A First-in-human Proof-of-concept Study With NVDX3, an Osteogenic Implant of Human Allogenic Origin, in the Treatment of Distal Radius Fractures in Adults.
Phase: PHASE1
Conditions: Distal Radius Fractures
Sponsor: Novadip Biosciences



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TABLE OF CONTENTS 
PROTOCOL HISTORY ................................................................................................................. 1 
TABLE OF CONTENTS ................................................................................................................ 4 
PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT - PIPA .......................................... 8 
SPONSOR PROTOCOL APPROVAL SIGNATURES - SPAS .................................................... 9 
LIST OF ABBREVIATIONS ....................................................................................................... 10 
PROTOCOL SYNOPSIS .............................................................................................................. 13 
TRIAL DESIGN SCHEME .......................................................................................................... 16 
1. 
INTRODUCTION ..................................................................................................... 17 
1.1. 
Background of Information and scientific rationale ............................... 17 
1.1.1. 
Background information ......................................................................... 17 
1.1.2. 
Study Rationale ....................................................................................... 20 
1.2. 
Risks/benefits assessment ....................................................................... 21 
1.2.1. 
Potential risks .......................................................................................... 21 
1.2.2. 
Known potential benefits ........................................................................ 24 
1.2.3. 
Conclusion risk/benefit assessment ........................................................ 24 
2. 
OBJECTIVES AND PURPOSE ................................................................................ 25 
2.1. 
Objectives ............................................................................................... 25 
2.2. 
Purpose .................................................................................................... 25 
3. 
STUDY DESIGN AND ENDPOINTS ...................................................................... 26 
3.1. 
Description of the study design .............................................................. 26 
3.2. 
Study endpoints ....................................................................................... 26 
4. 
STUDY ENROLLMENT AND WITHDRAWAL .................................................... 29 
4.1. 
Inclusion criteria ..................................................................................... 29 
4.2. 
Exclusion criteria .................................................................................... 29 
4.3. 
Strategy for recruitment and retention .................................................... 30 
4.4. 
Participant withdrawal or termination .................................................... 30 
4.4.1. 
Reason for withdrawal or termination .................................................... 30 
4.4.2. 
Handling of participant withdrawals or early termination ...................... 31 
4.5. 
Lost to follow up ..................................................................................... 31 
4.6. 
Premature termination or suspension of study ........................................ 32 
4.7. 
Definition Start and End of the trial ........................................................ 32 

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5. 
STUDY TREATMENT ............................................................................................. 33 
5.1. 
Study treatment and control description ................................................. 33 
5.1.1. 
Formulation, appearance, packaging and labeling .................................. 33 
5.1.2. 
Product storage and stability ................................................................... 33 
5.1.3. 
Preparation .............................................................................................. 34 
5.1.4. 
Dosing ..................................................................................................... 34 
5.1.5. 
Route of administration/ applied surgical technique .............................. 34 
5.1.6. 
Duration of therapy trial treatment ......................................................... 35 
5.2. 
IMP accountability .................................................................................. 35 
5.3. 
Prohibited medications, treatments, and procedures .............................. 35 
6. 
STUDY SCHEDULE ................................................................................................ 36 
6.1. 
Schedule of Activities Table ................................................................... 36 
6.1.1. 
Screening visit ......................................................................................... 37 
6.1.2. 
Implant Surgery ...................................................................................... 37 
6.1.3. 
Hospital discharge visit ........................................................................... 37 
6.1.4. 
(Early) Termination visit ........................................................................ 38 
6.1.5. 
Unscheduled visit .................................................................................... 38 
7. 
EFFICACY ASSESSMENTS AND- PROCEDURES .............................................. 39 
7.1. 
Study procedures/evaluations ................................................................. 39 
7.1.1. 
Grip strength test ..................................................................................... 39 
7.1.2. 
Physician reported Modified Mayo Wrist Score .................................... 39 
7.1.3. 
Patient reported Numeric Rating Scale for pain ..................................... 39 
7.1.4. 
Patient Reported Wrist Evaluation ......................................................... 40 
7.1.5. 
Efficacy assessment by the independent central radiologists ................. 40 
8. 
SAFETY ASSESSMENTS AND PROCEDURES ................................................... 41 
8.1. 
Specification of safety parameters .......................................................... 41 
8.1.1. 
Physical examination .............................................................................. 41 
8.1.2. 
Vital signs ............................................................................................... 41 
8.1.3. 
Electrocardiograms ................................................................................. 41 
8.1.4. 
Clinical laboratory evaluations ............................................................... 41 
8.1.5. 
Specimen preparation, handling, and storage ......................................... 42 
8.1.6. 
Safety assessment by local radiologist .................................................... 42 

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8.1.7. 
Adverse Events and Serious Adverse Events ......................................... 42 
Definition of serious adverse events (SAE) ............................................................... 43 
Treatment Emergent AEs ........................................................................................... 44 
AE of Special Interest (AESI) .................................................................................... 45 
Reportable AESI ........................................................................................................ 45 
AE classification ........................................................................................................ 45 
8.2. 
Safety Reporting procedures ................................................................... 46 
8.2.1. 
Time period and frequency for collecting AE/SAE information ............ 46 
8.2.2. 
Detection of AE/SAE information .......................................................... 47 
8.2.3. 
Follow-up of AE/SAE information ......................................................... 47 
8.2.4. 
Adverse Event reporting ......................................................................... 47 
8.2.5. 
Serious Adverse Event and reportable AESI reporting .......................... 47 
8.3. 
Study Halting rules ................................................................................. 48 
8.4. 
Safety Oversight ..................................................................................... 48 
9. 
STATISTICAL CONSIDERATIONS ....................................................................... 49 
9.1. 
Statistical and analytical plans ................................................................ 49 
9.2. 
Statistical Hypothesis .............................................................................. 49 
9.3. 
Analysis Datasets .................................................................................... 49 
9.4. 
Description of statistical methods ........................................................... 49 
9.4.1. 
General Approach ................................................................................... 49 
9.4.2. 
Analysis of the (primary) safety endpoint(s) .......................................... 49 
9.4.3. 
Analysis of the secondary endpoint(s) .................................................... 50 
9.4.4. 
Analysis of the exploratory endpoint(s) .................................................. 50 
9.4.5. 
Baseline and follow-up descriptive statistics .......................................... 50 
9.4.6. 
Planned interim analyses ........................................................................ 50 
9.4.7. 
Tabulation of individual response data ................................................... 50 
9.5. 
Sample size ............................................................................................. 50 
9.6. 
Measures to minimize bias ..................................................................... 50 
10. 
CLINICAL MONITORING ...................................................................................... 51 
11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS ............................................................................................... 52 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE ......................................... 53 

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13. 
ETHICS/PROTECTION OF HUMAN SUBJECTS ................................................. 54 
13.1. 
Ethical standard ....................................................................................... 54 
13.2. 
Ethics Committee .................................................................................... 54 
13.3. 
Informed consent process ....................................................................... 54 
13.4. 
Patient and data confidentiality ............................................................... 55 
13.5. 
Future use of stored specimens ............................................................... 57 
14. 
DATA HANDLING AND RECORD KEEPING ..................................................... 58 
14.1. 
Data collection and management responsibilities ................................... 58 
14.2. 
Study records retention ........................................................................... 58 
14.3. 
Protocol deviations ................................................................................. 58 
14.4. 
Publication and data sharing policy ........................................................ 59 
15. 
SERVICE PROVIDER MANAGEMENT ................................................................ 60 
16. 
CONFLICT OF INTEREST POLICY ....................................................................... 61 
17. 
REFERENCES CITED .............................................................................................. 62 
APPENDICES ............................................................................................................................... 65 
APPENDIX 1: Distal Radius Fracture Classification systems .................................. 65 
APPENDIX 2: Use of Dual Energy CT 37 ................................................................. 67 
APPENDIX 3: Specifications Carbofix Distal Volar Radius plates and screws ....... 68 
APPENDIX 4: Modified Mayo Wrist Score (MMWS) ............................................. 69 
APPENDIX 5: Numerical Rating Scale for Pain ....................................................... 70 
APPENDIX 6: Patient-Rated Wrist Evaluation ......................................................... 71 
APPENDIX 7: Safety assessments by local radiologist ............................................ 72 
APPENDIX 8: Extended Lane and Sandhu Scoring tool .......................................... 73 
 

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PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT - PIPA 
To be completed by all PIs participating in the trial 
PROTOCOL TITLE A first-in-human proof-of-concept study with NVDX3, an osteogenic implant 
of human allogenic origin, in the treatment of distal radius fractures in adults. 
EUDRACT NUMBER 
2022-002304-21 
PROTOCOL NUMBER 
NVDX3-CLN01 
VERSION NUMBER  
V6.0 
VERSION DATE 
 
25-JUNE-2023 
AMENDMENT NUMBER NA 
SPONSOR 
 
 
Novadip Biosciences 
I have read the protocol specified above and I will conduct the trial as outlined herein. In my formal 
capacity as Investigator, my duties include ensuring the safety of the trial patients enrolled under my 
supervision and providing the Sponsor with complete and timely information, as outlined in the 
protocol.   
I will not deviate from the protocol without prior written permission from the Sponsor and prior 
review and written approval from the IEC, and Health Authorities, except where necessary to 
prevent immediate danger to the patient. It is understood that all information pertaining to the trial 
will be held strictly confidential and that this confidentiality requirement applies to all trial staff at 
this site.  
Furthermore, on behalf of the trial staff and myself, I agree to maintain the procedures required to 
carry out the protocol and any approved protocol amendments in accordance with  
 
The International Conference on Harmonization Good Clinical Practice Guidelines (ICH GCP E6) current version 
 
Committee for Medicinal Products for Human Use (CHMP) Guideline on strategies to identify and mitigate risks for first-in-
human and early clinical trials with investigational medicinal products - 20 July 2017 EMEA/CHMP/SWP/28367/07 Rev. 1 
 
Guideline on safety and efficacy follow-up- Risk management of advanced therapy medicinal products – EMEA/149995/2008 
 
The Declaration of Helsinki, version 1996 and subsequent amendments 
 
All other applicable regulatory requirements and national legislation 
I agree to ensure that all staff members involved in the conduct of this study are informed about 
their obligations in meeting the above commitments. 
 
_______________________________ 
INVESTIGATOR NAME 
 
________________________________ 
 
______________________________ 
DATE  
 
 
 
 
 
INVESTIGATOR SIGNATURE 

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SPONSOR PROTOCOL APPROVAL SIGNATURES - SPAS 
To be completed by the Sponsor’s protocol approvers 
PROTOCOL TITLE A first-in-human proof-of-concept study with NVDX3, an osteogenic implant 
of human allogenic origin, in the treatment of distal radius fractures in adults. 
 
EUDRACT NUMBER 
2022-002304-21 
PROTOCOL NUMBER 
NVDX3-CLN01 
VERSION NUMBER  
V6.0 
VERSION DATE 
 
25-JUNE-2023 
AMENDMENT NUMBER NA 
SPONSOR 
 
 
Novadip Biosciences 
 
 
 
 
 
_______________________________ 
NAME 
_______________________________ 
DATE 
 
_______________________________ 
SIGNATURE 
 

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LIST OF ABBREVIATIONS 
AAOS 
American Academy of Orthopedic Surgeons 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest  
AO 
Arbeitsgemeinschaft für Osteosynthesefragen 
AP 
Antero-Posterior 
ATMP 
Advanced Therapy Medicinal Product 
ASC 
Adipose (Mesenchymal) Stem Cell 
BMP 
Bone Morphogenic Protein  
BP 
Blood Pressure 
βTCP 
Beta-Tricalcium Phosphate 
CA 
Competent Authority 
CHMP 
Committee for Medicinal Products for Human Use 
COLX 
Type X Collagen  
CTNNB1 
b-catenin  
CRF 
Case Report Form 
CT 
Computed Tomography 
DECT 
Dual Energy Computed Tomography Scans 
DLP 
Dose Length Product 
DP 
Drug Product 
DRF 
Distal Radius Fractures 
DS 
Drug Substance 
cc 
Cubic centimeter 
CSR 
Clinical Study Report 
eCRF 
Electronic Case Report Form 
ED 
Effective Dose 
EF 
External Fixation 
EMA 
European Medicines Agency 
ETV 
Early Termination Visit 
EU 
European Union 
EUDRA
CT 
European Union Drug Regulating Authorities Clinical Trials Database 
Fl 
Flerovium 
FPFV 
First Patient First Visit 
g 
Grams 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation (EU) 2016/679 
h 
hours 
HA 
Hydroxyapatite 
βTCP 
beta-tricalcium phosphate 
HBcAb 
Hepatitis B Core Antibody 
HBsAg 
Hepatitis B surface Antigen 

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HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HD 
Hospital Discharge 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ICH E6 
GCP 
International Conference on Harmonization Guidance for Industry, Good Clinical Practice: 
Consolidated Guidance 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
INN 
International Nonproprietary Names 
IGF1 
Insulin-like growth factor 1  
IS 
Implant Surgery 
keV 
kiloelectron Volt 
kVp 
kiloVolt peak 
LAT 
Lateral 
LPLV 
Last Patient last Visit 
M 
Month 
MCR 
Metaphyseal collapse ratio 
MedDRA Medical Dictionary for Regulatory Activities 
Mg 
Magnesium 
mGy.cm 
Milligray per centimeter 
MMWS 
Modified Mayo Wrist Score  
mSv 
Millisievert 
NA 
Not Applicable 
NRS 
Numeric Rating Scale 
NVD 
Novadip 
OB 
Leptin  
OPG 
Osteoprotegerin  
OTA   
Orthopedic Trauma Association 
PI 
Principal Investigator 
PIPA 
Principal Investigator Protocol Agreement 
PoC 
Proof-of-Concept 
PT 
Preferred Term 
rAESI 
Reportable Adverse Event of Special Interest 
PRO 
Patient Reported Outcomes 
PRWE 
Patient-Rated Wrist Evaluation 
QA 
Quality Assurance 
QC 
Quality Control 
RSI 
Reference Safety Information 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Serious Adverse Reaction 

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SDV 
Source Data Verification 
Si 
Silicium 
SoCa 
Standard of Care 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SPAS 
Sponsor Protocol Approval Signature 
Sr 
Strontium 
TEAE 
Treatment Emergent AE 
TMP 
Trial Monitoring Plan 
V 
Visit 
VEGF 
Vascular Endothelial Growth Factor 
W 
Week 
WOCBP 
Women Of Child Bearing Potential 
 
 
 

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PROTOCOL SYNOPSIS 
Title: 
A first-in-human proof-of-concept (PoC) study with NVDX3, an osteogenic 
implant of human allogenic origin, in the treatment of distal radius fractures 
in adults. 
Study description: 
A single arm, monocentric study in adult patients, suffering from a distal 
radius fracture, treated during the osteosynthesis intervention with NVDX3. 
After the Implant Surgery (IS) the safety follow-up will cover two distinct 
stages followed by a long-term safety follow-up study:  
 Phase 1: Acute safety phase up to 6 weeks post-IS (W6) 
 Phase 2: Long-term safety follow-up from W6 up to of 12-month post-IS  
 NVDX3-CLN0X: NVDX3 long-term safety study up to 10 years post-
NVDX3-CLN01 study  
Study Objectives and endpoints: 
 
Objectives 
Endpoints  
Primary  
Safety:  
To assess the safety of the 
NVDX3 implant in an 
orthotopic environment 
 
 Description of all SAEs and NVDX3 related 
AEs between screening (V1) and 12-months 
post-IS. 
Secondary  
Safety:  
To assess the acute- and long-
term safety of the NVDX3 
implant 
 
 Description of all acute SAEs and NVDX3 
related AEs between screening (V1) and 6 
weeks post-IS (V5). 
 Description of all SAEs and NVDX3 related 
AEs beyond 6 weeks (V5 excluded) until 12 
months post-IS 
 Description of Treatment Emergent AEs 
(TEAEs) for the periods: 
• 
Between screening and week 6 (V5 
included) 
• 
Between week 6 (V5 excluded) and 
month 12 (V8 included) 
• 
Full study duration  
 Description of related and unexpected 
(S)AEs between inclusion and study 
completion 

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 Description of AE of Special Interest (AESI) 
between inclusion and study completion 
 Description of lab data and vital signs 
obtained between inclusion and study 
completion 
Efficacy:  
To assess the efficacy of the 
NVDX3 implant radiologically 
and clinically 
 
 Description of bone formation status a, 3-,  
and 12-months post-IS compared to hospital 
discharge (HD) based on Computed 
Tomography scans (CT) and at HD, 2-, 6-
weeks, 3-,6-, and 12-months post-IS 
compared to the peri-operative x-ray 
acquisitions  
 Description of bone union status at  3-,  and 
12-months post-IS compared to HD based on 
Computed Tomography scans (CT) and at 
HD, 2-, 6-weeks, 3-,6-, and 12-months post-
IS compared to the peri-operative x-ray 
acquisitions 
 Description of bone remodeling status at , 3-, 
and 12-months post-IS compared to HD 
based on Computed Tomography scans (CT) 
and at HD, 2-, 6-weeks, 3-, 6-, and 12-months 
post-IS compared to the peri-operative x-ray 
acquisitions  
 Description of Total extended Lane and 
Sandhu Score at  3-,  and 12-months post-IS 
compared to HD based on Computed 
Tomography scans (CT) and at HD, 2-, 6-
weeks, 3-,6-, and 12-months post-IS 
compared to the peri-operative x-ray 
acquisitions  
 Description of the patient’s clinical status and 
evolution at 2-, 6 weeks, 3-, 6-, and 12-
months post-IS compared to HD using: 
o Grip Strength measure 
o Modified Mayo Wrist Score (MMWS) 
o Patient-Rated Wrist Evaluation questionnaire 
(PRWE)  
 Description of the patient’s pain status and 
evolution via Numeric Rating Scale pain 

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(NRS-pain) at HD, 2-, 6 weeks, 3-, 6-, and 
12-months post-IS compared to screening 
using: 
Exploratory  
 
 
 
 
 
 
  
 
  
 
  
 
  
 
 
Study Population: 
10 adult male and/or female patients with a native intra-articular Distal 
Radius Fracture (DRF). 
Phase: 
PhI/IIa Study (First-in-human proof-of-concept) 
Description of Sites/Facilities Enrolling Patients: 
This trial will be conducted by orthopedic surgeons  
Description of Study Treatment: 
NVDX3 is an osteogenic implant of human allogenic origin. This lyophilized 
and sterilized tissue engineered product is composed of extracellular matrix, 
biologically active growth factors and biomolecules, non-viable osteogenic 
cells associated with hydroxyapatite/beta-tricalcium phosphate (HA/TCP) 
particles.  NVDX3 is formulated as a lyophilized powder, sterilized by 
gamma radiation. 
NVD-X3 off-the-shelf implant is intended to induce bone formation between 
two bone segments 
 As well in an 
orthotopic as in a heterotopic environment. 
Study Duration: 
Protocol NVDX3-CLN01: Approximately 15 months. (From FPFV to LPLV) 
 
Protocol NVDX3-CLN0X: Up to 10 years after the LPLV in the NVDX3-
CLN01 study  
 Patient Duration: 
Protocol NVDX3-CLN01: Approximately 13 months (From DRF diagnosis 
to the 12-months post-implant surgery)  
Protocol NVDX3-CLN0X: Up to 10 years after the patient’s last  visit in  the 
NVDX3-CLN01 study

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1. 
INTRODUCTION 
1.1. 
Background of Information and scientific rationale 
1.1.1. 
Background information  
A. NVDX3 
NVDX3 is an osteogenic implant of human allogenic origin. This tissue engineered product is 
composed of extracellular matrix, biologically active growth factors and biomolecules, non-
viable osteogenic cells associated with hydroxyapatite/beta-tricalcium phosphate (HA/TCP) 
particles.  NVDX3 is formulated as a lyophilized powder, sterilized by gamma radiation. 
NVD-X3 off-the-shelf implant (powder for reconstitution) is intended to induce bone formation 
between two bone segments as well in an orthotopic as heterotopic environment. The pro-
osteogenic and anti-resorptive properties of the stem cell-derived biomolecules are driving the 
bone formation.  
It can be postulated that NVDX3’s mode of action is based on: 
I. 
The high degree of mineralization contributing to the direct formation of a hard bone 
callus, 
II. 
the promotion of angiogenesis with specific biological growth factors,  
III. 
the induction of osteogenesis (endochondral ossification) with specific biomolecules and, 
IV. 
the release of molecules implied in the control of the osteoclasts activity to reduce the bone 
resorption after implantation.  
For more detailed information on the mode of action of NVDX3, please refer to the latest version 
of the IB. 
 
B. Targeted indication: Distal radius fracture 
Description 
Fractures of the distal radius (DRF), often referred to as “wrist fractures”, are common in both 
children and adults. Most of the fractures are caused by a fall on the outstretched hand with the 
wrist in dorsiflexion. They are usually occurring in the distal radius within three centimeters of 
the radiocarpal joint. Most of these traumatic incidents are closed injuries, the overlying skin 
remaining intact. 
Acute DRF results in pain, limitations in disability stress, and the potential inability to work. 
Delayed fracture healing permanent loss in function, or continuous pain may cause substantial 
morbidity and impact on social and professional activities.  
Incidence 
DRF is one of the most common fractures with an incidence of 195.2/100,000 persons per year1. 
The distributive pattern of these injuries is bimodal, affecting young (predominantly male) adults 
through high-energy falls and elderly (predominantly female) adults through low-energy falls 

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of >10, volar angulation of >20, an articular gap or step-off of >2 mm, or radial 
inclination of <109-11.  
3. The metaphyseal collapse ratio (MCR), expressing the maximal radiolucent extent as a 
percentage of the intercortical distance, will be used to quantify metaphyseal 
comminution8. 
Treatment 
The aim of treatment is pain relief and return of function while weighing the risks and benefits of 
nonoperative and operative treatment. There are multiple treatment options, including closed 
reduction and cast immobilization, percutaneous K-wire fixation, fixation with volar or dorsal 
plates (locking or nonlocking), bridge plating, use of an external fixator, or a combination of 
these techniques. Although the best choice depends to some extent on the characteristics of the 
fracture (open/closed, nondisplaced/displaced, extra-/intraarticular), there is little high-quality 
evidence to inform this decision-making. The clinical practice guidelines for DRF published by 
the American Academy of Orthopaedic Surgeons (AAOS) made 29 recommendations; however, 
none of these recommendations was given a ‘‘strong’’ rating owing to limited strength of the 
evidence12,13. 
Volar plating is widely used because of its stability, early movement, and quick return to activity. 
This technique allows to perform a satisfactory surgical treatment in almost every kind of wrist 
fracture with a low complication rate providing an immediate stable fixation and distal radius 
fragment collapse prevention, even in most severe osteoporotic cases14. Dorsal plating may be 
preferred for buttressing of comminuted fractures, but risks extensor tendon injury. Percutaneous 
pins are a less invasive, cheaper surgical option, but may lack stability. External fixation is 
another less invasive procedure and may be augmented with Kirschner-wires for added stability. 
Casting is less costly and avoids surgical complications but may not provide adequate reduction. 
Several treatment methods for DRFs have been proven effective, but none have emerged as a 
clear treatment of choice14.  
Particularly in people with osteoporotic bone, metaphyseal comminution and/or high impaction 
may result in a bony void in the distal radius that may be associated with loss of reduction and 
malunion. This defect can be filled with some biocompatible material; for example, an autograft 
(autogenous bone graft) that is obtained from the patients themselves. Such bone is ’harvested’ 
or extracted from a donor site; usually the iliac crest (a part of the pelvic girdle). However, 
autograft harvesting carries a significant risk of complication, including donor site pain, 
haematoma, infection and nerve injury15. Besides donor site comorbidity prolonged intervention 
time due to the need to perform the graft harvesting, graft resorption, molding challenges and 
limited availability of grafting material, especially in pediatric patients, have been described 
extensively as potential hurdles linked to the use of autologous bone16. 
A common alternative is an allograft (allogenic bone graft), obtained from cadaveric donors or 
live donors undergoing procedures such as total hip replacement. Allografts are osteoconductive 
and weakly osteoinductive, though there are still concerns about the residual infective risks, costs 
and donor availability issues. As an alternative, xenograft substitutes are cheap, but their use 
provided contrasting results, so far. Ceramic-based synthetic bone substitutes are alternatively 

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based on hydroxyapatite (HA) and tricalcium phosphates, and are widely used in the clinical 
practice. Indeed, despite being completely resorbable and weaker than cortical bone, they have 
exhaustively proved to be effective. Biomimetic HA are the evolution of traditional HA and 
contains ions (carbonates, Si, Sr, Fl, Mg) that mimic natural HA (biomimetic HA). Injectable 
cements represent another evolution, enabling minimal invasive techniques. Bone morphogenetic 
proteins (namely BMP2 and 7) are the only bone inducing growth factors approved for human 
use but only in spine surgery and for the treatment of tibial nonunion. Demineralized bone matrix 
and platelet rich plasma did not prove to be effective and their use as bone substitutes remains17.  
Experimental cell-based approaches are considered the best suitable emerging strategies in 
several regenerative medicine application, including bone regeneration. In particular, 
mesenchymal stem cells have been widely exploited for this purpose, being multipotent cells 
capable of efficient osteogenic potential18. 
Conclusion 
Within the DRF indication, the metaphyseal comminution remains an important challenge. 
Autologous bone grafting is still considered the most effective material to fill the metaphyseal 
defect. Alternatives to autologous bone grafts lack one or more of the properties described in the 
‘‘Diamond theory’’ of Giannoudis: osteogenic cells and vascularization, mechanical stability, 
growth factors, osteoconductive scaffolds (in combination with growths factors), being the 
prerequisite for bone healing19. 
1.1.2. 
Study Rationale 
DRF was chosen as a clean model for exploring the bone formation potential of the NVDX3 
implant in a heterotopic environment. High impact metaphyseal comminution DRFs are 
underappreciated injuries and are a common cause of chronic wrist pain and limited range of 
motion, negatively impacting the quality of life of the patients. 
Autologous bone graft extracted mostly from the patient’s iliac crest, currently considered as the 
standard of care to fill the metaphyseal defect, carry a significant risk of complications, including 
donor site pain, haematoma, infection and nerve injury15. It also prolongs the duration of the 
intervention considerably. Additionally other associated complications such as graft resorption, 
molding challenges and limited availability of grafting material, can be potential hurdles for this 
technique16. 
MSC therapy has attracted attention due to the potential to improve the treatment outcome by 
promoting bone formation18. Based on the currently available pre-clinical data, NVDX3 has 
shown to be a potential alternative for both autologous bone and ceramic-based synthetic bone 
substitutes. 
 
 

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2. Due to a detection limit of the applied analytical methods, the presence of viable donor 
cells and related potential abnormal activity cannot completely be ruled out. This will be 
closely evaluated radiologically and clinically at each follow-up visit of this study and 
during the long-term safety study (NVDX3-CLN0X). 
Other historically reported risks related to ATMPs (but not observed for NVDX3) defined within 
the recommendations of the CHMP (“Guideline on safety and efficacy follow-up- Risk 
management of advanced therapy medicinal products – EMEA/149995/2008”), have been 
addressed more in detail in the latest version of the IB.  
 
Risks related to the study procedures: 
 DRF Surgery 
The surgical procedure, aiming fixation of the DRF will be performed as per standard of care of 
the clinical site (including the associated blood draws and sedative/anesthetic procedures). 
Although most patients do well with current fixation techniques, complications cannot be 
excluded20. Besides tendon irritation and rupture, nerve injury, malunion, nonunion, pain 
syndromes, loss of reduction, and posttraumatic arthritis must all be considered when treating 
DRFs 
 Imaging protocol  
Based on literature with HA21 
 a high 
radiopacity was observed related to the high mineral content. This opacity presents a challenge 
for the radiological evaluation of X-ray images. Consequently, the follow-up of the patients in 
this study would require CT imaging allowing a better visualization of the bone formation effect 
of NVDX3. The sponsor even introduced the use of DECT scans allowing, besides reducing 
metal and beam hardening artifacts, to investigate in much more detail the NVDX3 
characteristics and efficacy parameters (see also Appendix 2). 
Today, literature considers DECT to be dose-neutral compared to conventional CT. Effective 
dose (ED) (expressed in millisievert or mSv) to patients can be estimated by using dose length 
product DLP (mGy.cm) to effective dose (ED) conversion coefficients. The DLP represents the 
amount of radiation which is used for the exposure and is recorded by the scanner. Koivisto et al 
and Biswas et al reported an effective dose to scans of the wrist of respectively 0.001mSv and 
0.03mSv22. As per request of the Luxembourg Ministry of Health, and conform to art.78 of the 
Luxembourg Law on radioprotection, a radiation exposure estimation  has been completed by an 
expert on radioprotection of the Federation of Hospitals in Luxembourg (FHL). In this context, a 
series of lower arm phantom scans have been completed including samples of the targeted IMP. 
The FHL report called “Avis d’expert en physique medical concernant l'étude clinique was 
completed on 27JAN2023 and submitted to the Luxembourg Health Authorities.  

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1.2.2. 
Known potential benefits  
 Avoid bone graft harvesting and its related comorbidities 
The use of NVDX3 eliminates the need for an invasive and cumbersome iliac crest 
harvesting along with its known risks and complications 16,25-31. 
 Prolonged intervention time due to the need to perform the graft harvesting. 
 Peri- and post-operative complications like injury of the physis, pain, nerve 
damage, and wound healing complications such as bleeding, hematoma and 
infection.  
 Graft resorption. 
 Application/molding challenges. 
 Limited availability of autologous bone graft material. NVDX3, in the contrary, is 
manufactured in a controlled setting, guaranteeing the graft quantities needed to 
cover the surgical needs.  
 No need to add scaffolds/carriers 
The use of NVDX3 does not require an additional scaffold or carrier (eg. Collagen 
sponge) and consequently eliminates their associated potential side effects (e.g., 
hypersensitivity reactions). 
 No need to add bone modulating agents 
Since NVDX3 has the potential to promote osteogenesis the addition of other bone 
modulating agents, such as BMP and bisphosphonates is not required, eliminating the risk 
of associated side effects and contraindications. 
1.2.3. 
Conclusion risk/benefit assessment  
Based on the pre-clinical information, the implant procedure, and the expected osteogenic 
induction properties of IMP, NVDX3 can be considered to have a beneficial risk/benefit profile 
for use in human  
For the latest updates on potential risks and benefits linked to NVDX3 refer yourself to the 
latest version of the Investigator Brochure (IB). 
 

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2. 
OBJECTIVES AND PURPOSE 
2.1. 
Objectives 
This PoC study will assess the safety and the efficacy of NVDX3 supporting orthotopic 
ossification1 in adult patients suffering from a Distal Radius Fracture (DRF).  
Primary objective: 
 To assess the safety of the NVDX3 implant  
Secondary objectives 
 To assess the acute and long-term safety of the NVDX3 implant 
 To assess the efficacy of the NVDX3 implant radiologically and clinically 
 To explore and evaluate new radiological assessment methods for NVDX3  
2.2. 
Purpose 
The NVDX3-CLN01 study is designed as a first in human PoC aiming at assessing the safety 
and preliminary efficacy of the NVDX3 implant in an orthotopic bone fusion indication, i.e long 
bone non-union or DRF. 
 
1 Orthotopic bone formation refers to the presence of bone formation occurring at a normal place in the 
body, pertaining to a tissue transplant grafted within existing bone. In this study context, including distal 
radius fracture, bone formation is induced to fill the bone void induced by the trauma. 

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3. 
STUDY DESIGN AND ENDPOINTS 
3.1. 
Description of the study design 
This is a prospective, single arm, monocentric first-in-human PoC study in adult patients, 
suffering from a distal radius fracture, treated during the surgical intervention with NVDX3, an 
osteogenic implant from human allogeneic origin.  
As per standard of care, patients with DRF are followed up to 3 months post-intervention. In the 
context of this trial, patient safety and IMP efficacy will be followed up to 12 months post-
implant surgery. 
At the end of this study, the included patients will be invited to participate in a long-term safety 
follow-up study for an additional period of 10 years. 
3.2. 
Study endpoints 
Primary Endpoint 
Evaluation of all SAEs and NVDX3 related AEs between screening (V1) and 12-months post-
IS (V8). 
Secondary Endpoints 
Safety 
1. Description of all acute SAEs and NVDX3 related AEs between screening (V1) and 6 
weeks post-IS (V5). 
2. Description of all SAEs and NVDX3 related AEs beyond 6 weeks (V5 excluded) 
until 12 months post-IS 
3. Description of Treatment Emergent AEs (TEAEs) for the periods: 
a. Between screening and week 6 (V5 included) 
b. Between week 6 (V5 excluded) till month 12 (V8 included) 
c. Full study duration  
4. Description of related and unexpected (S)AEs between inclusion and study 
completion 
5. Description of AE of Special Interest (AESI) between inclusion and study completion 
6. Description of lab data and vital signs obtained between inclusion and study 
completion 
 
 

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Efficacy 
 
Radiological assessments on Computed Tomography data (CT2) using the 
extended Lane and Sandhu Scoring tool (eLSS) 
The following assessments will be performed at 3and 12-months post-IS compared to HD 
1. Evaluation of bone formation status  
2. Evaluation of bone union status  
3. Evaluation of bone remodeling status  
4. Evaluation of Total extended Lane and Sandhu Score 
 
Radiological assessments on X-ray Using the eLSS tool 
The following assessments will be performed at HD, 2-, 6-weeks, 3-,6- and 12-months 
post-IS compared to the peri-operative x-ray acquisitions 
1. Evaluation of bone formation status  
2. Evaluation of bone union status  
3. Evaluation of bone remodeling status  
4. Evaluation of Total extended Lane and Sandhu Score  
 
Clinical assessments  
The following assessments will be performed at 2-,6 weeks, 3-, 6-, and 12-months post-
IS compared to HD: 
1. Grip strength measure with a hydraulic hand dynamometer 
2. Modified Mayo Wrist Score (MMWS): A physician-based scoring evaluating the 
patients’ pain, active flexion/extension arc, grip strength and ability to return to 
regular employment or activities. 
3. PRWE Questionnaire: A patient reported scoring evaluating the patients’ wrist 
pain and disability 
NRS-pain, a patient reported scoring evaluating the patients’ pain, will be performed at 
HD, 2-,6 weeks, 3-, 6-, and 12-months post-IS compared to Screening. 
 
 
 
2 As per imaging requirements Dual energy CT (DECT) acquisiƟons will be obtained. The DECT acquisiƟon 
also contains the core data of the “normal” CT, enabling to ﬁlter and evaluate CT images separately. 

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Exploratory endpoints 
 
 
 
 
  
 
  
 
  
 
  
 
 

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4. 
STUDY ENROLLMENT AND WITHDRAWAL 
4.1. 
Inclusion criteria 
Patients must meet all the inclusion criteria to be eligible to participate in the study: 
1. Male or female patients within the age range of ≥18 years to ≤80 years. 
2. Patient diagnosed with DRF with confirmed: 
a. Classification AO/ATO: C2 and C3 - Intra-articular & multifragmentation. 
b. Estimated volume of the targeted bone void should not exceed 5cc. 
c. Availability of diagnostic AP and LAT X-ray or CT scan.  
3. Patient can undergo the targeted surgical intervention within 7 days post-DRF diagnosis. 
4. Patient fulfills criteria for undergoing a surgical intervention. 
5. Patient has understood and accepted to participate in the study according to all study 
procedures by signing the informed consent. 
4.2. 
Exclusion criteria 
A patient who meets any of the following criteria will be excluded from participation in this 
study: 
1. Open DRF or closed DRF with increased infection risk. 
2. Injury to the median nerve. 
3. Previous fracture of the target distal radius. 
4. Documented disease limiting mobility and functional assessments (eg. Grip strength test). 
5. Dependency on crutches or any comparable walking aids. 
6. Patient is overweight, has a BMI ≥35. 
7. Presence of clinically significant infection at the target implant site or systemic infection.  
8. History of allergic reaction or any anticipated hypersensitivity to any of the anticipated: 
a. Osteosynthesis materials (PEEK plate and screws). 
b. Anesthetic agents. 
c. Components of the NVDX3 implant. 
9. Presence of any auto-immune disease, with exception of well controlled diabetes type-1 
or II, or auto-immune thyroid disorders. 
10. Positive serology for human immunodeficiency virus (HIV), HBcAb and/or HBsAg. 
11. Presence of an active tumor. 
12. Documented metabolic bone disease or any disorder, such as but not limited to high-risk 
osteoporosis, that could interfere with the bone healing and bone metabolism. 

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13. Chronic, ongoing, or planned use of medications that might affect bone metabolism or 
bone quality such as bisphosphonates, steroids, methotrexate, anticoagulants, 
immunosuppressants or immunotherapy.  
14. Excessive smoking, history of chronic alcohol or drug abuse within the 12 months prior 
to screening. 
15. Any history of experimental therapy with another investigational drug within 60 days 
prior to screening. 
16. Pregnant women or women of childbearing potential (WOCBP) not agreeing to use an 
effective method of birth control3 during the course of the study. Note: WOCBP 
including peri-menopausal women who have had a menstrual period within 1 year prior 
to surgery have to have a negative pregnancy test before entering in the study. 
17. Any other psychosocial, mental, and physical condition which, in the opinion of the 
investigator, could interfere with the trial conduct, the patient’s compliance or influence 
interpretation of the results. 
18. Patient with historically elevated radiation exposure levels that could in the opinion of the 
investigator introduce unacceptable radiation risks for the patient, when being 
accumulated with the radiological examinations planned in this study. 
4.3. 
Strategy for recruitment and retention 
It is intended to enroll 10 evaluable patients. A patient is considered evaluable once he/she 
underwent the implant surgery with NVDX3. Non-evaluable patients will be replaced. 
No specific recruitment activities are envisioned. 
4.4. 
Participant withdrawal or termination 
4.4.1. 
Reason for withdrawal or termination 
All patient included will be followed for safety and efficacy assessments throughout the 
complete duration of the study unless the patient withdraws his/her consent. The patient and/or 
legal guardian(s) are free to withdraw from participation in the trial at any time without prejudice 
to their continued care and without any need for justification. 
 
3 an effective method of birth control is defined as a method which results in a failure rate of less than 1% per year such as 
combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, 
intravaginal, transdermal), Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, 
implantable), Intrauterine device (IUD), Intrauterine hormone-releasing system (IUS), Bilateral tubal occlusion, Vasectomised 
partner (provided that partner is the sole sexual partner of the trial participant and that the surgical success of vasectomy has 
been confirmed), Sexual abstinence  
 

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A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons. 
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
Participants should be withdrawn from the study if any of the following events occur: 
1. Participant develops an illness that would interfere with his/her continued participation. 
2. Participant is noncompliant with the study procedures or medications in the opinion of the 
investigator. 
3. Participant takes prohibited concomitant medications (that are not prescribed by the 
investigator) as defined in this protocol. 
4. Participant withdraws his/her consent. 
5. There is confirmation of a pregnancy during the study, as evidenced by a positive pregnancy 
test. 
6. The sponsor or a regulatory agency requests withdrawal of the participant. 
 
Note: An eligible study participant who withdraw or was withdrawn from the study will not be 
replaced  
4.4.2. 
Handling of participant withdrawals or early termination 
The Investigator should document the primary reason for a patient´s premature withdrawal from 
the trial, in the patient file and in the electronic Case Report Form (eCRF). Every effort must be 
made to perform the protocol-specified safety follow-up procedures to capture AEs and serious 
adverse events (SAEs) for the whole duration of the study. Refer to section 6.1.4  
4.5. 
Lost to follow up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
 The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible, counsel the participant on the importance of maintaining the assigned visit schedule 
and ascertain whether or not the participant wishes to and/or should continue in the study. 
 Before a participant is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the participant (at least 3 attempts including 1 phone call 
and 1 written message to the participant) and document his/her effort (date and summary of 
the phone call and copy of the written message in the source documents) to complete the 
final evaluation. All results of these evaluations and observations, together with a narrative 
description of the reason(s) for removing the participant, must be recorded in the source 
documents. The eCRF must document the primary reason for withdrawal. 

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Should the participant continue to be unreachable, he/she will be considered to have withdrawn 
from the study with a primary reason of lost to follow-up documented in the eCRF. 
 
4.6. 
Premature termination or suspension of study 
This study may be temporarily hold or prematurely terminated if there is sufficient reasonable 
cause.  
Section 8.3 describes the study halting rules, specifying the number of adverse events, as well as 
the nature and/or the severity of events, that would trigger the temporary suspension of the study, 
pending a safety investigation and potential subsequent premature termination of the study.   
Written notification, documenting the reason for study suspension or termination, will be 
provided to all involved parties. 
Study may resume once concerns about safety, protocol compliance, data quality are addressed 
and satisfy the IEC and CA. 
 
4.7. 
Definition Start and End of the trial 
The start of the trial is defined as the first patient first visit (FPFV) in the trial. 
The end of the trial is defined as completion of the last visit of the last patient (LPLV) in the 
trial. 

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5. 
STUDY TREATMENT 
5.1. 
Study treatment and control description 
Intervention name 
NVDX3 
Dose formulation 
Vial  
Unit dose Weight  
4g +/- 0.1g of dry powder 
Dosage level(s) 
Max 1 unit dose 
Route of administration 
Implant surgery  
Use 
Experimental 
IMP and NIMP 
IMP 
Sourcing 
Provided by Novadip Biosciences  
Packaging and labeling 
The IMP will be manufactured, packaged, and labeled according to 
Good Manufacturing Practice guidelines and in accordance with all 
applicable laws or regulations.  
Each IMP carton will be labeled according to the country 
requirements.  
Details of the packaging and labeling will be provided in the 
“NVDX3-CLN01 IMP Handling Manual” 
5.1.1. 
Formulation, appearance, packaging and labeling 
The active ingredient in the NVDX3 drug substance (DS) is a lyophilized powder composed of 
hydroxyapatite/beta-tricalcium phosphate (HA/TCP) particles embedded in an ECM, 
biologically active growth factors and non-viable osteogenic cells.   
The NVDX3 powder is presented in a vial (primary package) placed in a plastic bag (secondary 
package), both sterilized by gamma radiation.  
5.1.2. 
Product storage and stability 
NVDX3 vial should be stored at room temperature (15-25°C). 
 
 
 
The investigator or designee must confirm at receipt of the IMP the intactness of the vial and 
check that the temperature conditions have been maintained during transit, report any 
discrepancies and wait for further instructions by the Sponsor before using the IMP. All IMPs 
must be stored in a secure, controlled, and monitored area in accordance with the storage 
conditions, with access limited to the investigator and/or authorized site staff. 

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Any quality concern related to an IMP or temperature exposure must be immediately reported as 
per “NVDX3Handling Manual”. 
5.1.3. 
Preparation 
Before use/prior to implantation, the content of the vial 
 
must be reconstituted aseptically by the surgeon 
 
 
  
5.1.4. 
Dosing 
The total administered quantity of NVDX3 will depend on the bone defect size but cannot 
exceed the maximum reconstituted implant volume
 
 
 
5.1.5. 
Route of administration/ applied surgical technique 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 

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5.1.6. 
Duration of therapy trial treatment 
NVDX3 is administered during a single surgical intervention. 
5.2. 
IMP accountability  
The investigator is responsible for the IMP accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition of used/unused records). 
The volume of NVDX3 implanted will be estimated during the surgery and by using post-op CT 
scans. 
Refer to the “NVDX3-CLN01 IMP Handling Manual” for complete process description. 
 
5.3. 
Prohibited medications, treatments, and procedures 
Prohibited medications as per exclusion criteria are: 
 
Chronic, currently ongoing or planned during course of the trial, use of any medications 
that in the opinion of the investigator might affect bone metabolism or the quality of bone 
formation such as bisphosphonates, steroids, methotrexate, anticoagulant therapies, 
immunosuppressant therapy, or immunotherapy. 
 
The addition of any bone enhancing pharmacological agents (e.g., autogenous 
recombinant human bone morphogenetic protein-2), bone scaffolds/carriers or autologous 
bone, in addition to the NVDX3 graft, is not allowed. 

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6.1.1. 
Screening visit  
 Eligibility check  
 Medical history, including diabetes and osteoporosis status  
 Target DRF fracture classification according to the Distal Fracture Classification systems 
(Appendix 1)  
 Physical examination: (Refer to section 8.1.1) 
 NRS-pain (which will also be used as the reference NRS-pain to which the follow-up 
patient reported outcomes (PRO) will be compared) 
 
Screen failures  
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently enrolled in the study   
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened if the reason for failure has been resolved at the time of rescreening.  
Participants who have laboratory values that are marginally outside the defined range(s) for 
inclusion in the study may have those tests repeated once, if there is realistic chance of 
normalization having occurred. This should be discussed with the Sponsor Study Physician.  
6.1.2. 
Implant Surgery  
 For the standardized surgical technique and ostheosynthesis materials used please refer to 
section 5.1.5 and 0 

 
 
 
 
 
 
 
 
 Record (serious) adverse events as reported by the patient or observed by the investigator 
(including abnormal radiological observations). 
 Record changes in concomitant medication as reported by the patient or prescribed by the 
investigator 
6.1.3. 
Hospital discharge visit 
The timing of the hospital discharge is at the PI’s discretion taking into account the patient status. 
In case of any adverse events leading to hospital prolongation for any medical reason, a SAE 
should be completed. 

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This visit is considered as the reference timepoint for the safety and radiological and clinical 
efficacy (PRO and physician-based assessment) timepoints  
6.1.4. 
(Early) Termination visit 
If a patient ends the study prematurely (before 12 month Follow-up visit), either on own decision 
(withdrawal of IC or for any other reason), by decision of the investigator, for any other reason 
like lost to FU, or resulting from a halting rule and/or subsequent decision to terminate the study 
(described in more detail by the Safety Monitoring Plan) this  early termination should be reported 
through the completion of the “End-of study Form” including the following information: 
 Date of termination 
 Reason for termination 
 If lost to follow-up, a formal confirmation of the 3 contact attempts should be documented 
 
6.1.5. 
Unscheduled visit 
Additional visits as per standard of care (e.g., visits with the anesthesiologist before or after the 
orthopedic surgery, additional safety visit including blood sampling) are not part of the study 
schedule. Except for the reportable safety events (see safety reporting section for more instructions), 
non-safety related data generated during those unscheduled visits will not be recorded. 
 

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7. 
EFFICACY ASSESSMENTS AND- PROCEDURES 
7.1. Study procedures/evaluations 
Consecutive study visits, including clinical efficacy assessments should be conducted by the same 
clinician, in order to standardize that evaluation and reduce background noise (bias) as far as 
possible.  
The patient-reported outcome (PRO) questionnaires should be completed by the patient in a quiet 
place prior to any discussion regarding study-related issues, disease status, or treatment effect with 
the investigator/site staff. The PROs will be completed by the study participant on paper at the 
site, during study visits. The PROs and physician completed questionnaire should be checked for 
completeness by the clinical staff. 
7.1.1. 
Grip strength test 
Grip strength will be measured by using an hydraulic hand dynamometer with the elbow flexed 90 
and the forearm in neutral rotation. Values are expressed as the percentage of the strength on the 
contralateral (uninjured) side.  
7.1.2. 
Physician reported Modified Mayo Wrist Score 
The Modified Mayo Wrist Score (MMWS) is a modification of the Geen and O'Brien score 
(Appendix 4). There is a total of 100 points which are divided among the evaluator's assessment 
of pain (25 points), active flexion/extension arc as a percentage of the opposite side (25 points), 
grip strength as a percentage of the opposite side (25 points), and the ability to return to regular 
employment or activities (25 points). 
Pain is rated as none (25 points), mild (20 points), moderate (10 points), or severe (0 points) by 
the evaluator, based on the patient's subjective description.  
The total score ranges from 0 to 100 points with higher scores indicating a better result. An 
excellent result is defined as 90–100 points, good is 80–89, fair is 65–79 points, and poor is less 
than 65 points. 
7.1.3. 
Patient reported Numeric Rating Scale for pain 
Numerical rating scales (NRSs) are the simplest and most commonly used scales. The numerical 
scale is most commonly 0 to 10, with 0 being “no pain” and 10 being “the worst pain imaginable.” 
The patient draws a circle around the number that best describes the pain dimension, usually 
intensity. Advantages of NRSs include simplicity, reproducibility, easy comprehensibility, and 
sensitivity to small changes in pain35.  
For more details, please refer to Appendix 5. 

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7.1.4. 
Patient Reported Wrist Evaluation 
The PRWE is a 15-item questionnaire designed to measure wrist pain and disability in activities of 
daily living. The PRWE allows patients to rate their levels of wrist pain and disability from 0 to 
10, and consists of 2 subscales: 
 Pain subscale: contains 5 items each of which is further rated from 1-10. The maximum 
score in this section is 50 and minimum 0 
 Function subscale: contains total 10 items which are further divided into 2 sections i.e 
specific activities (having 6 items) and usual activities (having 4 items). The maximum 
score in this section is 50 and minimum 0. 
For more details, please refer to Appendix 6. 
7.1.5. 
Efficacy assessment by the independent central radiologists 
Besides bone formation, bone remodeling and bone union will be assessed as described in more 
detail in the Appendix 8 and/or the “Imaging Reading Manual”.  

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8. 
SAFETY ASSESSMENTS AND PROCEDURES 
8.1. Specification of safety parameters 
8.1.1. Physical examination 
A brief physical examination will include the assessments of the skin, respiratory system, 
cardiovascular system, and abdomen (liver and spleen). 
 Height and weight will also be measured, Body mass index is to be calculated and 
recorded. 
 Algodystrophy evaluation: Assessment of complex regional pain syndrome using the 
Budapest criteria 
 Skin inspection of the affected arm, in order to evaluate the potential surgical site 
infections 
o Skin color (Pale/cyanotic/other) 
o Signs of local infection (yes/no) 
o Swelling (oedema) (yes/no) 
o Arm temperature (Normal/cold/hot) 
Clinically relevant findings or worsening of previous findings will be recorded as AEs. 
8.1.2. Vital signs 
Body temperature, pulse rate, respiratory rate, and BP will be assessed. 
BP and pulse measurements will be assessed after 5 minutes of rest in a supine position (in a quiet 
setting without distractions such as a television or cell phones) with a completely automated 
device. Manual techniques will be used only if an automated device is not available. 
Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse and 
3 BP measurements (3 consecutive BP readings will be recorded at intervals of at least 1 minute). 
The average of the 3 BP readings will be recorded on the eCRF. 
8.1.3. Electrocardiograms 
Triplicate 12-lead ECG will be obtained as outlined in the Schedule of Activities  
All ECG recordings should be taken with the study participant resting in the supine position for at 
least 5 minutes before the recording. 
When ECG recording coincides with other, potentially disturbing procedures (such as blood 
sampling) the ECG should always be performed first, if at all possible. 
8.1.4. Clinical laboratory evaluations 
Clinical Laboratory will be obtained as outlined in the Schedule of Activities. 
List of clinical laboratory tests to be performed are: 
 

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 Hematology (Heamoglobin, Heamatocrit, Red blood cells, white blood cells, platelets, 
neutrophils, eosinophils, basophils, lymphocytes, monocytes and erythrocyte 
sedimentation rate) 
 Coagulation (activated partial thromboplastin time, prothrombin time-INR (Quick) (PT-
INR), Fibrinogen) 
 Biochemistry (NA+, K+, CL-, AST, ALT, AP, GGT, total protein, total bilirubin, CRP, 
Uric acid, LDH, CK, Glucose, Ca++, Phosphorus, TSH, Vit D) 
 Serology (at screening only): HIV, Hepatitis B and C (HBV& HBC) 
Blood testing is required up to 6 weeks post-grafting surgery supporting the evaluation of acute 
toxicity. 
However, upon any suspicion of a safety related issue the investigator needs to define, upon his 
medical judgement, if any required laboratory analysis should be required. All ad-hoc clinically 
significant out of range laboratory assessments, will be recorded though (S)AE reporting. 
The total amount of blood planned to be collected over the duration of the study will be 
approximately 300cc.  
8.1.5. Specimen preparation, handling, and storage 
All blood laboratory evaluations will be performed by the local laboratory in accordance with its 
standard of care preparation (including required blood volumes, the type and number of blood 
sampling tubes and other blood sampling materials), handling and storage procedures. 
All samples will be discarded after analysis and results records 
8.1.6. Safety assessment by local radiologist  
In order to identify potential safety signals, the local radiologist, at each study visit involving 
imaging needs to fill the safety questionnaire, as outlined in appendix 7. All potential safety 
findings need to be entered into the patient file and clinically relevant observations should be 
recorded though the (S)AE reporting. 
8.1.7. Adverse Events and Serious Adverse Events  
Definition adverse events (AE) 
Adverse event means any untoward medical occurrence associated with the use of an intervention 
in humans, whether or not considered intervention-related  
An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject 
administered the NVDX3 therapy and which does not necessarily have to have a causal 
relationship with this treatment 
Events meeting the AE definition: 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (e.g., radiological acquisitions, vital signs measurements), including those 

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that worsen from baseline, considered clinically significant in the medical and scientific 
judgment of the Principal Investigator (e.g. not related to progression of underlying disease). 
 Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
 New conditions detected or diagnosed after trial treatment administration even though it may 
have been present before the start of the trial. 
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 
Events NOT meeting the AE definition: 
 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Principal Investigator to be more severe than expected for the patient’s condition. 
 The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the patient’s condition. 
 Medical or surgical procedure (e.g. endoscopy, appendectomy): the condition that leads to the 
procedure is the AE. 
 Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
 Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the trial that do not worsen. 
 Pregnancy  
Definition of serious adverse events (SAE) 
A serious adverse event (AE) or suspected adverse event/reaction is any untoward medical 
occurrence that at any dose, in the view of either the Principal Investigator or the Sponsor, it 
results in any of the following outcomes:  
 Death 
 A life-threatening adverse event 
 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the patient 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
 Inpatient hospitalization or prolongation of existing hospitalization 
 
In general, hospitalization signifies that the patient has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment 
that would not have been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to 
whether “hospitalization” occurred or was necessary, the AE should be considered serious. 

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Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.  
 
Planned hospital stays would not be counted as SAEs, nor would stays in hospital for “social 
reasons” (e.g., respite care, the fact that there is no-one at home to care for the patient). 
 A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
 The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle) which may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption. 
 A congenital anomaly/birth defect 
 Any medically significant events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient and may require medical or surgical treatment to prevent one 
of the outcomes listed in this definition. 
 
Examples of such events include, but are not limited to, potential Hy’s law, invasive or 
malignant cancers, intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse 
 
Treatment Emergent AEs  
A Treatment-emergent adverse event (TEAE) is defined as an event that emerges after the 
NVDX3 was implanted, having been absent pre-implant surgery, or worsens relative to the pre-
implant state. 
 

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AE of Special Interest (AESI) 
The following adverse events will be considered as of special interest: 
 Hypersensitivity reaction 
 Immunological reaction 
 An AE requiring immunosuppressive medication 
 Ectopic bone formation 
 Tumor formation 
 Treatment failure: 
o Continued non-union/Non-fusion 
o Refracture of the targeted area 
o Revision surgery/intervention including removal of NVD-X3 
o Any other condition considered by the treating physician as treatment failure 
Reportable AESI 
An AESI that is assessed by the PI as possibly, probably or definitely related to NVDX3 is defined 
as a reportable AESI (rAESI) and will be evaluated throughout the same process as a SAE ( see 
section 8.2.5) 
 
AE classification 
a) Severity of the AE 
 Severity of adverse events (AEs) is assessed as follows: 
 Grade 1 - Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.  
 Grade 2 - Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL).  
 Grade 3 - Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL.  
 Grade 4 - Life-threatening consequences; urgent intervention indicated.  
 Grade 5 - Death related to AE. 
 
 

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b) Relationship to the NVDX3 treatment 
All adverse events (AEs) must have their relationship to the NVDX3 treatment (relatedness to the 
NVDX3 implant, the NVDX3 implant procedure and other study or non-study related procedures) 
assessed by the Principal Investigator who examines and evaluates the patient based on the 
Investigator Brochure, the temporal relationship of the event and his/her clinical judgment. 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors will 
be considered and investigated. The degree of certainty about causality will be graded using the 
categories below. 
For each AE/SAE, the Principal Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
There may be situations in which an SAE has occurred, and the Principal Investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important that the 
Principal Investigator always assesses the causality for every event before the initial transmission 
of the SAE data to the Sponsor. The Principal Investigator may change in the eCRF his/her 
opinion of causality in light of follow-up information: a SAE follow-up report with the updated 
causality assessment will be recorded in the eCRF. 
As part of medical review, the causal relationship will also be assessed by the safety officer of the 
Sponsor or his delegate. 
c) Expectedness 
An SAE will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the risk information previously described for NVDX3. The ‘expectedness’ of a 
serious adverse reaction (SAR) is assessed in the light of the reference safety information (RSI) 
included in the latest version of the approved Investigator Brochure. 
8.2. 
Safety Reporting procedures 
8.2.1. Time period and frequency for collecting AE/SAE information  
All AEs and SAEs will be collected from the signing of the ICF until the (early) Termination Visit 
at the time points specified in the Schedule of Activities (Section 6.1). 
Any medical condition that is present at the time of the patient’s screening will be considered as 
baseline and not reported as an AE. However, if the trial patient’s condition deteriorates at any 
time during the trial, it will be recorded as an AE.  
Changes in the severity of an AE/SAE will be documented to allow an assessment of the duration 
of the event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
Investigators are not obliged to actively seek AE or SAE in patients after their final discharge 
from the study. However, if the Principal Investigator learns of any SAE, including a death, at any 
time after a patient has been discharged from the trial, and he/she considers the event to be 
reasonably related to NVDX3 or trial participation, the Principal Investigator must promptly 
notify the Sponsor or designee.  

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Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of an IMP 
under clinical investigation are met. 
 
8.2.2. Detection of AE/SAE information  
AEs and SAEs may come to the attention of trial personnel during trial visits and interviews of the 
patient, his/her parent(s) and/or legal guardian(s) presenting for medical care, or upon review by a 
trial monitor.  
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the patient is the preferred method to inquire about AE occurrences. 
 
8.2.3. Follow-up of AE/SAE information 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts.  
All SAEs, and non-serious related AEs (excluding unlike related events) will be followed until 
resolution, stabilization, the investigator determines that it is no longer clinically significant, the 
event is otherwise explained, or the participant is lost to follow-up.  
 
8.2.4. Adverse Event reporting 
When an AE occurs, the Principal Investigator, or defined delegate(s), will review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics reports) related to 
the event and record all relevant AE information in the eCRF.  
All AEs including local and systemic reactions not meeting the criteria for SAEs will be 
captured on the case report form (eCRF) within 5 working days of event awareness. 
 Information to be collected includes event description, time of onset, investigator’s assessment of 
severity, relationship to surgical procedures and trial product (assessed only by those with the 
training and authority to make a diagnosis), and time of resolution/stabilization of the event.  
AEs occurring while on trial must be documented appropriately regardless of relationship.  
8.2.5. Serious Adverse Event and reportable AESI reporting 
The Principal Investigator is responsible to report to the Sponsor, all SAEs and reportable AESI ( 
rAESI) within 24 hours after obtaining knowledge of the event, whether or not considered trial 
treatment related.  
SAE and rAESI will be reported electronically through completion of the electronic safety form 
(eCRF).  
Note: An Initial notification via telephone does not replace the need for the investigator to 
complete and sign the safety CRF pages  

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Other supporting documentation of the event may be requested by the Sponsor or designee and 
should be provided as soon as possible. Hospital or patient records, attached to the safety form, 
need to be anonymized and proper identification (patient number) needs to replace the identifiers. 
All SAEs/rAESIs and updated SAE/rAESI data will be recorded and reported to the 
Sponsor, or designee, within 24 hours after obtaining knowledge of the event or updated 
information  
After the trial is completed at a given site, the electronic data collection tool will be taken off-line 
to prevent the entry of new data or changes to existing data. If a site staff receives information 
about a new safety from a trial patient or receives updated data on a previously reported SAE 
/rAESI after the electronic data collection tool has been taken off-line, the site can report this 
information to the Sponsor or designee on a paper safety form. 
 
8.3. 
 Study Halting rules  
As a consequent to the nature of the product, implanted through a single administration surgical 
intervention, study halting rules will only be applicable during the period between the first 
patient implant and last patient implant surgery visit. After completion of the last implant 
surgery, no more new patients will be added, and all implanted patients will need to be 
followed for safety for the whole study period. 
During this period, important safety events resulting from any study procedure, including NVDX3 
implant surgery, may temporarily suspend or prematurely terminate any planned surgical 
interventions or new study enrolment.  
Written notification, documenting the reason for trial suspension or termination, will be provided 
by the suspending, or terminating party to investigators, the Sponsor and regulatory authorities. 
Halting the study will allow time to review the safety concerns with CA/IEC and consider if is 
possible to construct a path forward. Trial may resume once concerns about safety, protocol 
compliance, and data quality are addressed, and satisfy the IEC and/or regulatory authorities.  
If the trial is prematurely terminated or suspended, the Principal Investigator will promptly inform 
the patients, the IEC, and the Sponsor will provide the reason(s) for the termination or suspension 
to the regulatory authorities. The parent(s) or the legal guardian(s) of the patient will be contacted, 
as applicable, and be informed of changes to trial visit schedule. 
If an event, corresponding to the above-mentioned study halting rules, occurs beyond the above-
mentioned period the study will not be halted as all 10 recruited patients have been implanted with 
NVDX3 and continued safety surveillance must be guaranteed. All concerned parties will be 
notified promptly in accordance with the drug safety reporting requirements, allowing proper 
review evaluation of the events and eventually decide on the path forward in the best interest of 
the patient. 
8.4. 
Safety Oversight 
A detailed overview of the roles and responsibilities, the safety process and timelines are detailed 
in the “Safety Monitoring Plan”. 

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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical and analytical plans 
A Statistical Analysis Plan (SAP) will be prepared to precisely define the final statistical analysis 
of the data. The SAP will be based on the study protocol and will be in compliance with ICH E9. 
9.2. 
Statistical Hypothesis 
Only descriptive statistics will be used.  
9.3. 
Analysis Datasets 
A Safety Set will include all patients treated with study medication. 
An Efficacy Set will include patients satisfying all inclusion criteria and none of the exclusion 
criteria and for whom any efficacy assessment is available. 
9.4. 
Description of statistical methods 
9.4.1. 
General Approach 
Descriptive statistics will be used throughout all the analyses.  
Continuous variables will be summarized using the mean, standard deviation, median, and range.  
Categorical variables will be summarized using frequency counts and percentages. 
9.4.2. 
Analysis of the (primary) safety endpoint(s) 
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA). The 
frequency, causal relationship, expectedness and severity of AEs and SAEs will be summarized 
for the overall study period and for the following treatment phases: 
 Acute phase: IS till 6 weeks post-IS (V5 included) 
 Long term phase: beyond 6 weeks post-IS (V5 excluded) till study completion (completion 
V8 or early termination whichever comes first) 
 
Besides a listing including all SAEs and NVDX3 related AEs occurring between screening (V1) 
and 12-months post-IS (Primary endpoint) tables will be generated for: 
 All TEAEs and SAEs summarized by System Organ Class (SOC) and Preferred Term (PT) 
 All related TEAEs and SAEs (according to the Principal Investigator) summarized by 
SOC and PT 
 All related TEAEs and SAEs (according to the sponsor) summarized by SOC and PT 
 All TEAEs and SAEs summarized by SOC, PT, and highest severity 
 All unexpected SAEs summarized by SOC and PT 

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 All AESIs and rAESIs summarized by SOC and PT 
 
More details on the descriptive tables will be given in the SAP. 
9.4.3. 
Analysis of the secondary endpoint(s) 
The analysis of secondary endpoints will be described in the SAP (same for exploratory 
endpoints) 
9.4.4. 
Analysis of the exploratory endpoint(s) 
 
 
9.4.5. 
Baseline and follow-up descriptive statistics 
Descriptive baseline characteristics will be listed. 
Concomitant medications will be tabulated and listed by International Nonproprietary Names 
(INN). Additionally, pain medication will also be listed separately in view of its importance for 
the clinical outcomes. 
9.4.6. 
Planned interim analyses 
Safety and efficacy analysis might be performed as needed on a patient-by-patient level. Interim 
descriptive study analysis can be initiated to support safety, scientific and regulatory needs at any 
time 
9.4.7. 
Tabulation of individual response data 
Individual patient data listings will be produced in accordance with ICH/E3 guidelines. 
9.5. 
Sample size 
No formal sample size calculation has been performed for this study since no formal hypothesis 
will have to be tested. However, as this is an early phase Proof of Concept study, the number of 
patients was limited to 10 individuals36. 
9.6. 
Measures to minimize bias 
To minimize bias, some potential variables have been standardized: 
 Centralized Image Reading  
 Maximum 2 sites, one orthopeadic surgeon per site performing the intervention (limit large 
inter-site and inter-surgeon variabilities)  
 Implant surgery:  
 The applied surgical technique and type of osteosynthesis devices has been 
standardized 
 Maximum volume of NVDX3 is fixed 
 

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10. 
CLINICAL MONITORING 
Site monitoring is conducted to ensure that the rights and well-being of trial patients are protected, 
that the reported trial data are accurate, complete, and verifiable, and that the conduct of the trial 
is in compliance with the currently approved protocol/amendment(s), with ICH E6 GCP current 
version including GCP for ATMPs and with applicable regulatory requirement(s).  
The Sponsor’s monitor or representative is responsible for the eCRF review at regular intervals 
throughout the trial to ensure adherence to the protocol and all applicable regulations on the 
conduct of clinical research. The monitor should have access to patients’ medical records and any 
other study -related records needed to verify the entries in the eCRF. 
The investigator(s)/institution(s) will permit trial-related monitoring, audits, IEC review, and 
regulatory inspection(s), providing direct access to source data/documents. 
It is important that the Principal Investigator and other trial personnel are available during the 
monitoring visits and that sufficient time is devoted to the process. The Principal Investigator 
agrees to cooperate with the monitor to ensure that any problems detected during the course of 
these monitoring visits are resolved. 
Details of site monitoring are documented in a Trial Monitoring Plan (TMP). The TMP describes 
in detail who will conduct the monitoring, at what frequency monitoring will be done, at what 
level of detail monitoring will be performed, and the distribution of monitoring reports. 
Independent audits may be conducted to ensure monitoring practices are performed consistently 
across all participating sites and that monitors are following the TMP. 

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11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
Source documents 
Source documents (paper or electronic) are those in which patient data are recorded and 
documented for the first time, including any copies of transcriptions that are certified as per GCP 
definition after verification as being accurate and complete.  
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the 
Principal Investigator. The Principal Investigator is responsible for ensuring the timeliness of the 
data reported and ensuring that the source data are attributable, legible, contemporaneous, 
original, accurate, and complete (ALCOAC principles) to ensure accurate interpretation of data. 
The Principal Investigator must list the location and the responsible person for the collection of 
the source data that will be used for data entry in the eCRF. This list must be signed and dated by 
the Principal Investigator before the start of the screening period. 
If required, in order to support the sites, hardcopies of the trial visit worksheets may be developed 
by the site for use as source document worksheets for recording data for each patient enrolled in 
the trial if not collected in the medical file.  Data recorded in the electronic case report form 
(eCRF) derived from source documents should be consistent with the data recorded on the source 
documents.  
The following data are source data in addition to the regular patient’s medical file: 
 Signed informed consent form (ICF) 
 Printouts of electronic devices 
 Laboratory reports 
 Study logs 
 
The scope of the Source Data Verification (SDV) is regulated in the Trial Monitoring Plan set up 
for this clinical trial. Source documents that are required to verify the validity and completeness of 
data entered in the eCRFs must not be obliterated or destroyed. 
The electronic clinical data system includes password protection and internal quality checks, such 
as automatic range checks, to identify data that appear inconsistent, incomplete, or inaccurate.  
 
Use of a site electronic system 
When clinical observations are entered directly into a site’s computerized medical record system (e.g. in 
lieu of original hardcopy records, which is not the Sponsor’s eCRF), the electronic record can 
serve as the source document if the system has been validated in accordance with health authority 
requirements pertaining to computerized systems used in clinical research.  An acceptable 
computerized data collection system allows preservation of the original entry of data.  If original 
data are modified, the system should maintain a viewable audit trail that shows the original data as 
well as the reason for the change, name of the person making the change, and date of the change. 
PI should provide adequate documented evidence on the validation process for electronic 
computerized systems used at hospital. 

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12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
The Sponsor is committed to ensure internal quality management of trial conduct, data and 
biological specimen collection, documentation and completion in accordance with the Quality 
Management System. 
Quality Control (QC) 
QC procedures will be implemented beginning with the data entry system and data QC checks that 
will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the site(s) for clarification/resolution. 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical 
trial is conducted, and data are generated (including radiological image acquisitions) and 
biological specimens are collected, documented (recorded), and reported in compliance with the 
protocol, with ICH E6 GCP current version including GCP for ATMPs and with applicable 
regulatory requirement(s).  
The site will provide direct access to all trial related source data/documents, and reports for the 
purpose of monitoring and auditing by the Sponsor, and inspection by local and regulatory 
authorities. 
In addition, an individualized quality management plan is developed for each Service Provider 
contracted by the Sponsor for the management of the trial. 
Quality Assurance (QA)  
ICH E6 GCP guidelines state that independent audits and inspections of clinical trials should be 
performed based on risk assessment. It is the responsibility of the Principal Investigator and trial 
staff to ensure all trial related documentation is filed accurately and to make this available to the 
Sponsor or designee, regulatory agencies, providing direct access to source data/documents. 
On-Site Audits 
In accordance with ICH E6 GCP and the Sponsor or designee’s audit plans, this trial may be 
selected for an audit. Inspection of site facilities (e.g. drug storage areas, laboratories) and review 
of trial related records may occur in order to evaluate the trial conduct and compliance with the 
protocol, ICH E6 GCP, and applicable regulatory requirements. 
The Principal Investigator will permit an independent audit by an auditor mandated by the 
Sponsor, after reasonable notice. An audit or a regulatory inspection is intended to determine if 
the trial was conducted as per protocol, ICH E6 GCP, and applicable regulatory requirements; if 
the rights and well-being of the patients were protected; and if the data relevant for the evaluation 
of the Investigational Medicinal Product (IMP) were captured, processed and reported in 
compliance with the planned arrangements. 
Regulatory authorities may perform an inspection of the trial until several years after its 
completion. As for an audit, the Principal Investigator will permit a direct access to all trial 
documents, IMP accountability records, source records, and source data. If an inspection is 
announced, the Sponsor must be informed without delay (by addressing this occurrence to 
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13. 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
13.1. 
Ethical standard 
The investigator will ensure that this study is conducted in full conformity with Regulations for 
the Protection of Human Subjects of Research codified in with ICH E6 GCP current version 
including GCP for ATMPs and with applicable regulatory requirement(s).  
13.2. 
 Ethics Committee 
This study is performed in Luxemburg only  
This clinical study is conducted after review and approval by the competent Luxembourg 
authority (Luxembourg Ministry of Health), and favorable opinion from the National Research 
Ethics Committee (CNER). 
The protocol, informed consent form(s), and all patient materials will be submitted to the IEC for 
review and favorable opinion   
Approval of both the protocol and the consent form must be obtained before any patient is 
enrolled. Any amendment to the protocol will require review and approval before the changes are 
implemented to the study. All changes to the consent form will be approved; a determination will 
be made regarding whether previously consented patients need to be re-consented. 
13.3. 
Informed consent process 
The Informed Consent Form (ICF) will include consent to participate in trial procedures, 
including all the surgical interventions (IS) as defined by ICH E6 GCP and applicable regulatory 
requirements. 
Prior to the start of the study at a site, the Principal Investigator must have obtained the IEC 
written approval/favorable opinion on the written ICF and on any other written information to be 
provided to the patient  
The written approval of the IEC together with the approved ICF must be filed in the study files 
and a copy of these documents must also be provided to the Sponsor. 
Obtaining informed consent is a process that is initiated prior to the participation of the patient in 
the trial and continues throughout the patient’s trial participation. 
The Principal Investigator or his/her delegate will explain the research purpose of the trial to the 
patient or its legal guardian(s) and answer any questions that may arise. A verbal explanation will 
be provided in terms suited to the patient/legal guardian(s)’s comprehension of the purposes, 
procedures, and potential risks of the trial and of the rights of the study participant.   
The patients or the legal representative(s) will have the opportunity to carefully review the ICF 
and can ask questions prior to confirming patient’s participation. The patient, if appropriate, 
and/or the legal representative(s) should have the opportunity to discuss the trial with their family 
or surrogates or think about it prior to agreeing to participate.  
The patient or the representative(s) will sign the ICF prior to any trial related procedures being 
started. The ICF is signed by the Principal Investigator or his representative. 

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The patient or the representative(s) must be informed that participation is voluntary and that he 
may withdraw from the trial at any time,without any need for justification and without prejudice.  
In addition, the patient and/or the representative(s) have to authorize in writing that the patient’s 
source records may be reviewed by third parties, such as a Sponsor representative, an auditor, or a 
regulatory inspector in accordance with applicable regulatory requirements.  
The ICF and any accompanied document (in accordance with regulations specified under section 
12.4) has to describe in detail how and to whom and for what purpose the personal data will be 
transmitted. 
A copy of the signed ICF will be given to the patient or the representative(s) for their records.  
The informed consent process will be documented in the source document (including the consent), 
and the form(s) signed before the patient undergoes any trial-specific procedures.  
The rights and welfare of the patient will be protected by emphasizing that the quality of the 
patient’s medical care will not be adversely affected if the patient or the legal guardian(s) decline 
to participate in this trial. 
13.4. 
Patient and data confidentiality 
Data Protection 
Sponsor staff (or designee) will affirm and uphold the participant’s confidentiality. Throughout 
this study, all data forwarded to the Sponsor (or designee) will be identified only by the 
participant number assigned at Screening. 
The investigator agrees that representatives of the Sponsor, its designee, representatives of the 
relevant IRB/IEC, or representatives of regulatory authorities will be allowed to review that 
portion of the participant’s primary medical records that directly concerns this study (including, 
but not limited to, laboratory test result reports, ECG reports, admission/discharge summaries for 
hospital admissions occurring during a participant’s study participation, and autopsy reports for 
deaths occurring during the study). 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with GDPR and all applicable privacy laws. The level of disclosure must 
also be explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities/Data protection authorities. 
Patient personal data 
Patient’s research data shall be adequate, relevant, and not excessive in relation to the purposes for 
which they are processed.  

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The processing4 of the personal data for scientific research purposes is subject to appropriate 
safeguards according to national/regional patient data protection legislations. 
As concerns the patient’s identification in the eCRF: 
Each patient will be identified in the clinical trial records by a unique trial identification number 
that includes several letters and digits, representing the screening number. The digits will not 
contain any number that could indirectly identify the patient such as his/her medical dossier 
number, social security number, etc. The initials of the patient will not be collected in the clinical 
trial records.  
The partial birth date (limited to month and year) will be collected in the clinical trial records to 
determine the approximate age of the patient.  
Sponsor’s responsibilities 
The Sponsor shall comply with all relevant national/regional patient data protection requirements 
laid applicable legislations, including GDPR in EU. 
Through the Informed Consent Form, the Sponsor shall inform (legal representatives of) the 
patients in the trial about their privacy rights to understand and control how their health 
information is used and shared, including rights to examine and obtain a copy of their health 
records as well as to request corrections. 
The Sponsor may transfer patient’s research data to a third country or an international 
organization in accordance with applicable legislation where the patients are enrolled. No 
information concerning the trial, or the data will be released to any unauthorized third party 
without prior written approval of the Sponsor. 
Investigators and research staff’s responsibilities 
Patient confidentiality and privacy are strictly held in trust by the participating investigators and 
their staff. This confidentiality is extended to cover all testing of biological samples in addition to 
the clinical information relating to patients. Therefore, the trial protocol, documentation, data, and 
all other information generated will be held in strict confidence by the site trial team. 
To comply with the national/regional patient data protection legislations, the Investigators and 
research staff undertake to: 
 Inform the parent(s) or the legal guardian(s) and the patient him/herself if applicable 
(age based) about his/her data protection rights and retain evidence of communication 
thereof.  
 Provide the parent(s) or the legal guardian(s) and the patient him/herself if applicable 
(age based) with evidence of communication when such evidence are requested either 
by the Sponsor and/or any legitimate authority. 
 Apply pseudonymization of patient’s research data prior to transmitting data as defined 
by the Sponsor. 
 
4 Processing patient’s research data concerns any operation that affects the data from a clinical trial during its entire 
life cycle, from its collection by the sites as source data to its reporting, archival and destruction. 

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 Maintain all documents and records including but not limited to, medical records 
(office, clinic, or hospital) and pharmacy records for the patients in this trial which 
may be subject to review by the trial monitor, other authorized representatives of the 
Sponsor, representatives of the IEC and regulatory agencies. The site will permit 
access to such records. 
 Store securely the trial patient’s contact information for internal use during the trial. At 
the end of the trial, all records will continue to be kept in a secure location for as long a 
period as dictated by the reviewing IEC, Institutional policies, Sponsor requirements or 
the applicable law. 
 Notify the defined Sponsor’s contact (specified in a mutual Site Agreement) about 
 any research data protection issue or breach upon awareness 
 any patient’s request to exercise his/her rights on research data 
 Notifying the concerned patient(s) as per local site’s data protection procedure about 
research data protection breach, whenever confirmed by the Sponsor. 
13.5. 
Future use of stored specimens 
 All blood samples are analyzed by the investigational site facilities and will not be 
stored. The overage (residuals) of IMP NVDX3 not being used during the surgery of 
the patient must be destroyed at the site according to local destruction procedure.  

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14. 
DATA HANDLING AND RECORD KEEPING 
14.1. 
Data collection and management responsibilities 
Data collected for this trial will be analyzed and stored at the Service Provider(s) designated by 
the Sponsor. After the trial is completed, the pseudonymized data will be transmitted to and stored 
at the Sponsor. Information about collected and transmitted data will be included in the 
Information for patients/parents/Legal guardians regarding the processing of the patient’s personal 
data. 
14.2. 
Study records retention 
Trial documents should be retained for 30 years after the closure of the trial according to the 
Guidelines on Good Clinical Practice specific to Advanced Therapy Medicinal Products (C(2019) 
7140 final) (ATMPs - EU specific terminology for, among others, stem cell therapy) dated 10-
Oct-2019.  
No records will be destroyed without the written consent of the Sponsor, if applicable. After the 
required retention period has expired, the site shall provide the Sponsor with a written notice at 
the latest 60 calendar days before destroying any of the Trial Deliverables, or in accordance with 
the site clinical trial agreement. The Sponsor will notify the Principal Investigator or the site when 
any records may be discarded. 
14.3. 
Protocol deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, ICH E6 GCP, 
Guidelines on Good Clinical Practice specific to Advanced Therapy Medicinal Products (C(2019) 
7140 final) or applicable regulatory requirements. The noncompliance may be either on the part of 
the patient, the investigator, or the site staff. As a result of deviations, a root cause analysis needs 
to be performed and a corrective and preventive actions are to be developed by the site and 
implemented promptly.  
These practices are consistent with the following sections of the ICH GCP E6 guidelines:  
 4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
 5.1 Quality Assurance and Quality Control, section 5.1.1  
 5.20 Noncompliance, sections 5.20.1, and 5.20.2. 
It is the responsibility of the Principal Investigator to use continuous vigilance to identify and 
report deviations within 1 working day of identification of the protocol deviation.  All deviations 
must be addressed in trial source documents.   
Protocol deviations (including deviations that might introduce additional patients safety risks) 
must be sent to the reviewing Independent Ethics Committee (IEC) and Luxemburg  Ministry of 
Health as per their policies. The Principal Investigator is responsible for knowing and adhering to 
the reviewing IEC requirements. 
 Further details about the handling of protocol deviations will be included in the Protocol 
Deviation Plan. The list of deviations will be provided to the site on an ongoing basis. 

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14.4. 
Publication and data sharing policy 
This trial will be conducted in accordance with the following publication and data sharing policies 
and regulations: 
All the relevant data and information will be reported in a Clinical Study Report (CSR) on safety 
and efficacy data of the trial, of all enrolled patients. 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 

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15. 
SERVICE PROVIDER MANAGEMENT 
The Sponsor will work in collaboration with different service providers supporting data and safety 
management (including statistics, medical writing, central image reading), medical and site 
monitoring. A service providers log, including names, contact details and responsibilities, is 
maintained and available in the clinical study documentation (available in the investigator site file 
and trial master file).  

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16. 
CONFLICT OF INTEREST POLICY 
The independence of this trial from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed. Furthermore, persons who have a perceived conflict of interest will be required to have 
such conflicts managed in a way that is appropriate to their participation in the design and conduct 
of this trial.  
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the trial and for 1 year after 
completion of the trial. 
The Sponsor has established policies and procedures for all trial group members to disclose all 
conflicts of interest and established a mechanism for the management of all reported dualities of 
interest. 
 

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17. 
REFERENCES CITED 
1. 
Court-Brown CM, Caesar B. Epidemiology of adult fractures: A review. Injury. 
2006;37(8):691-697. 
2. 
Chaudhry H, Kleinlugtenbelt YV, Mundi R, Ristevski B, Goslings JC, Bhandari M. Are 
Volar Locking Plates Superior to Percutaneous K-wires for Distal Radius Fractures? A 
Meta-analysis. Clin Orthop Relat Res. 2015;473(9):3017-3027. 
3. 
Chen NC, Jupiter JB. Management of distal radial fractures. J Bone Joint Surg Am. 
2007;89(9):2051-2062. 
4. 
Kreder HJ, Hanel DP, McKee M, Jupiter J, McGillivary G, Swiontkowski MF. 
Consistency of AO fracture classification for the distal radius. J Bone Joint Surg Br. 
1996;78(5):726-731. 
5. 
Frykman G. Fracture of the distal radius including sequelae--shoulder-hand-finger 
syndrome, disturbance in the distal radio-ulnar joint and impairment of nerve function. A 
clinical and experimental study. Acta Orthop Scand. 1967:Suppl 108:103+. 
6. 
Isani A, Melone CP, Jr. Classification and management of intra-articular fractures of the 
distal radius. Hand Clin. 1988;4(3):349-360. 
7. 
Fernandez DL. Distal radius fracture: the rationale of a classification. Chir Main. 
2001;20(6):411-425. 
8. 
Rhee SH, Kim J. Distal radius fracture metaphyseal comminution: a new radiographic 
parameter for quantifying, the metaphyseal collapse ratio (MCR). Orthop Traumatol Surg 
Res. 2013;99(6):713-718. 
9. 
Thuysbaert G, Ringburg A, Petronilia S, Vanden Berghe A, Hollevoet N. Measurement of 
ulnar variance and radial inclination on X-rays of healed distal radius fractures. With the 
axis of the distal radius or ulna? Acta Orthop Belg. 2015;81(2):308-314. 
10. 
Medoff RJ. Essential radiographic evaluation for distal radius fractures. Hand Clin. 
2005;21(3):279-288. 
11. 
Goldfarb CA, Yin Y, Gilula LA, Fisher AJ, Boyer MI. Wrist fractures: what the clinician 
wants to know. Radiology. 2001;219(1):11-28. 
12. 
Lichtman DM, Bindra RR, Boyer MI, et al. Treatment of distal radius fractures. J Am 
Acad Orthop Surg. 2010;18(3):180-189. 
13. 
Lichtman DM, Bindra RR, Boyer MI, et al. American Academy of Orthopaedic Surgeons 
clinical practice guideline on: the treatment of distal radius fractures. J Bone Joint Surg 
Am. 2011;93(8):775-778. 
14. 
Beyer J, Wynkoop E, Liu J, Ebraheim NA. Interventions for Distal Radius Fractures: A 
Meta-analysis of Comparison Studies. J Wrist Surg. 2021;10(5):440-457. 
15. 
Arrington ED, Smith WJ, Chambers HG, Bucknell AL, Davino NA. Complications of iliac 
crest bone graft harvesting. Clin Orthop Relat Res. 1996(329):300-309. 
16. 
Oryan A, Alidadi S, Moshiri A, Maffulli N. Bone regenerative medicine: classic options, 
novel strategies, and future directions. J Orthop Surg Res. 2014;9(1):18. 
17. 
Campana V, Milano G, Pagano E, et al. Bone substitutes in orthopaedic surgery: from 
basic science to clinical practice. J Mater Sci Mater Med. 2014;25(10):2445-2461. 
18. 
Dilogo IH, Mujadid F, Nurhayati RW, Kurniawan A. Evaluation of bone marrow-derived 
mesenchymal stem cell quality from patients with congenital pseudoarthrosis of the tibia. J 
Orthop Surg Res. 2018;13(1):266. 

Protocol NVDX3-CLN01
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19. 
Giannoudis PV, Einhorn TA, Marsh D. Fracture healing: the diamond concept. Injury. 
2007;38 Suppl 4:S3-6. 
20. 
Seigerman D, Lutsky K, Fletcher D, et al. Complications in the Management of Distal 
Radius Fractures: How Do We Avoid them? Curr Rev Musculoskelet Med. 
2019;12(2):204-212. 
21. 
Ajeesh M, Francis BF, Annie J, Harikrishna Varma PR. Nano iron oxide-hydroxyapatite 
composite ceramics with enhanced radiopacity. J Mater Sci Mater Med. 2010;21(5):1427-
1434. 
22. 
Saltybaeva N, Jafari ME, Hupfer M, Kalender WA. Estimates of effective dose for CT 
scans of the lower extremities. Radiology. 2014;273(1):153-159. 
23. 
Biswas D, Bible JE, Bohan M, Simpson AK, Whang PG, Grauer JN. Radiation exposure 
from musculoskeletal computerized tomographic scans. J Bone Joint Surg Am. 
2009;91(8):1882-1889. 
24. 
Koivisto J, van Eijnatten M, Kiljunen T, Shi XQ, Wolff J. Effective Radiation Dose in the 
Wrist Resulting from a Radiographic Device, Two CBCT Devices and One MSCT Device: 
A Comparative Study. Radiat Prot Dosimetry. 2018;179(1):58-68. 
25. 
Zenner J, Hitzl W, Mayer M, Koller H. Analysis of postoperative pain at the anterior iliac 
crest harvest site: a prospective study of the intraoperative local administration of 
ropivacaine. Asian Spine J. 2015;9(1):39-46. 
26. 
Kim DH, Rhim R, Li L, et al. Prospective study of iliac crest bone graft harvest site pain 
and morbidity. Spine J. 2009;9(11):886-892. 
27. 
Armaghani SJ, Even JL, Zern EK, Braly BA, Kang JD, Devin CJ. The Evaluation of 
Donor Site Pain After Harvest of Tricortical Anterior Iliac Crest Bone Graft for Spinal 
Surgery: A Prospective Study. Spine (Phila Pa 1976). 2016;41(4):E191-196. 
28. 
Willcox MJ. Lumbar Herniation of Kidney following Iliac Crest Bone Harvest. Case Rep 
Surg. 2016;2016:5365647. 
29. 
Fasolis M, Boffano P, Ramieri G. Morbidity associated with anterior iliac crest bone graft. 
Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;114(5):586-591. 
30. 
Zermatten P, Wettstein M. Iliac wing fracture following graft harvesting from the anterior 
iliac crest: literature review based on a case report. Orthop Traumatol Surg Res. 
2012;98(1):114-117. 
31. 
Boehm E, Minkus M, Moroder P, Scheibel M. Massive graft resorption after iliac crest 
allograft reconstruction for glenoid bone loss in recurrent anterior shoulder instability. 
Arch Orthop Trauma Surg. 2020;140(7):895-903. 
32. 
Conti Mica MA, Bindra R, Moran SL. Anatomic considerations when performing the 
modified Henry approach for exposure of distal radius fractures. J Orthop. 
2017;14(1):104-107. 
33. 
Perugia D, Guzzini M, Mazza D, Iorio C, Civitenga C, Ferretti A. Comparison between 
Carbon-Peek volar locking plates and titanium volar locking plates in the treatment of 
distal radius fractures. Injury. 2017;48 Suppl 3:S24-S29. 
34. 
Chloros GD, Prodromidis AD, Wilson J, Giannoudis PV. Fracture fixation in extremity 
trauma with carbon fiber-reinforced polyetheretherketone (CFR-PEEK) plates: evidence 
today. Eur J Trauma Emerg Surg. 2022;48(3):2387-2406. 
35. 
Walton DM, Elliott JM, Salim S, Al-Nasri I. A reconceptualization of the pain numeric 
rating scale: Anchors and clinically important differences. J Hand Ther. 2018;31(2):179-
183. 

Protocol NVDX3-CLN01
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36. 
Shen J, Swift B, Mamelok R, Pine S, Sinclair J, Attar M. Design and Conduct 
Considerations for First-in-Human Trials. Clin Transl Sci. 2019;12(1):6-19. 
37. 
Goo HW, Goo JM. Dual-Energy CT: New Horizon in Medical Imaging. Korean J Radiol. 
2017;18(4):555-569. 
38. 
Katsura M, Sato J, Akahane M, Kunimatsu A, Abe O. Current and Novel Techniques for 
Metal Artifact Reduction at CT: Practical Guide for Radiologists. Radiographics. 
2018;38(2):450-461. 
39. 
Guggenberger R, Winklhofer S, Osterhoff G, et al. Metallic artefact reduction with 
monoenergetic dual-energy CT: systematic ex vivo evaluation of posterior spinal fusion 
implants from various vendors and different spine levels. Eur Radiol. 2012;22(11):2357-
2364. 
40. 
Thomas C, Patschan O, Ketelsen D, et al. Dual-energy CT for the characterization of 
urinary calculi: In vitro and in vivo evaluation of a low-dose scanning protocol. Eur 
Radiol. 2009;19(6):1553-1559. 
41. 
Van Hedent S, Su KH, Jordan DW, et al. Improving Bone Mineral Density Assessment 
Using Spectral Detector CT. J Clin Densitom. 2019;22(3):374-381. 
42. 
Kawahara D, Ozawa S, Yokomachi K, et al. Synthesized effective atomic numbers for 
commercially available dual-energy CT. Rep Pract Oncol Radiother. 2020;25(4):692-697. 
43. 
Gomez-Barrena E, Padilla-Eguiluz NG, Garcia-Rey E, et al. Validation of a long bone 
fracture non-union healing score after treatment with mesenchymal stromal cells combined 
to biomaterials. Injury. 2020;51 Suppl 1:S55-S62. 
44. 
Lane JM, Sandhu HS. Current approaches to experimental bone grafting. Orthop Clin 
North Am. 1987;18(2):213-225. 
45. 
Tawonsawatruk T, Hamilton DF, Simpson AH. Validation of the use of radiographic 
fracture-healing scores in a small animal model. J Orthop Res. 2014;32(9):1117-1119. 
 

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APPENDICES 
APPENDIX 1: Distal Radius Fracture Classification systems 
AO/OTA Classification of Fractures and Dislocations:  
23A 
Extraarticular Fracture 
23A1 
Ulna fractured; radius intact 
23A2 
Radius, simple and impacted 
23A3 
Radius, multifragmentary 
23B 
Partial articular fracture of radius 
23B1 
Sagittal 
23B2 
Coronal, dorsal rim 
23B3 
Coronal, palmar rim 
23C 
Complete articular fracture of radius 
23C1 
Articular simple, metaphyseal simple 
23C2 
Articular simple, metaphyseal multifragmentary 
23C3 
Articular multifragmentary 
 
Frykman - Fracture 
Fractures 
Distal ulna fracture present 
Distal Ulna fracture absent 
Extra-Articular 
I 
II 
Intra-articular 
 
 
 
Radio-Carpal joint 
involved 
III 
IV 
 
Radio-Ulnar joint involved 
V 
VI 
 
Radio-Carpal and Radio-
Ulnar involved 
VII 
VIII 
 
Melone’s - intra-articular  
Fracture 
Description 
Type I 
Four components (radial shaft, radial styloid, dorsal medial and volar 
medial fragment) are undisplaced or show variable displacement of the 
medial complex as a unit. Such fractures show minimal comminution and 
are stable after closed reduction. 
Type II 
There is significant displacement of the medial complex as a unit with a 
communition of radial metaphysis and instability (the punch fracture) 
Type III 
Displacement and instability are similar to type II, with the spike fragment 
of the radial shaft often projection into the flexor compartment (spike 
fractures) 
Type IV 
There is severe disruption of the radial articular surface and the dorsal and 
volar medial fragments show wide separation or rotation. There are 
extensive soft tissue damage and nerve injury 
Type V 
Fracture results from a severe force comprising both compression and 
crush that cause extensive comminution, often extending from the articular 
surface of the diaphysis 
 
Fernandez - distal end 
Bending 
Metaphysis fails due to tensile stress (Colles’ and Smith fracture) 

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Compression 
Fracture of the surface of the joint with impaction of subchondral and 
metaphyseal bone (the punch fracture) 
Shearing 
Fracture of surface of the joint (Barton fracture and fracture of radial 
styloid process) 
Avulsion 
Fracture of ligamentous attachments (fracture of ulnar and radial styloid 
process) 
Combination 
Combination of (1) – (4) and high velocity injury 
 
 

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APPENDIX 2: Use of Dual Energy CT 37 
Conventional or single energy CT (SECT) utilizes a single polychromatic X-ray beam (ranging from 70 to 
140 kVp with a standard of 120 kVp) emitted from a single source and received by a single detector. The 
inherent contrast of the image dataset generated by this process depends on differences in photon 
attenuation of the various materials that constitute the human body (ie, soft tissue, air, calcium, fat). The 
degree that a material will attenuate the X-ray beam is dependent on (1) tissue composition and (2) photon 
energy level and how closely it exceeds the k-edge (ie, inner electron shell binding energy) of the material. 
Therefore, tissue attenuation can be manipulated by changing photon energy levels. In DECT, two energy 
levels (typically 80 and 140 kVp) are used to acquire images that can be processed to generate additional 
datasets allowing: 
 To reduce metal artifacts (induced by envisioned internal fixation devices) 
With dual-energy CT, creation of virtual monochromatic images at different kilovolt peak (photon 
energy) settings allow to freely select the optimal energy for maximum diagnostic image utility 
(usually between 40 and 140 keV). Researchers have evaluated the quality of virtual monochromatic 
images at different energy levels in several studies. Metal-artifact reduction with DECT has been 
extensively studies with all types of scanners Optimal keV level varies but is generally found to be 
effective between 100 and 160 keV 38,39. 
 To reduce beam hardening artifacts and improved CT-value stability 
Like any x-ray spectrum, the CT beam is composed of photons with a wide range of energies, with 
maximum energy expressed as the peak voltage (kilovolt peak, kVp). 
Beam hardening occurs due to a shift of the energy spectrum toward higher energies:  when traveling 
through a material, the low-energy photons of the polychromatic x-ray beams are preferentially 
attenuated, whereas the high-energy photons are not attenuated as easily. This will cause a shift of the 
CT-values (Hounsfield Units, HU) to lower numbers due to the fact that they are energy dependent: 
they represent the degree to which the X-ray intensity is reduced by the tissue. This effect will be 
amplified in the presence of metallic implants due to increased absorption of low energy photons. 
There are two important consequences of beam hardening for this study: firstly, the presence of dark 
bands in the vicinity of the metallic implant which can impair radiological evaluation (qualitatively), 
secondly a shift in HU values of the tissues which potentially impairs any reliable quantitative 
assessment of tissue density 39.  
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX 7: Safety assessments by local radiologist