......................................................... 102 
 Insurance ............................................................................................................... 103 
 Financial aspects ................................................................................................... 103 
 Archiving at the End of the Study ......................................................................... 104 
13 
REPORTING AND PUBLICATIONS POLICY ............................................................ 105 
 Clinical Study Report ............................................................................................ 105 
 Publications and Posters ....................................................................................... 105 
14 
REFERENCES ................................................................................................................ 107 


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STUDY SYNOPSIS 
EudraCT Number 
2009-012929-11 
Protocol Number: 000001/BT 
Protocol Code: PREOB-ON3 
Phase of Development: Pivotal Phase III Study 
Sponsor in the European Union 
Bone Therapeutics S.A., Gosselies, Belgium 
Sponsor's Representative in the United States of America 
Bone Therapeutics USA Inc., Boston, Massachusetts 
Planned Study Period 
- 12 months recruitment period  
- 24 months follow-up period 
- 24 months long term follow-up 
Objectives 
To determine the efficacy and safety of PREOB®, a proprietary population of autologous osteoblastic cells, in the 
treatment of early stage non-traumatic osteonecrosis of the femoral head. 
Planned Number of Patients: 118 patients randomised in 1:1 ratio  
- 59 patients in the control group: Core decompression/Placebo implantation  
- 59 patients in the PREOB® group: Core decompression/PREOB® implantation 
Medical Condition or Disease under Investigation 
Early stage (ARCO stages I or II) non-traumatic osteonecrosis of the femoral head. 
Patient Selection  
Men and women, aged 18 to 70 years old, diagnosed with non-fractural (ARCO stages I or II) osteonecrosis of 
the femoral head, confirmed by conventional X-ray and magnetic resonance imaging (MRI). 
All patients must be symptomatic, except ARCO stage II patients with a combined coronal and sagittal necrotic 
angular sum superior to 190°. 
Inclusion Criteria 
All patients must satisfy ALL the following criteria at study entry: 
- 
Men or women between 18 and 70 years (inclusive) with a diagnosis of ARCO Stage I or II non-
traumatic osteonecrosis of the femoral head, confirmed by central imaging analysis based on X-ray and 
MRI 
- 
Ability to provide a written, dated, and signed informed consent prior to any study related procedure 
and to understand and comply with study requirements 
- 
Diagnosis of Osteonecrosis: 
a. 
ARCO stage I associated with WOMAC® VA3.1 pain score ≥20 mm and necrotic angle sum 
≥190° based on sagittal and coronal MRI views  
or  


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b. ARCO stage II associated with WOMAC® VA3.1 pain score ≥20 mm if necrotic angle sum 
<190° based on sagittal and coronal MRI views  
or  
c. 
ARCO stage II associated or not with pain if necrotic angle sum is ≥190° based on sagittal and 
coronal MRI views 
d. Associated with corticosteroid and/or with alcohol abuse and/or idiopathic 
- 
Normal haematology function, defined as leukocytes ≥3000/mm3, absolute neutrophils count 
≥1500/mm3, platelets ≥140,000/mm3, and haemoglobin concentration ≥10g/dl (peripheral blood test) 
Exclusion Criteria 
The following criteria should be checked at the time of study entry. If any exclusion criterion applies, the patient 
must not be included in the study: 
Current symptoms and/or signs related to the disease under study 
- 
Exclusively diaphyseal or metaphyseal osteonecrotic lesion 
- 
Traumatic or hyperbaric osteonecrosis, or osteonecrosis associated with haemoglobinopathy or 
coagulopathy (e.g., thalassemia, sickle cell disease,…), or Gaucher’s disease 
- 
Any other focal or diffuse bone marrow lesion 
- 
Osteoarthritis at the hip under evaluation defined as Kellgrens stage ≥2, as assessed by the Central 
Radiologist 
- 
Patients suffering from any medical conditions interfering with patient’s pain evaluation of the hip under 
evaluation, such as knee arthritis.  
- 
Bone fracture or bone infection at hip under evaluation. 
- 
Patients who are candidates for any predictable joint replacement on the hip under evaluation.  
Current or previous diagnoses, signs and/or symptoms 
- 
Blood not qualifying for PREOB® production, including active hepatitis B (defined as positive HBs Ag 
and/or positive PCR), or active hepatitis C (defined as positive PCR), positive serology for HIV, or 
Syphilis, or HTLV-1, and any other tests that may be required by the authorities in case of a new disease 
outbreak that can affect the safety of the physicians and operators at the time of patient screening  
- 
Presence, or previous history, of risks factors for diseases caused by prions, and recipients of grafts of 
cornea, sclera, and dura mater 
- 
History of blood loss exceeding 450 ml (incl. donations) within 1 month of screening 
- 
Renal impairment, defined by an estimated creatinine clearance value < 30 ml per min, calculated with 
the Cockcroft-Gault formula 
- 
Hepatic impairment, defined as alanine aminotransferase or aspartate aminotransferase ≥ 3 times the 
upper limit of normal 
- 
Poorly controlled diabetes mellitus, defined as HbA1C > 9% 
- 
Global sepsis 
- 
Allergy to gentamicin or any substance or device the patient might be exposed to in the context of the 
study related interventions (i.e., bone marrow harvesting and implantation), as judged by the Investigator 
- 
History of hypersensitivity to human biological material, including blood and blood derived products, 
documented clinically or by laboratory tests 
- 
Current or past history of solid or haematological neoplasia (except for basal cell carcinoma of the skin 
and for carcinoma in situ of the cervix that has been treated with no evidence of recurrence)  
- 
History of bone marrow transplantation 


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- 
Patients with a life expectancy less than 2 years, as judged by the Investigator 
 
Current or previous treatment 
- 
Patients having participated in another clinical trial within 3 months of screening 
- 
Patients previously treated with PREOB®  
- 
Patients treated by core decompression of the hip under evaluation within 6 months of screening 
- 
Treatment with doses of prednisolone ≥15 mg per day (or equivalent) within 1 month from screening, and 
patients with anticipated needs of daily corticoid doses ≥15 mg prednisone (or equivalent) in the 6-month 
period following PREOB/Placebo implantation  
- 
Illicit drug or alcohol abuse interfering with patient’s ability to understand and comply with study 
requirements, as judged by the Investigator 
Safety aspects concerning female patients of childbearing potential 
- 
Pregnancy  
- 
Breast-feeding 
- 
Women with childbearing potential not willing or able to use reliable contraceptive method for at least 6 
weeks prior to screening and during the whole study period. Reliable contraceptive methods include orally 
administered hormonal contraceptives, surgical intervention (e.g., tubal ligation), and intrauterine device 
(IUD).  
Other exclusion criteria 
- 
Body Mass Index (BMI) ≥ 35 kg/m2 
- 
Patients unable to undergo MRI, e.g. patients with pace-maker, intra-ocular or intra-cerebral metallic 
foreign bodies, and mechanical artificial heart valves 
- 
Patients unable to undergo general anaesthesia or surgical intervention 
Test procedure, product, dose and mode of administration 
PREOB® Group: Core decompression with a small-diameter trephine and implantation of 5 ml PREOB® 
suspension into the necrotic lesion. 
Control Group: Core decompression with a small-diameter trephine and implantation of 5 ml Placebo solution 
into the necrotic lesion. 
Detailed Visit Schedule 
After informed consent is obtained, fulfilment of study inclusion and exclusion criteria and radiological 
assessment for baseline will be performed at Visit 1.  
Visit 2 is scheduled to take place at least 21 days* before Visit 3 for baseline clinical assessments and (sham) 
bone marrow harvest procedure performed by the Independent Physician.  
At Visit 3, the surgical procedure (Core decompression and implantation, PREOB® or Placebo) is performed by 
the Principal Investigator. Patients will be systematically evaluated 24 hours after the procedure. 
Patients will be followed during 24 months, at months 1, 3, 6, 12, 18 and 24 (Visit 4 to Visit 9).  
Long term follow-up visits (phone calls) are scheduled at months 36 and 48. 
*Visits 2 and 3 will be scheduled in conjunction with the Sponsor’s Manufacturing Unit and will take into account the travel 
time between the Investigating Site and the Sponsor’s Manufacturing Unit. 
 


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Duration of Study 
Patients will undergo a single administration of PREOB® or Placebo into the necrotic lesion under general 
anaesthesia. Patients will be considered as having completed the study upon completion of the last scheduled visit 
of the follow-up period, 24 months after the implantation procedure. 
Long term follow-up visits (phone calls) are scheduled at months 36 and 48. 
Main Study Objectives and Endpoints  
The main objectives of the study are to demonstrate that Core decompression/PREOB® implantation into necrotic 
lesion is superior to Core decompression/Placebo implantation in relieving hip symptoms and halting (or 
reverting) radiological progression to fractural stages (ARCO III or higher) in patients with non-traumatic early 
stage osteonecrosis of the femoral head, at 24 months. 
Efficacy endpoints 
Primary Efficacy Endpoint 
• 
Percentage of treatment responders at Month 24,  
a treatment responder at a studied timepoint being defined as a patient who responded both:  
o 
Clinically, i.e., if at the studied timepoint, the WOMAC® VA3.1 pain subscale score of the 
study treated hip improved from baseline by at least the minimal clinically important 
difference (MCID)a,  
and  
o 
Radiologically, i.e., if at the studied timepoint, the study treated hip did not progress to 
fractural stages (ARCO III or higher), as assessed by conventional X-ray.  
a The MCID value is set at 10 mm.  
For patients with a baseline WOMAC® VA3.1 pain subscale score ≥10 mm, the MCID can be used as a 
threshold value to define a clinically meaningful pain relief. These patients will be considered, at the 
studied timepoint, as a clinical responder if the WOMAC® VA3.1 pain subscale score of the study treated 
hip decreased from baseline by at least the MCID.  
For patients with a baseline WOMAC® VA3.1 pain subscale score <10 mm, the MCID cannot be used as 
a threshold value to define a clinically meaningful pain relief. These patients will be considered, at the 
studied timepoint, as a clinical responder if the WOMAC® VA3.1 pain subscale score of the study treated 
hip is found in the range [0; 4] (VAS pain range labelled as “no pain”). 
Secondary Efficacy Endpoint 
• 
Percentage of treatment responders at Month 6, 12 and 18, and over the 24-month follow-up period  
• 
Percentage of clinical responders at Month 1, 3, 6, 12, 18 and 24, and over the 24–month follow-up 
period; a clinical responder being defined as a patient whom the WOMAC® VA3.1 pain subscale score 
of the study treated hip improved from baseline by at least the MCIDb at the studied timepoint  
• 
Percentage of radiological responders at Month 6, 12, 18 and 24, and over the 24–month follow-up 
period; a radiological responder being defined as a patient whom the study treated hip did not progress 
to fractural stages (ARCO III or higher), as assessed by conventional X-ray, at the studied timepoint  
• 
Absolute change from baseline in WOMAC® VA3.1 total score and composite pain, stiffness, and 
function subscale scores of the study treated hip at Month 1, 3, 6, 12, 18 and 24, and over the 24-month 
follow-up period  
• 
Time to progression to fractural stages (ARCO III or higher) of the study treated hip  
• 
Percentage of patients requiring hip arthroplasty for the study treated hip at Month 1, 3, 6, 12, 18 and 24, 
and over the 24-month follow-up period  
• 
Time to hip arthroplasty for the study treated hip  


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b The MCID value is set at 10 mm.  
Patients with a baseline WOMAC® VA3.1 pain subscale score ≥10 mm will be considered, at the studied 
timepoint, as a clinical responder if the WOMAC® VA3.1 pain subscale score of the study treated hip 
decreased from baseline by at least the MCID.  
Patients with a baseline WOMAC® VA3.1 pain subscale score <10 mm will be considered, at the studied 
timepoint, as a clinical responder if the WOMAC® VA3.1 pain subscale score of the study treated hip is 
found in the range [0;4]. (VAS pain range labelled as “no pain”). 
Exploratory Endpoints  
• 
Change from baseline of the size of the necrotic lesion of the study treated hip, as assessed by MRI at 
Month 6, 12 and 24  
• 
Absolute change from baseline in WOMAC® VA3.1 total score and composite pain, stiffness, and 
function subscale scores of contralateral hip (i.e., the hip contralateral to the study treated hip) at Month 
1, 3, 6, 12, 18 and 24, and over the 24-month follow-up period  
• 
Radiological evolution of contralateral hip (i.e., the hip contralateral to the study treated hip), as assessed 
by conventional X-ray, at Month 6, 12, 18 and 24 and by MRI at Month 6, 12 and 24  
• 
Percentage of patients requiring hip arthroplasty on contralateral hip (i.e., the hip contralateral to the study 
treated hip) at Month 1, 3, 6, 12, 18 and 24  
• 
Assessment of serum biomarkers at Day +1 after IMP implantation, Month 1 and 6 (as applicable)  
Safety endpoints 
From the beginning to the end of the main study period at Month 24, patients will be systematically assessed for 
the potential occurrence of any AE or SAE, related to the product or related to the procedure by patient interview, 
physical examination (including body mass index and vital signs), and laboratory measurements.  
Moreover, a long term follow-up will be performed via phone calls (conventional X-ray to be performed only 
when the patient still feels pain on the treated hip) at 36 and 48 months after IMP implantation. This includes 
assessment of hip symptoms (pain, stiffness, and function) using WOMAC® LK3.1 (Likert Scale) and the 
potential occurrence of any AEs and SAEs (patient open questionnaire, including notably any changes in health 
status and need for total hip arthroplasty). 
Statistical Analysis 
Statistical methods will be exhaustively described in a Statistical Analysis Plan (SAP), which will constitute the 
only reference document. The SAP will be generated, reviewed, approved, and signed by the biostatistician and 
the Sponsor, prior to database lock, at the latest. 
Efficacy Analysis 
The full analysis set (FAS) consists in an modified Intention-To-Treat population and will be considered as the 
primary cohort for analysis of efficacy.  
The superiority of PREOB® over Placebo will be considered achieved if the percentage of treatment responders 
is statistically significantly higher in the PREOB® group than in the Placebo group at Month 24. The primary 
efficacy endpoint will be compared between the two groups by means of a Chi square or a Fisher’s exact test (as 
appropriate). The difference between the two groups will be considered significant if the p-value is less than or 
equal to the Type I error. 
Comparison between treatment groups of the secondary binary efficacy endpoints will be performed at each 
studied timepoint, by means of a Chi square test or a Fisher’s exact test (as appropriate). Treatment effect over 
the 24-month follow-up period will be assessed using a Generalized Estimating Equations (GEE) model taking 
into account correlations between the repeated measurements within patients.  
Comparisons between treatment groups of the secondary continuous efficacy endpoints will be performed at each 
studied timepoint by means of a parametric Student t-test or a non-parametric Wilcoxon rank-sum test (as 


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appropriate). Multivariate analyses including analyses over time will also be conducted to assess treatment effect 
over the 24-month follow-up period.  
Distributions of time-to-event variables will be estimated at each timepoint using the Kaplan-Meier product limit 
method. The log-rank test will be used for treatment group comparison.  
The same statistical methods as for the primary and secondary efficacy endpoints will be used to analyse the 
exploratory efficacy endpoints.  
Safety Analysis 
The safety set (SAF) will be considered as the primary cohort for analysis of safety.  
Safety variables include AEs, SAEs, vital signs, physical examination, laboratory tests and concomitant 
medications. All safety analyses will be described by treatment group actually received and overall on the SAF. 
Date and Version of the Study Protocol: May 15, 2017 - Version 6.1 


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LIST OF TABLES 
Table 1: Inclusion Criteria: Osteonecrosis Diagnosis ......................................................... 38 
Table 2: Follow-up Period: Schedule of visits and procedures .......................................... 44 
Table 3: Long Term Follow-up: schedule of phone calls and procedures ........................ 45 
Table 4: Summary of Procedures Performed in the PREOB® and Placebo Groups ....... 54 
Table 5: Identity of Investigational Medicinal Products .................................................... 58 
Table 6: Administration of the Investigational Medicinal Product ................................... 59 
Table 7: Blood collected ......................................................................................................... 61 
Table 8: Overview of Safety Parameters and Endpoints .................................................... 63 
Table 9: Classification of Adverse Events ............................................................................ 67 
Table 10: Assessment of drug-event causal relationship .................................................... 68 
Table 11: Observation period for the occurrence of AEs and SAEs ................................. 71 
Table 12: Summary of Possible Risks related to the Procedures ...................................... 72 
Table 13: Summary of Observed Adverse Events (AE) and Serious Adverse Events (SAE) 
possibly related to Study Treatment (i.e., PREOB® and/or to the Implantation 
Procedure) (33 subjects (hips)*) .................................................................................... 73 
Table 14: Sample size estimation - Chi-square test ............................................................. 87 
 
 
 
LIST OF ANNEXES 
 
Annex 1 : WOMAC® Index ................................................................................................. 114 
Annex 2 : Imaging Data Analysis ........................................................................................ 115 
 
 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ADR 
Adverse Drug Reaction 
ARCO 
Association Research of Circulation Osseous 
AST (SGOT) 
Aspartate aminotransferase (serum glutamic-oxaloacetic transaminase) 
ALT (SGPT) 
Alanine aminotransferase (serum glutamic-pyruvic transaminase) 
ATMP 
Advanced Therapy Medicinal Product (according to EMA) 
BMC 
Bone Marrow Concentrate 
BMI 
Body Mass Index 
BP 
Blood Pressure 
CAs 
Competent Authorities 
CAT 
Committee for Advanced Therapies (according to EMA) 
CBMP 
Cell-Based Medicinal Product 
CHMP 
Committee for Medicinal Product for Human Use (according to EMA) 
CI 
Confidence Interval 
CPMP 
Committee for Proprietary Medicinal Products (according to EMA) 
CRA 
Clinical Research Associate 
CRF/eCRF 
Case Report Form/electronic Case Report Form 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CT (scan) 
Computed Tomography 
CTA 
Clinical Trial Application 
CU 
Clinical Unit 
DCF 
Data Clarification Form 
 
DSMB 
Data Safety Monitoring Board 
DMP 
Data Management Plan 
EC 
European Commission 
ECs 
Ethics Committees 
EMA 
European Medicines Agency 
EPCs 
Endothelial Progenitor Cells 
EU 
European Union 
EudraCT 
European Clinical Trials Database 
FAS 
Full Analysis Set 
FDA 
Food And Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
HTLV 
Human T-lymphotropic Virus  
IB 
Investigator’s Brochure 


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ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IMPD 
Investigational Medicinal Product Dossier (according to EMA) 
IRB 
Institutional Review Board 
ITT 
Intention-To-Treat 
MCID 
Minimal Clinically Important Difference 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
MSC 
Mesenchymal Stromal/Stem Cell 
OECD 
Organisation for Economic Co-Operation and Development 
ON 
Osteonecrosis 
ORA 
Office of Regulatory Affairs 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PV-CRO 
Pharmacovigilance-CRO 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAF 
Safety Population 
SAP 
Statistical Analysis Plan 
SAR 
Serious Adverse Reaction 
SASQE 
Serious Adverse Safety/Quality Event 
SDV 
Source Data Verification 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SPM 
Study Procedure Manual 
SSO 
Study Safety Officer 
DCF 
DCF 
THA 
Total Hip Arthroplasty 
USA 
United States of America 
VAS 
Visual Analogue Scale 
WHO 
World Health Organization 
WOMAC® 
Western Ontario McMaster University Score® 
WMA 
World Medical Association 
 


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DEFINITIONS  
• Approval (in relation to ethics committees (ECs): the affirmative decision of the EC that the 
clinical trial has been reviewed and may be conducted at the investigating site within the constraints 
set forth by the EC, the Institution, Good Clinical Practice (GCP, and the applicable regulatory 
requirements. 
• Autologous: means that the donor of the human biological material and the recipient of the 
investigational medicinal product (IMP) is the same individual. 
• Case report form (CRF or eCRF): a printed, optical, or electronic document designed to record 
all of the protocol-required information to be reported to the Sponsor on each trial subject. 
• Clinical study: is any investigation in human subjects intended to discover or verify the clinical, 
pharmacological and/or other pharmacodynamic effects of an investigational medicinal product 
and/or to identify any adverse reactions to an investigational medicinal product, and/or to study 
absorption, distribution, metabolism, and excretion of an investigational medicinal product with the 
object of ascertaining its safety and/or efficacy - PREOB® in this case. 
• Completed patient: a patient who completed all scheduled visits up to last scheduled visit 
(inclusive). 
• Contract Research Organization (CRO): a person or an organization contracted by the Sponsor 
to perform one or more of the Sponsor's trial-related duties and functions. 
• Data Safety Monitoring Board (DSMB): an independent data monitoring committee established 
by the Sponsor to assess at intervals the progress of a clinical trial, the safety data, and the critical 
efficacy endpoints, and to recommend to the Sponsor whether to continue, modify or stop the trial. 
• Discontinued or withdrawn patient: a patient who has been enrolled, screened, randomised or 
treated but has withdrawn from the study before completion of the last scheduled visit.  
• Drop out: a patient who has been randomised but never treated. 
• Distribution: transportation and delivery of tissues and cells intended for human applications. 
• Eligible patient: a screened patient who is considered eligible according to selection criteria. 
• Enrolled patient: a patient who has dated and signed the Informed Consent Form (ICF). 
• Ethics Committee: a review panel that is responsible for ensuring the protection of the rights, 
safety, and well-being of human subjects involved in a clinical trial and is adequately constituted to 
provide assurance of that protection. 
• Good Clinical Practice (GCP): set of internationally recognized ethical and scientific requirements 
and standards as regards the design, conduct, performance, monitoring, auditing, recording, 
analyses, and reporting of clinical trials, that provides assurance that the data and reported results 
are credible and accurate, and that the rights, safety, well-being, and confidentiality of trial subjects 
are protected. 
• Independent Physician: the unblind physician who will perform both the (sham) bone marrow 
harvest and blood collection procedures. 


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• Informed Consent: a process by which a patient voluntarily confirms his/her willingness to 
participate in a particular trial, after having been informed of all aspects of the trial that are relevant 
to the patient's decision to participate. Informed consent is documented by means of a written, 
signed, and dated informed consent form. 
• Investigating Site: any public or private entity or medical facility where clinical trial and trial-
related activities are conducted. 
• Investigational Medicinal Product (IMP): a pharmaceutical form of an active substance or 
Placebo being tested or used as a reference in a clinical trial. 
• 
Investigator: a person responsible for the conduct of the clinical trial at a trial site. If a trial is 
conducted by a team of individuals at a trial site, the investigator is the responsible leader of the 
team and may be called the Principal Investigator (PI).. 
• 
Managing Physician: Managing Physician of Human Biological Material in the Production/Tissue 
Establishment is a Medical Doctor responsible to guaranty the traceability, the quality and safety of 
the Human Biological Material, as well as the quality and safety of all operations executed in the 
Production/Tissue Establishment. He is also responsible for the reporting of Serious Adverse Event 
and Serious Adverse Reaction related to Human Biological Material. His function can be delegated. 
• Mesenchymal stromal (stem) cells (MSC): “plastic-adherent” stem cells, expressing specific 
surface markers, and giving rise to bone, cartilage, and adipocyte cells.  
• Monitor: refers to Sponsor’s authorized CROs and/or CRAs. 
• Multicenter Trial: a clinical trial conducted according to a single protocol but at more than one 
site, and, therefore, carried out by more than one investigator. 
• Non-traumatic osteonecrosis: a bone disease characterized by necrosis of bone and medullary 
tissues, mainly at bone epiphyseal sites evolving towards articular collapse and joint destruction due 
to non-traumatic aetiological factors. 
• Osteoblastic cells: cells belonging to the osteoblastic lineage (bone forming cells) encompassing 
the osteoprogenitors, the pre-osteoblasts, the osteoblasts, the lining cells and the osteocytes. 
• Patient: an individual participating in the clinical trial. 
• PREOB®: a proprietary autologous osteoblastic cells (PREOB® cells) product, i.e., an advanced 
therapy medicinal product falling under the scope of the European Regulation 1394/2007/EC and 
the Directive 2001/83/EC manufactured by Bone Therapeutics S.A. 
• Processing: all operations involved in the preparation, manipulation, preservation, and packaging 
of tissues or cells intended for human applications. 
• Procurement: a process by which tissues or cells are made available. 
• Production/Tissue Establishment: a tissue bank or a unit of a hospital or another body where 
activities of procurement, testing, processing, preservation, storage, and/or distribution of human 
tissues and cells are undertaken. 
• Randomised patient: a patient to whom a randomisation number has been allocated. 


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• Screened patient: a patient who has dated and signed the Informed Consent Form (ICF) (enrolled 
patient) and who has performed the checking of the selection criteria. 
• Screening failure: a screened patient who is not eligible for the study after checking the selection 
criteria. 
• Serious Adverse Event (SAE): any adverse event (AE) or serious adverse reaction (SAR) that, in 
the view of the investigator or sponsor, results in any of the following outcomes (ICH E2a): Death, 
Life-threatening AE, Inpatient hospitalization or prolongation of existing hospitalization, Persistent 
or significant incapacity or substantial disruption of the ability to conduct normal life functions, 
Congenital anomaly/birth defect. Medical and scientific judgement should be exercised in deciding 
whether expedited reporting is appropriate in other situations, such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require intervention to prevent one of the other outcomes listed in the definition 
above.  
• Serious Adverse Reaction (SAR): any untoward and unintended responses to an investigational 
medicinal product related to any dose administered (having a reasonable causal relationship to the 
product), and that results in death, is life-threatening, requires patient hospitalization or prolongation 
of existing hospitalization, results in persistent or significant disability or incapacity, or is a 
congenital anomaly or birth defect. 
• Serious Adverse Safety/Quality Event (SASQE): any adverse event related to the any operation 
done on the collected human biological material under the responsibility of the Intermediary 
Structure (i.e., direct transport and distribution of the human biological material from the harvesting 
site to the Production/Tissue Establishment of Bone Therapeutics S.A.) that may cause death, be 
life-threatening, generate disability or incapacity to work to the patient, or that may cause morbidity 
•  Storage: maintenance of the IMP under appropriate controlled conditions until administration. 
• Study Safety Officer: an individual designated to perform the handling, notification, and reporting 
of safety issues. 
• Suspected Unexpected Serious Adverse Reaction (SUSAR): serious adverse reaction, the nature, 
severity, specificity, or outcome of which is not consistent with applicable product information (e.g., 
the Investigator’s Brochure). 
• Treated patient: a patient to whom a treatment has been administered. 


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1 
INTRODUCTION  
 
Background of the Study 
1.1.1 Osteonecrosis of the Femoral Head 
Non-traumatic osteonecrosis, also known as avascular necrosis, is a bone disease characterized 
by necrosis of bone and medullary tissues, mainly at bone epiphyseal sites evolving towards 
articular collapse and joint destruction due to non-traumatic aetiological factors.  
Osteonecrosis is a devastating disease with a dramatic natural evolution. Osteonecrosis mainly 
affects young patients (30-60 years old, with only 20% of patients older than 50 years of age). 
Natural history of symptomatic osteonecrosis of the femoral head is generally characterized by 
relentless progression to collapse of the femoral head, ultimately leading to total hip 
arthroplasty. Based on current practice and available therapeutic options, nearly one-half of 
patients will require total hip arthroplasty (THA) before the age of 40. Studies have shown that 
within two years, 93% of stage I and 70% of stage II osteonecrosis in untreated patients will 
show radiological progression, with a mean progression time of respectively 8 and 14 months, 
which ultimately leads to femoral head collapse thus requiring total hip arthroplasty (Steinberg 
et al., 1997; Steinberg et al., 2001). 
Non-traumatic osteonecrosis is generally associated with one or more risk factors. In 
Caucasians, over two thirds of non-traumatic osteonecrosis are associated with past or current 
corticosteroid therapy and/or alcohol overconsumption. The remaining third includes dysbaric 
phenomenon, haemoglobinopathies, and coagulopathies. In other rarer medical conditions, the 
incidence of non-traumatic osteonecrosis is known to be greater than 1%, including organ 
transplant recipients and patients with systemic lupus erythematosus (Vail & Covington, 1997). 
Idiopathic cases account for a small proportion of non-traumatic osteonecrosis (<5%). 
The exact incidence of osteonecrosis is unknown, but osteonecrosis is the underlying diagnosis 
in about 5% to 12% of total hip arthroplasty (Lieberman et al., 2003). With an average time to 
hip arthroplasty of less than two years, the estimated prevalence of osteonecrosis in the OECD 
countries ranges from 2.5 to 3.1 per 10,000 habitants. 
1.1.2 Current Therapeutic Strategies for Osteonecrosis 
Several conservative interventions are usually used to halt progression of the disease and 
stimulate repair, but no treatment has clearly demonstrated efficacy against progression of the 
lesion towards fractural stages. The best currently available therapeutic option for early stages 
(I or II) osteonecrosis of the femoral head is core decompression using trephines with a mean 


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diameter of 8-10 mm This surgical procedure was first described by Phemister (Phemister, 
1949), who proposed that core decompression acts to decompress rigid intra-osseous chamber, 
and thereby improves venous drainage and promotes revascularization of the femoral head. 
Interestingly, because of the potential occurrence of various complications with use of this 
technique, including notably articular cartilage damage and subchondral fractures, several 
groups developed smaller diameter (3-mm) core decompression method (Mont et al., 2004; 
Song et al., 2007; Marker et al., 2008; Marker et al., 2008b). This less invasive strategy is 
reportedly associated with lower morbidity and postoperative complication rates, as compared 
with those reported with conventional large-diameter method. 
However, although core decompression is currently considered as the treatment of choice and 
has now been in use for many years, it remains controversial because many surgeons have been 
unable to replicate the high levels of success that have been reported in the initially published 
series (Camp & Colwell, 1986; Hopson & Siverhus, 1988; Learmonth et al., 1990; Stulberg et 
al., 1991; Koo et al., 1995). This controversy points to the need to search for more effective 
conservative therapeutic options in the management of early stage osteonecrosis of the femoral 
head. 
1.1.3  Pathophysiological Mechanisms and Rationale for the Use of PREOB® in 
Osteonecrosis 
It has long been thought that osteonecrosis develops subsequently to a reduction in blood flow 
to the bone, resulting in local ischemia. Fat embolism (Jones, 1985), retrograde embolization 
of the marrow fat (Simkin & Downey, 1987), microvascular tamponade of blood vessels of the 
femoral head by marrow fat (Wang et al., 1977; Wenstrup et al., 2002), and trabecular bone 
microfracture (Laurent et al., 1973) are amongst the many hypotheses formulated. However, it 
has been postulated that osteonecrosis of the femoral head may also result from bone and/or 
mesenchymal cellular deficiency. Indeed, the proliferative activity and the number of 
mesenchymal stem cells in both the haematopoietic and stromal compartments of bone marrow 
have been shown to be decreased in patients with osteonecrosis (Gangji et al., 2003). A decrease 
in the stem cell pool may result in too low number of osteoblasts required for effective bone 
remodelling during the early stages of the disease (Hernigou & Beaujean, 1997). This decrease 
in osteoblast proliferative capacity may be indicative of the disruption in the mechanosensory 
role of the osteocyte-canalicular network and might also explain the observed transition from 
bone marrow ischemia and oedema to established necrosis. 


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 Previous Trials Treating Osteonecrosis with Cell-Based Products - Bone Marrow 
Grafts 
Early interventions with bone marrow implantation were reported to be effective in the 
treatment of osteonecrosis of the humeral head secondary to sickle cell disease (Hernigou et al., 
1997). Implanting bone marrow-containing stromal cells after the decompression procedure 
was also shown to be somehow effective in treating ARCO Stage I and II non-traumatic 
osteonecrosis of the femoral head in two pilot studies (Hernigou et al., 2002; Gangji et al., 
2004). These observations suggested that it may be possible to prevent osteonecrosis damage 
extension by implantation of bone marrow cells presumably possessing osteogenic potential. 
Interestingly, it has been proposed that the effectiveness of previous studies using autologous 
bone marrow cells for treating osteonecrosis may potentially be explained by the implantation 
of stem cells with osteogenic potential within the bone lesion (Hernigou et al., 1999; Gangji et 
al., 2003). It has been postulated that injected bone marrow stromal cells may further act 
through either the release of angiogenic cytokines, which can lead to an improvement in 
osteogenesis (Gangji et al., 2004), or the presence of endothelial progenitor cells (EPCs) within 
the CD34+ fraction (Tateishi-Yuyama et al., 2002). Altogether, the data supports the concept of 
developing a bone marrow cell derived medicinal product to test its efficacy and safety in 
patients with osteonecrosis.  
 PREOB® Phase II Randomised Reference-Controlled Proof-of-Concept Study 
Based on these observations, a proprietary cell population of osteoblastic cells (PREOB®) has 
been developed and subsequently optimised to solely include the efficacious cell types by Bone 
Therapeutics S.A. Indeed, using selected and specific osteoblastic cells would allow a more 
focused, effective, and safe approach to clinical trials. In this respect, a proof-of-concept, 
randomised, controlled, single-blind, Phase IIb study has documented both the efficacy and 
safety of a single local implantation of PREOB® in patients with osteonecrosis of the femoral 
head for up to 5 years, in comparison with an active reference treatment (bone marrow 
concentrate: BMC). 
In this study, subjects (patient’s hips) with early stage osteonecrosis of femoral head were 
randomly assigned to receive Core decompression/PREOB® (20 × 106 cells; 4 × 106 cells/ml) 
implantation or Core decompression/ BMC implantation, with a ratio 1:1.  The main efficacy 
outcome was the proportion of treatment responders – a responder subject being defined as a 
hip which (i) showed a clinically relevant pain relief and (ii) did not radiologically progress to 
fractural stages. Results show that 2 years after implantation, there were almost twice as many 
treatment responders in the PREOB® group (70.0%) than in the BMC group (36.7%) (p<0.05; 
adjusted Chi-Square test). A 33% absolute difference in treatment responder proportions in 


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favour of PREOB® appeared as soon as 3 months after implantation and was maintained 
unchanged at all time points up to 3 years after implantation. PREOB® was associated with less 
radiological progression of the disease to fractural stages: as compared to BMC, PREOB® 
decreased the risk of hip fracture during the 3 years post-treatment (hazard ratio of 0.370, Cox 
proportional hazards model). In particular, at 2 years after implantation, the proportions of hips 
that progressed to fracture in the PREOB® and BMC groups were 20% and 40% respectively, 
corresponding to a 50% reduction in fracture risk. Consistent with these observations, a lower 
rate of THA was observed in the PREOB® group (13.3%) compared to the BMC group (36.7%) 
over the complete study follow-up (i.e., up to 5 years after implantation). PREOB® was also 
associated with a rapid (within the first 3 months) clinically relevant hip pain relief and function 
improvement, which lasted for up to 4 years after implantation. In particular, at 2 years after 
implantation, 76.7% of the PREOB®-treated subjects achieved a clinically relevant (>10 mm) 
VAS pain relief with a mean reduction of 21.6 mm, versus 50.0% of the BMC-treated subjects 
with a mean reduction of 4.9 mm. 
From a safety perspective, a high number of adverse events (n=578) and serious adverse events 
(n=128) were reported in the study, as expected with this patient’s population (chronic 
alcoholism and/or long-term corticosteroid use due to transplantation, chronic obstructive 
bronchitis, refractory asthma or others). Most of SAEs were related to concomitant conditions 
or to repeated hospitalisations for the treatment of osteonecrosis on other sites than the hip 
treated in the study (e.g., contralateral hip, knee(s), ankle(s), shoulder(s)), but not related to the 
PREOB® or BMC treatments. 
The sole non-serious adverse event possibly related to study treatment reported was transient 
fever reported in about 9% of PREOB®-treated subjects – this was comparable to the rate 
reported in the BMC group and in accordance with the possible risks linked to the study 
procedures as described in the literature, i.e., core decompression and/or local implantation of 
a cellular product (such as stem cells or BMC) (Lalu et al., 2012, Liebergal et al., 2013).  
Two (2) patients experienced serious adverse events possibly related to PREOB® treatment and 
requiring prolonged hospitalization: one patient experienced severe pyrexia with altered state 
of consciousness and hypotension, the two latter being considered as possibly related to the 
underlying and/or concomitant diseases and treatments; the other patient developed an 
inflammatory syndrome due to an unknown cause. Still for both patients, a causal relationship 
with PREOB® treatment could not be excluded. The narratives of these events are further 
described in the Investigator’s Brochure. 
In conclusion, data from this Phase IIb clinical trial supports the clinical benefits of PREOB® 
on pain and function in early stage osteonecrosis patients, as well as on a reduction in 


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progression to fractural stages, in comparison to Bone Marrow Concentrate. These data form 
the basis of the clinical Phase III program of PREOB® in osteonecrosis. 


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Study Rationale 
Primary Efficacy Outcomes  
Monitoring of osteonecrosis evolution is usually measured by two parameters: 
- 
Clinical presentation and clinical failure defined as surgical intervention (e.g., hip 
arthroplasty as a result of intractable pain); 
- 
Radiological progression defined as an advance in Association Research Circulation 
Osseous (ARCO) stage, mainly to fractural stage III or higher. 
Indeed, once fracture occurs, the femoral head evolves towards collapse within 6 to 18 months 
with the need for total hip arthroplasty. With respect to this dramatic evolution, the objective 
of the treatment is therefore to delay the evolution towards fractural stage. 
Clinical Evaluation 
Clinical evaluation of the hip is usually performed using dedicated open questionnaires and/or 
scores, which have been developed and established in order to assess hip pain, hip stiffness, 
and/or hip function in patients with osteoarthritis primarily, but also for other hip diseases and 
following total hip arthroplasty. These include the Merle d’Aubigné, Lequesne, Harris Hip, and 
WOMAC® Scores. 
Although all these scores are frequently used and cited in the literature, the scores of Merle 
d’Aubigné, Lequesne, and Harris present a number of limitations and pitfalls regarding their 
use in clinical practice: 
- 
Initially developed and studied to assess pain and function in patients after total hip 
arthroplasty (d’Aubigné & Postel., 1954), the Merle d’Aubigné Clinical Hip Score has 
never been systematically evaluated and validated in large trials since its initial 
description; 
- 
The algofunctional Lequesne’s Index for hip and knee osteoarthritis has demonstrated 
its usefulness and efficacy as an outcome functional measure after hip surgery only 
(Lequesne, 1997; Stucki et al., 1998; Lequesne & Maheu, 2003); 
- 
Finally, the Harris Hip Score has been tested and validated only to study the clinical 
outcome of total hip arthroplasty (Söderman & Malchau, 2001). 
By contrast, the Western Ontario and McMaster Universities (WOMAC®) Index, which allows 
a thorough evaluation of pain, stiffness, and function (through 3 subscales with a total of 24 
questions), has been widely validated and used: it has been standardised and tested for 
reliability, validity, and responsiveness in patients with osteoarthritis of the hip (and/or the 


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knee) in various clinical settings, including both medical (pharmacological) and surgical 
management (total hip arthroplasty) of patients (Bellamy et al., 1988; Bellamy 2002; Bellamy 
2005; Bellamy 2009). 
Moreover, and contrarily to the other hip scores, the WOMAC® Index is available not only in 
Likert scaled format but also in Visual Analogue Scaled format, which scaling has been 
suggested to be more reproducible and sensitive as compared to Likert scales (Gerich, 2007). 
In this study, the WOMAC® pain subscale has been selected as primary efficacy outcome. 
Indeed, as illustrated by the questions below, functional hip evaluation inherently implies 
bilateral hip assessment, making difficult to distinguish one hip function (hip under evaluation) 
from the other (opposite hip), which may potentially bias the results, either positively or 
negatively. For example, the function and disease(s) of the non-studied hip could obviously 
interfere with the evaluation of the studied hip when answering to the following questions: 
“What degree of difficulty do you have descending or ascending stairs?”, “What degree of 
difficulty do you have walking on a flat surface?”, or “What degree of difficulty do you have 
getting in or out of a car, or getting in or out of a bus?”.  
Nevertheless, the total WOMAC® Index (including composite pain, stiffness, and function 
subscales) will be used as a secondary efficacy endpoint. 
Finally, in support of WOMAC® against the other hip scores, the additional post study long 
term follow-up (phone call visits) will be performed using the WOMAC® LK3.1 (Likert) scale, 
which has also been validated when administered by phone, to assess pain, stiffness, and 
function (Bellamy et al., 2002). 
Radiological Evaluation 
Radiologically, patients will be assessed using both conventional X-ray and magnetic resonance 
imaging (MRI) of the hips, which are well established imaging tools for both the diagnosis and 
staging (according to ARCO Classification) of femoral head osteonecrosis, achieving excellent 
sensitivity and specificity. CT scan of the hips will also be performed once during the trial 
(during the Screening Period only), for additional diagnostic and exploratory purposes. 
Detailed description of imaging analysis (performed by a Radiologist from the Central 
Evaluating Centre, hereafter referred to as the “Central Radiologist”), including diagnosis of 
femoral head osteonecrosis, presence of perilesional changes, detection of femoral head 
fracture, staging (according to ARCO staging), quantitative evaluation of the extent of necrotic 
area, and additional MRI findings, is provided in Annex 2. 
Based on existing literature and PREOB® Phase IIb trial data disclosed in Section 1.1.3, (i) 
pain, as clinically assessed by the WOMAC® VA3.1 pain subscale score (using Visual Analog 


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Scale), and (ii) radiological progression to fractural stages (ARCO stages III or higher), as 
assessed by conventional X-ray, are therefore considered to represent valid and robust primary 
efficacy outcomes to assess the clinical benefits of PREOB® implantation. 
Primary Efficacy Endpoint 
In the advanced stages of non-traumatic osteonecrosis (ARCO stages III or higher), patients 
experience severe pain continuously, with negative impact on their day-to-day life (Fine et al., 
2011). In these advanced stages, pain not only results from fracture occurrence but also from 
osteoarthritic degenerative changes of the hip joint (Ficat, 1985; Jagadale et al., 2014; Mont et 
al., 2015).  
In the early stages of the disease (ARCO stages I and II), before the occurrence of fracture or 
of the osteoarthritic degenerative changes, patients experience mild to moderate pain that may 
be present before any observable X-ray abnormalities (Koo et al., 1999). In these early stages, 
pain is therefore rather the consequence of sub-radiological structural changes due to bone 
ischemia and necrosis (Jagadale et al., 2014, Mwale et al., 2011). The radiological evaluation 
of the osteonecrotic hips is not suitable - nor validated - to detect microscopic structural 
improvement of a therapeutic intervention (Trăistaru et al., 2015). Therefore, in early stage 
osteonecrosis, pain will be the key variable to assess the efficacy of treatment in addition to 
radiological evaluation.  
Accordingly, in early stage osteonecrosis, to be considered effective, a therapeutic intervention 
must not only delay/stop the progression of the disease to fractural stages but also relieve pain 
and symptoms if these mainly result from subclinical fractures. Therefore, a composite 
responder endpoint has been chosen as the primary efficacy endpoint since it is important that 
improvement in each variable, pain and fracture, occurs at the patient level. This endpoint 
determines for each patient individually whether s/he has had responded to treatment by taking 
into account whether s/he had responded to each of the clinical (pain) and radiological efficacy 
outcomes (described above).  
This composite responder approach complies with the regulatory requirements since a single 
suitable variable is not available and the clinical and radiological components of the composite: 
- 
are the most commonly reported evaluation parameters of osteonecrosis of the femoral 
head, 
- 
have similar occurrence, 
- 
are unweighted,  
- 
are both dichotomized, and importantly, 


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- 
are both taken into consideration to claim a treatment success.  
Response threshold for clinical efficacy outcome (WOMAC VA3.1 pain subscale) 
The MCID value is set at 10 mm in accordance with the literature for WOMAC® VAS pain 
subscale (Ehrich et al., 2000; Angst et al., 2001) and with the absolute MCIDs reported in 
controlled, randomised, parallel group studies that evaluate treatment for hip disorders (Puopolo 
et al., 2007; Altman et al., 2007; Prior et al., 2014).  
For patients with a baseline WOMAC® VA3.1 pain subscale score ≥10 mm, the MCID can be 
used as a threshold value to define a clinically meaningful pain relief. These patients will be 
considered, at the studied timepoint, as a clinical responder if the WOMAC® VA3.1 pain 
subscale score of the study treated hip decreased from baseline by at least the MCID.  
For patients with a baseline WOMAC® VA3.1 pain subscale score <10 mm, the MCID cannot 
be used as a threshold value to define a clinically meaningful pain relief. These patients will be 
considered, at the studied timepoint, as a clinical responder if the WOMAC® VA3.1 pain 
subscale score of the study treated hip is found in the range [0; 4]. This definition is based on 
the literature, which states that any VAS pain rating ≤4 mm is labelled as “no pain” (Jensen et 
al., 2003). 
Study Population 
As previously described, non-traumatic osteonecrosis is generally associated with one or more 
risk factors. In Caucasians, it is considered that about two thirds of non-traumatic osteonecrosis 
are related to corticosteroid therapy and/or alcohol abuse. The remaining third includes a 
heterogeneous group of diseases, notably dysbaric phenomenon, haemoglobinopathies, 
coagulopathies, and other rare medical conditions such as organ transplant recipients and 
systemic lupus erythematosus (Vail & Covington, 1997). Finally, idiopathic cases occur for a 
small proportion (<5%) of non-traumatic osteonecrosis. 
In order to address the question of both sample size and heterogeneity of patients across the 
variety of osteonecrosis aetiologies, the proposed Phase III study has been designed to include 
a relatively homogeneous patient population, focusing on the most frequent aetiologies of the 
disease, i.e., corticosteroid and alcohol associated osteonecrosis, as well as the idiopathic forms 
of osteonecrosis. It will therefore exclude others aetiologies such as trauma, sickle cell disease, 
other haemoglobinopathies, and dysbaric osteonecrosis. 
Besides, it is interesting to note that, even if the exact pathophysiological mechanisms involved 
in osteonecrosis have yet to be fully elucidated, it is increasingly recognized that osteonecrosis 
of the femoral head is a disease of bone and/or MSCs (Hernigou & Beaujean, 1997; Gangji et 


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al., 2003). Indeed, the number and levels of activity of mesenchymal stem cells in both the 
haematopoietic and stromal compartments of bone marrow have been shown to be depressed 
in patients with osteonecrosis of the femoral head (Hernigou et al., 1999) as well as the 
proliferative capacity of osteoblastic cells, as measured by cell population doubling time 
(Gangji et al., 2003). Moreover, this decreased proliferative capacity was found not only in 
glucocorticoid-induced osteonecrosis (Weinstein et al., 2000), but also in osteonecrosis due to 
other risk factors (Gangji et al., 2003).  
Hernigou et al. have also reported a decrease in the number and activity of fibroblast colony-
forming units (CFU-F; reflecting the number of MSCs that could potentially give rise to mature 
osteoblasts) in the proximal femur of patients with osteonecrosis (Hernigou et al., 1997; 
Hernigou et al., 1999). The same group further showed that patients with osteonecrosis due to 
different aetiological factors, including steroids, alcohol abuse, and transplantation, disclosed 
comparable decrease in the number of CFU-F and similar response to treatment (Hernigou et 
al., 2002). This strongly suggests common pathophysiological pathways across the various 
aetiologies of the disease (except sickle cell disease). 
Finally, our own experiments revealed no significant differences in both yield and identity of 
PREOB® cultures from osteonecrosis patients according to aetiologies (corticosteroid versus 
alcoholic versus idiopathic patients, unpublished observations). 
Study blindness 
In order to ensure the blindness of both patient and Investigator, both treatment groups will 
undergo the same procedures: (i) patients randomised in the PREOB® group will undergo a 
bone marrow harvesting and a core decompression procedure with PREOB® implantation into 
the necrotic lesion, and (ii) patients randomised in the Placebo group will undergo a sham bone 
marrow harvesting and a core decompression procedure with Placebo implantation into the 
necrotic lesion.  
The only patient procedure that can identify group assignment will be the Bone Marrow 
Harvest. This procedure will therefore be performed by an Independent Physician who will not 
be involved in patient selection, treatment, and follow-up.  
The Investigational Medicinal Product (IMP), PREOB® and Placebo, will be supplied in 
identical packaging conditions, and will be blind to the Investigator.  
Core decompression is the most commonly proposed treatment for ARCO stage I and II 
osteonecrosis of the femoral head. As standard of care, 8 to 10-mm trephines are commonly 
used (over 1500 cases published, Arlet & Ficat, 1964; Ficat 1999; Aaron, 2001; Marker et al., 
2008). However, such large-diameter trephines cannot be used to perform the core 


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decompression when cell implantation, such as PREOB®, is contemplated because of an 
increased risk of product leakage. An increasing number of groups - both in the US with the 
group of Marker and Mont, and elsewhere in the world with the group of Song and Kim - have 
recently published data using smaller diameter trephines. Indeed, use of multiple small-
diameter trephines has been shown to decrease the occurrence of postoperative complications, 
such as articular cartilage damage and subchondral fractures, and was associated with lower 
morbidity together with comparable clinical benefits as compared to conventional large-
diameter method (Mont et al., 2004; Marker et al., 2008; Marker et al., 2008b; Song et al., 
2007). 
A detailed description of methods and procedures to ensure a correct blinding is provided in 
Section 2.3. 
 
Risks and Benefit Assessment  
PREOB® is a cell-based medicinal product (CBMP), consisting in human autologous bone 
marrow-derived osteoblastic cells.  
Characterization studies have shown that PREOB® cells express and exhibit features of 
“trabecular osteoblasts”, including the expression of typical cell surface marker profile and 
bone matrix proteins, expression of bone enzymes and related osteogenic biological activity 
such as alkaline phosphatase, as well as bone matrix synthesis and mineralization capacity. 
Non clinical studies in vitro have further demonstrated that PREOB® cells have the ability to 
adhere, multiply, produce bone matrix, and mineralized new bone matrix. PREOB® 
engraftment at lesion site and PREOB® bone formation capacity have been confirmed in vivo in 
femoral fracture model and a calvaria bone formation model in immunodeficient mice. Taken 
together, these results show the ability of PREOB® cells to produce new bone at the bone defect 
site as well as to re-establish a healthy bone environment, and hence support its use in patients 
affected by osteonecrosis of the femoral head. 
No in vivo toxicity has been observed. PREOB® cells, when administered locally at the fracture 
site (in a femoral fracture mouse model), persisted at the fracture site and did not invade non-
bone organs (i.e., brain, heart, lungs, kidneys, liver and spleen). PREOB® appeared to be safe 
and devoid from toxicity even at very high doses. A long-term (26 weeks) GLP toxicity study 
performed in immunodeficient nude mice showed that PREOB® administered intravenously at 
the dose of 1×106 cells (> 100 times the clinical human intended dose) did not cause any excess 
mortality, or morbidity and did not induce any organ toxicity or ectopic bone formation. 
Moreover, karyotype analyses have shown no relevant chromosomal abnormalities, and in vitro 
tumourigenesis studies revealed no abnormal proliferation and no tumoural characteristics 
(anchorage independent growth). Results of the in vivo tumourigenic study confirms the 


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absence of tumourigenic potential of PREOB® cells at a dose largely >100 times the clinical 
human intended dose. As such, there are no non-intended effects or unwanted biological 
activities expected from PREOB® administration to patients, and no expected toxicity. 
Finally, the human proof-of-concept Phase IIb study documents both the efficacy and safety of 
a single local implantation of PREOB® in patients with early stage ONFH for up to 5 years, in 
comparison with a reference active treatment (bone marrow concentrate: BMC). Study efficacy 
data analyses reveal a better efficiency of PREOB® over BMC in relieving clinical hip pain and 
delaying radiological progression to fractural stages. The primary efficacy variable analysis at 
24 months after implantation shows that the proportion of treatment responders was statistically 
significantly higher in the PREOB® group (70.0%) than in the BMC group (36.7%) (p<0.05, 
adjusted Chi-square). 
Taken together, non-clinical and clinical results (exposed in sections 1.3 and 1.1.3.2) 
demonstrate the favourable benefit-risk profile of PREOB®, and strongly support the proposed 
pivotal Phase III study to evaluate the efficacy and safety of the association of core 
decompression and PREOB® (total dose 20×106 cells) implantation into necrotic lesion in 
patients with early stage non-traumatic osteonecrosis of the femoral head.  


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2 
INVESTIGATIONAL PLAN 
 
Overall Study Design  
The present study is a 24-month prospective, multicentre, randomised, double-blind, controlled, 
pivotal Phase III trial comparing the efficacy and safety of Core decompression/PREOB® 
implantation (PREOB® Group; 1 dose, 20×106 cells) to Core decompression/Placebo 
implantation (Control Group) in patients with non-traumatic early stage (ARCO I or II) 
osteonecrosis of the femoral head, as diagnosed by conventional bilateral X-ray and bilateral 
MRI of the hips. 
An additional long term follow-up at 36 and 48 months will assess some selected efficacy and 
safety data. 
 
Main Study Objectives and Endpoints 
The study objectives are to demonstrate that Core decompression/PREOB® implantation is 
superior to Core decompression/Placebo implantation in relieving clinical hip symptoms and 
halting (or reverting) radiological progression to fractural stages (ARCO III or higher) in 
patients with non-traumatic early stage osteonecrosis of the femoral head, at 24 months. 
Patients will be assessed using the Western Ontario and McMaster Universities (WOMAC®) 
index. Central Radiological evaluation will include conventional bilateral X-ray and bilateral 
MRI of the hips to assess the ARCO staging and to measure the sum of the coronal and sagittal 
necrotic angles. 
2.2.1 Follow-up Period 
Efficacy endpoints 
Primary Efficacy Endpoint  
• Percentage of treatment responders at Month 24,  
a treatment responder at a studied timepoint being defined as a patient who responded both:  
• Clinically, i.e., if at the studied timepoint, the WOMAC® VA3.1 pain subscale score of 
the study treated hip improved from baseline by at least the minimal clinically important 
difference (MCID)a, 
and 
• Radiologically, i.e., if at the studied timepoint, the study treated hip did not progress to 
fractural stages (ARCO III or higher), as assessed by conventional X-ray. 


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a The MCID value is set at 10 mm in accordance with the literature for WOMAC® VAS pain subscale (Ehrich et 
al., 2000; Angst et al., 2001) and with the absolute MCIDs reported in controlled, randomised, parallel group 
studies that evaluate treatment for hip disorders (Puopolo et al., 2007; Altman et al., 2007; Prior et al., 2014). 
For patients with a baseline WOMAC® VA3.1 pain subscale score ≥10 mm, the MCID can be used as a threshold 
value to define a clinically meaningful pain relief. These patients will be considered, at the studied timepoint, as a 
clinical responder if the WOMAC® VA3.1 pain subscale score of the study treated hip decreased from baseline by 
at least the MCID. 
For patients with a baseline WOMAC® VA3.1 pain subscale score <10 mm, the MCID cannot be used as a 
threshold value to define a clinically meaningful pain relief. These patients will be considered, at the studied 
timepoint, as a clinical responder if the WOMAC® VA3.1 pain subscale score of the study treated hip is found in 
the range [0; 4]. This definition is based on the literature, which states that any VAS pain rating ≤4 mm is labelled 
as “no pain” (Jensen et al., 2003). 
 
Secondary Efficacy Endpoint 
• Percentage of treatment responders at Month 6, 12 and 18, and over the 24-month follow-
up period 
• Percentage of clinical responders at Month 1, 3, 6, 12, 18 and 24, and over the 24–month 
follow-up period; a clinical responder being defined as a patient whom the WOMAC® 
VA3.1 pain subscale score of the study treated hip improved from baseline by at least the 
MCIDb at the studied timepoint 
• Percentage of radiological responders at Month 6, 12, 18 and 24, and over the 24–month 
follow-up period; a radiological responder being defined as a patient whom the study treated 
hip did not progress to fractural stages (ARCO III or higher), as assessed by conventional 
X-ray, at the studied timepoint 
• Absolute change from baseline in WOMAC® VA3.1 total score and composite pain, 
stiffness, and function subscale scores of the study treated hip at Month 1, 3, 6, 12, 18 and 
24, and over the 24-month follow-up period 
• Time to progression to fractural stages (ARCO III or higher) of the study treated hip 
• Percentage of patients requiring hip arthroplasty for the study treated hip at Month 1, 3, 6, 
12, 18 and 24, and over the 24-month follow-up period 
• Time to hip arthroplasty for the study treated hip 
b The MCID value is set at 10 mm. 
Patients with a baseline WOMAC® VA3.1 pain subscale score ≥10 mm will be considered, at the studied timepoint, 
as a clinical responder if the WOMAC® VA3.1 pain subscale score of the study treated hip decreased from baseline 
by at least the MCID. 
Patients with a baseline WOMAC® VA3.1 pain subscale score <10 mm will be considered, at the studied timepoint, 
as a clinical responder if the WOMAC® VA3.1 pain subscale score of the study treated hip is found in the range 
[0;4] (VAS pain range labelled as “no pain”).  


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Exploratory Endpoints  
• Change from baseline of the size of the necrotic lesion of the study treated hip, as assessed 
by MRI at Month 6, 12 and 24 
•  Absolute change from baseline in WOMAC® VA3.1 total score and composite pain, 
stiffness, and function subscale scores of contralateral hip (i.e., the hip contralateral to the 
study treated hip) at Month 1, 3, 6, 12, 18 and 24, and over the 24-month follow-up period 
• Radiological evolution of contralateral hip (i.e., the hip contralateral to the study treated 
hip) as assessed by conventional X-ray at Month 6, 12, 18 and 24 and by MRI at Month 6, 
12 and 24 
• Percentage of patients requiring hip arthroplasty on contralateral hip (i.e., the hip 
contralateral to the study treated hip) at Month 1, 3, 6, 12, 18 and 24 
• Assessment of serum biomarkers at Day +1 after IMP implantation, Month 1 and 6 (as 
applicable)  
Safety endpoints 
From the beginning till the end of the main study period at Month 24, patients will be 
systematically assessed for the potential occurrence of any AE or SAE, related to the product 
or related to the procedure by patient interview, physical examination (including body mass 
index and vital signs) and laboratory measurements.  
2.2.2 Long Term Follow-up 
A long-term follow-up will be performed via phone calls at 36 and 48 months after IMP 
implantation. This includes assessment of hip symptoms (pain, stiffness, and function) using 
WOMAC® LK3.1 (Likert Scale), radiological progression (conventional X-ray to be performed 
only when the patient still feels pain on the treated hip), and the potential occurrence of any 
AEs and SAEs (patient open questionnaire, including notably any changes in health status and 
need for total hip arthroplasty). 
2.2.3 Clinical Study Report 
The Final Clinical Study Report will be established based on the efficacy and safety data 
collected up to Month 24. The long-term follow-up data will be analysed and reported as 
Annexes and Supplementary Data to the Final Clinical Study Report. 


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Main Study Plan and Procedures 
2.3.1 Patient Information and Informed Consent 
Before any study-related procedure, the Principal Investigator (or delegate) will give detailed 
and comprehensive information regarding all aspects of the trial to the patient (or, when the 
patient is not capable of giving informed consent, his/her legal representative), including: 
• Purpose, objectives, and nature of the trial (including all performed procedures) 
• Conditions under which the trial and procurement of blood/bone marrow are conducted 
• Expected benefits for the patient and for the research 
• Inconveniences and risks 
• Appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the patient 
• Trial treatments and the probability for random assignment to each treatment arm 
• Right to receive the results of the tests performed, excluding those that could lead to 
potential unblinding 
• Rights of the patient to physical, mental, and social integrity, dignity, privacy, 
confidentiality, and protection of his/her personal data and medical records, in accordance 
with the Declaration of Helsinki on Ethical Principles for Medical Research involving 
Human Subjects, adopted by the General Assembly of the World Medical Association 
(1996), with amendments, and any other applicable laws, regulations, guidance, guidelines, 
and principles  
• Right to refuse to participate or right to withdraw from the clinical trial, at any time, without 
any resulting detriment, penalty or loss of benefits to which the patient is otherwise entitled, 
notably in terms of medical care, follow-up, and patient-physician relationship 
• Medical confidentiality - Recording and protection of patient data 
• Access and scrutiny of personal data and information during inspection by the CAs and 
any other properly authorized persons, provided that such information is treated as strictly 
confidential and is not made publicly available 
• Provision has been made for insurance or indemnity to cover the liability of both the 
Sponsor and Investigator (including all members of the investigating team and any other 
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This detailed information will be given in both oral and written forms (Subject Information 
Sheet and Informed Consent Form (ICF)), in appropriate and clear manner, worded in the 
patient’s mother tongue, using non-technical and practical language and terms that are easily 
understood by the patient (or his/her legal representative). The information provided will not 
include any term or sentence that appears to waive any of the patient's legal rights, or appears 
to release the Investigator, Institution/Investigating Site, Sponsor, or any representative of the 
Sponsor, from liability for negligence. 
The patient (or his/her legal representative) will then be given sufficient time (as needed) and 
opportunity to inquire about details and ask any questions about the trial to the Investigator (or 
the person who conducts the Informed Consent discussion) and to decide whether or not to 
participate to the trial. All questions about the trial will be answered to the satisfaction of the 
patient (or his/her legal representative). 
If the patient (or his/her legal representative) agrees to participate, he/she will be invited to date 
and sign two copies of the ICF. The Investigator (or the person who conducted the Informed 
Consent discussion) will also sign and date the document on the same day. One original signed 
copy will be given to the patient (or his/her legal representative), the other original signed copy 
will be kept in the Investigator’s Site File. 
The Investigator will then complete the patient’s records, thereby attesting and recording that 
signed ICF has been obtained from the patient. 
2.3.2 Inclusion and Exclusion Criteria 
Inclusion criteria 
To be eligible for the study, patients must satisfy ALL the following criteria: 
1. Men or women between 18 and 70 years (inclusive) with a diagnosis of ARCO Stage I 
or II non-traumatic osteonecrosis of the femoral head, confirmed by central imaging 
analysis based on X-ray and MRI 
2. Ability to provide a written, dated, and signed informed consent prior to any study 
related procedure and to understand and comply with study requirements 
3. Diagnosis of osteonecrosis: 
a. ARCO stage I associated with WOMAC® VA3.1 pain score ≥20 mm and 
necrotic angle sum ≥190° based on sagittal and coronal MRI views  
or  


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b. ARCO stage II associated with WOMAC® VA3.1 pain score ≥20 mm if necrotic 
angle sum <190° based on sagittal and coronal MRI views  
or  
c. ARCO stage II associated or not with pain if necrotic angle sum is ≥190° based 
on sagittal and coronal MRI views 
d. Associated with corticosteroid and/or with alcohol abuse and/or idiopathic. 
Table 1: Inclusion Criteria: Osteonecrosis Diagnosis 
ARCO Stage 
Necrotic Angles* 
Pain** 
Stage I 
≥ 190° 
≥ 20 mm 
Stage II 
< 190° 
≥ 20 mm 
Stage II 
≥ 190° 
- 
* Sum of coronal and sagittal necrotic angles 
** WOMAC® VA3.1 pain during the 48 hours before screening 
 
4. Normal haematology function, defined as leukocytes ≥3000/mm3, absolute neutrophils 
count ≥1500/mm3, platelets ≥140,000/mm3, and haemoglobin concentration ≥10g/dl 
(peripheral blood test) 
 
Exclusion criteria 
To be eligible for the study, patients must NOT present any of the following criteria: 
Current symptoms and/or signs related to the disease under study 
1. 
Exclusively diaphyseal or metaphyseal osteonecrotic lesion 
2. 
Traumatic 
or 
hyperbaric 
osteonecrosis, 
or 
osteonecrosis 
associated 
with 
haemoglobinopathy or coagulopathy (e.g., thalassemia, sickle cell disease,…), or 
Gaucher’s disease 
3. 
Any other focal or diffuse bone marrow lesion 
4. 
Osteoarthritis at the hip under evaluation defined as Kellgrens stage ≥2, as assessed by 
the Central Radiologist 
5. 
Patients suffering from any medical conditions interfering with patient’s pain evaluation 
of the hip under evaluation, such as knee arthritis.  


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6. 
Bone fracture or bone infection at hip under evaluation. 
7. 
Patients who are candidates for any predictable joint replacement on the hip under 
evaluation  
Current or previous diagnoses, signs and/or symptoms 
8. 
Blood not qualifying for PREOB® production, including active hepatitis B (defined as 
positive HBs Ag and/or positive PCR), active hepatitis C (defined as positive PCR), positive 
serology for HIV1, or Syphilis1, or HTLV-11, and any other tests that may be required by 
the authorities in case of a new disease outbreak that can affect the safety of the physicians 
and operators at the time of patient screening 
9. 
Presence, or previous history, of risks factors for diseases caused by prions, and 
recipients of grafts of cornea, sclera, and dura mater 
10. 
History of blood loss exceeding 450 ml (incl. donations) within 1 month of screening 
11. 
Renal impairment defined by an estimated creatinine clearance value < 30 ml per min, 
calculated with the Cockcroft-Gault formula 
12. 
Hepatic impairment, defined as alanine aminotransferase or aspartate aminotransferase 
≥ 3 times the upper limit of normal 
13. 
Poorly controlled diabetes mellitus, defined as HbA1C > 9% 
14. 
Global sepsis 
15. 
Allergy to gentamicin or any substance or device the patient might be exposed to in the 
context of the study related interventions (i.e., bone marrow harvesting and 
implantation), as judged by the Investigator 
16. 
History of hypersensitivity to human biological material, including blood and blood 
derived products, documented clinically or by laboratory tests 
17. 
Current or past history of solid or haematological neoplasia (except for basal cell 
carcinoma of the skin and for carcinoma in situ of the cervix that has been treated with 
no evidence of recurrence)  
18. 
History of bone marrow transplantation 
19. 
Patients with a life expectancy less than 2 years, as judged by the Investigator 
 
1 For patients whose seropositivity is revealed from the study procedures, the Investigator should ensure that 
adequate medical care will be provided to the patient and that his/her confidentiality will be preserved. 


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Current or previous treatment 
20. 
Patients having participated in another clinical trial within 3 months of screening 
21. 
Patients previously treated with PREOB®  
22. 
Patients treated by core decompression of the hip under evaluation within 6 months of 
screening 
23. 
Treatment with doses of prednisolone ≥15 mg per day (or equivalent) within 1 month 
from screening, and patients with anticipated needs of daily corticoid doses ≥15 mg 
prednisone (or equivalent) in the 6-month period following PREOB/Placebo 
implantation  
24. 
Illicit drug or alcohol abuse interfering with patient’s ability to understand and comply 
with study requirements, as judged by the Investigator 
Safety aspects concerning female patients of childbearing potential 
25. 
Pregnancy  
26. 
Breast-feeding 
27. 
Women with childbearing potential not willing or able to use reliable contraceptive 
method for at least 6 weeks prior to screening and during the whole study period. 
Reliable contraceptive methods include orally administered hormonal contraceptives, 
surgical intervention (e.g., tubal ligation), and intrauterine device (IUD).  
Other exclusion criteria 
28. 
Body Mass Index (BMI) ≥ 35 kg/m2 
29. 
Patients unable to undergo MRI, e.g. patients with pace-maker, intra-ocular or intra-
cerebral metallic foreign bodies, and mechanical artificial heart valves 
Patients unable to undergo general anaesthesia or surgical intervention 
2.3.3 Randomisation 
Eligible patients will be randomly assigned to one of the two study treatments, PREOB® or 
Placebo, in a 1:1 ratio.  


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Patients will be allocated a Patient Randomisation Number via the randomisation process 
(through the eCRF). Stratification according to ARCO Stage I or Stage II will automatically be 
made at the time of randomisation.  
2.3.4 Blinding 
The study will be conducted double-blind with reference to the evaluation of trial results. 
Briefly: 
• The only physician to know patient group assignment is the Independent Physician, 
performing the (sham) bone marrow harvesting procedure. 
• Investigators and Patients are blind to treatment assignment. Both patient groups 
undergo a bone marrow harvest, real or sham, performed by the Independent Physician, 
and a Core decompression/Implantation procedure performed by the Investigator, 
following identical procedures. 
• The Investigational Medicinal Product, PREOB® and Placebo, are supplied in identical 
packaging conditions. The final product is packaged in a blind ready to use syringe.  
• Radiologists are blind to the group assignment. All images (conventional X-ray, MRI 
and CT) will be processed to ensure blinding, notably coding and masking of posterior 
iliac crest through a Centralized Medical Imaging System. Processed images (i.e. blind) 
will be analysed by a single reader (Central Radiologist).  
• To ensure the blinding of the study, imaging data should not be distributed to the patient 
and/or to the blinded study staff. However, if distribution is required (for any reasons), 
the imaging data should be masked at the harvesting region (iliac crest) prior to 
distribution, or depending on local Hospital policy. 
• Blinding will only be lifted after completion of all study visits from all patients. 
2.3.5 Bone Marrow Harvest and Blood Collection Procedures 
Bone marrow harvest will be performed by the Independent Physician, under local anaesthesia, 
at least 21 days2 before the IMP implantation procedure. However, if the patient has signs of 
 
2 The bone marrow harvest and the core decompression procedure will be scheduled in conjunction with the 
Sponsor’s Manufacturing Unit and will take into account the travel time between the Investigating Site and the 
Sponsor’s Manufacturing Unit. 


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acute or chronic infection, the harvesting procedure should be postponed until the infection is 
resolved, as judged by the Investigator. 
• In the PREOB® Group, bone marrow harvest will consist of a 50 ml bone marrow 
aspiration from the posterior iliac crest. 
• In the Control Group, bone marrow harvest will consist of a sham procedure in order to 
ensure blindness of the patient to the group assignment. 
• In both groups, peripheral blood will be collected for IMP production and research in 
the PREOB®, and Placebo Group, respectively. 
2.3.6 Core decompression and Implantation Procedures 
All patients will undergo a core decompression performed by the Investigator (or delegate) 
(with a small diameter trephine) under general anaesthesia combined with the implantation of 
5 ml of either PREOB® (20×106 cells) or Placebo into the necrotic lesion (single 
administration).  
2.3.7 Follow-up Period 
Efficacy and safety endpoints will be determined in all patients at each scheduled visit over the 
24-month follow-up period (planned at 1, 3, 6, 12, 18, and 24 months). 
 
Long -Term Follow-up 
A long-term follow-up will be performed via phone calls at 36 and 48 months after IMP 
implantation. This includes assessment of hip symptoms (pain, stiffness, and function) using 
WOMAC® LK3.1 (Likert Scale), radiological progression (conventional X-ray to be performed 
only when the patient still feels pain on the treated hip) and the potential occurrence of any AEs 
and SAEs (patient open questionnaire, including notably any changes in health status and need 
for total hip arthroplasty). 


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3 
DETAILED SCHEDULE OF VISITS AND PROCEDURES 
An overview of the study assessments and procedures is given in the Flow Chart below. Study 
procedures are described separately for the PREOB® study and the long term follow-up in table 
2 and table 3 respectively. These Tables show how efficacy and safety endpoints relate to the 
study objectives, and describe involvement of the Investigator (in white), Independent 
Physician (in red), and Central Radiologist (in blue). 
Figure 1: Study Flow-Chart 
 
*In case V1A and V1B are performed separately: X-ray shall be performed during visit 1A. If >4weeks have elapsed 
between the 2 visits, X-Ray must be repeated at V1B, only. 
‡Procedure performed by the Independent Physician (UNBLIND). Principal Investigator and other staff members 
are BLIND. 
 


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Table 2: Follow-up Period: Schedule of visits and procedures 
 
Screening Period  
(Visit 1)1 
(Sham) Bone 
Marrow 
Harvest 
Core decompression/ 
Product Implantation 
Follow-up Visits 
Month 1 
Month 3 
Month 6 
Month 12 
Month 18 
Month 24** 
Visits 
Visit 1A 
Visit 1B* 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Study Day (visit window) 
Day – 21*** 
Day 0 
Day +1 
4 ± 1 week 
12 ± 2 weeks 
24 ± 4 weeks 
48 ± 4 weeks 
72 ± 4 weeks 
96 ± 4 weeks 
Dated and signed Informed Consent Form 
X 
 
 
 
 
 
 
 
 
 
 
Check of inclusion and exclusion criteria 
X 
 
X 
X 
 
 
 
 
 
 
 
Demographic data and medical history 
X 
 
 
 
 
 
 
 
 
 
 
Assessment of changes in health status 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
Physical examination and vital signs 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood samplings for laboratory test 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Blood samplings for biomarker test (if applicable) 
 
X 
 
 
X 
X 
 
X 
 
 
 
Serology for HIV, HBV, HCV, Syphilis, HTLV-1, 
and any other disease required by the authorities in 
case of a new disease outbreak that can affect the 
safety of the physicians and operators at the time of 
patient screening 
X2 
X3**** 
 
 
 
 
 
 
 
 
 
For women: Urine Pregnancy test 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Bilateral WOMAC® VA3.1  
X 
X **** 
X 
 
 
X 
X 
X 
X 
X 
X 
Bilateral Conventional X-ray of the hips 
X 
X4**** 
 
 
 
 
 
X 
X 
X 
X  
Bilateral MRI of the hips 
 
X 
 
 
 
 
 
X 
X 
 
X 
Bilateral CT Scan of the hips 
 
X 
 
 
 
 
 
 
 
 
 
Patient Identification number allocation 
X 
 
 
 
 
 
 
 
 
 
 
Randomisation Number allocation 
 
X 
 
 
 
 
 
 
 
 
 
(Sham) Bone Marrow Harvest and Blood collection 
 
 
X 
 
 
 
 
 
 
 
 
Core decompression and Product Implantation 
 
 
 
X 
 
 
 
 
 
 
 
Documentation of AE / SAE 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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* These tests must be ideally performed no more than 30 days before the (Sham) Bone Marrow Harvest procedure (Day -21, Visit 2), or according to local law. 
** In case of an early discontinuation, the early discontinuation visit/Exit visit will be completed at the time of discontinuation and a follow-up visit will be performed at Month 24 via phone 
call, with the same assessments as visits Month 36 and Month 48. 
*** The bone marrow harvest and the core decompression procedure will be scheduled in conjunction with the Sponsor’s Manufacturing Unit and will take into account the travel time 
between the Investigating Site and the Sponsor’s Manufacturing Unit. 
****If the time period between Visit 1B and Visit 2 exceeds 6 weeks, serology, WOMAC® VA3.1 questionnaire, and conventional X-ray of the hips should be re-evaluated and will be 
considered as clinical and radiological baseline. Serology must be done maximum 30 days prior to visit 2, at the latest. 
 
Table 3: Long Term Follow-up: schedule of phone calls and procedures  
These procedures (except for the conventional X-ray) will be done via phone contact. Study staff will call all the patients to get the requested 
information. 
1If the site can arrange to do all the imaging modalities on the same day, (e.g., in case of MRI availability), all screening assessments can be performed in one single visit (i.e. merge Visit 
1A and Visit 1B. 
2Related Medical History/Risk Factors only. 
3HTLV-1 only performed on patients presenting evidence of risk factors, or according to local law. 
4In case V1A and V1B are performed separately: X-ray shall be performed during visit 1A. If >4weeks have elapsed between the 2 visits, X-Ray must be repeated at V1B, only. 
5Only performed for patients who still feel pain at the treated hip. 
 
Long term follow-up 
Month 36 
Month 48 
Visits 
Visit 10 
Visit 11 
Study Day (visit window) 
144 ± 4 weeks 
192 ± 4 weeks 
Assessment of changes in health status 
X 
X 
Concomitant medication 
X 
X 
WOMAC® LK 3.1 (Likert Scale) 
X 
X 
Documentation of AE/SAE 
X 
X 
Conventional X-ray of the hips4 
X 
X 


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Screening Period (Visit 1) 
Visit 1 (Screening Period) will include the following procedures, which can either be performed 
in one single visit (if the site can arrange to perform all the assessment on the same day) or split 
into Visit 1a and Visit 1b 
The first visit day of the Screening Period (Visit 1a) includes: 
• 
Informed Consent has been obtained 
• 
Evaluation and verification of inclusion and exclusion criteria 
• 
Collection of demographic data  
• 
Record of past and current relevant medical history, including viral infection (HIV, 
hepatitis B & C and HTLV-1, and any other disease required by the authorities in case 
of a new disease outbreak that can affect the safety of the physicians and operators at 
the time of patient screening) and syphilis, alcohol consumption and smoking 
• 
Record of past and current medications within 1 month of screening  
• 
Physical examination and vital signs (see Section 7.1) 
• 
For women with childbearing potential: Urine Pregnancy test  
• 
Bilateral WOMAC® VA 3.1 
• 
Conventional X-ray (bilateral imaging) of the hips (see Annex 2) 
• 
Documentation of any AE/SAE (if applicable) 
•
Allocation of the Patient Identification Number (eCRF)
• 
Record of the Patient Identification Number in the screening log 
• 
Completion of eCRF 
If the screening visit was split into Visit 1a and Visit 1b and the patient does not meet any 
exclusion criteria after Visit 1a, the second visit of the Screening Period (Visit 1b) will be 
performed and will include: 


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• 
Serology3 for HIV1 & 2, HBV, HCV, HTLV-1,syphilis, and any other disease required 
by the authorities in case of a new disease outbreak that can affect the safety of the 
physicians and operators at the time of patient screening (see Section 6.1) 
• 
Laboratory testing and blood sampling (fasting blood sample) (see Section 6.1) 
• 
Biomarkers testing and blood sampling (if applicable) (see Section 6.1) 
• 
For women with childbearing potential: Urine Pregnancy test 
• 
Bilateral imaging: Conventional X-ray (if not performed during V1a or if older than 4 
weeks when performed during V1a), MRI, and CT Scan of the hips (see Annex 2)
• 
Delivery of patient card 
• 
Completion of eCRF 
• 
Documentation of any AE/SAE 
If the time period between Visit 1b and Visit 2 exceeds 6 weeks, WOMAC® VA3.1 
questionnaire and conventional X-ray of the hips should be re-performed and will be 
considered as clinical and radiological baselines. 
Prior to patient randomisation, radiological eligibility must be confirmed by the central 
radiologist. Subsequently full eligibility will be confirmed by the PI (or delegate) through 
the eligibility form in the eCRF.  
 
Randomisation  
In case of patient eligibility, 
• 
Randomisation is performed by the Principal Investigator (or delegate) through the 
eCRF.  
• 
The eCRF will automatically allocate a unique Randomisation Number for the patient. 
• 
Upon randomisation, the eCRF will automatically inform the study team that a new 
patient has been randomised.  
 
3 Serology must be done maximum 30 days prior to the (sham) Bone Marrow Harvest procedure (Day -21, Visit 
2), at the latest, or according to local law. 


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• 
Both the unblind Independent Physician and the Sponsor’s Managing Physician must 
log into the eCRF system to obtain the patient’s treatment allocation. 
 
(Sham) Bone Marrow Harvest and Blood Collection (Visit 2, Day -21) 
The (sham) bone marrow harvest and blood collection (Visit 2, Day -21) will be performed at 
least 21 days4 before the Core decompression/implantation procedure (Visit 3, Day 0).  
Before the actual (sham) bone marrow harvest and blood collection procedures, the following 
evaluations must be performed either by the Independent Physician or by the Principal 
Investigator (or delegate): 
• 
Assessment of any changes in inclusion and exclusion criteria 
• 
Assessment of any changes in health status 
•
Review of concomitant medication
• 
Physical examination and vital signs (see Section 7.1) (In case body temperature is 
>38.5°C (any route) or the patient presents signs of acute or chronic infections, the bone 
marrow harvesting should be postponed until resolution as judged by the physician) 
• 
For women with childbearing potential: Urine Pregnancy test 
• 
Bilateral WOMAC® VA3.1 
• 
Documentation of AE and SAE 
• 
Completion of eCRF 
The (sham) bone marrow harvest and blood collection procedures must be conducted by 
the Independent Physician exclusively: 
(Sham) Bone Marrow Harvest procedure (see detailed description in Section 4.1) will be 
performed by the Independent Physician. (Sham) bone marrow and blood samples will then be 
immediately labelled and packed by the Independent Physician himself, and immediately 
shipped to the Sponsor’s Manufacturing Unit for further processing (see detailed description of 
packaging, labelling, and shipment procedures in Study Procedure Manual (SPM) for IP). 
4 The bone marrow harvest and the core decompression procedure will be scheduled in conjunction with the 
Sponsor’s Manufacturing Unit and will take into account the travel time between the Investigating Site and the 
Sponsor’s Manufacturing Unit. 


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Patients will then be allowed to leave the Clinic on the same day, following thorough clinical 
evaluation and documentation of any potential AEs or SAEs. 
 
Product Implantation (Visit 3, Day 0 and Day +1) 
Day 0 
The patient will be admitted to the Clinic on Day 0. The following examinations and procedures 
will then be performed by the Investigator: 
• 
Assessment of any changes in inclusion and exclusion criteria 
• 
Assessment of any changes in health status 
• 
Review of concomitant medication 
• 
Physical examination and vital signs (see Section 7.1) 
• 
For women with childbearing potential: Urine Pregnancy test 
• 
Documentation of AE and SAE 
• 
Completion of eCRF 
On the same day, the shipping box containing the Investigational Medicinal Product (PREOB® 
or Placebo) will be shipped by the Manufacturer to the Pharmacy Department of the 
Investigating Site.  
If the IMP is not useable due to a technical problem that occurred during the production process, 
the Managing Physician will immediately notify the CAs and SSO, and record relevant 
information in the eCRF. Once completed, the eCRF will automatically send e-mail alerts to 
the Study Safety Officer (SSO), and PI.  
In case the IMP is not available for the implantation, the PI will inform the patient about the 
cancellation of the latter procedure. In this case, the patient will be considered as drop out, but 
the Investigator is however allowed to re-include the patient after 2 months (novel inclusion 
procedure). 
Upon IMP receipt the Pharmacist will check if all the conditions listed on the Release Form for 
the Hospital - Hospital Pharmacist Section -  are met, and subsequently release the IMP and 
immediately inform the Principal Investigator (and/or delegate) (see detailed description of 
related procedures in the SPM for Pharmacist). If released by the pharmacist, the IMP will be 
transferred to the Operating Room. 


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In the Operating Room, the Principal investigator will check if all the conditions listed on the 
Release Form for the Hospital - Principal Investigator Section - are met, and subsequently 
release the IMP and perform the surgical procedure (core decompression and implantation, 
PREOB® or Placebo) (see detailed procedures in Section 4.2 and in the SPM for PI). 
After implantation, the empty PREOB® or Placebo syringe will be kept and stored by the 
Investigator (or a member of the investigating team designated by the Investigator) until the 
next Monitoring visit. 
Day +1 
Patients will be systematically evaluated 24 hours after the core decompression/implantation 
procedure, and will then be discharged from the Clinic after the following examinations: 
• 
Assessment of any changes in health status 
• 
Physical examination and vital signs (see Section 7.1) 
• 
Laboratory testing and blood sampling (see Section 6.1) 
• 
Biomarkers testing and blood sampling (if applicable) (see Section 6.1) 
• 
Documentation of AE and SAE 
• 
Completion of eCRF 
 
Follow-up Visits - up to Month 24 
Following the IMP implantation (Visit 3), 6 follow-up visits will be performed at the 
investigating site at Month 1, 3, 6, 12, 18 and 24.   
However, if a treated patient is withdrawn/discontinued from the study any time before visit 9 
at Month 24, he/she will no longer be asked to come for the remaining follow-up visits. In this 
case, an early discontinuation visit/Exit visit will be completed at the time of discontinuation 
and a follow-up visit will be performed at Month 24 (via phone call). The reason for 
withdrawal/discontinuation must be documented clinically and/or by the central radiologist if 
applicable.
3.5.1 Follow-up Visit 4 (Month 1 ± 1 week) and Visit 5 (Month 3 ± 2 weeks) 
Patients will be evaluated as follows: 
• 
Assessment of any changes in health status 
• 
Review of concomitant medication 


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• 
Physical examination and vital signs (see Section 7.1) 
• 
Laboratory testing and blood sampling (see section 6.1) 
• 
Biomarkers testing and blood sampling (if applicable, only at Month 1, Visit 4) (see 
Section 6.1) 
• 
For women with childbearing potential: Urine Pregnancy test 
• 
Bilateral WOMAC® VA3.1 
• 
Documentation of AE and SAE 
• 
Completion of eCRF 
3.5.2 Follow-up Visit 6 (Month 6 ± 4 weeks) and Visit 7 (Month 12 ± 4 weeks) 
Patients will be evaluated as follows: 
• 
Assessment of any changes in health status 
• 
Review of concomitant medication 
• Physical examination and vital signs (see Section 7.1) 
• 
Laboratory testing and blood sampling (see section 6.1)  
• 
Biomarkers testing and blood sampling (if applicable, only at Month 6, Visit 6) (see 
Section 6.1) 
• 
For women with childbearing potential: Urine Pregnancy test 
• 
Bilateral WOMAC® VA3.1 
• 
Bilateral Imaging: Conventional X-ray and MRI of the hips  
• 
Documentation of AE and SAE 
• 
Completion of eCRF 
3.5.3 Follow-up Visit 8 (Month 18 ± 4 weeks) 
Patients will be evaluated as follows: 
• 
Assessment of any changes in health status 
• 
Review of concomitant medication 
• 
Physical examination and vital signs (see Section 7.1) 


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• 
Laboratory testing and blood sampling (see section 6.1)  
• 
For women with childbearing potential: Urine Pregnancy test 
• 
Bilateral WOMAC® VA3.1 
• 
Bilateral Imaging: Conventional X-ray of the hips (see Annex 2) 
• 
Documentation of AE and SAE 
• 
Completion of eCRF 
3.5.4 Follow-up Visit 9 (Month 24 ± 4 weeks) 
Patients will be evaluated as follows: 
• 
Assessment of any changes in health status 
• 
Review of concomitant medication 
• 
Physical examination and vital signs (see Section 7.1) 
• 
Laboratory testing and blood sampling (see section 6.1) 
• 
For women with childbearing potential: Urine Pregnancy test 
• 
Bilateral WOMAC® VA3.1 
• 
Bilateral Imaging: Conventional X-ray and MRI of the hips (see Annex 2) 
• 
Documentation of AE and SAE 
• 
Completion of eCRF 
End-of-period examination: This 24-month visit corresponds to the end of study examinations 
at the Investigating Site. 
 
Long Term Follow-up (Months 36 and 48 ± 4 weeks) 
For all treated patients (i.e., even for patients who have been withdrawn/discontinued from the 
study before the end of the 24-month follow-up period), phone call “visits” will be performed 
by the Investigator at 36 months ± 4 weeks (Visit 10) and 48 months ± 4 weeks (Visit 11) after 
IMP implantation, to evaluate the following safety data:  
• 
Assessment of any changes in health status 
• 
Review of concomitant medication 
•
Documentation of SAE (notably in case of THA)


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Patients who have completed all the follow-up visits (i.e. up to Month 24 included) will also be 
evaluated for the following clinical variables: 
• 
WOMAC® LK3.1 (Likert Scale) evaluation of the treated hip 
• 
Bilateral conventional X-ray of the hips (only performed for patients who still feel pain 
at the treated hip) 
After the phone call “visits”, PI or delegate performs: 
• 
Completion of eCRF 
• 
Study conclusion page to be completed and signed by the Investigator (at Month 48) 


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4 
DETAILED DESCRIPTION OF THE PROCEDURES AND INVESTIGATIONAL 
MEDICINAL PRODUCT 
Site staff will be trained on the trial-related procedures and Standard Operating Procedures, 
including step-by-step instructions during the Site Initiation Visit (SIV) at the latest. 
Table 4: Summary of Procedures Performed in the PREOB® and Placebo Groups 
Procedures 
Timepoints 
PREOB® Group 
Placebo Group 
Bone Marrow Harvest 
Day-21 
Yes (≥50 ml) 
Yes (Sham, 0 ml) 
Peripheral Blood Sampling 
Day-21 
Yes (300 ml) 
Yes (30 ml) 
Core decompression (using a 5mm 
trephine)  
Day 0 
Yes 
Yes 
Intra-osseous Implantation (blind vials)  
Day 0 
Yes 
Yes 
 
Bone Marrow Harvest and Blood Collection Procedures (performed by the 
Independent Physician) 
PREOB® Group - Bone Marrow Harvest Procedure 
At least twenty-one days5 before the surgical procedure (Implantation Visit, Visit 3), the patient 
will be admitted to the hospital in order to undergo a bone marrow aspiration (Visit 2). In the 
operating room or another aseptic environment, the patient will be placed on the left or right 
side (on the target hip side or not, as judged by the Independent Physician), and local 
anaesthesia of the skin, muscles, and periosteum of the right or left posterior iliac crest will be 
performed using 5-10 ml of a local anaesthetic (e.g., lidocaïn hydrochloride). Sedation can be 
administered as per Independent Physician judgement. After 5 to 10 minutes, a 5-mm incision 
will be made at the level of the posterior iliac crest, the bone marrow aspiration needle is 
introduced into the iliac crest, and at least 50 ml of bone marrow is aspirated and used for the 
culture of PREOB®. If the bone marrow harvesting is difficult or insufficient, the orientation of 
the needle within the same incision can be modified according to the need. The patient will then 
be placed in a supine position and 300 ml of peripheral blood will be taken. The patient will be 
5 The bone marrow harvest and the core decompression procedure should be scheduled in conjunction with the 
Sponsor’s Manufacturing Unit and should take into account the travel time between the Investigating Site and the 
Sponsor’s Manufacturing Unit. 


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allowed to leave the hospital 30 minutes after vital signs have been checked (see detailed 
procedures in the SPM for the Independent Physician). 
Control Group - Sham Bone Marrow Harvest Procedure 
At least twenty-one days6 before the surgical procedure (Implantation Visit, Visit 3), the patient 
will be admitted to the hospital in order to undergo a sham bone marrow aspiration (Visit 2). In 
the operating room or another aseptic environment, the patient will be placed on the left or right 
side (on the target hip side or not, as judged by the Independent Physician), and local 
anaesthesia of the skin, muscles, and periosteum of the right or left posterior iliac crest will be 
performed using 5-10 ml of a local anaesthetic (e.g., lidocaïn hydrochloride). Sedation can be 
administered as per Independent Physician judgement. After 5 to 10 minutes, a 5-mm incision 
will be made at the level of the posterior iliac crest, and the bone marrow aspiration needle is 
placed in contact with the iliac crest for 5 minutes without penetration of the bone. There will 
be no bone marrow aspiration. The patient will then be placed in a supine position for 10 
minutes and 30 ml of peripheral blood will be taken. The patient will be allowed to leave the 
hospital 30 minutes after vital signs are checked (see detailed procedures in the SPM for the 
Independent Physician). 
 
Core Decompression and Implantation Procedures  
4.2.1 Control of the Investigational Medicinal Product Quality 
On the core decompression and IMP (PREOB® or Placebo) implantation day, the shipping box, 
containing the IMP will be shipped to the Pharmacy Department of the Investigating Site by 
the Manufacturer.  
Upon reception, the Pharmacist will check the external product package and, if all the 
conditions listed on the Release Form for the Hospital – Hospital Pharmacist Section are met, 
subsequently release the IMP. The pharmacist immediately informs the Principal Investigator 
(and/or delegate) of the IMP release status (see detailed description of related procedures in 
SPM for the Pharmacist). If released by the pharmacist, the IMP will be transferred to the 
Operating Room. 
In the Operating Room, the Principal Investigator will check the internal product package, IMP 
syringe, and labelling (including Patient Identification Number, name and surname) himself and 
6 The bone marrow harvest and the core decompression procedure will be scheduled in conjunction with the 
Sponsor’s Manufacturing Unit and will take into account the travel time between the Investigating Site and the 
Sponsor’s Manufacturing Unit. 


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complete the Release Form for the Hospital – Principal Investigator Section (see detailed 
description of procedures in the SPM for Principal Investigator). If any problem occurred and 
the IMP is not released by the Principal Investigator (i.e. the Patient cannot be treated), the 
Investigator completes the eCRF, and the IMP will be labelled with “Medication return - to be 
destroyed” label and shipped to the Manufacturer within 72 hours of receipt together with the 
« Medication Return Form » duly completed and signed by the Investigator.  
If the IMP is not released due to any problem linked to the production process, the Managing 
Physician will notify the Competent Authorities (CA) and Study Safety Officer (SSO), and 
record relevant information in the eCRF. Once completed, the eCRF will automatically send e-
mail alerts to the SSO and the Investigator.  
In case the IMP is not available for the implantation, the Investigator will inform the patient 
about the cancellation of the procedure. In this case, the patient will be considered as drop out, 
but the Investigator is however allowed to re-include the patient after 2 months (novel inclusion 
procedure). 
4.2.2 Core decompression/Investigational Medicinal Product implantation (PREOB® or 
Placebo) 
A C-arm fluoroscope is draped with a sterile sleeve and is positioned over the hip region to 
allow an antero-posterior view and, after flexion of the knee and abduction of the hip, a frog 
leg lateral view of the proximal part of the femur. A 5 to 10 mm incision is then made laterally 
through the skin and the fascia at the level or just under the great trochanter and a drill hole is 
made manually in the lateral femoral cortex (mechanical drill is allowed until reaching the 
intertrochanteric region using the same diameter trephine, followed by manual drill with the 
provided core decompression material). Under fluoroscopic control, the external trephine is 
then drilled further manually through the neck and head of the femur to reach the necrotic lesion, 
usually located below the articular cartilage. In doing so, the direction of the trephine must be 
adjusted in both planes so that it is pointing towards the necrotic zone. The position of the 
trephine will be checked in both antero-posterior and lateral fluoroscopic views; the tip of the 
external trephine should be placed inside the necrotic zone. The internal trephine is then 
introduced into the external trephine in order to perform the core decompression, as previously 
described (Hauzeur et al., 1986). For this purpose, the tip of the internal trephine is drilled up 
to a few mm distance from the chondral plate.  
After core decompression, the internal trephine is removed and a 3-waystopcock is connected 
at the extremity of the external trephine and set in a closed position. The blind syringe is gently 
tapped and rolled between hands to properly re-suspend its content, and is then connected to 


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the 3-waystopcock. The 3-waystopcock is then opened and the content of the syringe (5ml) is 
fully pushed through the trephine into the necrotic lesion. The injection is performed slowly for 
approximately 1 to 2 minutes. In case of resistance during the injection, it is recommended to 
pause and close the 3-waystopcock for 1 or 2 minutes and then re-open it to continue and 
finalize the injection into the necrotic area.  
Finally, the trephine is washed with a rinse solution (NaCl 0.9%) to ensure that the entire IMP 
(5ml) was injected into the necrotic lesion. The syringe is then removed and the 3-waystopcock 
is closed. The 3-waystopcock is removed and gel foam (Gelfoam®, Pfizer) or equivalent is 
pushed through the external trephine towards the necrotic lesion to allow clotting and closing 
of the hole made by the trephine in the necrotic lesion. The external trephine is removed and 
stitches are applied to close the skin. 
4.2.3 Peri-operative antibiotic therapy and other medications 
All patients will receive a single intravenous infusion of Cefazolin (2 g) or any standard-of-care 
antibiotic therapy used at the Investigating Site at induction. In case of allergy to Cefazolin or 
Penicillin, intravenous administration of Clindamycin (3 × 600 mg a day) during 24 hours can 
be performed. Drugs used during anaesthesia will not be systematically recorded in the eCRF, 
except if an Adverse Event should have occurred. 
 
Postoperative Management 
Following the core decompression and implantation procedure, all patients will remain non-
weight-bearing on the operated leg for 1 to 3 weeks. Following this period of time, total weight 
bearing will be permitted. No specific rehabilitation procedure will be conducted (either 
immediately or on a long-term basis). More specifically, patients will be allowed to 
progressively mobilise the hip without any physiotherapy management. Stitches (if any) will 
be removed 7 to 14 days after surgery as per standard of care. 


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5 
INVESTIGATIONAL PRODUCT AND STARTING MATERIALS 
 
Investigational Medicinal Products 
Table 5: Identity of Investigational Medicinal Products 
 
PREOB® 
Placebo 
CBMP 
Human autologous bone marrow-
derived osteoblastic cells 
N.A. 
Cellular concentration 4×106 cells/ml - 5 ml suspension 
solution 
N.A. – 5 ml solution 
Container 
Blind ready-to-use syringe 
Blind ready-to-use syringe  
Batch number 
Provided on the label 
Provided on the label 
Expiry date 
Provided on the label 
Provided on the label 
Manufacturer 
Bone Therapeutics S.A. 
Bone Therapeutics S.A. 
Trade name 
PREOB® 
N.A. 
Storage requirements 
Provided on the label 
Provided on the label 
 
Treatment administered 
Each patient will receive a single dose of:  
• PREOB® (20×106 cells)  
or 
• Placebo 


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Table 6: Administration of the Investigational Medicinal Product 
 
PREOB®  
Placebo  
Procedure/ Route 
of administration 
Core decompression and intra-osseous 
implantation with trephines 
Core decompression and intra-osseous 
implantation with trephines 
Single dose 
5 ml – 20×106 cells 
5 ml 
Dosage schedule 
One single dose per patient on Visit 3 
(Day 0) 
One single dose per patient on Visit 3 
(Day 0) 
 
Investigational Medicinal Product Post-administration Sterility Testing  
PREOB®, due to its nature as a cell product with limited shelf life, will conditionally be released 
for clinical use. The compendial sterility and mycoplasma tests to be performed on the 
Investigational Medicinal Product usually require at least 14 days to be completed. Conditional 
release of the final product is thus done on the basis of alternative rapid tests, without having 
the final results available (conditional release - first step). The IMP Final Release Certificate 
will be sent to the Investigating Site about 30 days post-implantation, upon completion of 
compendial sterility and mycoplasma testing (final release - second step). 
This procedure therefore bears the possibility that the IMP could be “refused” after 
administration if the post-administration sterility tests are positive. Once a post-administration 
sterility test is reported positive, an investigation will be started in order to verify that sterility 
results are valid. If confirmed, the Manufacturer will immediately inform the Principal 
Investigator through the eCRF (eCRF completion automatically triggers e-mail notifications). 
Additional microbiological analyses and antibiogram will be conducted to identify the micro-
organism(s) involved. The result of these tests will be reported to the Investigator as soon as 
available in order to allow immediate and appropriate therapeutic measures (including the need 
for adequate antibiotic therapy). In all cases, blinding will be maintained, unless unblinding is 
required for patient safety issues. 
 
Tracking, Traceability, and Accountability of Investigational Medicinal Product 
A coding tracking system allowing complete traceability of both the Starting Materials and the 
IMP at all stages will be established and maintained (by Sponsor, Manufacturer, Managing 
Physician of the Production/Tissue Establishment, Investigator, Independent Physician, and 
Monitor). This tracking system will ensure that: 


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• The Starting Materials and IMP (PREOB® and Placebo), are tracked and traced during the 
whole process, from harvest to implantation, each procedure and step being described in 
Standard Operating Procedures, and systematically collected, verified, and recorded using 
specific Forms and Receipts (and in the eCRF). 
• The patient is implanted with an autologous batch of PREOB® or Placebo 
• Data from the Quality Control tests of each batch (and documentation of completion of each 
step in batch production and testing records) are accurately tracked and recorded. 
• A unique identification code (Patient Identification Number) is allocated by the CRF system 
upon registration performed during patient screening (and will be associated to both the 
Starting Materials and IMP, at all stages and steps of the process and trial). The link between 
the identity of the patient and the identification code will be protected and kept strictly 
confidential. This information will be known, (identity of the patient (i.e. name and 
surname)), collected, and recorded only by the Investigator and his/her team and the 
Managing Physician of the Production/Tissue Establishment (and will be kept and recorded 
in restricted access files: Investigator’s Site File at Investigating Site and a register 
maintained for the purpose at the Manufacturer (Production/Tissue Establishment), 
respectively).  
• Used syringes (without needles) will be kept and stored in each Investigating Site until 
Monitor’s verification visits, and destroyed after drug accountability and reconciliation. 
Finally, data and records required for full traceability will be kept by the Sponsor, Managing 
Physician of the Production/Tissue Establishment, Manufacturer, and Investigator for a 
minimum of 30 years after clinical use. 
 


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6 
LABORATORY ASSESSMENT 
 
Blood for Laboratory Testing 
Table 7: Blood collected  
Type of sample and 
volume collected 
Assay 
Visits 
Laboratory 
Whole Blood sampling for 
serology tests 
(approximately 9 ml) 
HIV, HCV, HBV,
Syphilis, HTLV-1* 
** 
Visit 1 
Local lab 
Whole Blood sampling for 
laboratory tests 
(approximately 11 ml) 
Biochemistry 
Hematology 
Visit 1,  
Visit 3 (Day +1) 
Visits 4, 5, 6, 7, 8, and 9 
Local Lab 
Whole Blood sampling for 
biomarkers tests 
(approximately 9 ml) 
Biomarkers* 
Visit 1,  
Visit 3 (Day +1) 
Visits 4 and 6 
Bone Therapeutics 
* if applicable 
** other tests may be done if required by the authorities in case of a new disease outbreak that can affect the safety 
of the physicians and operators at the time of patient screening 
Blood testing for biochemistry, haematology, and serology will be done at the Investigating 
Site’s laboratories. The Sponsor will obtain a copy of the Certification of these laboratories as 
well as up-to-date normal ranges. 
When applicable, in order to assess potential changes of systemic biomarkers of the patients 
enrolled in the study, the levels of biomarkers will be measured at the Screening Period (Visit 
1), one day after treatment (Visit 3, Day+1), 1 month (Visits 4) and 6 months (Visit 6) after 
treatment.  
The total amount of blood collected is expected not to exceed 135 ml.  
Storage of collected Blood and exceeding Starting Materials
All collected samples or excess of Starting Materials will be stored for up to 2 years after last 
patient’s last visit unless local rules, regulations or guidelines require different timeframes or 
different procedures.  


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Use of exceeding Bone Marrow, Peripheral Blood, and PREOB® product 
If excess of Starting Materials (bone marrow and peripheral blood) or PREOB® cells is 
available, these materials can be used for additional research experiments within the context of 
this study (genotyping excluded). 


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7 
SAFETY: TOLERABILITY MEASUREMENTS AND ENDPOINTS 
 
Overview of Safety Parameters and Endpoints 
The treatment safety and tolerability will be systematically investigated throughout the study 
period. Patients will be evaluated at each follow-up visit for the potential occurrence of any AE 
or SAE, related to either the product or any study procedures (see Section 8 for Definitions of 
AE/SAE).  
Table 8 below shows how the safety endpoints of this study relate to the study objectives. 
Assessments and measurements will be carried out at the timepoints specified in the main study 
schedule of visits and procedures (Table 2). 
Table 8: Overview of Safety Parameters and Endpoints 
Objectives 
Variables 
Visits 
Evaluate the safety and 
tolerability of core 
decompression/PREOB® 
implantation during the 
follow-up period 
 
Vital signs and Physical 
Examination 
Visit 1 (Screening) 
Visit 2 (Day -21) 
Visit 3 (Day 0 and Day +1) 
Visits 4, 5, 6, 7, 8, and 9 
Laboratory parameters 
Haematology and Biochemistry 
Visits 1, 3 (Day +1), 4, 5, 6, 7, 
8, and 9 
AEs and SAEs 
Visit 1 (Screening) 
Visit 2 (Day -21) 
Visit 3 (Day 0 and Day +1) 
Visits 4, 5, 6, 7, 8, and 9 
Evaluate the safety and 
tolerability of core 
decompression/PREOB® 
implantation during the long-
term follow-up 
AEs and SAEs 
Patient Questionnaire (via phone 
call) 
Visits 10 and 11 
7.1.1 Vital Signs 
• Blood pressure (BP) will be assessed in all patients on site by standardised cuff 
measurements. Preferably, the same person should do all the measurements on the same 
patient. 


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• Heart rate will be measured, in beats per minutes (bpm) after the patient has been in a 
resting state (seated) for at least 5 minutes. Heart rate will be counted for 30 seconds, 
multiplied by 2 and recorded in bpm. 
• The Body temperature and Respiratory rate will also be recorded. 
• Results of measurements should only be reported as AE if, in the Investigator’s opinion, 
they are outside of “expected values or variations”. Also they must be considered as SAE 
if they fulfil the SAE definition. 
7.1.2 Physical Examination 
• Physical examination, including assessment of general appearance, skin, head, and neck 
(including eyes, ears, nose, and throat), lymph nodes, thyroid, musculoskeletal/extremities, 
cardiovascular system, lungs, abdomen, and neurological status will be performed 
preferably by the same person.  
• Height will be measured in centimetres (cm). Weight will be measured in kilograms (kg) 
using a scale. Body Mass Index (BMI) will be calculated as follows: Weight (Kg)/Height2 
(m) = BMI. 
7.1.3 Laboratory Safety Measurements 
Serology testing (HIV1 & 2, HBV, HCV, Syphilis, HTLV-1, and any other disease required by 
the authorities in case of a new disease outbreak that can affect the safety of the physicians and 
operators at the time of patient screening) will have to be performed during the Screening Period 
(Visit 1), no more than 30 days before Visit 2 (D-21), or according to local law. 
Blood will be sampled during the Screening Period (Visit 1), at Visit 3 (Day+1), and at the 
follow-up visits 4, 5, 6, 7, 8, and 9 (fasting samples). 
The following parameters will be analysed for the safety measurements: 
• Haematology: red blood cell count, haematocrit, haemoglobin, leukocyte, neutrophil, 
lymphocyte, monocyte, basophil, eosinophil, and platelet counts. 
• Biochemistry: creatinine, urea nitrogen, uric acid, sodium, potassium, calcium, 
phosphorus, albumin, total proteins, CPK, alanine aminotransferase (SGPT), aspartate 
aminotransferase 
(SGOT), 
total 
bilirubin, 
gammaglutamyltransferase, 
alkaline 
phosphatase, LDH, amylases, glucose, HbA1C, C-reactive protein (both “standard” CRP 
and hs CRP, highly sensitive CRP), lipids (total cholesterol, LDL cholesterol, and 
triglycerides), and coagulation parameters (including PT and APTT). 


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Other Safety Measurements 
7.2.1 Women with childbearing potential 
Women with childbearing potential must use a reliable method of contraception for at least 6 
weeks prior to Screening Period and during the whole study period. Reliable contraceptive 
methods include orally administered hormonal contraceptives, surgical intervention (e.g., tubal 
ligation), and intrauterine device (IUD). 
Moreover, women with childbearing potential will systematically undergo urine pregnancy test 
at each visit performed (from Screening Period up to Month 24). Pregnancy test kits will be 
provided by the Sponsor, performed on site according to manufacturer’s instructions, and 
results will be recorded in the eCRF. 
7.2.2 Additional safety examinations and procedures 
If any unclear clinical event, including symptoms, signs, or other observations or abnormalities, 
should occur, the Investigator, or any other physician in charge, may perform additional clinical 
examinations and procedures (other than outlined in this protocol), including any clinical, 
laboratory, imaging and/or technical testing, in order to clarify and establish the aetiology and 
diagnosis of this clinical event. 


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8 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
Definitions 
Adverse Event (AE)  
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject who has been administered a pharmaceutical product and/or any 
investigational medicinal product and which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavourable and unintended sign (including 
any abnormal laboratory findings), symptom, or disease temporally associated with the use of 
a medicinal product, without any judgment about causality (ICH E2a).  
Adverse events will be graded with respect to intensity and classified as either serious or non-
serious according to the World Health Organisation Classification. 
Serious Adverse Event (SAE) 
A Serious Adverse Event (SAE) is defined as any AE or suspected adverse reaction (SAR) that, 
in the view of the Investigator or Sponsor, results in any of the following outcomes (ICH E2a 
and ICHE6): 
• Death 
• Life-threatening AE  
• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions 
• Congenital anomaly/birth defect 
Medical and scientific judgement should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the patient or may 
require intervention to prevent one of the other outcomes listed in the definition above.  
 


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Table 9: Classification of Adverse Events 
Intensity 
Mild 
Some awareness of symptoms or signs that does not 
interfere with the patient’s usual activities or is transient, 
easily tolerated and resolved without treatment and with 
no sequelae 
 
Moderate 
Symptoms or signs causing enough discomfort to interfere 
with the patient’s usual activities, and/or requires 
symptomatic treatment 
 
Severe 
Incapacitating event, including symptoms or signs, 
causing severe discomfort and inability to work or to 
perform usual activities, and requires treatment 
Seriousness 
Serious (SAE) 
Any untoward medical occurrence that at any dose: 
– Results in death, or 
– Is life-threatening, or 
– Requires patient hospitalization or prolongation of 
existing hospitalization, or 
– Results in persistent or significant disability/incapacity, 
or 
– Is a congenital anomaly / birth defect or 
– Is medically important  
 
Non-serious 
Any other adverse event 
 
Notes 
1. The term "life-threatening" in the definition of SAE refers to an event that in the view of the 
Investigator places the patient at immediate risk of death at the time of the event; it does not 
include an AE or suspected adverse reaction that, had it occurred in a more severe form, might 
have caused death. The term "life-threatening" does not imply a possible future course which 
might or might not have happened, but was prevented due to adequate physician's action. For 
example, a simple bacterial wound infection can potentially lead to gangrene, sepsis, and 
eventually death; while sepsis is usually regarded as a SAE because of known high mortality, 
the primary wound infection itself is usually not regarded as a SAE. In analogy, a newly 
diagnosed malignant disease is usually regarded as a SAE because malignant diseases usually 
have a high mortality rate and are therefore life-threatening. 
2. To ensure no confusion or misunderstanding of the difference between the terms "serious" 
and "severe", which are not synonymous, the following clarification is provided: the term 


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"severe" is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself however may be of relatively minor 
medical significance (such as severe headache). This is not the same as "serious," which is 
based on patient/event outcome or action criteria usually associated with events that pose a 
threat to the patient's life or functioning. 
3. In addition, events that may not meet the criteria indicated above, but which the Investigator 
finds very unusual and/or potentially serious, will be reported as SAE. Indeed, medical and 
scientific judgments should be exercised in deciding whether reporting is appropriate in other 
situations, such as important medical events that may not be immediately life-threatening or 
result in death or hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the other outcomes listed in the definition above. These events should also 
usually be considered as SAEs. Examples of such events include intensive treatment in the 
Emergency Room or at home for allergic bronchospasm, blood dyscrasias or convulsions that 
do not results in hospitalization, and/or development of drug dependency or drug abuse. 
4. A hospitalization planned by the patient prior to signing the ICF is considered a therapeutic 
intervention and not the result of a new SAE and should be recorded as medical history. If the 
planned hospitalization or procedure occurs as planned, the record in the patient’s medical 
history is considered complete. However, complications or other events that may occur during 
hospitalization will be considered as AEs or SAEs and will be captured accordingly. 
Causal relationship with the Investigational Medicinal Product 
The term “causality” describes the degree of attributability (causality) between an 
investigational medicinal product and an event. Causality assessment of AEs is the structured 
and standardised assessment of individual patients / case reports for the likelihood of 
involvement of suspected drug in causing a particular event in a given patient. 
The drug-event causal relationship will be assessed using the following criteria, approved by 
the WHO Collaborating Centre for International Drug Monitoring (Edwards & Biriell, 1994). 
It should be noted that, for classification, all criteria of a category have to be met. 
Table 10: Assessment of drug-event causal relationship 
Certain 
A clinical event, including laboratory test abnormality, occurring in 
a plausible time relationship to drug administration, and which 
cannot be explained by concurrent disease or other drugs or 
chemicals. The response to withdrawal of the drug (dechallenge) 
should be clinically plausible. The event must be definitive 
pharmacologically or phenomenologically, using a satisfactory 
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Probable/Likely  
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, unlikely to 
be attributed to concurrent disease or other drugs or chemicals, and 
which follows a clinically reasonable response on withdrawal 
(dechallenge). Rechallenge information is not required to fulfil this 
definition. 
Possible  
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, but which 
could also be explained by concurrent disease or other drugs or 
chemicals. Information on drug withdrawal may be lacking or 
unclear. 
Unlikely 
A clinical event, including laboratory test abnormality, with a 
temporal relationship to drug administration which makes a causal 
relationship improbable, and in which other drugs, chemicals or 
underlying disease provide plausible explanations. 
Conditional/Unclassified  
A clinical event, including laboratory test abnormality, reported as 
an adverse reaction, about which more data is essential for a proper 
assessment or the additional data are under examination. 
Not assessable/Unclassifiable 
A report suggesting an adverse reaction, which cannot be judged 
because information is insufficient or contradictory, and which 
cannot be supplemented or verified 
In practice, determination of the causal relationship between an AE/SAE and the trial 
medication must be made by the Investigator by answering the following question: "Is the 
causal relationship between the medicinal product and this AE/SAE reasonably possible”? 
• 
Yes: related 
• 
No: not related 
Indeed, causality assessment is a clinical decision based on all available information at the time 
of and after the occurrence of the event. The factors which may be considered when evaluating 
the causal relationship of an AE/SAE to the IMP administration include the followings: 
• Underlying, concomitant, and/or intercurrent diseases: each report should be evaluated in 
the context of the natural history and course of the disease being treated and any other 
diseases the patient may have had prior to, or developed during the course of the study 
• Concomitant medication or treatment: other drugs the patient is taking or treatment the 
patient is receiving at the time of the event should be examined to determine whether any of 
them may be recognized to cause the event in question 
• Known response pattern for this class of drug 


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• The pharmacology and pharmacokinetic of the IMP: absorption, distribution, metabolism, 
and excretion of the IMP or other medications the patient is receiving coupled with the 
pharmacodynamic responses should be considered when evaluating an event 
Adverse Drug Reaction (ADR) 
An Adverse Drug reaction (ADR) is any untoward and unintended responses to an 
investigational medicinal product related to any dose administered (having a reasonable causal 
relationship to the product, the term “reasonable causal relationship” meaning that there is 
evidence or arguments to suggest a causal relationship). 
Serious Adverse Reaction (SAR)  
A Serious Adverse Reaction (SAR) is any untoward and unintended responses to an 
investigational medicinal product related to any dose administered (having a reasonable causal 
relationship to the product), and that results in death, is life-threatening, requires patient 
hospitalization or prolongation of existing hospitalization, results in persistent or significant 
disability or incapacity, or is a congenital anomaly or birth defect or is medically important. 
Serious Adverse Safety/Quality Event (SASQE) 
A Serious Adverse Safety/Quality Event (SASQE) is any adverse event related to any operation 
done on the collected human biological material under the responsibility of the Intermediary 
Structure (i.e., direct transport and distribution of the human biological material from the 
harvesting site to the Production/Tissue Establishment of Bone Therapeutics S.A.) that may 
cause death, be life-threatening, generate disability or incapacity to work to the patient, or that 
may cause morbidity. 
Expectedness 
An (S)AE or ADR/SAR is considered unexpected if it is not listed in the Investigator’s 
Brochure or is not listed at the specificity or severity that has been observed or, if an 
Investigator’s Brochure is not required or available, is not consistent with the risk information 
described elsewhere (for example, approved prescribing information). 
The Reference Safety Information for this study is in Section entitled “Reference Safety 
Information” of the current Investigator’s Brochure.   
 
Assessment of Adverse Events 
The occurrence of AE/SAE (drug- or procedure or study-related) will be assessed by non-
directive questioning of the patient since the beginning of the study at the screening Period, and 


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each follow-up visit searching for any changes in health status (e.g., "Have any Adverse events 
or Serious adverse events occurred since the last visit?"). Furthermore, AE/SAE spontaneously 
reported by the patient during or between the follow-up visits, or detected through observation, 
physical examination (including body mass index and vital signs), laboratory testing, or other 
clinical procedures during the observation period will be documented. Patients will be 
instructed that they must immediately report any adverse events, subjective complaints, or 
objective changes in their wellbeing to the investigator or the Investigating Site’s personnel, 
regardless of the perceived relationship between the event and the test product. 
If it is determined that an AE/SAE has occurred, the Investigator should obtain all the 
information required to complete the corresponding AE or SAE Form of the eCRF, and 
establish potential causality relationship with the product or study procedures, including the 
bone marrow harvesting, the blood sampling and the product implantation (core decompression, 
implantation surgery, and general anaesthesia).  
8.2.1 Observation period for the occurrence of AEs and SAEs 
Table 11 below defines the observation period for the occurrence of AE and SAE during both 
the follow-up period (up to 24 months) and the long term follow-up (at 36 and 48 months). 
These safety observation periods must be respected for all treated patients (i.e., regardless of 
the patient’s outcome in the study, whether the patient has been withdrawn/discontinued early 
or not). 
Table 11: Observation period for the occurrence of AEs and SAEs 
Follow-up: AE/SAE Observation Period 
From Screening Period up to 24 months 
after implantation (Visit 3) 
Long term follow-up: AE/ SAE Observation 
Period 
At 36 and 48 months after implantation 
(Visit 3) 
 
If the investigator learns of any SAE, including a death, any time after the two defined 
observation period for the occurrence of AEs and SAEs (Table 11), and considers the event 
reasonably related to the Investigational Medicinal Product, the investigator will promptly 
notify the Study contact for reporting SAEs.  
 


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8.2.2 Summary of Possible Risks related to the Procedures 
Table 12: Summary of Possible Risks related to the Procedures 
 
AE 
SAE (Fatal and Non-Fatal) 
Bone Marrow Harvest 
Pain at the aspiration site 
Local haematoma 
- 
 
Bone Marrow 
Concentrate/Mesenchymal 
Stromal Cells 
Implantation 
Fever 
- 
Core Decompression and 
Implantation Procedure 
Surgery 
Pain at the implantation site 
Local haematoma 
Infectious complications 
Surgery 
Femoral neck fracture 
Femoral head blow-up 
Haemorrhage 
Sepsis 
Shock 
 
General anaesthesia 
Transient hypotension 
Nausea and vomiting 
 
 
 
 
 
 
 
 
General anaesthesia 
Cardiac complications 
• 
Myocardial infarction 
• 
Cardiopulmonary arrest 
• 
Ventricular tachycardia 
Neurological complications 
• 
Stroke 
Pulmonary complications 
• 
Inhalation pneumonia 
• 
Pulmonary embolism 
Anaphylactic shock 
Blood Sampling 
Pain at the sampling site 
Local haematoma 
Superficial vein thrombosis 
Transient 
hypotension/lypothymia 
Syncope 
 
 
 
 


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8.2.3 Summary of Observed Adverse Events (AE) and Serious Adverse Events (SAE) possibly 
related to Study Treatment in Osteonecrosis  
Table 13: Summary of Observed Adverse Events (AE) and Serious Adverse Events (SAE) 
possibly related to Study Treatment (i.e., PREOB® and/or to the Implantation Procedure) (33 
subjects (hips)*) 
Non-Serious AE 
SAE (Non-Fatal) 
Total 
Fever  
9.1% 
9.1% 
Total 
Systemic inflammatory 
response syndrome 
 
Pancytopenia** 
Pyrexia** 
Altered status of 
consciousness** 
Hypotension** 
6.1% 
3.0% 
 
3.0% 
3.0% 
3.0% 
3.0% 
* Based on the Phase IIb study with the product under investigation in osteonecrosis. For more detailed information, see the 
Investigator’s Brochure. AEs and SAEs were limited to treatment emergent adverse events (TEAEs) and serious treatment 
emergent adverse events (STEAEs) and reported per Preferred Term (PT) (MedDRA coding), along with their frequency of 
occurrence in subjects. Subjects were counted once for each PT. An AE/SAE was considered as treatment-emergent if it 
occurred on or after the date of the IMP implantation. In case of missing start date, the AE was considered as treatment-
emergent 
** 4 SAEs were reported in the same patient.  
 
Management of Safety Issues 
• In the event of an AE/SAE, the Investigator will immediately initiate appropriate therapy 
and management according to his/her medical judgment and will decide whether to withdraw 
the patient from the study.  
• The patient must be followed-up by additional examinations according to the medical 
judgment of the Investigator, until the AE/SAE and/or abnormal condition is resolved or the 
Investigator deems further observations or examinations are no longer medically indicated. 
8.3.1 Safety Data Notification Reporting, and Monitoring 
 Reporting of Adverse Events (AEs) 
All AEs will be recorded on the appropriate and corresponding AE Form of the eCRF by the 
Investigator. All AEs must be reported whether or not considered causally related to the IMP 
or any related study procedures. For every AE, the Investigator will provide an assessment of 


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the severity and causal relationship to the IMP or any related study procedures and document 
all actions taken with regard to the IMP, and any other treatment modalities for the AE. 
Treatment of any AE is at the sole discretion of the investigator and according to current good 
medical practice. Any medication administered for the treatment of an AE should be recorded 
in the patient’s eCRF. 
If the outcome of an AE is not available at the time of the initial report or at study exit 
(premature or not), follow-up will proceed until outcome is known. All collected data will be 
recorded in source documents. 
 Notification and reporting of Serious Adverse Events (SAEs)  
Any SAE, whether deemed drug/procedure-related or not, must be recorded on the 
corresponding eCRF Form (SAE form), which will, upon completion, be automatically 
followed by e-mail alerts to Pharmacovigilance-CRO (PV-CRO), Investigator (if completed by 
Independent Physician), Monitor, Sponsor, and Managing Physician of the Production/Tissue 
Establishment. In case of technical problem with the eCRF, a paper version of the Form will be 
sent by fax to the SSO (+49(0) 621 570 5971) who will immediately inform the Managing 
Physician of the safety event occurrence, and the eCRF will be completed (by the Investigator 
or Independent Physician) thereafter as soon as possible.  
In the event of any SAE, occurring from the Screening Period up to the end of the long term 
follow-up (48 months after Product Implantation (Visit 3)), the Investigator (or Independent 
Physician for visit 2) will within 24 hours of event occurrence or awareness:  
1. the Study Safety Officer (SSO) by phone: Safety Events Phone Number, 24/7 cover: 
+49(0) 620 184 64065  
2. Record the SAE on the corresponding eCRF Form (SAE form) or send it by fax (+49(0) 
621 570 5971) or per email (BoneTherapeutics-phv@spm2-safety.com) to the SSO 
who will immediately inform the Sponsor of the safety event occurrence  
The eCRF will be completed (by the Investigator or Independent Physician) thereafter as 
soon as possible.  
Briefly, the SAE Form (and the related Follow-up Forms if needed) will include the following 
information and differentiated assessment:  
• Patient identification: Patient Identification Number, age, and sex 
• SAE diagnosis and description, start and end dates, concomitant drugs and history 


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• Outcome (recovery with or without sequelae, unchanged, improvement, worsening, 
death, or other) and action taken (none, patient discontinuation and withdrawal from the 
study, change in concomitant medication(s) and/or new medication(s), other treatment(s) 
and/or therapeutic procedure(s) (i.e. invasive procedures, surgery, or unknown) 
• Criteria for seriousness (death, life-threatening, persistent or significant disability or 
incapacity, new or prolonged hospitalization, congenital abnormality or birth defect, 
important medical event), severity (mild, moderate, severe), and frequency (intermittent, 
continuous, or other) 
• Causal relationship with the IMP (assessment of drug-event causal relationship and 
consistency with applicable product information, e.g., the Investigator’s Brochure and 
evaluated as certain, probable or likely, possible, unlikely, unrelated, unknown or not 
assessable) 
• Causal relationship with the trial procedures, including the bone marrow harvesting and 
blood sampling, and the product implantation (core decompression, implantation surgery, 
and general anaesthesia) 
• Relationship with the study disease and/or underlying, concomitant, and/or intercurrent 
diseases, relationship with concomitant medication or treatment, and/or drug interactions 
• Suspected or confirmed cases of infection 
• Suspected or confirmed cases of ectopic calcification or myositis ossificans 
• 
Unexpected reactions (e.g., hypersensitivity, allergic, immunogenic, autoimmune, and/or 
toxic) 
In Europe 
Based on data and information available in both the SAE Form and in the Investigation and 
Conclusion Report (see below) (and additional queries, if needed), the SSO will notify the 
occurrence of SUSAR, SAR, and/or SAE related to the trial procedures to both EudraVigilance 
database and Ethics Committees (all Member States concerned), and to all concerned 
Investigators and Sponsor in agreement with all applicable legislation. 
This notification will be sent by the unblinded SSO to both Eudravigilance database and Ethics 
Committees while blinding will be preserved for both the Investigators and Sponsor. 
In the United States of America 
Based on data and information available in both the SAE Form and in the Investigation and 
Conclusion Report (see below) (and additional queries, if needed), the Sponsor will notify the 


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FDA and all participating investigators in an IND safety report of potential serious risks, 
including any suspected adverse reaction that is both serious and unexpected.  
This notification will be sent by the SSO to the FDA and Investigators.  
The Sponsor or designee (PV-CRO) must submit a written summary of the clinical course of 
any life-threatening SAE and related patient information to the FDA within 15 days. Serious 
and unexpected ADRs that are not-life-threatening must be reported to the FDA within 15 
calendar days. Any serious and unexpected AE (including all deaths) must also be reported to 
the IRB by the Investigator according to IRB reporting requirements (where applicable) and 
documentation of this report sent to the Sponsor and designee (PV-CRO). 
All SAEs will be followed to resolution, defined as patient’s health has returned to his/her 
baseline status or all variables have returned to normal). If the Investigator does not expect any 
further improvement or worsening of the event the SAE is followed until stabilization of the 
event. The event is otherwise explained regard less of whether the patient is still participating 
in the study. 
 Notification and Reporting of Serious Adverse Safety/Quality Events (SASQE) 
Based on the information available in the eCRF SAE Form, the Managing Physician will 
immediately investigate. If the investigation indicates that the safety event is actually related to 
the procurement, testing, processing, storage, labelling and packaging, delivery, transport, 
and/or distribution of Investigational Medicinal Product, and/or to the quality and safety of the 
product the event will then be considered as a serious and unexpected adverse reaction to the 
product, or SAE related to the trial procedures, and the Managing Physician will within 24 
hours of the event occurrence or awareness notify (through an Immediate Notification Report) 
the CAs and SSO (the Investigator, Monitor, and Sponsor will also be notified via an automatic 
e-mail alert generated from the eCRF page completed by the Managing Physician).  
An Investigation and Conclusion Report - prepared by the Managing Physician - will be sent to 
the CAs and SSO (with a blind copy sent to the Investigator and Sponsor) as soon as possible 
and no later than 5 calendar days after knowledge of event for the initial report (or for the 
additional follow-up reports if needed). The SSO will record this event in the Eudravigilance 
database.
If the SASQE has occurred during the harvest or implantation procedure in Investigating Site, 
or between reception of the IMP at the Investigating Site and IMP implantation, the Independent 
Physician or the Investigator, respectively, will immediately record the relevant information in 
the corresponding eCRF Form (completion of this Form will be followed by automatic e-mail 


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alerts to the Managing Physician, SSO, Investigator (in case of completion by Independent 
Physician ), Monitor, and Sponsor).  
If a serious safety issue is identified, either upon receipt of an individual case report or upon 
review of aggregate data, the Sponsor will issue a communication to all Investigators as soon 
as possible. A safety issue that impacts upon the course of the trial, including suspension of the 
trial, safety-related amendments to the Study Protocol, change or update of Subject Information 
Sheet and Informed Consent Form or Investigator’s Brochure, will also be reported to the 
Investigators (after prior submission and approval by the CAs and ECs). 
8.3.2 Annual Safety Reports – Development Safety Update reports (DSURs) 
EU Annual Safety Reports 
In addition to the expedited reporting, the SSO will provide annual development safety update 
reports (DSUR) to CAs, ECs, and Sponsor, including but not limited to all SARs, and/or SAEs 
related to the trial procedures, together with an overview of all other SAEs, AEs, and SARs that 
have occurred during the reporting period (in all sites and countries). The report will be 
provided in the format laid down in Guideline ICH topic E2 F.  
IND Annual Safety Reports 
In addition to the expedited reporting, the SSO will provide annual development safety update 
reports for submission to the FDA according to 21 CFR 312.33, including but not limited to all 
IND safety letters, SARs, and/or SAEs related to the trial procedures, together with an overview 
of all other SAEs, AEs, and SASQEs that have occurred during the reporting period (in all sites 
and countries). The report will be provided in the format laid down in Guideline ICH E2 F. 
8.3.3 Safety Data Monitoring 
The occurrence of AEs, SAEs, and SASQEs will be monitored during the whole study period 
(from Screening Period) on an ongoing basis by the Study Safety Officer, the Managing 
Physician of the Production/Tissue Establishment, and the Sponsor. The Sponsor will also 
receive from the Study Safety Officer a regular detailed updated listing of all AEs, SAEs, and 
SASQEs. 
8.3.4  Data Safety Monitoring Board 
An independent data-monitoring committee will be established to assess at intervals the 
progress of the study, the safety data and the critical efficacy endpoints. This board will 


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recommend to the Sponsor whether to continue, modify or stop the trial. The members of the 
board will be unblind for the study while the Sponsor and Investigators will remain blind. 
 
Procedure in Case of Pregnancy 
Women included in the study must be post-menopausal (defined as at least 12 months post 
cessation of menses), surgically sterile or, for women with childbearing potential, using a 
reliable method of contraception for at least 6 weeks prior to study entry (Screening Period, 
Visit 1) and during the whole study period. Women with childbearing potential will undergo 
pregnancy tests at all study visits, and at the last visit to the clinic in case of premature 
discontinuation. However, if a female patient becomes pregnant during the trial, she will be 
followed as per study procedure but will NOT undergo bilateral X-ray and MRI of the hip.  
Any pregnancy will be systematically followed and reported within 24 hours of diagnosis to 
the Study Safety Officer and Monitor (Pregnancy Form will be immediately completed in the 
eCRF, with subsequent urgent notification), and their outcomes will be reported to the Study 
Safety Officer and Monitor. 
Any pregnancy will be handled as an SAE regardless the relationship between the 
Investigational Medicinal Product and the event. Any complication arising during pregnancy 
will be recorded as an AE and will constitute a SAE if it fulfils any of the specified criteria for 
a SAE. 
At the end of the pregnancy, whether that be full-term or premature, information on the status 
of the mother and child will be forwarded to Study Safety Officer. 
If the outcome of pregnancy is: 
• Elective abortions without complications, they will be recorded, documented and 
reported to the Study Safety Officer and Monitor, but they should not be handled as 
AEs; 
• Any spontaneous miscarriages or abortions for medical reasons, or congenital 
abnormalities or birth defects, will be recorded, documented, reported, and handled as 
SAEs and full details will be requested. 
 
Emergency Procedures 
8.5.1 Emergency Contact Procedure 
• In case of SAE or any other safety event or medical concern, the following contact will 
be available (24/7 cover) for continuous support and assistance (Study Safety Officer): 


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Emergency and Safety Events Phone Number: +49(0) 620 184 64065 
The Investigator is responsible for ensuring that procedures and expertise are available to cope 
with medical emergencies during the study. Each patient will receive a Patient Study Card with 
the name and surname, the Patient Identification Number, Title and Number of the study, type 
of treatment received (cell product), and Name of the Sponsor. This card will also record the 
name, surname, full address, and phone number of the Investigator, the address and phone 
number of the Emergency Room of the Investigating Site, and the Emergency and Safety Events 
Phone Number (24/7 cover). The aim of this card is to inform any physician having to deal with 
a patient in an emergency situation that the patient is in a clinical trial and that he/she can contact 
the trial investigator for more relevant information. Patients will be instructed to carry this card 
around at any time during the study. 
• For any other questions or study information, the following contact will be available 
(office hours) for continuous support and assistance: 
Hotline - Phone Number: +49(0) 620 184 64065 
Hotline - E-mail: bonetherapeutics-phv@spm2-safety.com  
8.5.2 Methods for Breaking the Blind 
The treatment code must not be broken. However, the Investigator can unblind the patient's 
treatment assignment in case of medical emergency of safety concerns if knowledge of the 
treatment allocation is able to improve or modify the management of the patient. However, it 
is important to note that the unblinding procedure should not been used in order to assess the 
causality of an AE or SAE. The code may also have to be broken if someone not in the study 
received the IMP or if pregnancy of a randomised patient occurs. Once the decision taken, the 
Investigator will promptly inform the Study Safety Officer and document the reasons for the 
premature unblinding.  
The unblinding/decoding process will be performed by the Investigator via the eCRF system. 
Additionally, a progress note summarising these events should be documented as part of the 
patient's study file, with clarification as to patient SAE outcome. 
Investigators must always keep in mind that unblinding procedures will have a serious impact 
on the validity and analysis of the data. 


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Long-Term Pharmacovigilance System  
Finally, during the course of the trial, the Sponsor plans to design, develop, and submit to the 
relevant CAs if needed, a detailed long-term follow-up strategy, under Pharmacovigilance Plan 
in line with Guideline ICH Topic E2 E. 


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9 
PREMATURE REMOVAL FROM THE STUDY 
 
Reasons for Early Discontinuation
Notification of patient study discontinuation (and reasons for discontinuation) will be 
communicated by the Investigator as soon as possible. The Investigator will document the 
circumstances for premature discontinuation in the patient's electronic Case Report Form as 
follows: 
• Violation of eligibility criteria 
Patients will be withdrawn if incorrectly randomised (i.e., not in compliance with one or more 
eligibility criteria). The Investigator may contact the Monitor in order to discuss the potential 
continuation of wrongly included patients if judged that is in the interest of the patient to 
continue the study. 
In any case, and especially if the patient is withdrawn for safety reasons, the explanation for 
this discontinuation due to violation of eligibility criteria should be documented in the patient's 
eCRF. 
• Adverse Events / Serious Adverse Events 
Any patients may be withdrawn from the study at the Investigator’s discretion in case of a safety 
concern. However, patients can be withdrawn from the study for AEs or SAEs only if the 
Investigator has clearly determined that the patient’s withdrawal would reduce the safety risks. 
In this case, the eCRF AE/SAE Form must be completed, explaining the rationale for 
withdrawal. In addition, the Investigator should ensure that adequate medical care and 
management will be provided to the patient. 
• Withdrawn consent 
Participation in the study is strictly voluntary. A patient has the right to withdraw his/her 
consent from the study at any time, and for any reason, without prejudice to further treatment, 
care, and patient-physician relationship. Under these circumstances, an adequate standard of 
care will always be adopted by the Investigator. The reason(s) for withdrawing consent will 
also be documented in source documentation and the eCRF.  
• Lack of patient compliance to the protocol 
• Study termination 
The Sponsor has the right to terminate the study at any time. 


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• Lost to follow-up 
Intensive efforts will be made to re-contact patients who do not return for scheduled visits in 
order to, at minimum, determine health status and the potential occurrence of AE and/or SAE. 
All efforts to re-contact will be documented in the source documentation and the eCRF.
• Reaching of endpoint 
Severe pain and/or femoral head fracture of the treated hip are the composites of the primary 
efficacy responder endpoint of this study. These events must carefully be documented either 
clinically for pain (WOMAC® VA 3.1) or radiologically for fracture (central radiologist 
assessment) before a patient is discontinued from the study. If severe enough to justify or 
warrant THA, these events will also be reported as SAE. 
These events will be reported as study endpoints via the eCRF.  
• Other reasons 
If no above-mentioned reasons are applicable in case of early discontinuation, the other 
reason(s) will be clearly documented and explained in the eCRF and source documents. 
 
Procedure for Early Discontinuation 
In case of early discontinuation and whenever possible, Investigators will ask patients to 
perform Visit 9 (Exit Visit) as the Premature Discontinuation Visit. At the end of the Exit visit, 
the Investigator will declare early discontinuation in the eCRF. However, the Investigator will 
continue to follow the patient (via phone calls) for the occurrence of any AEs and SAEs at 
Month 24, 36 and 48 post-treatment (See Table 11).  
All collected data, during the visits and phone calls, should be recorded in the source documents 
and eCRF. 
 
Replacement of Patients 
As evaluation of the patient number to be randomised in the study took into account the 
percentage of discontinued patients, patients withdrawn from the study will not be replaced. 


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10 STATISTICAL CONSIDERATIONS AND METHODS OF ANALYSIS 
A Statistical Analysis Plan (SAP) exhaustively detailing statistical methods will be generated, 
reviewed, approved, and signed by the biostatistician and the Sponsor, prior to database lock, 
at the latest. This document will be the main reference document as far as statistical analyses 
are concerned and therefore the description provided in this Study Protocol will not be 
exhaustive. 
 Collection and Derivation of Efficacy Assessments 
10.1.1 Primary Efficacy Endpoint 
Efficacy will be assessed by the following primary endpoint: 
• Percentage of treatment responders at Month 24,  
a treatment responder at a studied timepoint being defined as a patient who responded 
both:  
o Clinically, i.e., if at the studied timepoint, the WOMAC® VA3.1 pain subscale 
score of the study treated hip improved from baseline by at least the minimal 
clinically important difference (MCID)a, 
and 
o Radiologically, i.e., if at the studied timepoint, the study treated hip did not 
progress to fractural stages (ARCO III or higher), as assessed by conventional 
X-ray. 
aThe MCID value is set at 10 mm in accordance with the literature for WOMAC® VAS pain subscale (Ehrich et 
al., 2000; Angst et al., 2001) and with the absolute MCIDs reported in controlled, randomised, parallel group 
studies that evaluate treatment for hip disorders (Puopolo et al., 2007; Altman et al., 2007; Prior et al., 2014). 
For patients with a baseline WOMAC® VA3.1 pain subscale score ≥10 mm, the MCID can be used as a threshold 
value to define a clinically meaningful pain relief. These patients will be considered, at the studied timepoint, as a 
clinical responder if the WOMAC® VA3.1 pain subscale score of the study treated hip decreased from baseline by 
at least the MCID. 
For patients with a baseline WOMAC® VA3.1 pain subscale score <10 mm, the MCID cannot be used as a 
threshold value to define a clinically meaningful pain relief. These patients will be considered, at the studied 
timepoint, as a clinical responder if the WOMAC® VA3.1 pain subscale score of the study treated hip is found in 
the range [0; 4]. This definition is based on the literature, which states that any VAS pain rating ≤4 mm is labelled 
as “no pain” (Jensen et al., 2003). 


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10.1.2 Secondary Efficacy Endpoints 
Efficacy will be assessed by the following secondary endpoints: 
• Percentage of treatment responders at Month 6, 12 and 18, and over the 24-month follow-
up period 
• Percentage of clinical responders at Month 1, 3, 6, 12, 18 and 24, and over the 24-month 
follow-up period; a clinical responder being defined as a patient whom the WOMAC® 
VA3.1 pain subscale score of the study treated hip improved from baseline by at least the 
MCIDb at the studied timepoint 
• Percentage of radiological responders at Month 6, 12, 18 and 24, and over the 24-month 
follow-up period; a radiological responder being defined as a patient whom the study treated 
hip did not progress to fractural stages (ARCO III or higher), as assessed by conventional 
X-ray, at the studied timepoint 
• Absolute change from baseline in WOMAC® VA3.1 total score and composite pain, 
stiffness, and function subscale scores of the study treated hip at Month 1, 3, 6, 12, 18 and 
24, and over the 24-month follow-up period 
• Time to progression to fractural stages (ARCO III or higher) of the study treated hip 
• Percentage of patients requiring hip arthroplasty for the study treated hip at Month 1, 3, 6, 
12, 18 and 24, and over the 24-month follow-up period 
• Time to hip arthroplasty for the study treated hip 
b The MCID value is set at 10 mm. 
Patients with a baseline WOMAC® VA3.1 pain subscale score ≥10 mm will be considered, at the studied timepoint, 
as a clinical responder if the WOMAC® VA3.1 pain subscale score of the study treated hip decreased from baseline 
by at least the MCID. 
Patients with a baseline WOMAC® VA3.1 pain subscale score <10 mm will be considered, at the studied timepoint, 
as a clinical responder if the WOMAC® VA3.1 pain subscale score of the study treated hip is found in the range 
[0;4] (VAS pain range labelled as “no pain”). 
10.1.3 Exploratory Efficacy Endpoints 
Efficacy will be assessed by several exploratory endpoints: 
• Absolute change from baseline of the size of the necrotic lesion of the study treated hip, as 
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• Absolute change from baseline in WOMAC® VA3.1 total score and composite pain, 
stiffness, and function subscale scores of contralateral hip (i.e., the hip contralateral to the 
study treated hip) at Month 1, 3, 6, 12, 18 and 24, and over the 24-month follow-up period 
• Radiological evolution of contralateral hip (i.e., the hip contralateral to the study treated 
hip) as assessed by conventional X-ray at Month 6, 12, 18 and 24 and by MRI at Month 6, 
12 and 24 
• Percentage of patients requiring hip arthroplasty on contralateral hip (i.e., the hip 
contralateral to the study treated hip) at Month 1, 3, 6, 12, 18 and 24 
• Assessment of serum biomarkers at Day +1 after IMP implantation, Month 1 and 6 (as 
applicable)  
 Collection and Derivation of Safety Assessments 
Safety will be assessed using the following variables: 
• Adverse events (AEs) occurring throughout the study period 
• Serious adverse events (SAEs) occurring throughout the study period 
• Occurrence of any abnormality at physical examination at Month 1, 3, 6, 12, 18 and 24 
• Vital signs (blood pressure, heart rate, body temperature and respiratory rate) evaluations 
and absolute change from baseline at Month 1, 3, 6, 12, 18 and 24 
• Body Mass Index and absolute change from baseline at Month 1, 3, 6, 12, 18 and 24 
• Hematologic and biochemical values and absolute change from baseline at Month 1, 3, 6, 
12, 18 and 24 
• Hematologic and biochemical values outside the normal ranges at Month 1, 3, 6, 12, 18 and 
24 
• Concomitant medications throughout the study period  
 Statistical Considerations 
10.3.1 General Considerations 
Continuous data will be summarized using the number of observations, mean, 95% confidence 
interval of the mean (unless specified otherwise), standard deviation, median, 25% (Q1) and 
75% (Q3) percentiles, minimum and maximum.  


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Categorical data will be presented in contingency tables along with number of patients, 
percentages and their 95% confidence interval (unless specified otherwise). 
Statistical tests will be two-sided at 5% significance level. Adjustment to control the type I error 
for multiplicity will be performed as described in Section 10.7 on interim analysis. Except for 
the adjustment made for the interim analysis, no additional adjustments for multiple 
comparisons will be done in this study. 
AEs, SAEs and medical history terms will be coded using the most recent version of the Medical 
Dictionary for Regulatory Activities (MedDRA). Concomitant medications will be coded using 
the most recent version of the WHO drug dictionary. 
Statistical analyses will be performed using the SAS® software (SAS Institute, Cary, NC, USA) 
version 9.2 or higher. 
The Final Clinical Study Report will be established based on the efficacy and safety data 
collected up to 24 months. The long-term follow-up data (collected at 36 and 48 months after 
IMP implantation) will be analysed and reported as Annexes and Supplementary Data to the 
Final Clinical Study Report. 
10.3.2 Statistical Hypotheses for the Primary Endpoint 
The superiority of PREOB® over Placebo will be considered achieved if the percentage of 
treatment responders is statistically significantly higher in the PREOB® group than in the 
Placebo group at Month 24 (primary endpoint). 
• H0 (null hypothesis): the difference in percentages between PREOB® and 
Placebo is equal to 0,  
• H1 (alternative two-sided hypothesis): the difference in percentages between 
PREOB® and Placebo is different from 0 (with percentage PREOB® ≥ 
percentage Placebo).  
Superiority will be proven if the p-value of the statistical test comparing the percentages of 
treatment responders between PREOB® and Placebo is less than or equal to the Type I error 
(two-sided) as defined in Section 10.7 in which case the null hypothesis H0 will be rejected in 
favor of the alternative hypothesis H1. 
 Sample Size 
The single sample size test is planned with a two-sided 5% significance level and a power of 
90% assuming the use of Chi-square test (see Table 14). The proportion of treatment responders 


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is assumed to be equal to 63% for the PREOB® group and 30% for the Placebo group. Theses 
hypotheses have been estimated on the basis of the Phase IIb data set. 
Table 14: Sample size estimation - Chi-square test 
Test?  
Chi-square 
Test significance level, α  
0.05 
1 or 2-sided test?  
2 
Group 1, PREOB® proportion, π1  
0.63 
Group 2, Placebo proportion, π2  
0.30 
Power (%)  
90 
N per arm 
46 
A Chi-square test with a 5% two-sided significance level will have 90% power to detect the 
difference between a Group 1 proportion, π1, of 0.63 and a Group 2 proportion, π2, of 0.30 
when the overall sample size is 92 patients (46 patients in the PREOB® group and 46 patients 
in the Placebo group). 
As an interim analysis is planned in the study using a group sequential design approach, the 
maximum sample size must be increased to achieve the desired power of 90% at final analysis. 
The increase in sample size depends on the overall significance level, the statistical power, the 
number of interim analyses and the type of boundaries being used (See section 10.7). Thus, the 
maximum sample size is obtained by multiplying the above fixed sample size by a constant 
determined by these parameters. For the current study, the maximum sample size is 110 patients 
(1.19 * 92 patients).  
Taking into account a drop out and lost to follow-up rate of 7.5%, the overall sample size should 
be of 118 patients (59 patients in the PREOB® group and 59 patients in the Placebo group) to 
ensure around 110 evaluable patients at Month 24. 
Sample size was computed using the procedure seqdesign of SAS® software version 9.2. 
Additional considerations for sample size estimation  
Although no claim is intended for the comparison of efficacy endpoints other than the primary 
endpoint, sample size calculations have been conducted to ensure that such comparisons may 
be performed with sufficient power to provide additional characterization of the treatment effect 
and yield supportive evidence related to the primary objective. 


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 Analysis Sets 
Three different sets of population will be used in the analysis of this study: a safety set (SAF), 
a full analysis set (FAS), and a per-protocol set (PP). 
The safety set (SAF) will include all treated patients, i.e., patients with both (i) core 
decompression and (ii) PREOB® or Placebo implantation. Analyses on the SAF will be 
performed according to the IMP actually received. 
The full analysis set (FAS) consists in a modified Intention-To-Treat population and will 
include all randomised and treated patients, with a baseline value available of both the ARCO 
stage and the WOMAC® pain subscale score, and at least one post-baseline value available of 
both the ARCO stage and the WOMAC® pain subscale score. Analyses on the FAS will be 
performed according to the randomisation group regardless of the IMP actually received.
The per-protocol set (PP) will be a subset of the FAS including all randomised and treated 
patients who had no major protocol deviations during the study. Analyses on the PP will be 
performed if the PP differs by more than 10% from the FAS. 
 Statistical Methods 
10.6.1 Primary Efficacy Endpoint Analyses 
The primary endpoint is the percentage of treatment responders at Month 24. 
Main analysis of primary endpoint 
The percentage of patients fulfilling the criteria for treatment response (primary efficacy 
endpoint), as obtained after applying the rules for replacement of post-baseline missing data 
detailed in the SAP, will be presented by treatment group. 
The primary efficacy endpoint will be compared between the two treatment groups by means 
of a Chi square test or a Fisher’s exact test (as appropriate). The relative risk (PREOB® vs. 
Placebo) will be reported along with the associated confidence interval. The difference between 
the two groups will be considered significant if the p-value is lower than the significance level 
as defined in Section 10.7. 
10.6.2 Secondary Efficacy Endpoint Analyses 
Detailed statistical methodology for the analysis of secondary efficacy endpoints will be 
provided in the SAP. Secondary endpoints will be tested at a 0.05 significance level The 
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Comparison between treatment groups of the secondary efficacy binary endpoints will be 
performed at each studied timepoint using the same analyses as for the primary endpoint, i.e. 
by means of a Chi square test or a Fisher’s exact test (as appropriate). Treatment effect over the 
24-month follow-up period will be assessed using a Generalized Estimating Equations (GEE) 
model taking into account correlations between the repeated measurements within patients.  
Comparisons between treatment groups of the secondary efficacy continuous endpoints will be 
performed at each studied timepoint by means of a parametric Student t-test or a non-parametric 
Wilcoxon rank-sum test (as appropriate). Multivariate analyses including analyses over time 
will also be conducted to assess treatment effect over the 24-month follow-up period. 
Distributions of time-to-event variables will be estimated at each studied timepoint using the 
Kaplan-Meier product limit method. The log rank test will be used for treatment group 
comparison.  
10.6.3 Exploratory Efficacy Endpoint Analyses 
The same statistical methods as for primary and secondary efficacy endpoints will be used to 
analyse the exploratory efficacy endpoints. Detailed statistical methodology will be provided 
in the SAP. Exploratory endpoints will be tested at a 0.05 significance level. The significance 
of p-values lower than 0.05 will be considered with caution.  
Other exploratory analyses will include subgroup analyses according to: 
• ARCO Stage I / Stage II at baseline,  
• Location and/or size of the necrotic lesion at baseline, 
• Severity of WOMAC® VA3.1 pain subscale at baseline,  
• Osteonecrosis etiology (corticosteroid-induced, alcohol abuse, or idiopathic forms of 
osteonecrosis).  
10.6.4 Safety Endpoint Analyses 
Detailed statistical methodology for the safety analyses will be provided in the SAP. 
Safety variables include AEs, SAEs, vital signs, physical examination, laboratory tests and 
concomitant medications. All safety analyses will be described by treatment group actually 
received and overall on the SAF. No replacement of missing safety data will be performed. 
For each AE reported, the number and percentage of patients will be tabulated based on the 
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relationship to treatment and by severity. AEs will be distinguished between treatment-
emergent AEs and non-emergent AEs (i.e., AEs pre-implantation and AEs post-implantation).  
Standard summary statistics of clinical and laboratory values, as well as shift tables presenting 
incidence of physical and laboratory abnormalities will also be provided by treatment group. 
 Interim Analysis 
A Data Safety Monitoring Board (DSMB) will be responsible for reviewing accumulated safety 
and efficacy data at intervals throughout the study.  
In particular, the DSMB will evaluate the results of a formal pre-planned interim efficacy 
analysis in order to assess the efficacy effect of PREOB® versus Placebo with the intent to stop 
the study early if there is overwhelming evidence of treatment benefit or futility. The DSMB 
will recommend to the Sponsor whether to continue, modify or stop the clinical trial based on 
efficacy or futility but also on safety issues or other considerations not related to efficacy or 
safety. 
The interim analysis will be performed after approximately 40% of required patients have been 
included in the study with available efficacy data at 12 months. A group-sequential stopping 
boundary will be used to preserve the overall Type I error rate at 5%. 
The Lan-DeMets (Lan et al., 1983) alpha-spending approach will be applied with Pocock 
(Pocock et al., 1977) stopping boundaries to evaluate the difference in proportions of treatment 
responders between the treatment groups. A significance level of 0.01341 on the upper and 
lower boundaries will be used for the interim analysis to support early termination for efficacy. 
The significance level at the final analysis is expected to be of the order of 0.01341 on each of 
the upper and lower tails. Significance levels may be adjusted depending on the exact number 
of patients evaluated at the interim analysis. Futility will be assessed with conditional power 
(Lachin et al., 2005), i.e., probability of success at the end of the trial given the interim results. 
To provide the DSMB with supporting data for recommendation following review of results of 
the interim analysis, the DSMB may request the analysis results for main secondary endpoints. 
If the study is stopped based on the recommendation of the DSMB, then all planned analyses 
will be performed according to what is described for the final analysis in this protocol and the 
SAP. 
The Sponsor and other trial personnel will receive the DSMB recommendations only. No 
analysis results on the interim results will be communicated. 
The specific activities of the DSMB as well as statistical procedures and rules for interim and 
final analyses are further described in the SAP and the DSMB charter. 


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11 STUDY MANAGEMENT 
 Monitoring 
Before study initiation, the Monitor will visit Investigating Sites to evaluate feasibility of 
participation in the study (e.g., patient recruitment, staff availability, facilities, equipment), 
initiate site staff, train site staff on the Study Protocol and trial-related procedures, and verify 
good understanding of GCP (e.g., Investigator's and Sponsor's responsibilities) as well as any 
other applicable legal and regulatory requirements, notably as regards standards of quality and 
safety for the procurement (including patient selection and inclusion), testing, distribution, 
administration, and traceability of human tissues and cells, as well as notification and reporting of 
any SAE. 
Very shortly after the first patient inclusion, an on-site monitoring visit will take place in order 
to verify the adherence to the protocol and study procedures, and thus avoiding any 
miscompliance in the future inclusions, if applicable. 
During the course of the study, on-site monitoring visits and regular contacts with Investigating 
Sites will be conducted by a monitor in order to provide detailed information and support the 
Investigator(s), and to assess that the study is performed in strict compliance and accordance to 
the Study Protocol, ICH-GCP, and all applicable regulatory requirements. 
For instance, the following aspects will be closely verified: 
• Procurement of signed and dated Informed Consent 
• Patient rights, including as regards protection of privacy and confidentiality of personal 
data and medical records, welfare, and safety 
• Patient recruitment, eligibility, selection, and inclusion 
• Study procedures 
• IMP receipt, verification, and final delivery by the Pharmacist 
• IMP receipt and verification by the Investigator 
• IMP administration to the patient by the Investigator 
• IMP accountability and traceability 
• Blinding process, including the respective roles of the Investigator and Independent 
Physician 
• SAE notification and reporting 


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• Emergency and pregnancy procedures 
• Data generation and collection processes 
• Accuracy of data collected and recorded in the eCRF 
• Investigator’s Trial Master File (and other on-site source documentation) 
Any detected non-compliance with the approved Study Protocol, GCP, or any other applicable 
legal and regulatory requirements, as well as notification and reporting of any SAE will be fully 
documented by the monitor with the explanation provided by the Investigator on a deviation 
log. 
During monitoring visits, the Investigator and clinical study staff should be available for 
questions, verification of data from the source documentation, and possible corrections to the 
eCRF. 
Following each monitoring visit, the Investigator will be sent a follow-up letter detailing any 
actions required by either the Investigating Site staff or the monitor. Any actions must, wherever 
possible, be addressed immediately, or by the next scheduled monitoring visit. 
The monitor will continuously be reachable and available between visits if the Investigator(s), 
or other study staff at the Investigating site, needs additional information and/or advice. 
 Source Documents 
Each Investigating Site will maintain and archive all appropriate medical and research records 
related to the trial, in compliance with Guideline ICH topic E6 - Section 4.9., and regulatory 
and institutional requirements for the protection of patient confidentiality. 
Source data are all information, original records of clinical findings, observations, or other 
documents in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Source documents may include, but are not limited to, a patient's medical records, hospital 
charts if any, clinic charts if any, the Investigator's patient study files, pharmacy dispensing 
records, recorded data from automated instruments, as well as the results of diagnostic tests, 
such as radiographs, laboratory and urine pregnancy tests. 
The following information should be entered into the patient's medical record: 
•
Patient name, surname and date of birth
• Patient's contact information 
• Medical chart (e.g., hospital source document tracking number), if any 


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• A statement that ICF was obtained with the date of ICF collection and a documentation 
on the person who conducted the Informed Consent discussion 
• Dates of initial screening and all patient visits 
• The patient identification number obtained at Visit 1 (Screening Period) 
• The study title and/or the protocol number of the study and the name of the Sponsor 
• Medical/surgical history and physical examination (including weight and height)  
• Results of BP, heart rate, respiratory rate and body temperature 
• Results of urine pregnancy tests (only for female with childbearing potential) 
• Smoking habits (including the number of cigarettes, cigars, and/or pipes per day) 
• Evidence of risk factors for HTLV-1 infection, including patients living in, or 
originating from, high-incidence areas 
• Alcohol consumption (including the number of drinks per day) 
• Results of radiographs, MRI, and CT Scan 
• Laboratory results reports 
• All concomitant medications and concurrent procedures (list all prescription and non-
prescription medications being taken at the time of entry in the Screening Period of the 
study. At each subsequent visit, changes to the list of medications will be recorded.) 
• Occurrence and status of any AE and SAE 
• The date the patient exited the study, and a notation as to whether the patient completed 
the study or the reason for discontinuation 
The WOMAC® subscales are to be completed directly by the patient. The original pages, 
considered as source data, will be kept and filed on site (in the Investigator’s Trial Master File). 
 Source Data Verification 
To ensure that data in the eCRF are accurate and complete, and in accordance with patient 
source documents and other source data (e.g., laboratory results forms), 100% of source data 
verification (SDV) will be performed by the Monitor on all data and eCRFs including SAE and 
pregnancy-related documents, consisting in a comparison of the source documentation data 
with the eCRFs and other records relevant to the study. This will require direct access to all 
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For WOMAC® VA 3.1 pain subscale questionnaires, 100% SDV will be performed by the 
Monitor on site. Following this SDV, any errors (discrepancies) greater than 1 mm discovered 
during independent verification by/on behalf of the Sponsor (e.g., audits) must trigger 
appropriate corrective actions to ensure exactness of all WOMAC® VA 3.1 pain subscale values 
in the study. 
The process of obtaining IC and the presence on file of the signed and dated ICF will be verified 
for all patients screened, whether or not they were randomised into the study. 
The back-transcription of data from the eCRF into source documents is not allowed, including 
when discrepancies/omissions are detected by SDV. 
As some data will be directly entered into the eCRF, the eCRF will be considered as source 
document for these data. The “Source Data Location List” will be completed confirming the 
location of the source data. 
 Completion of Electronic Case Report Forms, Signing, and Filing 
The patients will be monitored throughout the course of the trial and all results of evaluations 
will be recorded in the eCRF. 
Electronic CRFs will be completed for each patient screened in the trial, including screening 
failure patients. They will be completed as soon as possible after the patient visit. All eCRFs 
will be checked for consistency, accuracy, and completeness, and will be dated and signed on 
an ongoing basis by the Investigator. This will be done as soon as possible after each patient 
study visit. 
In addition, a personal log, detailing each site staff member working on the trial, will be kept 
up to date in the Investigator File. This log will record examples of each individual's 
handwriting, signature/initials and job title as well as the tasks the Investigator has delegated to 
his staff (with date of delegation). The Investigator must sign this log to indicate his/her 
authorisation. 
The Investigator will be responsible for the punctuality, completeness, consistency, and 
accuracy of eCRFs. Electronic CRFs and related source data will be made available by the 
Investigator for data verification at each scheduled monitoring visit. 
Completed eCRF and SAE/Pregnancy-related documents will be collected by the monitor for 
analysis and filing. A copy of all these documents will be stored in the Investigator's archives 
after completion or discontinuation of the trial for of 30 years duration according to Sponsor’s 
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 Data Management 
The study Data Management Plan (DMP) will describe methods used to collect, check, and 
process clinical data, as well as the procedure to follow for database lock. The DMP will be 
developed by the data manager and approved by the Sponsor. It will also list the roles and 
responsibilities of the personnel (with the corresponding functions) involved in data 
management process. 
The database lock will be possible after approval by at least 2 authorised representatives of the 
Sponsor. 
 Audits and Inspections 
Authorised representatives of the Sponsor, Monitor, CAs, and/or ECs may visit the 
Investigating site at any time during or after the study to perform audits and/or inspections, 
including SDV. The purpose of such audit or inspection is to systematically and independently 
examine all study-related procedures and documents and to determine whether these data and 
procedures were conducted, collected, recorded, analysed, and reported accurately and in 
accordance with the approved Study Protocol, GCP, and all applicable legal and regulatory 
requirements (see reference documents in Section 12.1). 
The Investigator must immediately inform the Monitor if contacted by the CAs and/or ECs 
about an inspection at his/ her site. 
The presence of the Monitor on the Investigating site is mandatory in case of visit/audit (at least 
for the SDV audit and Debriefing with the Investigator) by any authorised representative of the 
Sponsor.  
During these audits and inspections, protection of the patient rights and privacy, and 
confidentiality of the patient personnel data and medical records, will be strictly respected, and 
patients will be informed that authorised representatives from the Sponsor, CAs and/or ECs 
may wish to inspect their medical records. 
Any results and information arising from the inspections by the CAs and/or ECs will be 
immediately communicated by the Investigator to the Monitor (and Sponsor). 
The Investigator should take all the corrective actions for any issue or problem identified and 
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 Access to Source Data 
Authorised representatives of the Monitor, Sponsor, CAs and/or ECs will be allowed to have 
full and direct access to the various records relating to the trial (i.e. paper Medical Records and 
other patient data records, including laboratory results reports and radiographs) to verify 
adherence to the Study Protocol, GCP, and any applicable legislation and regulatory 
requirements, and the completeness, consistency, and accuracy of the data being reported. 
 Training of Staff 
The Investigator will maintain records of all individuals involved in the study conduct (medical, 
nursing, and other staff). The Investigator will ensure that appropriate information relevant to 
the study is given to the study staff, and that any new information of relevance to the 
performance of the study will be provided to the staff involved. The Investigator must inform 
the monitor, in a timely manner, of any change in the study site staff. 
 Changes to the Protocol 
The Investigator cannot implement any deviation from or changes to the Study Protocol without 
prior approval by the Sponsor and prior submission, review and documented 
approval/favourable opinion from the CAs and ECs (except when necessary to eliminate 
immediate hazards to study patients, or when changes involve only logistical or administrative 
aspects of the study, e.g., changes in monitors or phone numbers). Any deviation from the Study 
Protocol will be identified, reviewed, and reported by the Monitor with an explanation provided 
by the Investigator, when applicable. 
If it is necessary for the Study Protocol to be amended, the amendment or a new version of the 
Study Protocol will be submitted to and approved by the CAs and ECs before implementation. 
If a protocol amendment requires a change to a particular site's ICF, the Monitor, Sponsor, and 
site's CA will be notified. Approval of the revised ICF by the, Sponsor, and concerned CAs and 
ECs, if applicable, is required before the revised form is used. 
The Monitor (under the supervision of the Sponsor) will distribute amendments and new 
versions of the Study Protocol to each Investigator for review and approval, and to the site staff. 
The distribution of these documents to the CAs and ECs will be handled according to local 
practice. 
Amendments to the trial are regarded as “substantial” if they are likely to have a significant 
impact on: 
• The safety, physical health, and mental integrity of the patients; 


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• The scientific value of the trial; 
• The conduct or management of the trial; 
• The quality and/or safety of any IMP used in the trial. 
If any new event occurs or any information becomes available regarding either conduct of the 
trial or development of the IMP, which may impact safety of the patient population or 
evaluation of the risk-benefit ratio for the clinical trial, the Sponsor will immediately inform 
the Investigators, and appropriate safety measures will be taken to protect patients against any 
immediate hazard. The Study Safety Officer (under the supervision of the Sponsor) will also 
immediately inform CAs and ECs of these events and/or data, and the measures taken. 
Detailed description of the notification, reporting, investigation, and implications of safety 
events for the conduct of the clinical trial, including suspension of the trial, safety-related 
amendments to the Study Protocol, change or update of the Subject Information Sheet and ICF, 
and/or Investigator’s Brochure, is provided in Section 8. 
 


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12 ADMINISTRATIVE, LEGAL, AND ETHICAL ASPECTS 
 Ethical Principles and Conduct of the Trial
The trial will be conducted in accordance with all applicable laws, regulations, guidance, 
guidelines, and principles regarding: 
• Protection of the rights, safety, privacy, and welfare of human subjects 
• Ethical principles for medical research involving human subjects 
• Good Clinical Practice as regards conduct of clinical trials and investigational medicinal 
products for human use 
• Clinical safety data management, notification, and reporting within the context of 
clinical trials 
• Advanced Therapy Medicinal Products 
• Requirements and standards of quality and safety for donation, procurement, testing, 
processing, preservation, storage, traceability, and distribution of human tissues and 
cells 
• Good Manufacturing Practice and quality requirements for manufacture of 
investigational medicinal products for human use 
• Standard Operating Procedures (SOPs) of the relevant institutions 
This includes notably the followings reference documents: 
• World Medical Association Declaration of Helsinki on Ethical Principles for Medical 
Research involving Human Subjects (with amendments) 
• Charter of Fundamental Rights of the European Union (2000/C 364/01) 
• Directive 95/46/EC of the European Parliament and of the Council of 24 October 1995 
on the protection of individuals with regard to the processing of personal data and on 
the free movement of such data 
• Standards for Privacy of Individually Identifiable Health Information - 45 CFR Parts 
160 and 164 (August 14, 2002, Privacy Rule, United States Department of Health and 
Human Services) 
• Health Insurance Portability and Accountability Act of 1996, Public Law 104-91 
(August, 21, 1996, 104th Congress, United States of America) 


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• ICH Topic E2 A - Clinical Safety Data Management : Definitions and Standards for 
Expedited Reporting - Note for Guidance (June 1995, European Medicines Agency, 
CPMP/ICH/377/95) 
• ICH Topic E2 F - Development Safety Update Report - Note for Guidance (September 
2011, European Medicines Agency, EMA/CHMP/ICH/309348/2008) 
• ICH Topic E3 – Structure and Content of Clinical Study Reports – Note for Guidance 
(July 1996, European Medicines Agency, CPMP/ICH/137/95) 
• ICH Topic E6 (R1) - Guideline for Good Clinical Practice - Note for Guidance (July 
2002, European Medicines Agency, CPMP/ICH/135/95) 
• ICH Topic E8 - General Considerations for Clinical Trials - Note for Guidance (March 
1998, European Medicines Agency, CPMP/ICH/291/95) 
• ICH Topic E9 - Note for guidance on statistical principles for clinical trials 
(CPMP/ICH/363/96) 
• ICH Topic E10 - Choice of Control Group and Related issues in Clinical Trials- ICH 
harmonized tripartite guidelines (July 2000) 
• Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 
on the approximation of the laws, regulations and administrative provisions of the 
Member States relating to the implementation of good clinical practice in the conduct 
of clinical trials on medicinal products for human use 
• Commission Directive 2005/28/EC of 8 April 2005 laying down principles and detailed 
guidelines for good clinical practice as regards investigational medicinal products for 
human use, as well as the requirements for authorisation of the manufacturing or 
importation of such products 
• Detailed Guidelines on Good Clinical Practice specific to Advanced Therapy Medicinal 
Products - European Commission (2009, ENTR/F/2/SF/dn D) 
• Guideline on Human Cell-Based Medicinal Products (21 May 2008, European 
Medicines 
Agency, 
Committee 
for 
Medicinal 
Product 
for 
Human 
Use, 
EMEA/CHMP/410869/2006) 
• Reflection Paper on Stem Cell-Based Medicinal Products (14 January 2011, European 
Medicines Agency, Committee for Advanced Therapies, EMA/CAT/571134/2009) 


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• Detailed Guidance on the Collection, Verification and Presentation of Adverse Reaction 
Reports arising from Clinical Trials on Medicinal Products for Human Use - European 
Commission (April 2006, ENTR/CT3) 
• Detailed Guidance on the European database of Suspected Unexpected Serious Adverse 
Reactions (Eudravigilance, Clinical Trial Module) - European Commission (April 2004, 
ENTR/CT4) 
• Guideline on Safety and Efficacy Follow-up Risk Management of Advanced Therapy 
Medicinal Products (20 November, 2008, European Medicines Agency, Committee for 
Medical Products for Human Use (CHMP), EMEA/149995/2008) 
• Guideline on the Risk-Based Approach according to Annex I, Part IV of Directive 
2001/83/EC Applied to Advanced Therapy Medicinal Products (11 February 2013, 
European Medicines Agency, Committee for Medicinal Products for Human Use 
(CHMP), EMA/CAT/CPWP/686637/2011) 
• Directive 2004/23/EC of the European Parliament and of the Council of 31 March 2004 
on setting the standards of quality and safety for the donation, procurement, testing, 
processing, preservation, storage and distribution of human tissues and cells 
• Commission Directive 2006/17/EC of 8 February 2006 implementing Directive 
2004/23/EC of the European Parliament and of the Council as regards certain technical 
requirements for the donation, procurement and testing of human tissues and cells 
• Directive 2012/39/EU of 26 November 2012 amending Directive 2006/17/EC of the 
European Parliament and of the Council as regards certain technical requirements for 
the testing of human tissues and cells 
• Directive 2006/86/EC of 24 October 2006 implementing Directive 2004/23/EC of the 
European Parliament and of the Council as regards traceability requirements, 
notification of serious adverse reactions and events and certain technical requirements 
for the coding, processing, preservation, storage and distribution of human tissues and 
cells 
• Commission Directive 2009/120/EC of 14 September 2009 amending Directive 
2001/83/EC of the European Parliament and of the Council on the Community code 
relating to medicinal products for human use as regards advanced therapy medicinal 
products 


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• Regulation (EC) 1394/2007 of the European Parliament and of the Council of 13 
November 2007 on advanced therapy medicinal products and amending Directive 
2001/83/EC and Regulation (EC) 726/2004 
• Commission Directive 2003/94/EC of 8 October 2003 laying down the principles and 
guidelines of good manufacturing practice in respect of medicinal products for human 
use and investigational medicinal products for human use 
• European Union Guidelines to Good Manufacturing Practice - Medicinal Products for 
Human and Veterinary Use - Investigational Medicinal Products (Rules Governing 
Products in the European Union, Eudralex Volume 4, Annexe 13, February 2010, 
ENTR/F/2/AM/an D (2010) 3374) 
• Guideline on the Requirements to the Chemical and Pharmaceutical Quality 
Documentation concerning Investigational Medicinal Products in Clinical Trials - (31 
March 2006, European Medicines Agency, Committee for Medicinal Products for 
Human Use (CHMP), CHMP/QWP/185401/2004) 
• Guidance on Investigational Medicinal Products (IMPs) and other Medicinal Products 
used in Clinical Trials - European Commission (Eudralex Volume 10 - Clinical Trials, 
Notice to Applicants) 
• Points to Consider on the Manufacture and Quality Control of Human Somatic Cell 
Therapy Medicinal Products (31 May 2001, European Medicines Agency, Committee 
for Proprietary Medicinal Products (CPMP), CPMP/BWP/41450/98) 
• Code of Federal Regulation Title 21 part 312: Investigational New Drug Application 
 Health Authorities and Independent Ethics Committees/Institutional Review 
Board 
Before the beginning of the trial: 
• The Clinical Trial Application (CTA) will be submitted to and approved/authorized by 
the CAs 
• The relevant ECs will approve and/or provide favourable opinion on the clinical trial, 
based on a comprehensive file, including the Study Protocol (with amendments), written 
Subject Information Sheet and Informed Consent Form, other written information to be 
provided to patients (such as the Patient Study Card), patient recruitment procedures, 
Investigator's Brochure, available safety information, information about payments and 
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other documentation evidencing qualifications, a list of involved ECs and attendees, and 
any other documents that the ECs may need to fulfil its responsibilities, the suitability 
of the investigator(s), facilities, and the methods and material to be used in obtaining 
and documenting informed consent of the trial subjects. 
The Investigator and Investigating Site will not initiate nor apply any study procedure or deliver 
IMP until approvals have been obtained from the CAs and ECs. Copies of any correspondence 
between the Investigator and the CAs and/or ECs will be given to the Monitor. 
The Investigator will immediately notify the Study Safety Officer and/or the Managing 
Physician of the Production/Tissue Establishment (Manufacturer) about the occurrence of any 
SAE and other relevant Serious Adverse Safety/Quality Events, in order to allow proper 
notification and reporting of these events to the CAs, ECs, and Investigators involved in the 
trial. Detailed description of Safety Data Notification, Reporting, and Management procedures 
is provided in Section 8.3). 
The Sponsor (with support from the Monitor) is responsible for submitting to the CAs and ECs 
any amendment to the Study Protocol, and any changes to the Subject Information Sheet and 
Informed Consent and/or Investigator’s Brochure, for approval prior to implementation. 
The Investigator will prepare and submit (with support from the Monitor) the “Annual Progress 
Reports” to the CAs and ECs, and according to local regulations and guidelines. The 
Investigator (with support from the Study Safety Officer) must also provide the CAs and ECs 
with any reports of SAEs from the Investigating site, as dictated by the CAs and ECs 
requirements. 
 Patient Data Protection and Confidentiality 
The confidentiality of data and records that could identify patients will be protected in order to 
respect privacy and confidentiality rules, in accordance with all applicable legislation and 
regulatory requirements (see the reference documents in Section 12.1). 
A report of the results of the study may be published or sent to the appropriate CAs in any 
country in which the study drug may ultimately be marketed, but the patient's name will not be 
disclosed in these documents. The patient's name may be disclosed to the Sponsor (or any 
authorized representatives, including the Monitor) or the CAs, during inspections of trial 
records and data. Appropriate precautions will always be taken to maintain confidentiality of 
medical records and personal information. 
By the way of the ICF, written authorisation will be obtained from each patient prior to entry 
into the study, in accordance with applicable legislation and regulatory requirements (see the 


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reference documents in Section 12.1). The patients will be informed that the results will be kept 
and analysed in a computer but that nothing apart from what has been recorded in the eCRF 
will be registered. They will also be informed that their data will only be available to the above-
mentioned entities. 
The written ICF will explain that study data will be stored in a computer database, maintaining 
confidentiality in accordance with all applicable legislation and regulatory requirements. The 
patient‘s names will not be recorded in this database. The written ICF will also explain that, for 
data verification purposes, authorised representatives of the Sponsor (or any authorized 
representatives, including the Monitor), CAs, and/or ECs may require direct access to parts of 
the Hospital or practice records relevant to the study, including patients' medical history. 
Finally, in order to ensure proper identification of the patient and verification of the patient 
identity (as required for the production process of a cell therapy product), and traceability of 
Starting Materials and the IMP, together with the requirements as regards protection of privacy 
and confidentiality of personal data and medical records, a unique identification code (Patient 
Identification Number) will be allocated during screening of the patient. The link between the 
identity of the patient and the identification code will be protected and kept strictly confidential. 
This information will be known (identity of the patient (name and surname) will appear on the 
labels of the bone marrow, blood, and IMP), collected, and recorded by the Investigator and the 
Managing Physician of the Production/Tissue Establishment (and will be kept and recorded in 
restricted access files).  
 Insurance 
The Sponsor liabilities in connection with the study will be covered by an insurance policy, 
including any event, damage, injury, or death of the patient, occurring during the course of the 
study and being or not, directly or indirectly, linked to the study, and in accordance with any 
applicable legislation and regulatory requirements. 
The Sponsor insurance will also cover all individuals participating to and/or intervening in the 
study, independently from the nature of the existing link between the Sponsor, participant, and 
patient. 
 Financial aspects 
Financial details regarding performance of the study will be specified in an Investigational 
Study Agreement signed by the Sponsor and the Investigator before start of the study (each 
party will receive an original signed copy). 


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The Investigator at each Investigating site must comply with all the terms, conditions, and 
obligations of the Investigational Study Agreement. 
 Archiving at the End of the Study 
After the close-out visit at each Investigating site, a copy of the following documentation (non-
exhaustive list) will be stored in the Investigator's archives for a period of time of 30 years 
according to Sponsor’s SOP and ICH-GCP guideline. Archiving responsibilities cannot be 
transferred to the Sponsor. 
• Investigator's Trial Master Site File with the final Protocol and current Investigator 
Brochure 
• Copy of completed eCRFs, SAE, and Pregnancy Forms 
• Signed ICFs 
• Patient screening/randomisation log and Patient Identification Code List 
• Source documentation 
• All required regulatory documents required by ICH-GCP, and any other applicable laws 
and regulations 
 
All study-related documentation must be stored in a secure manner and must remain available 
upon request from the Sponsor or any CAs and/or ECs. 
Before or at the end of the archiving period, the Sponsor can request an extension of the storage 
of all materials, or part of them, for a further period. An appropriate agreement will be drawn 
up accordingly. If an extension of the storage is not required, it is the responsibility of the 
Investigator to decide to destroy or keep these study-related materials after this archiving 
period. 
It is the responsibility of the Sponsor to inform the sites when archiving is no longer needed. 


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13 REPORTING AND PUBLICATIONS POLICY 
 Clinical Study Report 
When all completed eCRFs and Data Clarification Forms (DCFs) have been collected, and data 
have been analysed, a draft of the Clinical Study Report (CSR) will be produced by the Medical 
Writer, and sent to both the Investigators (designated prior to writing) and Sponsor, for review 
and comments. When agreement on the contents has been reached, the report will be signed by 
all parties. 
The CSR will include the "Individual Patient Data Listing" (16.4 of CSR according to the ICH). 
The results will be tabulated, evaluated, and issued as a complete final Clinical Study Report 
by the Monitor according to the Guideline ICH topic E3. This report will be written in English. 
The Sponsor will send a summary of this Clinical Study Report to both the CAs and ECs within 
one year after the end of the trial.  
 Publications and Posters 
Any and all Sponsor Confidential Information, including but not limited to scientific, technical, 
clinical, medical and/or regulatory information, documents, data and databases, basic and/or 
clinical research results, product information and methods, materials, patents and patent 
applications, knowledge, know-how, ideas, concepts, design, algorithms, trade secrets, research 
and development activities, projects, and plans, strategic orientations, society structure, 
organization and collaborations, contracts and agreements, business, financial and/or marketing 
plans and information, whether in oral, written (including but not limited to written documents, 
memorandum, minutes, correspondence, reports), graphic (including but not limited to 
drawings, figures, schema or other material) or computer-readable form, will remain the sole 
property of the Sponsor. 
Any and all Study data, databases, results, materials, analysis, information, documents, and 
reports (including but not limited to eCRFs), collected, generated, created, written, and/or 
otherwise obtained during (or in connection with) the Study under the Study Protocol (except 
for Study patient’s medical records), whether in oral, written (including but not limited to 
documents, memorandum, minutes, reports, correspondence), graphic (including but not 
limited to drawings, figures, schema or other material) or computer-readable form, will become 
the property of the Sponsor. 
The Investigator will retain any information or data of any kind pertaining to the Study, 
including but not limited to Study results from individual Study sites, as well as any Sponsor 
Confidential Information for the purpose of the Study, whether in any and all intangible and/or 


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tangible expressions, in any media, in strict confidence, and shall not directly or indirectly 
publish, communicate, disseminate, display, deliver, distribute, reproduce, disclose, or 
otherwise make available such information and/or data to any third party prior written approval 
from the Sponsor. 
Publication, communication (including but not limited to abstracts and posters), disclosure, 
release, or dissemination of any information or data of any kind pertaining to the study, 
including study results from individual study sites, is however possible in mutual agreement 
between the Investigator and the Sponsor, provided that:  
• Any proposed communication (including, but not limited to abstracts and posters) or 
publication will be submitted to the Sponsor prior to any submission; and 
• Any proposed communication or publication will reflect the collaboration and respective 
roles of the Investigators, Investigating Sites, and Sponsor' personnel; and 
• The Sponsor shall be given thirty (30) days to review communications (abstracts and 
posters), and sixty (60) days to review publications; and 
• In the event that the Sponsor does not object to the proposed communication or publication 
within thirty (30) days or sixty (60) days of its receipt, as the case may be, it will be deemed 
to have been approved; and 
• In the event that the Sponsor objects to the proposed communication or publication for 
reasons relating to the patentability of an invention or the protection of any other forms of 
intellectual property rights that would be disclosed by such proposed communication or 
publication, then submission of the communication or publication will be delayed for a 
maximum of six (6) months to enable the Sponsor to protect its rights; and 
• In the event that the Sponsor reasonably objects to the proposed communication or 
publication as conflicting with or compromising Sponsor' intellectual property rights or 
interests, the proposed communication or publication shall be modified in order to fully 
address Sponsor' concerns and requests of modifications (including, but not limited to 
deletion of any Sponsor Confidential Information from the proposed communication or 
publication), and such modified communication or publication may not be submitted, 
published, disclosed, or disseminated until the Sponsor has confirmed its agreement in 
writing; and 
• Any objection/requested modification made by the Sponsor concerning a proposed 
communication or publication shall be with due regards of the importance of scientific 
dissemination of the study results. 


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ANNEXES 


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Annex 1 : WOMAC® Index 
See the documents attached 
 


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Annex 2 : Imaging Data Analysis 
1. Diagnosis of Femoral Head Osteonecrosis (based on MRI) 
Lesion Definition 
The diagnosis of osteonecrosis of the femoral head is based on analysis of SE T1-weighted 
images (bilateral hip evaluation). It is defined as the presence of a femoral head marrow lesion 
surrounded by a rim or a band of low signal intensity. The signal of the lesion is variable but a 
component with high signal intensity (fat-like) must be present, at least in some areas of the 
lesions. 
Lesion Topography 
The lesion must involve the epiphysis of the proximal femur (the so-called femoral head) which 
is delimited by subchondral bone plate and the physeal scar. The lesion may also extend in the 
femoral neck but its centre should be located above the physeal scar. If centre of the lesion is 
located below the physeal scar, it is considered to be a femoral neck lesion (to be excluded). 
Perilesional Changes 
- 
Presence (or absence) of marrow oedema in adjacent marrow defined by the presence 
of decreased signal intensity on T1-weighted images and intermediate to high signal 
intensity on T2-weighted images with ill-delimited margins (large transitional zone 
towards normal adjacent marrow) 
- 
Presence (or absence) of fluid in the articular space defined by the presence of a high 
signal intensity component within the articular space on T2-weighted images. A small 
amount of fluid located inferior to the femoral head with preservation of acetabular fat 
pad is considered to be normal. 
2. Diagnosis of Fracture in Femoral Head Osteonecrosis (based on MRI and Radiographs) 
Lesion Definition 
- 
On Radiographs 
1. Focal loss of femoral head sphericity (does not include chronic and often bilateral 
changes in sphericity) 
2. Subchondral fracture cleft (crescent sign) 
- 
On MRI 
1. Focal loss of femoral head sphericity 
2. Subchondral fracture cleft (hyperintense line on T2-weighted images in lesion) 


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3. Crescent-shaped area of low signal intensity on T1- and T2-weighted images 
Flow Chart for the Detection of Fracture 
In visits in which both MRI and conventional X-ray are obtained (Screening Period, and Visits 
6, 7, and 9 at months 6, 12 and 24), the reader will focus first on MRI studies for detection of 
femoral head fracture. Fracture will be diagnosed if obvious signs of fracture are present (overt 
fracture - i.e., obvious lack of sphericity or obvious line of high signal intensity). Oedema at 
periphery of the lesion will not be considered as a definite sign for fracture. Oedema-like 
changes involving the bone marrow, synovium, or periarticular muscles will be mentioned but 
not used in staging. If MRI is considered to be equivocal or not contributive for accurate 
demonstration of fracture, conventional X-ray will then be analysed, alone (during the 
Screening Period) or in comparison with previous imaging studies. In this case, any alteration 
of femoral head contour or cleft sign will be considered as fracture. 
In visits in which conventional X-ray are obtained only (Visit 8 at month 18; and long term 
safety and efficacy follow-upVisits at months 36 and 48), the reader will analyse conventional 
X-ray in comparison with previous X-ray studies. Any alteration of femoral head contour or 
cleft sign will be considered as fracture.  


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3. Staging of Femoral Head Osteonecrosis (based on MRI and Radiographs) 
 
- 
Stage 0 -  Negative radiographs and negative MRI 
- 
Stage I -  Negative radiographs and positive MRI 
- 
Stage II - Positive radiographs and MRI without femoral head deformity or subchondral 
bone fracture.  Normal joint space. 
- 
Stage III - Positive radiographs and MRI with subchondral bone fracture (crescent 
sign) but without deformity of the femoral head 
- 
Stage IV - Positive radiographs and MRI with deformity of the femoral head without 
osteoarthritic changes 
- 
Stage V - Positive radiographs and MRI with deformity of the femoral head and 
osteoarthritic changes.  
- 
Stage VI - Complete joint destruction 


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Femoral Head Osteononecrosis Staging 
Adapted from ARCO Staging (Enneking, 1997) 
 
 
Conventional X-ray 
MRI 
Stage 
Femoral Head Contour 
Bone Structure 
Joint Space 
 
0 
Normal 
Normal 
Normal 
Normal or equivocal 
I 
Normal 
Normal or 
equivocal 
Normal 
Osteonecrosis without 
fracture 
II 
Normal 
Bone sclerosis 
or mixed 
changes 
Normal 
Osteonecrosis without 
fracture 
III 
Subchondral bone fracture 
 
Bone sclerosis 
or mixed 
changes 
Crescent sign 
Normal 
Osteonecrosis with 
fracture and  femoral head 
deformity  
IV 
Subchondral bone fracture 
Femoral head deformity 
Any bone 
changes 
Normal  joint 
space 
Osteonecrosis with 
fracture and abnormal 
cartilage 
V 
Subchondral bone fracture 
Femoral head deformity  
Any bone 
changes 
Abnormal 
joint space 
Osteonecrosis with 
fracture and femoral head 
deformity and abnormal 
cartilage 
VI 
Massive femoral head 
destruction  
Any bone 
changes  
Abnormal 
joint space 
 
The stage 0 will never be used as no biopsy of the femoral head lesion will be performed at 
inclusion. 


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4. Additional MRI Findings 
- 
Presence (or absence) of marrow oedema in adjacent marrow defined by the presence of 
decreased signal intensity on T1-weighted images and intermediate to high signal intensity 
on T2-weighted images with ill-delimited margins (large transitional zone towards normal 
adjacent marrow) 
- 
Presence (or absence) of fluid in the articular space defined by the presence of a high signal 
intensity component within the articular space on T2-weighted images. A small amount of 
fluid located inferior to the femoral head with preservation of acetabular fat pad is 
considered to be normal. 
- 
Labral cyst and/or tears (expressed in mm determined on coronal T2-weighted SE images) 
(presence or absence) 
- 
Adjacent muscle oedema (presence or absence) 
- 
Focal femoral and/or acetabular cartilage changes with normal conventional X-ray (Noyes 
grading system; < 50%, > 50% and < 100%, 100%). Limited femoral and acetabular 
cartilage defect (less than 50% loss of cartilage thickness) will be recorded and quantified 
as < 50% or > 50% head, < 50% or > 50% acetabulum) 
- 
Subchondral cyst in acetabular roof (largest axis in mm on coronal T2-weighted SE 
images) 
- 
Hamstring or gluteus muscle tendon lesions (presence or absence), defined as thickening 
of tendons with moderate increase in signal intensity on T2-weighted SE images 
5. Quantitative Analysis of MR Imaging Data - Evaluation of the Extent of the Necrotic 
Area 
Combined Necrotic Angle (Ha, 2006) 
The combined necrotic angle takes into account the arc of the femoral articular surface reached 
by the necrotic area on coronal (angle A) and sagittal (angle B) MR images passing through the 
mid-plane of the femoral head (all images will be archived, including lines and values of angles 
measured). The necrotic angle corresponds to the sum of angles A and B.   
Lesions with a necrotic angle > 190 ° will be included. ARCO stage I (and asymptomatic stage 
II, see Inclusion/Exclusion Criteria) lesions with a necrotic angle < 190° will be excluded. 


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Percent Necrotic Area (Nam, 2008) 
The percent necrotic area takes into account the length of the infarct / maximum diameter of 
femoral head on mid-coronal (value A / value R) and mid-sagittal (value B /value R’) MR 
images (all images will be archived, including lines and values of angles measured). The 
percentage of femoral head involved by necrosis corresponds to the ratio between the products 
of these values: (A × B) / (R × R’) × 100. The lesions with a percentage of necrotic surface > 
30% are included. 
 
 
 
 
 
 
 
6. Qualitative analysis of MRI, CT scan and X-ray images 
During the Screening Period, each hip will be classified by an independent musculoskeletal 
radiologist (Central Reader), according to the ARCO staging system. The Central Reader’s 
results will be encoded in the eCRF.  
In order to evaluate the interobserver reliability and reproducibility of ARCO staging for MRI, 
CT scan and Radiographs images, a second independent musculoskeletal radiologist will 
separately classify the hips treated in this study.  


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The reproducibility evaluation will be performed before database lock. If any discrepancies are 
revealed, they shall be discussed between the two independent radiologists. If no consensus is 
reached by the two readers, the patient will not be considered for the final analysis. 
7. Overview of Radiological Criteria 
Exclusion Criteria 
- 
Normal MRI 
Fat-like signal intensity marrow in the femoral head; physeal scar not to be confused 
with the infarct margin 
• Osteonecrosis ARCO stage I with necrotic angle sum <190° 
• Osteonecrosis ARCO stage II with necrotic angle sum <190° and with WOMAC® 
VA3.1 pain score <20 mm during the 48 hours preceding the screening 
• Osteonecrosis ARCO stage I or II located either in the femoral neck or femoral head but 
without contact with the subchondral bone plate 
• Osteonecrosis ARCO stage III or higher 
• Osteoarthritis defined as Kellgrens stage II or above on conventional X-ray. On MRI, 
presence of limited cartilage changes (more than 50% of loss of cartilage thickness) in 
femoral head or acetabular cartilage. 
• Any other focal or diffuse bone marrow lesion 
• Bone fracture(s) that may interfere with the study evaluation procedures 
Incidental findings on conventional X-ray (compact bone islands, herniation pits, acetabular 
ossicle or calcification, healed fractures, Paget’s disease) will not be considered as radiological 
exclusion criteria and will be recorded in an open fashion. They will not be used in data analysis. 
The percentage of necrotic area will be calculated and recorded at each evaluation but will not 
be considered as an inclusion criteria.  


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Annex 3: Overview of Patient Data Protection, Confidentiality, and Blinding 
 
Access to Patient 
Personal 
Data/Identity and 
to the Link with the 
Identification Code 
* 
Access to 
Patient 
Identification 
Code  
Blinding to 
Treatment 
Allocation 
Patient 
- 
- 
Yes 
Principal Investigator 
Yes 
Yes 
Yes 
Independent Physician 
Yes 
Yes 
No 
Pharmacist (Investigating Site) 
No 
Yes 
Yes 
Radiologist (Central Evaluating Centre) 
No 
Yes** 
Yes 
Managing Physician (Production/Tissue Establ.) 
Yes 
Yes 
No 
Manufacturer  
No 
Yes 
No 
Sponsor 
No 
Yes 
Yes 
Monitor (blind) 
Yes 
Yes 
Yes 
Study Safety Officer 
No 
Yes 
No*** 
 
* Restricted access - Personal data and medical records, as well as the link between the Identification Code and 
the identity of the Patient, will be kept protected and strictly confidential. 
** The Radiologist of the Central Evaluating Centre will have an access code number for the Patient identification 
number. 
*** For the management of SAEs and SUSARs, and their reporting and notification to the ECs and CAs.