Observational Retrospective Study to Assess the Clinical Benefit and Safety Profile of the Intramedullary Nail CHIMAERA in Adult Patient Who Have Suffered Pertrochanteric, Intertrochanteric and Subtrochanteric Fractures of the Femur in Daily Practice: CHIMAERA Study
Conditions: Pertrochanteric Fracture of Femur, Intertrochanteric Fracture of Femur, Subtrochanteric Fracture of Femur
Sponsor: Orthofix s.r.l.

 
CI code: OCI_2206 
CIP date: 13/07/2023 
CIP version: 1.0 
 
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1. 
CLINICAL INVESTIGATION PLAN IDENTIFICATION 
 
Clinical Investigation Plan (CIP) 
Post-Market Clinical Follow-up Observational Study  
 
13/07/2023 
 
 V1.0 
 
CI code: OCI_2206 
 
 
 
Observational retrospective study to assess the clinical benefit and safety profile 
of the intramedullary nail CHIMAERA in adult patient who have suffered 
pertrochanteric, intertrochanteric and subtrochanteric fractures of the femur in 
daily practice: CHIMAERA Study 
 
 
 
 
 
 
 
 
 
Confidential Material 
The information in this document is the property of Orthofix S.r.l. and is confidential. Neither the document 
nor the information contained therein be reproduced or disclosed outside Orthofix S.r.l. without the written 
consent of the company. 

 
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CIP AUTHORS / CONTRIBUTORS SIGNATURES PAGE  
 
Silvia Resimini  
Clinical Research Associate 
ORTHOFIX S.r.l 
 
 
 
 
 
 
 
Signature 
 
Date  
 
 
 
 
 
 
Daniela Cangiano 
 
Clinical Program Manager 
ORTHOFIX S.r.l 
 
 
 
 
 
 
 
Signature 
 
Date  
 
 
 
 
 
 
Diego Maisonave Berdasco 
 
Evidenze Generation Specialist 
Evidenze Health S.L 
 
 
 
 
 
 
 
Signature 
 
Date  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diego Maisonave (Jul 13, 2023 13:51 GMT+2)
Diego Maisonave
Jul 13, 2023
Silvia Resimini (Jul 13, 2023 14:15 GMT+2)
Silvia Resimini
Jul 13, 2023
Daniela Cangiano (Jul 13, 2023 14:17 GMT+2)
Daniela Cangiano
Jul 13, 2023

 
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INVESTIGATOR SIGNATURE PAGE 
 
By my signature below, I acknowledge that I have read this Clinical Investigation Plan and I agree that 
it contains all necessary details for carrying out the clinical investigation described therein. Furthermore, 
I agree to conduct this study in compliance with said Clinical Investigation Plan, the ICH Good Clinical 
Practice guideline, as well as with any and all applicable federal, state or local laws and regulations and 
with my contractual obligations towards Orthofix S.r.l. or its representatives. 
 
 
Site code: ITA01 
 
Principal Investigator:  
Roberto Civinini, Professor 
Director of Complex Orthopaedic SOD 
 
______________________________       __________________ 
 
 
 
 
 
 
 
 
Signature 
 
Date 
Site contact details: 
 
Investigation site: Azienda USL Toscana Centro 
Azienda Ospedaliero Universitaria Careggi 
Address: Largo Piero Palagi 1, 50139 - Firenze 
Phone: 055 / 794 111 
Email: roberto.civinini@unifi.it 
 
 
 

 
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2. 
CONTACT INFORMATION 
 
Sponsor  
Orthofix S.r.l.,  
Via Delle azioni 9, 37012 Bussolengo (Verona), Italy 
Contact Person: Edo Knijff 
email: edoknijff@orthofix.it 
Office landline: (+39) 045 6719 000 
 
SAE Reporting 
& Safety Related Issues   
Device Deficiency & 
Complaint Reporting  
 
safetyclinicalstudiesintl@orthofix.com 
  
complaintintl@orthofix.com 
 
 
 
 
CRO 
Evidenze Health S.r.l 
Viale Abruzzi 13/a 
20131 Milan, Italy 
Contact person: Marina Chiesa 
email: m.chiesa@evidenze.com 
Phone: (+39) 3459549489 
 
 
 
 

 
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Contributors: 
Study Physician (Study related questions)  
Name: 
Roberto Civinini, Professor 
Address: 
Largo Piero Palagi 1, 50139 - 
Firenze 
 
Phone: 
055 / 794 111 
 
email 
roberto.civinini@unifi.it 
 
Project Manager  
Name: 
Silvia Resimini 
 
Address:  
Via Delle Nazioni 9, 
Bussolengo (VR) Italy 
 
Phone: 
(+39) 045 6719 000 
 
Email: 
silviaresimini@orthofix.it 
 
Fax: 
 
(+39) 045/6719380 
 

 
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3. 
TABLE OF CONTENTS 
1. 
CLINICAL INVESTIGATION PLAN IDENTIFICATION ................................................................. 1 
2. 
CONTACT INFORMATION .................................................................................................................. 4 
3. 
TABLE OF CONTENTS .......................................................................................................................... 6 
4. 
LIST OF ABBREVIATIONS ................................................................................................................... 8 
5. 
SYNOPSIS ................................................................................................................................................. 9 
5.1 
Schematic Diagram ..................................................................................................... 14 
6. 
INTRODUCTION ................................................................................................................................... 15 
6.1 
Background Information .............................................................................................. 15 
6.2 
Rationale of the Clinical Investigation ......................................................................... 18 
7. 
STUDY OBJECTIVES ........................................................................................................................... 19 
7.1 
Primary Objective ........................................................................................................ 19 
7.2 
Secondary Objectives ................................................................................................. 19 
8. 
STUDY DESIGN ..................................................................................................................................... 19 
8.1 
Research Type ............................................................................................................ 19 
8.2 
Subjects and Sites Numbers ....................................................................................... 20 
8.3 
Study duration ............................................................................................................. 20 
8.4 
Measures to Minimize or Avoid Bias ........................................................................... 21 
8.5 
Prematurely End of the Study (EOS) .......................................................................... 21 
9. 
SELECTION AND WITHDRAWAL OF SUBJECTS ........................................................................ 22 
9.1 
Subject Inclusion Criteria ............................................................................................. 22 
9.2 
Subject Exclusion Criteria ........................................................................................... 22 
10. 
TREATMENT OF SUBJECTS .............................................................................................................. 22 
10.1 
Study Investigational Product(s) .................................................................................. 22 
10.1.1 
Intended purpose / Intended Use of the Investigational Device .................. 23 
10.2 
Application of the device ............................................................................................. 24 
11. 
STUDY PROCEDURES ......................................................................................................................... 24 
11.1 
Description of Procedures ........................................................................................... 24 
11.2 
Study data collection ................................................................................................... 25 
12. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS .............................................................. 26 
12.1 
Definitions .................................................................................................................... 26 
12.2 
Procedures for Reporting and Recording Adverse / Serious Adverse Events ............ 27 
12.3 
Assessment of causality .............................................................................................. 28 
12.4 
Assessment of expectedness ...................................................................................... 31 
13. 
STATISTICS ........................................................................................................................................... 31 
13.1 
Statistical and Analytical Plans .................................................................................... 31 
13.1.1 
Population(s) of analysis .............................................................................. 31 
13.1.2 
Efficacy, Safety and Other Variables ........................................................... 31 
13.1.2.1 
Efficacy Variables .................................................................... 31 
13.1.2.2 
Safety Variables ...................................................................... 32 
13.1.3 
Statistical Evaluation .................................................................................... 33 
13.1.3.1 
Evaluation of Efficacy .............................................................. 33 
13.1.3.2 
Evaluation of Safety ................................................................. 33 
13.2 
Determination of the Sample Size ............................................................................... 33 
13.3 
Changes in the Conduct of the Study or the Planned Analyses ................................. 34 
13.4 
Statistical and Analytical Issues .................................................................................. 34 
13.4.1 
Handling of Dropouts or Missing Data ......................................................... 34 

 
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13.4.2 
Interim Analysis ............................................................................................ 34 
14. 
ETHICS AND REGULATORY REQUIREMENTS ........................................................................... 34 
14.1 
Approval ...................................................................................................................... 34 
14.2 
Subject Information and Consent ................................................................................ 35 
14.3 
Subject Confidentiality ................................................................................................. 36 
14.4 
Informing the General Practitioner .............................................................................. 37 
15. 
STUDY MANAGEMENT AND ADMINISTRATION........................................................................ 38 
15.1 
Monitoring .................................................................................................................... 38 
15.2 
Direct Access to Source Data/Documents .................................................................. 38 
15.2.1 
Source Documents....................................................................................... 38 
15.2.2 
Source Data ................................................................................................. 38 
15.2.3 
Direct Access ............................................................................................... 38 
15.2.4 
Permission of Access ................................................................................... 38 
15.3 
Audit and Inspection .................................................................................................... 39 
15.4 
Patient Data collection ................................................................................................. 39 
15.5 
Adherence to Clinical Investigation Plan ..................................................................... 39 
15.6 
Investigator Site File .................................................................................................... 39 
15.7 
Data Handling .............................................................................................................. 40 
15.7.1 
Data management........................................................................................ 40 
15.7.2 
Quality assurance ........................................................................................ 41 
15.8 
Clinical Study Report ................................................................................................... 42 
15.9 
Archiving and Data Retention ...................................................................................... 42 
15.10 
Allocation of Responsibilities ....................................................................................... 42 
15.11 
Financial Disclosure .................................................................................................... 42 
15.12 
Disclosure of Clinical study Information and publication ............................................. 43 
16. 
REFERENCES ........................................................................................................................................ 44 
17. 
APPENDICES ......................................................................................................................................... 50 
17.1 
CASE REPORT FORM ............................................................................................... 50 
17.2 
Instructions for Use (ORTHOFIX CHIMAERA HIP FRACTURE SYSTEM 3
TROCHANTERIC NAILING SYSTEM TM) ................................................................... 51 
17.3 
IEC/IRB AGREEMENT ................................................................................................ 52 
17.4 
FINANCIAL SCHEDULE ............................................................................................. 53 
 
List of Figures 
Figure 5:1 
Study schematic diagram ....................................................................................... 14 
 
 
 
 
 
 
 

 
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4. 
LIST OF ABBREVIATIONS 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
ASADE 
Anticipated serious adverse device effect 
CI 
Confidence Interval 
CIP 
Clinical Investigation Plan 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
DHS 
Dynamic Hip Screw 
DPD 
Data Protection Delegate 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
IC 
Informed Consent 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC/IRB 
Independent Ethics Committee/Institutional Review Board 
IFU 
Instructions for Use 
MDD 
Medical Device Deficiency 
MDR 
Medical Device Regulation 
MR 
Magnetic Resonance 
PMCF 
Post Market Clinical Follow-up 
Q 
Quarter 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOP 
Standard Operating Procedure 
THA 
Total Hip Arthroplasty 
TMF 
Trial Master File 
USADE 
Unanticipated serious adverse device effect 
 

 
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5. 
SYNOPSIS 
 
TITLE 
Observational retrospective study to assess the clinical benefit and 
safety profile of the intramedullary nail CHIMAERA in adult patient who 
have suffered pertrochanteric, intertrochanteric and subtrochanteric 
fractures of the femur in daily practice: CHIMAERA Study 
ACRONYM 
CHIMAERA 
INVESTIGATIONAL 
DEVICE 
Orthofix® Chimaera Hip Fracture SystemTM  
PROCEDURES 
The CHIMERA study intends to evaluate the clinical benefits of the 
study medical/investigational device in the standard clinical practice. 
The study will be conducted in two sites located in Italy; both considered 
reference sites for the treatment of adult patients with pertrochanteric, 
intertrochanteric and subtrochanteric fractures of the femur, where the 
usage of Orthofix® Chimaera Hip Fracture SystemTM (from now on 
CHIMAERATM) was part of the normal clinical practice. 
The CHIMAERATM, is an internal fixation system intended intended for 
insertion into the medullary canal of a femur in individuals suffering from 
stable 
and 
unstable 
pertrochanteric, 
intertrochanteric 
and 
subtrochanteric fractures of the femur alone or when these fractures 
occur in combination with shaft fractures extending distally to a point 
approximately 10cm proximal to the intercondylar notch. 
The participant investigators will retrospectively include a maximum of 
44 patients meeting inclusion and exclusion criteria (considering an 
imprecision of 5%) that will contribute for approximately 44 patients in 
which CHIMAERATM was used.  
The study is designed to analyze medical records of adult patients who 
underwent CHIMAERATM implantation from 2018 to 2023 in the 
standard clinical practice setting.  
No diagnostic or therapeutic intervention outside routine clinical 
practice will be applied. 
At inclusion, data will be retrospectively collected from patient medical 
records since the surgery and up to 12 months follow-up after nail 
implant. No study visit will be performed.  
Medical records of the participating sites are expected to contain all the 
required information. Due to the pure retrospective design of the study 
with exclusive use of primary data sources, no study visit will be 
required but according to local legislation, it will be essential that before 
collecting any information from medical records, participants or their 
guardians are asked for specific informed consent to be signed by them 
before any collection of patient information takes place. 
PRIMARY OBJECTIVE 
The primary objective of this study is to evaluate the clinical benefit of 
the long variant of the CHIMAERATM used in adult patients according 
to the manufacturer Instructions For Use (IFU) in routine clinical 

 
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practice from the time of surgery within 12 months follow-up after nail 
implant.  
SECONDARY OBJECTIVE 
The secondary objective of this study is to evaluate the safety profile of 
the long variant of the CHIMAERATM used in adult patients according 
to the manufacturer IFU in routine clinical practice from the time of 
surgery until 6 months follow-up after nail implant.   
TYPE OF THE 
INVESTIGATION 
This clinical investigation is a post-market, retrospective, observational, 
multicenter study, namely a Post Market Clinical Follow-up (PMCF) 
study. By definition, it is designed as a single arm and will not involve 
randomization. 
PLANNED INVESTIGATION 
PERIOD  
Planned 
data 
collection 
3 months 
 
Start of data 
collection 
3Q 
2023 
 
End of data 
collection 
3Q 
2024 
 
STUDY DURATION PER 
SUBJECT 
Not applicable 
CENTER(S) 
/ COUNTRY(IES)  
 
Hospital 
 
Country 
(EU) 
 
City 
Principal Investigator 
2 
 
Italy 
Florence 
and Caserta 
Prof. Roberto Civinini 
and Dr Gaetano Bruno 
PATIENTS  
It is planned to include 44 patients from 2 sites in Italy. Clinical data will 
be collected only from patients with a regular indication for 
CHIMAERATM as per IFU (no off-label use will be included) and who 
underwent surgery performed with the specific device. 
INCLUSION CRITERIA 
Patients eligible for inclusion in this study must meet all of the following 
criteria: 
1. The patient expressed his willingness to participate in the Study 
by signing and dating informed consent.  
2. Patients who had a regular indication for surgical intervention with 
the long variant of CHIMAERATM according to the manufacturer9s 
IFU. 
3. Patients equal or older than 18 years at the time of surgery. 
4. Patients who underwent surgery performed with CHIMAERATM. 
5. Patients with clinical data registered in her/his medical records 
sufficient to assess the safety and efficacy endpoints of the study. 
EXCLUSION CRITERIA 
Patients eligible for inclusion in this study must not meet any of the 
following criteria: 
1. Patient who had/has a medical condition that is a contraindication 
according to the manufacturer9s IFU leaflet. 
2. Patient has been diagnosed with bilateral proximal femur fractures. 
3. Patient who needed the application of, or ha already in-situ a 
concomitant not permitted device which cannot be safely removed. 

 
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4. Patient with other concurrent medical or non-medical condition that 
in the opinion of the participating investigator may prevent 
participation or otherwise render the patient ineligible for the study. 
5. The patient is participating in other clinical studies, or he/she has 
participated in other clinical studies in the 3 months prior signing 
the informed consent  
CONCOMITANT 
MEDICATION/CON-
COMITANT DEVICE 
K-wires, bone graft and any other concomitant devices, i.e. bone 
screws, that were applied to fix any bone fragments but that were not 
considered critical for the maintenance of treated bone alignment, are 
permitted during the study. 
Examples of not permitted devices on the same CHIMAERATM-treated 
bone: plates providing fixation; external fixators; other intramedullary 
nails or elastic nails. 
It is understood that any necessary medical devices applied on any 
other bones than the one treated by CHIMAERATM are permitted. 
PRIMARY EFFICACY 
ENDPOINTS 
The clinical benefit of CHIMAERATM will be assessed by the percentage 
of patients in which bone union has been achieved within 12 months 
from the nail implant. 
The clinical benefit analysis will be performed in those patients who 
meet the following criteria:  
- 
Patient has achieved bone union at the 12 months follow-up 
visit and this is the only evaluation available.  
- 
Patient has achieved bone union at first follow-up this being the 
only evaluation available. 
- 
Patient has both bone union evaluations (first follow up visit and 
last follow up visit) completed and achieved bone union at the 
end of the follow-up period. (considered a responder) 
- 
Patient underwent reoperation but the reason for this was 
secondary dynamization. 
- 
Patient with fractures on the upper limbs not caused by the 
CHIMAERATM (e.g. simply stumbled or had a car accident) 
- 
Patient underwent reoperation after first bone union evaluation. 
- 
Patient who has not suffered contralateral leg fracture. 
- 
Patient in whom no refraction occurred where the nail was 
applied. 
 A double evaluation will be required (observer 1 and observer 2). Only 
if both evaluations are positive, the treatment goal will be considered 
achieved. 
SECONDARY 
TOLERABILITY / SAFETY 
ENDPOINTS 
The safety profile of CHIMAERATM will be assessed through the 
percentage of patients that required a reoperation (i.e., additional 
surgery) caused by at least one of the following safety events:  

 
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- 
Expected or unexpected adverse effect potentially or certainly 
related to the CHIMAERATM (Adverse Device Effects 
(ADEs)/Serious Adverse Device Effects (SADEs)) since the 
nail application until until 6 months follow-up after nail implant. 
- 
Medical Device Deficiency (MDDs) (i.e., breaking, loosening, 
or bending of the nail or of the screws) that caused an effect on 
the patient since the nail application until 6 months follow-up 
after nail implant. 
All the reoperations that have occurred are considered but also those 
that have not occurred but that could have occurred (e.g., a patient who 
had a cut out but for any reasons has not been operated). It should be 
considered also all ADE/SADE/MDD that could have caused an 
additional operation. 
STATISTICAL 
METHODOLOGY  
Sample size calculation: 
The sample size calculation is based on the number of patients that 
allow the consecution of the study primary objective: to evaluate the 
clinical benefit of the long variant of the CHIMAERATM used in adult 
patients according to the IFU in routine clinical practice from the time of 
surgery within 12 months follow-up after nail implant. The clinical 
benefit will be evaluated with the percentage of patients in which 
achieved bone union within 12 months from the nail implant.  
The scientific literature reports that the percentage of patients in which 
bone union rate was achieved is 98.3% (IC95% 93%-100%) (1-26). 
Assuming a bone union rate aligned or better than the weighted mean 
observed in literature (98.3%) with a confidence interval between 93% 
and 100% using a bilateral confidence interval with an alpha error of 
5%, a sample size among 120 and 44 patients would be needed to 
estimate this proportion with an imprecision of 5%. 
Table 1. Sample size considering different Expected Proportions 
Confidence Level 
Expected proportion 
Sample Size (N) 
95% 
93% 
120 
95% 
94% 
107 
95% 
95% 
94 
95% 
96% 
81 
95% 
97% 
98 
95% 
98.3% 
51 
95% 
99.9% 
44 
For this clinical study, the sample size of 44 patients was chosen. The 
choice is based on sales data and considering the available timeframe 
of implanted nails. The study is designed to analyze medical records of 
adult patients who underwent CHIMAERATM implantation from 2018 
to 2023 in the standard clinical practice setting. 
 
Statistical methodology: 

 
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Analysis will be performed using IBM SPSS Vs 22.0. When an 
inferential analysis is required, parametric tests will be used for 
continuous variables and nonparametric tests in the case of ordinal or 
categorical or nonparametric variables. All hypothesis tests will be two-
sided and with a significance level of 0.05. For variables not fitting a 
normal (or parametric) distribution, the Mann-Whitney test (for unpaired 
data) and the Wilcoxon test (paired data) will be used. Contingency 
tables and the comparison of proportions and/or frequency distributions 
will be analyzed using the chi-square test (or Fischer9s exact test when 
appropriate) will be used.  
Primary objective: the primary objective of this study is to evaluate the 
clinical benefit of the long variant of the CHIMAERATM used in adult 
patients according to the IFU in routine clinical practice from the time of 
surgery within 12 months follow-up after nail implant. 
It is required a double evaluation with two positive opinions from both 
observers (observer 1 and observer 2) to consider the treatment goal 
achieved.   
The number and percentage of patients in which bone union was 
achieved will be provided both as continuous and categorical variables. 
The 95% CI will also be presented. 
Secondary objective: to evaluate the safety profile of the long variant of 
the CHIMAERATM used in adult patients according to the manufacturer 
IFU in routine clinical practice from the time of surgery until 6 months 
follow-up after nail implant.   
The safety analysis will be performed in the <safety population= which 
includes all patients who have undergone an intramedullary nailing 
technique with the CHIMAERATM medical device.  
The number and percentage of patients that required a reoperation due 
to at least one ADE/SADE/MDD will be calculated with a 95% 
confidence interval (CI). An analysis will be carried out according to 
degree of severity, seriousness and relationship with the medical 
device. 
All the reoperations that have occurred are considered but also those 
that have not occurred but that could have occurred (e.g., a patient who 
had a cut out but for any reasons has not been operated). It should be 
considered also all ADE/SADE/MDD that could have caused an 
additional operation. Therefore, the number and percentage of patients 
that hypothetically would have caused a reoperation due to at least one 
safety event will be described and calculated with a 95% CI. 

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5.1 Schematic Diagram 
 
Figure 5:1 
Study schematic diagram 
 
 
 

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6. 
INTRODUCTION 
This document is a Clinical Investigation Plan for a human research study to be conducted 
according to the ethical principles set out in the Declaration of Helsinki, the International 
Conference on Harmonisation (ICH) Tripartite Harmonised Guidelines for Good Clinical 
Practice and the legislation and normative on Clinical Trials and Medical Devices (ISO14155: 
2020 regulating Clinical Investigation of Medical Devices for Human Subjects - Good Clinical 
Practice) (27), data protection (Regulation (EU) 2016/679 of the European Parliament and the 
Council, on 26 April 2016, GDPR first implemented on 25 May 2018), national and 
international regulations in force (the Medical Devices Regulation (MDR) (EU) 2017/745 of 5 
April 2017) and its guidelines as MDCG 2020-10/1 and any further local applicable regulations 
(28, 29). 
6.1 Background Information   
Bone fractures are most common in youth and in the elderly, with differences in incidence over 
time and between regions. Of all the fractures recorded in older population, it is important to 
note that these occur mainly in the hip, affecting approximately 6% of the male population and 
18% of females.(30) With the rapid increase in the elderly population, the annual worldwide 
incidence of hip fractures is estimated to be up to 21.3 million by 2050.(31-40) Hip fractures 
have an incidence of approximately 1 per 1000 head of population in western countries and 
are associated with a very significant cost to any healthcare system.(37) The number of 
patients hospitalized due to hip fracture has been reported to be around 620,000 in the 
European Union.(41) 
Hip fracture is the general term for fracture of the proximal (upper) femur. These fractures can 
be subdivided into trochanteric, subtrochanteric, pertrochanteric and intertrochanteric 
fractures. These terms reflect the proximity of these fractures to the greater and lesser 
trochanters, which are two bony protuberances (bulges) at the upper end of the femur outside 
the joint capsule. (34, 42)  
The most common site was the intertrochanteric region which approximately accounted for 
50%. (33, 43-48) There is a 15% mortality rate among elderly patients with intertrochanteric 
fractures, which accounts for the highest mortality rate for all hip fractures among this age 
group.(49, 50) Subtrochanteric fractures involve the segment of the proximal femur from the 
lesser trochanter to the isthmus. The major fracture involves a zone between the inferior 
border of the lesser trochanter and the junction of the proximal and middle one third of the 
femur (approximately a 5-cm segment).(51-53) The subtrochanteric femoral fractures, which 
account for 10334% of all hip fractures. (51, 52, 54) Although subtrochanteric fractures are 
the least frequent type of hip fracture, they provide unique challenges because of the inherent 
instability of the fracture fragments. (40, 55) These fractures are notorious for intraoperative 
difficulty in reduction and post-operative complications like non-union and malunion.(47) 
Anatomically, surgical reduction is difficult in subtrochanteric fractures because of the muscles 
attached to fractured fragments generates various deforming forces.(56) 

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Underlying causes of hip fractures are most commonly low-energy trauma (e.g., falling), high-
energy trauma (e.g., traffic accidents) or pathological lesions (e.g., osteoporosis, cancer). 
Fractures caused by high‑energy injuries happen in both genders and in all ages. However, 
spontaneous fractures or fractures resulting from mild injuries are only found in older 
individuals. (57) Pathologic lesions affecting the skeletal system in adults are most often 
caused by metastatic disease, being the most common site outside of the axial skeleton, the 
femur (58). Another common cause of hip fracture events, particularly in older population, is 
osteoporosis. Osteoporosis is a group of bone disorders of diminished bone resorption due to 
osteoclastic abnormality resulting in hard and brittle bones.(59, 60) When pathologic femur 
fractures occur, they are associated with increases in morbidity and mortality. (58) 
Hip fractures are a leading cause of disability and mortality among adult population, with 1-
year mortality surpassing 20%. Survivors often experience diminished walking ability, reduced 
activities of daily living, and loss of independence. (30, 61, 62) Despite the development in 
implant technology and surgical techniques, the mortality rates remained similar: 24% in the 
1980s to 23% in the 1990s, and to 21% after 1999 (p = 0.7).(63) In addition to the direct 
economic impact of hip fracture treatment, there is a considerable societal impact because 
elderly hip fracture patients are at risk for increased rate of mortality, inability to return to prior 
living circumstances, the need for an increased level of care and supervision, decreased 
quality of life, decreased level of mobility and ambulation, and secondary osteoporotic 
fractures, including a second or contralateral side hip fracture. (64, 65) 
Therefore, due to the high incidence of hip fractures in adult population and the great economic 
and psychosocial burden it entails, it is important to treat them adequately. Currently, there 
are different treatment options, differentiating between non-operative treatment and operative 
treatment.  
Non-operative treatments are mainly focused on those patients who may be non-ambulatory, 
with valgus-impacted femoral neck fractures, or medically unfit for general anesthesia.(38) 
Most trochanteric fractures are usually non-operative since some parts of the trochanter and 
not all of it are involved, the abductor mechanism is usually not affected, reason why treatment 
is mainly symptomatic. (57) In subtrochanteric fractures is usually performed with traction by 
distal femur pin traction and formation of 90‑90 traction (hip and knee in 90° flexion) that is 
performed only on children and patients with medical comorbidities who do not tolerate surgery 
or general anesthesia. (57) Finally, for intertrochanteric fractures, a conservative treatment by 
immobilization carries the risk of high morbidity and mortality, so early surgical intervention is 
indicated for early mobilization and to increase survival rate.(66) 
To gain the safe mobility in early time, operative intervention, which can provide strength and 
stability of the fracture fixation, is the primary goal of treatment. (43) Among the operative 
treatments, we can highlight the plating systems, external fixation, Total Hip Arthroplasty 
(THA) and hemiarthoplasty, dynamic hip screw (DHS) and intramedullary nailing.  
The plating systems minimizes operative trauma by way of two small percutaneous portals, 
and small-diameter drilling prevents additional bone damage in the remaining lateral 

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trochanteric wall. (67) This device is indicated for the treatment of pertrochanteric and 
basicervical fractures with intact lateral walls, consisting of a plate of a predetermined length 
with three diaphyseal screws and two telescopic cervical screws angled at 135◦ to the plate to 
allow controlled fracture compression. The theoretical advantages of this design are the 
provision of rotational stability, by using two screws in the femoral neck, and a reduction in the 
lateral cortical damage, which can be created by a 12-mm single drill hole. (44, 68) 
External fixation was initially introduced for intertrochanteric fractures at about the same time 
as DHS was used, however, since the early results of external fixations were not so 
encouraging, the method was overshadowed by the use of DHS which had become the 
standard treatment in the last few decades.(69) Specific advantages of plate fixation include 
that the technique is simple, direct visual control of the fracture fragment and biomechanically 
more rigid fixation and stability which requires minimal postoperative immobilization (70, 71). 
Disadvantages include the direct approach to the fracture site increases the risk of infection, 
the scar is longer and subsequent lengthening maybe more common. Refracture may occur, 
as stress shielding results in thinning of the cortices. Removal of the material is associated 
with specific morbidity. (72) 
THA is an effective treatment for unstable intertrochanteric fracture with the loss of 
posteromedial cortex support, a fracture pattern that is unlikely to be reduced satisfactorily 
using a intramedullary nail, with serious osteoporosis; with ipsilateral femoral head necrosis 
or osteoarthritis.(73) In patients who are physiologically fit and have failed conservative 
management, THA can provide appropriate pain control and functional restoration. (74) If the 
patient is an independent individual and cooperative and has a normal pattern of daily living, 
THA will be performed, and if the patient is old with conscious disorder and is not cooperative 
and lives at home most of the time, hemiarthroplasty would be a suitable treatment. (57) 
Complications after conversion THA after previous fracture fixation are, predictably, higher 
than in cases of primary THA. In the perioperative period, patients have longer surgeries, with 
greater blood loss and longer hospital stays. In the postoperative period, instability, heterotopic 
ossification, infection, leg length discrepancy, nerve injury, and loosening have been the major 
reported complications. (74) 
DHS is an extramedullary fixation system, which consist in an implant which has a nail, or 
screw, which is passed up the femoral neck to the femoral head, used most commonly in 
intertrochanteric fractures. (34, 75) These are considered 'dynamic' implants as they have the 
capacity for sliding at the plate/screw junction to allow for collapse at the fracture site.(34) For 
this conventional procedure, the lateral vastus muscle must be split broadly (10 cm), which is 
associated with significant soft tissue damage and inevitable blood loss, both of which may 
worsen multiple existing comorbidities of elderly patients. (44, 68)  
Intramedullary nailing of proximal femur fractures is characteristically performed via a 
cephalocondylic approach, with the insertion of a metal nail through the greater trochanter, 
but is also used for reverse oblique and unstable fractures. (76, 77) The biomechanical 
rationale of using the intramedullary nailing in unstable trochanteric fractures is that the weight-
bearing force acts through a shorter lever arm from the center of hip rotation, thereby placing 

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less stress on the implant. (78) Internal fixation is the treatment of choice for the 
subtrochanteric femoral fractures aiming to obtain the best stability for early mobilization and 
reduces the complications associated with prolonged recumbency with the maximum 
restoration of function. (54) Proximal femoral nail (PFN) and Gamma nail are two most 
commonly used devices in the intramedullary fixation. PFN has become prevalent in treatment 
of intertrochanteric fractures in recent years because it was improved by addition of an 
antirotation hip screw proximal to the main lag screw. However, both benefits and technical 
failures of PFN have been reported. (79-81) There is a debate on whether the short or long 
nails have been more beneficial for patients with hip fractures. Short nails are more cost-
effective and are associated with less operating room time and blood loss and ensuring a good 
biomechanical stability; however, lack adequate diaphyseal fixation leading to increased pain 
or fracture risk at the tip of the implant.(82-84) On the other hand, long nails may decrease 
periimplant fracture rate by spanning entire femoral diaphysis.(82, 83)  
Intramedullary nailing systems used for hip fracture are generally associated with improved 
functional outcomes compared to the baseline and comparable complication rates with the 
other treatment options. Several meta-analyses and systematic reviews demonstrated that, 
the intramedullary nailing is a safe and effective option for different hip fracture patterns with 
similar safety profile. In terms of clinical benefit, results shown a bone union range of 93%-
98% with an average of 98.3% while in terms of safety profile, results shown a range rate of 
reoperations due to ADEs/SADEs range of 0.0%-27.5% with an average of 5.9%. (1-26)  
6.2 Rationale of the Clinical Investigation 
CHIMAERATM is an internal fixation system designed for Intramedullary nailing fixation 
intended for insertion into the medullary canal of a femur in individuals suffering from stable 
and unstable pertrochanteric, intertrochanteric and subtrochanteric fractures of the femur.  
This study has been planned as part of the Orthofix S.r.l post-market active surveillance plan 
for data collection on both the clinical performance and the safety profile of the CHIMAERATM.  
The MDR (EU) 2017/745 states that demonstration of compliance with the general 
performance and safety should be based on clinical data that, for class II devices and 
implantable devices should, as a general rule, be sourced from clinical investigations that have 
been carried out under the responsibility of a sponsor (28) 
The rationale of the proposed study is to update and support the pre-market clinical evaluation 
of the CHIMAERATM with Real World Evidence clinical data in a real-life surgical setting, in 
order to confirm the benefit/risk ratio of this medical device in terms of clinical benefit and 
safety profile and to keep the CE mark under MDR requirements. 
 

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7. 
STUDY OBJECTIVES 
7.1 Primary Objective 
The primary objective of this study is to evaluate the clinical benefit of the long variant of the 
CHIMAERATM used in adult patients according to the manufacturer IFU in routine clinical 
practice from the time of surgery within 12 months follow-up after nail implant. 
7.2 Secondary Objectives 
The secondary objective of this study is to evaluate the safety profile of the long variant of the 
CHIMAERATM used in adult patients according to the manufacturer IFU in routine clinical 
practice since nail application until 6 months after nail implant.   
8. 
STUDY DESIGN 
8.1 Research Type  
The CHIMAERA study is designed as a retrospective, non-interventional, multicenter, PMCF 
study intended to evaluate both clinical benefit and safety profile of CHIMAERATM device in 
adult patients according to the manufacturer IFU in routine clinical practice.  
The study has been designed to retrospectively analyze the patient9s medical records of 
patients who underwent a surgical implantation of CHIMAERATM part of the site routine clinical 
practice. Data collection will be carried out during the study observation period, from the 
surgery until the last follow-up visit within 12-months after nail implant. Information will be 
collected from the different evaluations made by the subject in accordance with routine clinical 
practice, including the day of surgery, the hospital discharge, the bone consolidation 
assessment (1st follow up visit), the second follow up visit (2nd follow up visit), the last follow-
up visit (3rd follow up visit), and additional surgeries if it occurred within 12 months after nail 
implant. Surgeons belonging to the 2 study sites who will participate in the study must have 
full awareness of orthopedic fixation procedures and should be familiar with the devices, 
instruments and surgical procedure, including the application and removal. After reviewing the 
selection criteria and confirming patient eligibility, demographic, and clinical and safety 
information from the time of surgery until the last follow-up visit will be collected from medical 
records.  
To ensure the observational nature of the study, study data (demographics, clinical 
performance and safety data) will be collected from data already recorded in the medical 
records according to routine clinical practice. No diagnostic or therapeutic intervention outside 
of routine clinical practice will be applied.  
The use of primary data sources is justified since it can provide the information needed to 
answer the primary objective in a cost-effective manner and using already available data. 
Patients8 medical records are expected to contain all the required information. Due to the pure 

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retrospective design of the study with exclusive use of primary data sources, no study visit will 
be required, but according to local legislation, it will be essential that before collecting any 
information from medical records, participants or their guardians are asked for informed 
consent (IC). Once the IC is signed and the patient's eligibility is confirmed, the investigator 
will initiate accurate and appropriate data collection. 
Due to the retrospective nature of the study, the decision on the prescription of Intramedullary 
nailing technique with CHIMAERATM was under the discretion of the physician and it was made 
prior to the inclusion of the patient in the study. All participant patients had already undergone 
surgery through the intramedullary nailing technique using CHIMAERATM under clinical 
practice conditions. 
Individual patient data will be collected as pseudonymized in an electronic database designed 
specifically for this study. 
Data collection will be carried during 4Q 2023-1Q 2024. 
8.2 Subjects and Sites Numbers 
It is planned to include non-competitively a consecutively a maximum of 44 subjects meeting 
the inclusion and exclusion criteria (Considering an imprecision of 5%) in two investigational 
sites located both in Italy. Clinical data will be collected only on adult patients with a regular 
indication for the CHIMAERATM as per IFU (no off-label use will be included) and who 
underwent surgery performed with the specific device. 
8.3 Study duration 
The study will start in 4Q 2023, but these times may be modified by the administrative 
processing periods for initiation of the study. The enrollment period will be for 3 months, and 
the study will last approximately 6 months from the start of recruitment until the report of 
results. 
Start of data collection (Start of recruitment) 
4Q 2023 
End of data collection  
1Q 2024 
Database lock  
1Q 2024 
Statistical analysis 
2Q 2024 
Final report on operations and results 
2Q 2024 
Study duration  
12 months  
 

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8.4 Measures to Minimize or Avoid Bias 
The herein proposed study design presents some methodological limitations that deserve to 
be highlighted. First, this study was designed to collect available information derived from 
clinical practice, so some of the assessments might not be available for some participants or 
at certain evaluations. Therefore, a reporting bias could occur. This bias refers to errors 
introduced during the measurement of study variables, which may affect the study results and 
estimates. To minimize this risk of bias, unavailable data/assessments will be declared as 
unavailable and left as missing in the statistical analysis. However, it is expected that most of 
the data of interest in this study will be recorded in the medical records, as they are part of the 
usual clinical practice of these patients in Italy.  
In addition, the possible occurrence of selection bias cannot be ruled out. However, to 
minimize their occurrence, the investigator will begin inclusion of patients in the study with the 
last patient meeting the inclusion/exclusion criteria. It will then continue with the inclusion of 
patients meeting the inclusion/exclusion criteria following a chronological order prospectively 
over time according to the list of subjects with a regular indication for CHIMAERATM as per 
IFU.  
On the other hand, the fact that it is a multicenter study that includes information in different 
ways could generate variability in data collection between study sites and countries. This 
variability is part of real clinical practice and is therefore an intrinsic limitation of this type of 
study.  
Finally, like most observational studies, potential confounding bias should be considered. 
When an exposure of interest is strongly associated with another exposure that is also related 
to the outcome, confounding bias could exist. According to previous data obtained with the 
use of CHIMAERATM, in the present study it is expected that the results obtained from the 
primary endpoint regarding the clinical benefit will be in line with those obtained in previous 
studies in order to support the pre-market clinical evaluation of the CHIMAERATM with Real 
World Evidence clinical data in a real-life surgical setting confirming his benefit/risk ratio. 
8.5 Prematurely End of the Study (EOS) 
The end of study is defined as all close out visits and database lock performed.  
This study may be prematurely terminated by decision of the regulatory authorities or at the 
sponsor9s discretion. This decision will be communicated in writing to the investigator.  
The study sponsor has the right to replace a site at any time for poor recruitment, poor Clinical 
Investigation Plan adherence, inaccurate or incomplete data recording, noncompliance with 
the Guidelines for Good Pharmacoepidemiology Practice or any other pertinent local law or 
guideline.  
Likewise, if the investigator decides to withdraw from the study, he/she must notify the sponsor 
immediately in writing.  

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9. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
9.1 Subject Inclusion Criteria 
Patients eligible for inclusion in this study must meet all of the following criteria: 
1. Patients who had a regular indication for surgical intervention with the long variant of 
CHIMAERATM according to the manufacturer9s IFU. 
2. Patients equal or older than 18 years at the time of surgery. 
3. Patients who underwent surgery performed with CHIMAERATM. 
4. Patients with clinical data registered in her/his medical records sufficient to assess the 
safety and efficacy endpoints of the study. 
9.2 Subject Exclusion Criteria 
Patients eligible for inclusion in this study must not meet any of the following criteria: 
1. The patient expressed his willingness to participate in the Study by signing and dating 
informed consent.  
2. Patient who had/has a medical condition that is a contraindication according to the 
manufacturer9s instruction for use leaflet. 
3. Patient has been diagnosed with bilateral proximal femur fractures. 
4. Patient who needed the application of, or had already in-situ a concomitant not permitted 
device which cannot be safely removed. 
5. Patient with other concurrent medical or non-medical conditions that in the opinion of the 
participating investigator may prevent participation or otherwise render the patient 
ineligible for the study. 
6. The patient is participating in other clinical studies, or he/she has participated in other 
clinical studies in the 3 months prior signing the informed consent. 
10. 
TREATMENT OF SUBJECTS 
10.1 Study Investigational Product(s) 
The CHIMAERATM, is an internal fixation system intended for insertion into the medullary canal 
of a femur in individuals suffering from stable and unstable pertrochanteric, intertrochanteric 
and subtrochanteric fractures of the femur. Its unique and distinguishing feature is the 
revolutionary locking mechanism of the lag screw that efficiently secures it to the nail without 
the need for a set screw. This implant is composed by 2 nails of sterile titanium (1 short and 1 
long) with diameters of 10 and 11 mm for distal and 15.5 mm for proximal, differents lenghts 
comprises from 280 to 450 mm and with a 125° or 130° CCD angle in order to assure 
compatibility with patient anatomy. The device is also composed by end caps, lag screws, 

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threaded locking screw and an supplementary lag screw made all of stainless steel, aluminum 
alloy, carbon fiber, composite and plastic (85).  
It is a class I, IIa and IIb non-absorbable and long-term surgically invasive implantable device 
manufactured by Orthofix S.r.l that has been CE marketed since 2018. CHIMAERATM is 
intended for insertion into the medullary canal of a femur for the alignment, stabilization and 
fixation of various types of fractures of deformities. It is indicated for treatment of stable and 
unstable pertrochanteric, intertrochanteric and subtrochanteric fractures of the femur alone or 
when these fractures occur in combination with shaft fractures extending distally to a point 
approximately 10cm proximal to the intercondylar notch. These include traumatic fractures, 
re-fractures, non-union, reconstruction, malunion, malalignment, pathological fratures, and 
impending pathological fractures (86).  
The Use of the CHIMAERA™ is contraindicated for patients with general medical conditions 
not suitable for surgery, active or suspected latent infections in the fracture area and 
suspected or documented metal allergy or intolerance (86). 
Through the use experience of CHIMAERATM, the following adverse effects are registered: 
delayed union or non-union of the fracture site; breakage of the device when subjected to the 
increased loading with delayed union and/or non-unions, conditions attributable to non union 
(osteoporosis, osteomalicia, diabetes, inhibited revascularization and poor bone formation 
causing loosening, bending, cracking, fracture of the device or premature loss of rigid fixation 
with the bone); mal-union of the bone and/or bending, cracking or even breakage of the device 
due to improper alignment; increased fibrous tissue response around the fracture site due to 
unstable comminuted fractures; early or late infection, both deep or superficial; 
thromboembolic events; fat embolism; avascular necrosis; shortening of the effected 
bone/fracture site; subclinical nerve damage due to the surgical trauma; material sensitivity 
reactions in patients following surgical implantation. Further details are provided in the IFU 
(17.2) (86). 
CHIMAERATM nail has not been evaluated for safety and compatibility in the Magnetic 
Resonance (MR) environment. It has not been tested for heating, migration, or image artifact 
in the MR environment. The safety of CHIMAERATM nail in the MR environment is unknown. 
Scanning a patient who has this device may result in patient injury (85). 
10.1.1 
Intended purpose / Intended Use of the Investigational Device 
In this study, the intended use of CHIMAERATM is focused on adult patients that have been 
treated for of stable and unstable pertrochanteric, intertrochanteric and subtrochanteric 
fractures of the femur alone or when these fractures occur in combination with shaft fractures 
extending distally to a point approximately 10cm proximal to the intercondylar notch.  
The target population is broad, with no restrictions apart from those stated in the 
inclusion/exclusion criteria. Details on the routine intended purpose/use of CHIMAERATM are 
provided in the IFU (17.2) (86). 

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10.2 Application of the device 
The application of CHIMAERATM has been performed according to routine clinical practice, 
without restrictions derived from patient participation in the study. 
How to proceed in a particular surgery depends on the surgical requirements, where nails 
should be inserted depending on the bone to be treated, fracture severity, product knowdlege, 
the patient9s condition and surgeon9s experience. Details on the routine application of 
CHIMERATM are provided in the IFU (17.2) (86). 
For further information on CHIMAERATM nail, please refer to the Operative Technique 
published in: https://abscdn.orthofix.it/resources/HF-1501-OPT-E0.pdf (85). 
11. 
STUDY PROCEDURES 
11.1 Description of Procedures 
To ensure the observational nature of the study, all data will be collected if they are available 
in the patient9s medical record. The degree of detail and completeness of data collected will 
therefore be dependent on the availability of data in medical charts and the routine clinical 
practice of the two participating sites. There are no Clinical Investigation Plan visits imposed, 
or procedures outside the usual clinical practice to guarantee that the study does not modify 
in any way the healthcare professional prescription habits or his/her healthcare practice. 
Unavailable data/assessments will be stated in the electronic Case Report Form (eCRF) as 
not available. 
At the screening phase, only to patients who meet all inclusion and exclusion criteria the 
investigator will ask if he/she is willing to participate to the study and provide the Information 
sheet to the patient (and to the legal representative/guardian if applicable). Together with 
providing the Information sheet, the investigator (or an authorized designee) must also orally 
inform the patient (and the legal representative/guardian if applicable) about the objectives, 
procedures and duration of the study as well as the foreseeable risks and potential benefits 
deriving from participation in the same. 
According to local legislation, it will be essential that before collecting any information from 
patient9s medical records, participants or their guardians are asked for informed consent (IC). 
Once the IC is signed and the patient's eligibility is confirmed, the investigator will initiate 
accurate and appropriate data collection.  
Upon confirmation that the patient meets all the selection criteria, the physician participating 
in the study will proceed to extract the available study data (previously registered) in the 
patient9s medical records. 
The clinical benefit and the safety profile will be assessed since surgery within 12 months and 
until 6 months follow-up respectively after nail implant through the information collected from 
the medical records of the two participating sites.  
All data, recorded in an electronic CRF, will be analyzed at the end of the study. 

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11.2 Study data collection 
At the time of data collection, once the eligibility of patients has been confirmed, patients will 
be considered included and they will be assigned a permanent identification number so that 
the information managed does not contain personal data.  
The procedures and data required are the following: 
• 
Review of selection criteria and obtaining informed consent 
• 
Sociodemographic characteristics (Age at surgery, gender, ethnicity) 
• 
Anthropometric data (weight, height, Body Mass Index (BMI)) 
• 
Anamnesis data (worker, smoker, alcohol user) 
• 
Relevant medical history (specifically related to other fractures that have occurred 
previously) 
• 
Comorbidities (other acquired or congenital deformities) 
• 
Clinical diagnosis: date of trauma, type and classification of fracture, cause of fracture, 
non-union, pathological fracture, results of RX diagnosis performed if available. 
• 
Related surgery data:  
- 
Date of surgery 
- 
Femur-treated 
- 
Operation time 
- 
Antibiotic prophylaxis 
- 
CHIMAERATM specification device (use of CHIMAERATM, nail composition, CCD 
angle, distal diameter, height and length of nail, type of lag screw, use of additional 
lag screw, distally lock of the nail, other synthetic media applied and device code) 
- 
Post-operative ADEs/SADEs and MDDs related to CHIMAERATM (including blood 
loss)  
- 
Intraoperative fluoroscopy and time of fluoroscopy  
- 
Tip Apex Distance (TAD) calculation 
- 
Need of blood transfusion and number of blood bags used 
- 
Intraoperative measures (for corrections) (number of osteotomies, rotational 
correction, varus/valgus correction, shortening) 
• 
Hospital stay data (date of hospital admission, date of hospital discharges, stay 
duration, presence of pain at the site of nail insertion) 
• 
1st follow up visit (Bone consolidation assessment data): date of assessment, 
fluoroscopy or RX performed, TAD calculation, bone consolidation/union (yes/no) by 
both observers, presence of pain at the site of nail insertion.  
• 
2nd follow up visit (): date of visit, presence of pain at the site of nail insertion. 

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• 
Last Follow-up visit (date of assessment, fluoroscopy or RX performed, TAD 
calculation, bone consolidation/union (yes/no) by both observers if not achieved in the 
last visit, presence of pain at the site of nail insertion.  
• 
Reoperations (date, duration, post-operative x-ray, need of blood transfusion, 
intraoperative fluoroscopy and measures and main reasons of reoperation) performed 
within the 12 months after nail implant. 
• 
ADEs/SADEs reported since the day of surgery until the last follow-up visit.  
• 
MDDs reported since the day of surgery until the last follow-up visit. 
• 
Concomitant medication prescribed since surgery until the last follow-up visit. 
12. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
As this is a study based on primary use of data, safety monitoring and safety reporting, where 
there is a safety relevant result, will be provided on an aggregate level only, no reporting on 
an individual case level. 
In studies based on primary use of data with a safety relevant result, reports of adverse 
events/adverse reactions will be summarized in the study report, i.e. the overall association 
between an exposure and an outcome will be presented. All Adverse Events (AEs) and device 
deficiencies will be collected and reported to the sponsor. 
The following definitions are provided in accordance with MDR (EU) 2017/745 of the European 
Parliament and of the Council on medical devices (28) and its guidelines as MDCG 2020-10/1 
(29) and ISO/DIS 14155:2020 (27). 
12.1 Definitions 
Adverse event (AE) 
Any untoward medical occurrence, unintended disease or injury, or untoward clinical signs, 
symptom or medical condition (including abnormal laboratory findings) in patients, users or 
other persons, whether or not related to the investigational medical device (MDR Article 2(57)).  
a. This definition includes events that are anticipated as well as unanticipated events. 
b. This definition includes events occurring in the context of a clinical investigation related to 
the investigational device, the comparator or the procedures involved (MDCG 2020-10/1) 
(29). 
Adverse Device Effect (ADE) 
Any AE related to the use of an investigational medical device, including adverse events 
resulting from insufficient or inadequate IFU, deployment, implantation, installation, or 
operation, or any malfunction of the investigational medical device and any event resulting 
from use error or from intentional misuse of the investigational medical device. (ISO 
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Serious Adverse Event (SAE) 
AE that led or could have led to any of the following: 
a) Death, 
b) Serious deterioration in the health of the patient, users or other persons as defined by one 
or more of the following: 
1) a life-threatening illness or injury, or 
2) a permanent impairment of a body structure or a body function including chronic 
diseases, or 
3) in-patient or prolonged hospitalization, or 
4) medical or surgical intervention to prevent life-threatening illness or injury or permanent 
impairment to a body structure or a body function, 
c) Fetal distress, fetal death or a congenital abnormality or birth defect including physical or 
mental impairment (MDR Article 2(58) 
Serious Adverse Device Effect (SADE) 
ADE that has resulted in any of the consequences characteristic of a serious adverse event 
(ISO 14155:2020).  
Medical Device Deficiency (MDD) 
Inadequacy of a medical device with respect to its identity, quality, durability, reliability, 
usability, safety or performance. Device deficiencies include malfunctions, use errors, and 
inadequacy in the information supplied by the manufacturer including labelling (Article 2(59) 
of the MDR).  
Unanticipated serious adverse device effect (USADE) 
Any SADE which by its nature, incidence, severity or outcome has not been identified in the 
current version of the risk analysis report and is therefore not included in the IFU (ISO 
14155:2020).  
Anticipated serious adverse device effect (ASADE)  
SADE which by its nature, incidence, severity or outcome has been identified in the risk 
analysis report and is therefore included in the IFU (ISO 14155:2020).  
12.2 Procedures for Reporting and Recording Adverse / Serious Adverse 
Events 
Since this study is intended to collect safety information retrospectively related to the use of 
CHIMAERATM, the Investigators must record and document in detail all adverse events 
according to the designated eCRF page. All serious adverse events, whether or not deemed 

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investigational device related or expected, and all serious adverse device effects will be 
collected. 
The following information on all AEs/SAEs will be recorded on the Adverse Event Form in the 
CRDe: 
• Description of the event. 
• Start and end dates. 
• Maximum intensity reached. 
• Causal relationship to the study device/procedure (unrelated, unlikely, possible, probable, 
causal relationship). 
• Severity (yes/no).  
• Actions taken in relation to the study product/device. 
• Status of the event (resolved, resolved with sequelae, fatal, improved, ongoing, worsening, 
unknown). 
• If serious: Severity criteria (death, life-threatening, hospitalisation or prolonged 
hospitalisation, permanent or significant disability, congenital anomaly, medically 
significant, transmission of infectious agent, serious injury or death due to device 
malfunction, medical or surgical intervention to prevent permanent damage). 
As this is a non-interventional post-authorisation study, reporting of both serious and non-
serious adverse events will not be required. In addition, as this is a retrospective study, 
adverse events are considered to have been previously reported. However, All SAEs will be 
reported to the sponsor through the SAE form and recorded into the safety database of the 
sponsor at the end of the study. 
12.3 Assessment of causality 
The relationship between the use of the medical device (including the medical-surgical 
procedure) and the occurrence of each adverse event shall be assessed and categorized. 
During causality assessment activity, clinical judgement shall be used and the relevant 
documents, such as the Investigator9s Brochure, the Clinical Investigation Plan or the Risk 
Analysis Report shall be consulted, as all the foreseeable serious adverse events and the 
potential risks are listed and assessed there. The presence of confounding factors, such as 
concomitant medication/treatment, the natural history of the underlying disease, other 
concurrent illness or risk factors shall also be considered. 
The above considerations apply also to the serious adverse events occurring in the 
comparison group. 
For the purpose of harmonizing reports, each SAE will be classified according to four different 
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1.   Not related. 
2.   Possible. 
3.   Probable. 
4.   Causal relationship, 
The sponsor and the investigators will use the following definitions to assess the relationship 
of the serious adverse event to the investigational device, the comparator or the investigation 
procedure. 
1.   Not related: Relationship to the device, comparator or procedures can be excluded when: 
• 
the event has no temporal relationship with the use of the investigational device, or the 
procedures related to application of the investigational device. 
• 
the   serious adverse   event   does   not   follow   a   known   response   pattern   to    the 
medical   device (if   the   response pattern is previously known) and is biologically 
implausible. 
• 
the discontinuation of medical device application or the reduction of the level of 
activation/exposure - when clinically feasible - and reintroduction of its use (or increase of 
the level of activation/exposure), do not impact on the serious adverse event. 
• 
the event involves a body-site or an organ that cannot be affected by the device or 
procedure. 
• 
the serious adverse event can be attributed to another cause (e.g. an underlying or 
concurrent illness/clinical condition, an effect of another device, drug, treatment or other 
risk factors). 
• 
the event does not depend on a false result given by the investigational device used for 
diagnosis, when applicable. 
In order to establish the non-relatedness, not all the criteria listed above might be met at the 
same time, depending on the type of device/procedures and the serious adverse event. 
2.   Possible: The relationship with the use of the investigational device or comparator, or the 
relationship with procedures, is weak but cannot be ruled out completely. Alternative causes 
are also possible (e.g., an underlying or concurrent illness/ clinical condition or/and an effect 
of another device, drug or treatment). Cases where relatedness cannot be assessed, or no 
information has been obtained should also be classified as possible. 
3.   Probable: The   relationship   with   the   use   of   the   investigational   device   or 
comparator, or the relationship with procedures, seems relevant and/or the event cannot be 
reasonably explained by another cause. 
4.   Causal relationship: the serious adverse event is associated with the investigational 
device, comparator or with procedures beyond reasonable doubt when: 
• 
the event is a known side effect of the product category the device belongs to or of similar 

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devices and procedures. 
• 
the event has a temporal relationship with investigational device use/application or 
procedures. 
• 
the event involves a body-site or organ that: 
o the investigational device or procedures are applied to. 
o the investigational device or procedures have an effect on. 
• 
the serious adverse event follows a known response pattern to the medical device (if the 
response pattern is previously known). 
• 
the discontinuation of medical device application (or reduction of the level of 
activation/exposure) and reintroduction of its use (or increase of the level of 
activation/exposure), impact on the serious adverse event (when clinically feasible). 
• 
other possible causes (e.g. an underlying or concurrent illness/ clinical condition or/and an 
effect of another device, drug or treatment) have been adequately ruled out. 
• 
harm to the subject is due to error in use. 
• 
the event depends on a false result given by the investigational device used for diagnosis, 
when applicable. 
In order to establish the relatedness, not all the criteria listed above might be met at the same 
time, depending on the type of device/procedures and the serious adverse event. 
The sponsor and the investigators will distinguish between the serious adverse events related 
to the investigational device and those related to the procedures (any procedure specific to 
the clinical investigation). An adverse event can be related both to procedures and the 
investigational device. Complications caused by concomitant treatments not imposed by the 
clinical investigation plan are considered not related. Similarly, several routine diagnostic or 
patient management procedures are applied to patients regardless of the clinical investigation 
plan. If routine procedures are not imposed by the clinical investigation plan, complications 
caused by them are also considered not related. 
In some particular cases the event may not be adequately assessed because information is 
insufficient or contradictory and/or the data cannot be verified or supplemented. The sponsor 
and the Investigators will make the maximum effort to define and categorize the event and 
avoid these situations. Where an investigator assessment is not available and/or the sponsor 
remains uncertain about classifying the serious adverse event, the sponsor should not exclude 
the relatedness; the event should be classified as <possible= and the reporting as not delayed. 
Particular attention shall be given to the causality evaluation of unanticipated serious adverse 
events. The occurrence of unanticipated events related could suggest that the clinical 
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12.4 Assessment of expectedness  
The assessment of expectedness of AEs related to the use of the investigational medical 
device will be made according to the expected risks described in the investigational plan and 
in the IFU. 
13. 
STATISTICS 
13.1 Statistical and Analytical Plans 
Prior to any statistical analysis, a statistical analysis plan (SAP) shall be prepared and 
approved, which shall provide the technical details of the statistical analysis described below. 
Any deviation from the SAP shall be described and justified in the final study report. 
All patients meeting the screening criteria will be included in the analysis, a list will be given of 
the patients removed from the analysis, as well as the reason for their removal. A general 
description of the variables included in the study will be provided. The distributions of absolute 
and relative frequencies for qualitative variables will be presented, as well as mean, standard 
deviation (SD), median, minimum and maximum for quantitative variables. If considered 
appropriate, 95% confidence intervals will also be presented. No imputation for missing data 
will be considered. 
Analysis will be performed using IBM SPSS Vs 22.0. When an inferential analysis is required, 
parametric tests will be used for continuous variables and nonparametric tests in the case of 
ordinal or categorical or nonparametric variables. All hypothesis tests will be two-sided and 
with a significance level of 0.05. For variables not fitting a normal (or parametric) distribution, 
the Mann-Whitney test (for unpaired data) and the Wilcoxon test (paired data) will be used. 
Contingency tables and the comparison of proportions and/or frequency distributions will be 
analyzed using the chi-square test (or Fischer9s exact test when appropriate) will be used.  
13.1.1 Population(s) of analysis 
The full analysis set (FAS) population consists of all patients included in the study after 
selection criteria review. The full analysis set will be used for all raw data listings.  
The clinical benefit population consists of patients who have available data that allow the 
primary efficacy endpoint assessment.  
The safety population includes all adult patients in whom CHIMAERATM has been used.  
13.1.2 Efficacy, Safety and Other Variables 
13.1.2.1 
Efficacy Variables 
The clinical benefit of CHIMAERATM will be assessed by the percentage of patients in which 
bone union has been achieved within 12 months from the nail implant. 

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The clinical benefit analysis will be performed in those patients who meet the following criteria:  
- 
Patient has achieved bone union at the 12 months follow-up visit and this is the only 
evaluation available.  
- 
Patient has achieved bone union at first follow-up this being the only evaluation 
available. 
- 
Patient has both bone union evaluations completed (first follow up visit and last follow 
up visit) and achieved bony union at the end of the follow-up period. (considered a 
responder) 
- 
Patient underwent reoperation but the reason for this was secondary dynamization. 
- 
Patient with fractures on the upper limbs not caused by the CHIMAERATM (e.g. simply 
stumbled or had a car accident) 
- 
Patient underwent reoperation after first bone union evaluation. 
- 
Patient who has not suffered contralateral leg fracture. 
- 
Patient in whom no refraction occurred where the nail was applied. 
A double evaluation will be required (observer 1 and observer 2). Only if both evaluations are 
positive, the treatment goal will be considered achieved. 
13.1.2.2 
Safety Variables 
The safety profile of CHIMAERATM will be assessed through the percentage of patients that 
required a reoperation (i.e., additional surgery) caused by at least one of the following safety 
events:  
- 
Expected or unexpected adverse effect potentially or certainly related to the 
CHIMAERATM (Adverse Device Effects (ADEs)/Serious Adverse Device Effects 
(SADEs)) since the nail application until 6 months follow-up after nail implant. 
- 
Medical Device Deficiency (MDDs) (i.e., breaking, loosening, or bending of the nail 
or of the screws) that caused an effect on the patient since the nail application until 
6 months follow-up after nail implant. 
All the reoperations that have occurred are considered but also those that have not occurred 
but that could have occurred (e.g., a patient who had a cut out but for any reasons has not 
been operated). It should be considered also all ADE/SADE/MDD that could have caused an 
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13.1.3 Statistical Evaluation 
13.1.3.1 
Evaluation of Efficacy 
Evaluation of efficacy will be performed through the analysis of the primary objective of this 
study: to evaluate the clinical benefit of the long variant of the CHIMAERATM used in adult 
patients according to the IFU in routine clinical practice from the time of surgery within 12 
months follow-up after nail implant. 
. It is required a double evaluation with two positive opinions from both observers (observer 1 
and observer 2) to consider the treatment goal achieved.   
For this objective, descriptive statistics of the number and percentage of patients in which 
bone union was achieved will be provided both as continuous and categorical variables. The 
95% CI will also be presented. 
13.1.3.2 
Evaluation of Safety 
The evaluation of safety will be performed through the analysis of the secondary objective of 
the study: to evaluate the safety profile of the long variant of the CHIMAERATM used in adult 
patients according to the manufacturer IFU in routine clinical practice from the time of surgery 
until 6 months follow-up after nail implant.   
The safety analysis will be performed in the <safety population= which includes all patients who 
have undergone an intramedullary nailing technique with the CHIMAERATM medical device.  
The number and percentage of patients that required a reoperation due to at least one 
ADE/SADE/MDD will be calculated with a 95% confidence interval (CI). An analysis will be 
carried out according to degree of severity, seriousness, and relationship with the medical 
device. 
All the reoperations that have occurred are considered but also those that have not occurred 
but that could have occurred (e.g., a patient who had a cut out but for any reasons has not 
been operated). It should be considered also all ADE/SADE/MDD that could have caused an 
additional operation. Therefore, the number and percentage of patients that hypothetically 
would have caused a reoperation due to at least one safety event will be described and 
calculated with a 95% CI. 
13.2 Determination of the Sample Size 
The sample size calculation is based on the number of patients that allow the consecution of 
the study primary objective: to evaluate the clinical benefit of the long variant of the 
CHIMAERATM used in adult patients according to the IFU in routine clinical practice from the 
time of surgery within 12 months follow-up after nail implant. The clinical benefit will be 
evaluated with the percentage of patients in which achieved bone union within 12 months from 
the nail implant.  

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The scientific literature reports that the percentage of patients which bone union rate was 
achieved is 98.3% (IC95% 93%-100%) (1-26). Assuming a bone union rate aligned or better 
than the weighted mean observed in literature (98.3%) with a confidence interval between 
93% and 100% using a bilateral confidence interval with an alpha error of 5%, a sample size 
among 120 and 44 patients would be needed to estimate this proportion with an imprecision 
of 5%. 
Table 2. Sample size considering different Expected Proportions 
Confidence Level 
Expected proportion 
Sample Size (N) 
95% 
93% 
120 
95% 
94% 
107 
95% 
95% 
94 
95% 
96% 
81 
95% 
97% 
98 
95% 
98.3% 
51 
95% 
99.9% 
44 
For this clinical study, the sample size of 44 patients were chosen.  
13.3 Changes in the Conduct of the Study or the Planned Analyses 
As this is a retrospective study with a clearly defined population, no changes are expected 
either in the conduct of the study or in the planned analyses. 
13.4 Statistical and Analytical Issues 
No adjustment for multiple comparisons will be performed. 
13.4.1 Handling of Dropouts or Missing Data 
The number of observations (N) and missing data (N missing) will be specified. There is no 
plan to impute missing data. 
13.4.2 Interim Analysis 
During the study development and if the sponsor considers it necessary, an interim analysis 
could be performed after at least 22 subjects will be enrolled and completed the treatment in 
which bone union has been achieved within 12 months from the nail implant in order to 
preliminary confirm the results obtained. 
14. 
ETHICS AND REGULATORY REQUIREMENTS 
14.1 Approval 
The study complies with the basic ethical principles contained in the (ICH) Harmonized 
Tripartite Guidelines for Good Clinical Practice (GCP), the World Medical Association9s 
Declaration of Helsinki on the ethical principles for medical research involving human subjects 
(87), and subsequent amendments. 

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The study will be submitted for evaluation by an accredited Independent Ethics Committee/ 
Institutional Review Board (IEC/IRB), where applicable.  
This study will be conducted according to the procedures described in this CIP, with the 
Ministerial Decree 30 November 2021 <Misure volte a facilitare e sostenere la realizzazione 
degli studi clinici di medicinali senza scopo di lucro e degli studi osservazionali e a disciplinare 
la cessione di dati e risultati di sperimentazioni senza scopo di lucro a fini registrativi, ai sensi 
dell9art. 1, comma 1, lettera c), del decreto legislativo 14 maggio 2019, n. 52=, where 
applicable, with the guideline of the Italian National coordination centre of local ethics 
committees for clinical trials concerning medicinal products for human use and medical 
devices issued on 26 July 2022 3 Version n. 1 (88),  and the Regulation (EU) 2017/745 of the 
European Parliament and the Council on medical devices (28) and its guidelines as MDCG 
2020-10/1 (29) and ISO 14155:2020 Clinical investigation of medical devices for human 
subjects - Good clinical practice (27). 
In addition, the study complies with Regulation (EU) 2016/679 of the European Parliament 
and of the Council of 27 April 2016 on the protection of natural persons with regard to the 
processing of personal data and on the free movement of such data (89) and with the 
Legislative Decree 10 August 2018, n. 101 <Disposizioni per l'adeguamento della normativa 
nazionale alle disposizioni del regolamento (UE) 2016/679 del Parlamento europeo e del 
Consiglio, del 27 aprile 2016, relativo alla protezione delle persone fisiche con riguardo al 
trattamento dei dati personali, nonche' alla libera circolazione di tali dati e che abroga la 
direttiva 95/46/CE (regolamento generale sulla protezione dei dati)= (90).  
It will be also conducted in compliance with this Clinical Investigation Plan, Standard Operating 
Procedures (SOPs) and referred to ISO 14155 where applicable and with local laws and 
regulations relevant to the research of medical devices in the country of conduct. 
By signing the CIP, the investigator agrees to adhere to the instructions and procedures 
described in the CIP and thereby to adhere to the principles of good clinical practice that it 
conforms to. 
The sponsor will submit the pertinent documentation to the ethics committee and applicable 
regulatory agency. The study must not be started until their approval has been obtained. Any 
amendment changing the risk-benefit relationship for the patient must, after signature by the 
sponsor, be submitted for evaluation by the ethics committee and applicable regulatory agency 
for approval. 
The study staff involved in the conduct of this clinical investigation will have appropriately 
qualified training and experience to perform the assigned tasks.  
14.2 Subject Information and Consent 
Patients will be identified via an existing database held by the Primary care team. A member 
of the primary care team will invite the patient to be part of the study. This invitation may be in 
person at an existing standard of care follow up appointment or via the post. Each patient who 
is invited to participate in the study will be provided with an information sheet in which the 

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study objectives, methods, planned duration, the number of participating patients, the 
expected benefits and potential risks will be explained in detail. This document will be written 
with a vocabulary that allows its content to be completely readable and understandable for the 
patient. Patients will also be explained that they are free to refuse to participate in the study 
and to withdraw from the study at any time without it affecting their future treatment and 
medical care.  
The willingness of the patient to participate in the study will be documented in writing in a 
consent form. The patient or legal representative will sign the informed consent form indicating 
the date of signature. A legal representative signature will be requested if the subject is legally 
incapable, or is incapable of making decisions or his/her physical or mental state does not 
allow him/her to take charge of his/her situation, or an impartial witness if the subject or his/her 
legal representatives cannot read. Each investigator will keep the original consent documents 
and give a copy to the patients. In the case of deceased patients, the ethics committee may 
waive the need for consent. 
Patients may revoke at any time their consent to continue participating in the study and for 
use of their data in the analysis.  
14.3 Subject Confidentiality 
The information disclosed and obtained during this study will be considered confidential and 
must be treated as such at all times.  
The study sponsor and investigators should ensure the confidentiality of the subjects9 data 
and that the study complies at all times with the Legislative Decree 10 August 2018, n. 101 
<Disposizioni per l'adeguamento della normativa nazionale alle disposizioni del regolamento 
(UE) 2016/679 del Parlamento europeo e del Consiglio, del 27 aprile 2016, relativo alla 
protezione delle persone fisiche con riguardo al trattamento dei dati personali, nonche' alla 
libera circolazione di tali dati e che abroga la direttiva 95/46/CE (regolamento generale sulla 
protezione dei dati)= (90). This Law is the adaptation of the Italy legal system of the Regulation 
(EU) 2016/679 of the European Parliament and the Council, on 26 April 2016, GDPR first 
implemented on 25 May 2018 (89). 
For this purpose, each patient recruited for the study will be assigned a unique subject 
identification number. This means that the names of the participating patients are not included 
in the study data sets that are transmitted to promotor sites, and that in no study document or 
material will patients be identified by their name but only by an identification number.  
In compliance with current legislation on data protection, when the treating physician receives 
a request for the exercise of rights from a patient included in the study, he/she must verify the 
ownership of the data by means of a legal document (ID card, driving license) and proceed to 
contact the sponsor by e-mail or by post to the attention of the Data Protection Delegate 
(DPD), without disclosing in any case the patient's personal data, but indicating only the code 
to which the holder corresponds, the code of the study and the code of the study site; as well 
as the right that the patient has been asked to exercise. The physician should not send to the 

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sponsor or any of its delegate the document proving the identity, since it was verified by him 
at the time of the request.  The sponsor or its possible DPD will manage the request and will 
issue an answer according to the case. 
All materials, information (oral or written) and unpublished documentation provided to the 
investigator, including this Clinical Investigation Plan and the CRFs, will be considered the 
property of the sponsor. The study data and materials may not be disclosed in part or in full 
by the investigator or his/her staff to any unauthorized person without the prior formal written 
consent of the sponsor. 
The study database and the CRF will be coded and protected from nonpermitted uses by 
persons unrelated to the research and, therefore, will be considered strictly confidential and 
will not be disclosed to third parties. However, the study data must be available for inspection 
upon request by the regulatory authorities, ethics committees and the sponsor (or its 
representatives), as appropriate.  
The data generated by the study must be available for inspection upon request by 
representatives of the national and local health authorities, monitors of the marketing 
authorization holder, representatives and collaborators of the sponsor, and the IEC/IRB of 
each study site, as appropriate. 
Only medical history data that are related to the study will be subject to verification. This 
verification will be done to the extent possible in the presence of the principal 
investigator/coinvestigators, and the confidentiality of all personal data of the subjects 
participating in the clinical investigation will be maintained at all times in accordance with the 
EU data protection regulation.  
Regarding the eCRF, each investigator will be given a sealed document with a username and 
a password of between 4 to 6 digits. These codes will be considered confidential and 
nontransferable and are subject to the same confidentiality requirements as the rest of the 
documents, including the Clinical Investigation Plan. The investigators are responsible for 
keeping their passwords secret and not disclosing them to third parties. The study sponsor 
and its representatives will have access codes permitting only read-only access to eCRFs, but 
at no time will they be able to modify the information entered by the investigators. 
14.4 Informing the General Practitioner  
Given that the proposed research project has a post authorization observational retrospective 
design, no type of diagnostic or therapeutic intervention outside of routine clinical practice 
were applied. It involves collection of data from the medical history of selected patients in 
whom a specific therapeutic strategic has already been assigned based on routine practice, 
without interference with the physician9s prescription habits.   
 
 

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15. 
STUDY MANAGEMENT AND ADMINISTRATION 
15.1 Monitoring 
Authorized, qualified representatives of the Sponsor or designated personnel of a Contract 
Research Organization (CRO) may visit investigational sites in regular intervals as defined in 
the monitoring guidelines to verify adherence to Clinical Investigation Plan and local legal 
requirements, to perform source data verification and to assist the Investigator in his/her study 
related activities.  
15.2 Direct Access to Source Data/Documents 
15.2.1 Source Documents 
A source document is an original or certified copy of printed, optical, or electronic document 
containing source data, where documented data are recorded for the first time. Examples of 
source documents include hospital records, laboratory notes, physician reports, appointment 
books, and records kept at the investigation site, laboratories, and medico-technical 
departments involved in the clinical investigation. 
15.2.2 Source Data 
Source data are all information in original records, certified copies of original records of clinical 
findings, observations, or other activities, necessary for the reconstruction and evaluation of 
this retrospective observational study. These also include electronic source data initially 
recorded in an electronic format. The data source will be the medical records on both 
participating study sites, including medical charts. 
15.2.3 Direct Access 
Direct access is defined as the permission to examine, analyze, verify, and reproduce any 
records and reports that are important to the evaluation of this retrospective observational 
study. 
15.2.4 Permission of Access 
The investigator will permit study-related monitoring, audits, IEC/IRB review, and regulatory 
inspections, providing direct access to primary patient data (i.e. source data) which supports 
the data on the eCRFs for the study, e.g. general practice charts, hospital notes, appointment 
books, original laboratory records. 
Any party (e.g. domestic and foreign regulatory authorities, the sponsor and/or authorized 
representatives of the sponsor such as monitors and auditors) with direct access should take 
all reasonable precautions within the constraints of the applicable regulatory requirements to 
maintain the confidentiality of patient identities and sponsor proprietary information. 
 

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15.3 Audit and Inspection 
The competent health authorities, within the scope of their competences, will verify compliance 
with the legal requirement related to post-authorization studies conducted in Italy through the 
pertinent inspections and according to the procedures that may be established. 
Inspections will be carried out before, during, or after the conduct of the study by duly qualified 
inspectors. Inspections may be performed in sites related to the conduct of the study and, 
among others, at the research site or healthcare sites where the study is conducted, at any 
analytical laboratory or diagnostic center used, at the facilities of the sponsor and/or contract 
research organizations or companies involved in the conduct of the study, and at the IEC/IRB 
which evaluated the study.   
15.4 Patient Data collection  
All study data will be collected from the patient9s medical history during scheduled visits 
according to local clinical practice for patient´s disease follow-up. The investigator or 
designated site staff will be solely responsible for entering the data in the CRF and must 
ensure the data recorded in the CRF are legible, accurate and complete, and within the 
established time period. 
Data recording will be performed through an eCRF. The data received using the e-Clinical 
methodology will be submitted to the appropriate work procedures to comply with the FDA 21 
CFR Part 11 regulation, which ensures that the data received via electronic transmission are 
as valid as the originals received on paper. This regulation establishes the rules for the use of 
electronic data and defines the requirements of all the systems for collection, storage, 
maintenance and security of the data. An automatic validation program will check for data 
discrepancies, thus allowing modification or verification of the data entered by the investigator 
or designated person.  
15.5 Adherence to Clinical Investigation Plan 
By signing the Clinical Investigation Plan, the investigator agrees to adhere to the instructions 
and procedures described in the Clinical Investigation Plan and thereby to adhere to the 
principles of good clinical practice that it conforms to. 
15.6 Investigator Site File 
The documentation related to the study comprises the study file and will consist of the 
essential documents that allow evaluation of its conduct and the quality of the data obtained. 
These documents demonstrate compliance by the investigator and the sponsor of the 
requirements established for the study. 
The master study file will provide the basis for the audits that may be performed by the sponsor 
through independent auditors and for inspections by the competent authorities. 

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The sponsor and the investigator will retain the essential study documents and materials for 
the time required by currently applicable legislation after completion of the study, or during a 
longer period if provided by other applicable requirements. 
The essential documents and materials must be filed so they can be made readily available 
to the competent authorities if requested. 
The sponsor will designate the persons of its organization responsible for the study files and 
access to the files must be restricted to designated persons. 
The media used for storage of the essential documents must ensure that the document and 
materials remain complete and readable for the expected storage period and that they can be 
made readily available to the competent authorities if requested. Any changes to the records 
must be traceable, allowing the original and corrected entry to be known, as well as the date 
and signature of the author of the change. 
15.7 Data Handling 
15.7.1 Data management 
The patients included in the study will be identified only by a numerical code, such a way that 
no personally identifiable patient data will be collected in the sponsor's study database. Thus, 
the sponsor will work with pseudonymized (coded) data. The pseudonymization procedure will 
be carried out by the study investigator, who will create a list in which the patients' personal 
data will be related to the codes assigned by the sponsor that will identify the patient during 
the study. This list will be kept at the study site and in the investigator's file at all times. 
When the database is closed, it will be transferred to Evidenze Health España S.L, for 
debugging and analysis. Once the study is finished, the database will be transferred to the 
sponsor as its owner. 
For the development of the proposed study, both the Data Controller and the Data Processor 
undertake that the present research will be carried out using health data obtained in routine 
medical practice and/or previous research, always under the current legislation at the time 
they were collected; and that they have been pseudonymized for further processing. The 
recorded information is encrypted for its transfer to the study database.  
The teams in charge of performing the pseudonymization are technically and functionally 
independent of the researchers who have collected the data, so re-identification and 
unauthorized access by third parties is not possible. This is broken down according to the 
following organization: 
• 
Research team: corresponds to the healthcare team delegated to the study with direct 
access to the patients' original data and knowledge of their identity. These personnel 
are hired and perform their functions at the health site where the study is carried out 
and have no direct or indirect contact or relationship with the personnel responsible for 

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programming 
the 
eCRD, 
a 
system 
designed 
to 
automatically 
perform 
pseudonymization when a patient is included in the study. 
• 
IT technical team: corresponds to Orthofix S.r.l IT department, whose functions include 
the programming of the CRDs contracted by the clients. This staff is composed of IT 
programmers with exclusive training in the area. Their physical offices are located in 
the company's facilities, and they have no contact of any kind (direct or indirect) with 
the research team. The Orthofix S.r.l Project manager of the study is the internal 
responsible in the company for the verification of the user requirements foreseen in 
the system, and this role (CTL) corresponds to the sponsor operations department. 
This implies that between the research team located in the health study site and the 
sponsor team of programmers there is no possibility of communication since they do 
not participate, cooperate, or relate to each other for any phase of the development of 
the system or later once the data entry begins. 
Likewise, a daily, weekly and monthly backup of all servers that keep the pseudonymized data 
is performed. All computer equipment has antivirus protection, firewalls, controlled access, 
permanent surveillance, alarms, in addition to other relevant security measures to ensure that 
the information is protected against attacks and accidental losses. In case of serious security 
breaches, Orthofix S.r.l Data protection officer or its possible DPD will notify the corresponding 
entities within 72 hours. 
On the other hand, Orthofix S.r.l, through its Data Protection Delegate, states that it has 
conducted an impact assessment to determine the risks arising from the processing of health 
research data foreseen in the study, and technical and organizational measures have been 
taken according to the levels of risk detected. 
15.7.2 Quality assurance  
The data generated by this study may be reviewed by the sponsor (or its representatives), the 
competent health authorities and the ethics committees of each site, as appropriate. 
Therefore, the investigator and the site will ensure the sponsor or its representative (including 
the monitor), the ethics committee and the competent authorities have access to the study 
documents. 
Any discrepancies detected requiring resolution will be corrected by authorized study site staff. 
Data clarification requests may be created describing the nature of the problem and requesting 
clarification of all other discrepancies and missing values and sent to the research site. The 
designated staff of the research site must respond to the clarification request and confirm or 
correct the data. Once these actions have been completed and the database has been 
declared complete and correct, database closure will be performed, and the data will be 
available for analysis.  

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15.8 Clinical Study Report 
The sponsor will notify the end of the study according to the Regulation (EU) 2017/745 of the 
European Parliament and the Council on medical devices (28), and its guidelines as MDCG 
2020-10/1 (29) and local regulations. The end of the study is defined as all close out visits and 
database lock performed.  
The sponsor will also notify any temporary halt of the study or the premature end of the study, 
including the reason for such an action, as per the Regulation (EU) 2017/745 of the European 
Parliament and the Council on medical devices (28), and its guidelines as MDCG 2020-10/1 
(29) and local regulations.  
Irrespective of the outcome of the retrospective observational study, the sponsor shall submit 
to the member states in which a clinical investigation was conducted a clinical investigation 
report, accompanied by a summary presented in terms that are easily understandable to the 
intended user, within the timelines laid down in the Regulation (EU) 2017/745 of the European 
Parliament and the Council on medical devices (28) and its guidelines as MDCG 2020-10/1 
(29) and local regulations. 
15.9 Archiving and Data Retention 
Essential documents are to be retained for the periods required by applicable national and 
international legislation but not less than 15 years after routine/premature termination of a 
clinical study. 
The final report shall be retained for at least 2 years after the Investigational devices are 
removed from the last market.  
15.10 
Allocation of Responsibilities 
The responsibilities of the Investigator, Monitor and Sponsor of the clinical study as regards 
handling of data, storage of data, planning, assessment and quality assurance are regulated 
by ISO 14155-1 <Clinical investigation of medical devices for human subjects 4 Good clinical 
practice= (27). 
15.11 
Financial Disclosure 
Orthofix S.r.l will provide funding for the study according to the guidelines of the present clinical 
investigation plan. This funding includes all materials required for the conduct of the study, the 
cost of the processes of authorization and control before the IEC/IRB and health authorities, 
the design, maintenance and management of the database and statistical analysis of the 
information generated. Funding will be completely independent of the study results. 
Given that this is an observational study according to routine clinical practice conditions, its 
conduct will not entail any extra expense for the site other than the dedication of the 
investigator to complete the information required in the eCRF. In any case, the study sponsor 

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will have a financial schedule of the study that will be available for consultation whenever it 
should be necessary.  
15.12 
Disclosure of Clinical study Information and publication 
The Sponsor and all Investigators shall agree on the final study report. A publication of the 
results of the study in a scientific journal is intended.  
Results may also be used in submissions to regulatory authorities. The following conditions 
aim to protect commercial confidential materials (patents etc.), rather than restrict publication. 
All information concerning CHIMAERATM (such as patent applications, technical drawings, 
manufacturing processes, basic scientific data supplied to the Investigator by the Sponsor and 
not previously published) is considered confidential and shall remain the sole property of the 
Sponsor. The Investigator agrees not to use it for other purposes without the Sponsor9s written 
consent. 
It is understood by the Investigator that the Sponsor will use the information developed in this 
clinical study in connection with the development of CHIMAERATM and therefore may be 
disclosed as required to other Investigators or any appropriate international Regulatory 
Authorities. In order to allow for the use of information derived from this clinical study, the 
Investigator understands that he/she has an obligation to provide the Sponsor with complete 
test results and all data developed during this study. 
 
 

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16. 
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86. S.r.l O. CHIMAERATM Instructions for use. 2022. 
87. Asociación Médica Mundial (AMM). Declaración de Helsinki 3 principios éticos para las 
investigaciones médicas en seres humanos (64ª Asamblea General, Fortaleza, Brasil, 
octubre 2013). 2013. 
88. DECRETO 30 novembre 2021. 
89. The European Parliament and the Council of the European Union. Regulation (EU) 
2016/679 of the European Parliament and of the Council of 27 April 2016. 2016. 
90. DECRETO LEGISLATIVO 10 agosto 2018, n. 101. 
91. CIOMS in collaboration with the WHO. International Ethical Guidelines for Health-related 
Research Involving Humans. 2016. 
 

CI code: OCI_2206 
CIP date: 13/07/2023 
CIP version: 1.0 
 
CONFIDENTIAL 
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PO216-01 
17. 
APPENDICES 
17.1 CASE REPORT FORM 
Attached as a separate document. 
 
 

CI code: OCI_2206 
CIP date: 13/07/2023 
CIP version: 1.0 
 
CONFIDENTIAL 
Page 51 of 53 
___________________________________________________________________________________________________________________________________ 
 
 
PO216-01 
17.2 Instructions for Use (ORTHOFIX CHIMAERA HIP FRACTURE SYSTEM –
TROCHANTERIC NAILING SYSTEM TM)  
Attached as a separate document.  
 
 

CI code: OCI_2206 
CIP date: 13/07/2023 
CIP version: 1.0 
 
CONFIDENTIAL 
Page 52 of 53 
___________________________________________________________________________________________________________________________________ 
 
 
PO216-01 
17.3 IEC/IRB AGREEMENT 
Attached as a separate document. 
 
 

CI code: OCI_2206 
CIP date: 13/07/2023 
CIP version: 1.0 
 
CONFIDENTIAL 
Page 53 of 53 
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PO216-01 
17.4 FINANCIAL SCHEDULE 
Attached as a separate document. 
 
 
 

RESSIL_CIP_OCI 2206_Version
1.0_13.07.2023
Final Audit Report
2023-07-13
Created:
2023-07-13
By:
Eco Sign QA (esign-qa@orthofix.com)
Status:
Signed
Transaction ID:
CBJCHBCAABAAgwqI6i4J8_70c0eTcJoKEOvH-Htgyw4E
"RESSIL_CIP_OCI 2206_Version 1.0_13.07.2023" History
Document created by Eco Sign QA (esign-qa@orthofix.com)
2023-07-13 - 11:49:29 GMT- IP address: 193.17.45.5
Document emailed to d.maisonave@evidenze.com for signature
2023-07-13 - 11:50:40 GMT
Email viewed by d.maisonave@evidenze.com
2023-07-13 - 11:51:16 GMT- IP address: 81.41.180.229
Signer d.maisonave@evidenze.com entered name at signing as Diego Maisonave
2023-07-13 - 11:51:41 GMT- IP address: 81.41.180.229
Document e-signed by Diego Maisonave (d.maisonave@evidenze.com)
Signature Date: 2023-07-13 - 11:51:43 GMT - Time Source: server- IP address: 81.41.180.229
Agreement completed.
2023-07-13 - 11:51:43 GMT