Total Knee Arthroplasty With Vitamin E Polyethylene
Conditions: Knee Osteoarthritis
Sponsor: Permedica spa

 
 
 
Page 1/20 
VITALECOQ2020 v01 protocol dated 09/18/2020 
Total knee arthroplasty with vitamin E polyethylene 
 
CLINICAL STUDY PROTOCOL 
 
 
Title: Total Knee Arthroplasty with Vitamin E Polyethylene 
Short Title: VITALECOQ2020 
ClinicalTrials.gov ID: NCT05810285 
 
Document date 
Version 
Document history 
Ethics Committee 
approval date 
September 18, 2020 
01 
First protocol release 
June 11, 2021 
February 9, 2023 
02 
Substantial amendment for 
principal investigator change 
April 14, 2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
Page 2/20 
VITALECOQ2020 v01 protocol dated 09/18/2020 
Total knee arthroplasty with vitamin E polyethylene 
 
Table of Contents 
1. 
Synopsis ......................................................................................................... 4 
2. 
Introduction and state of the art .................................................................. 6 
3. 
Study design .................................................................................................. 8 
4. 
Study objective .............................................................................................. 9 
4.1 
Primary endpoint 
9 
4.2 
Secondary endpoints 
9 
5. 
Prosthetic device ........................................................................................... 9 
6. 
Study population ......................................................................................... 10 
6.1 
Study group 
11 
6.2 
Control group 
11 
6.3 
Eligibility criteria 
11 
7. 
Study procedure .......................................................................................... 11 
7.1 
Screening 
11 
7.2 
Enrolment 
11 
7.3 
Follow-up visit 
12 
7.4 
End of the study 
12 
8. 
Data recording and management .............................................................. 12 
8.1 
Case Report Forms (CRF) 
12 
8.2 
CRFs completion 
13 
8.3 
Data entry, analysis and storage 
13 
9. 
Duration of the study .................................................................................. 14 
10. 
Statistical analysis ...................................................................................... 14 
10.1 Sample size 
14 
10.2 Outcome analysis 
14 
11. 
Ethical and regulatory considerations ..................................................... 15 
11.1 Regulations 
15 
11.2 Ethical considerations on the patient 
15 
11.3 Ethics Committee 
15 
11.4 Insurance coverage 
16 

 
 
 
Page 3/20 
VITALECOQ2020 v01 protocol dated 09/18/2020 
Total knee arthroplasty with vitamin E polyethylene 
 
11.5 Confidentiality and protection of patients' personal data 
16 
12. 
Publication Policy ........................................................................................ 16 
13. 
Costs ............................................................................................................. 16 
14. 
Amendments to the protocol ..................................................................... 16 
15. 
References .................................................................................................... 17 
16. 
PROTOCOL APPROVAL ............................................................................. 19 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
Page 4/20 
VITALECOQ2020 v01 protocol dated 09/18/2020 
Total knee arthroplasty with vitamin E polyethylene 
 
1. Synopsis 
 
Study title: 
Total knee arthroplasty with vitamin E polyethylene. 
 
Protocol ID: 
VITALECOQ2020 
Protocol versions and 
dates: 
Version number 01 released on 09/18/2020 
Version number 02 released on 02/09/2023 
Study design: 
Single-centre comparative cross-sectional observational 
clinical study with medical device. 
Promoter/Sponsor: 
Permedica S.p.A., Via Como 38, 23807 Merate (LC), Italy. 
https://www.permedica.it/  
Study center: 
Quadrante Orthopedic Center (C.O.Q.), Lungolago Buozzi 
25, 28887 Omegna (VB), Italy. 
Principal investigator 
(Responsible): 
Marco Spezia - Head of Surgical Unit and Director of the 
C.O.Q. Orthopedic Unit, Omegna, Italy (Danilo Mellano - 
Head of Surgical Unit and Director of the C.O.Q. 
Orthopedic Unit, Omegna, Italy, after study substantial 
amendment) 
Co-investigators: 
• 
Alessandro Masse' - Director of the Complex Structure 
Unit 1 Orthopaedics and Traumatology, Città della 
Salute Hospital / CTO of Turin, Italy. 
• 
Alessandro Bistolfi - 1st level Medical Director of Unit 1 
Orthopaedics and Traumatology, Città della Salute 
Hospital/CTO of Turin, Italy and Cardinal Massaia 
Hospital, Asti, Italy. 
Sponsor contact person: Lorenzo Banci – Clinical Research Manager at Permedica 
S.p.A. 
Study rationale 
The clinical evidence for outcomes after primary total knee 
arthroplasty with vitamin E polyethylene is still scarce in the 
short term and published clinical studies on vitamin E 
polyethylene total knee arthroplasty with medium term 
results are lacking. 
Objective 
The aim of the study is to investigate on the survival rate 
and mid-term clinical and radiographic results of a 
consecutive series of primary total knee arthroplasty 
performed using a cemented total knee prosthesis with a 
mobile insert in polyethylene with vitamin E, comparing 
them with the same implant with a mobile insert in 
conventional polyethylene. 

 
 
 
Page 5/20 
VITALECOQ2020 v01 protocol dated 09/18/2020 
Total knee arthroplasty with vitamin E polyethylene 
 
Primary endpoint 
Cumulative implant survival with revision for aseptic 
loosening as the end-point. 
Secondary end-points 
Cumulative implant survival with revision for any reason as 
the end-point.  
Reinterventions and non-surgical complications 
Forgotten Joint Score (FJS-12).  
America Knee Society Score (Knee / Function). 
Radiographic signs of radiolucencies and osteolysis. 
Study group 
Minimum 152 total knee arthroplasties with vitamin E 
polyethylene insert. 
Control group 
Minimum 152 total knee arthroplasties with the same 
implant but with conventional polyethylene insert without 
vitamin E. 
Medical device 
GKS Prime Flex Mobile Bioloy, cemented TiNbN-coated 
mobile bearing knee prosthesis by Permedica with vitamin 
E polyethylene (VitalE®) or conventional polyethylene 
rotating ultra-congruent tibial insert. 
Inclusion criteria 
• 
Patient who received primary total knee arthroplasty 
with GKS Prime Flex Mobile Bioloy by Permedica with 
vitamin E polyethylene or conventional polyethylene 
insert. 
• 
Minimum follow-up of 7 years. 
• 
Patient aged ≥ 18 years and < 85 years. 
• 
Patients who signed the informed consent. 
Exclusion criteria 
• 
Patient who received knee prosthesis different from 
Permedica's GKS Prime Flex Mobile Bioloy. 
• 
Patients already included in other clinical investigations. 
• 
Patients who do not sign the informed consent. 
Telephone contact 
Telephone contact of all eligible patients for recording FJS-
12, any adverse events, if lost to follow-up or deceased and 
for scheduling the follow-up visit.  
Follow-up visit 
Physical examination, AKSS compilation, FJS-12, 
recording of complications, adverse events, radiographic 
assessment for periprosthetic radiolucent lines and 
osteolysis. 
 
 
 

 
 
 
Page 6/20 
VITALECOQ2020 v01 protocol dated 09/18/2020 
Total knee arthroplasty with vitamin E polyethylene 
 
2. Introduction and state of the art 
 
One of the most limiting factors for the longevity of a prosthetic implant in hip and knee arthroplasty 
is the resistance to wear and degradation of the polyethylene acetabular inserts. 
The degradation of ultra-high molecular weight polyethylene (UHMWPE) is that process whereby 
there is an alteration of the chemical structure of the material with a decrease in the molecular 
weight. Degradation decreases the mechanical characteristics of the polyethylene and, therefore, 
potentially reduces the longevity of the polyethylene joint insert. Degradation occurs when the 
polymeric material is exposed to a quantity of energy greater than that of the chemical bonds of 
which the polymer chains are made up, so that some chemical bonds are broken. and new free 
radicals are created. This process in the presence of oxygen is called oxidative degradation or 
more simply oxidation. Once triggered, the oxidative process is irreversible and self-sustaining with 
the formation of new radicals that react with oxygen, thus creating a chain reaction. 
In orthopaedics, polyethylene acetabular inserts are typically subjected to high doses of energy in 
the form of irradiation with the aim of increasing the degree of cross-linking or sterilizing the device. 
This radiation, through the splitting of bonds within the polymer chains, produces the formation of 
active free radicals within the material. Most free radicals recombine, forming new bonds in the 
amorphous phase of polyethylene, i.e. cross-linking. The free radicals formed inside the crystalline 
phase remain trapped for a long time and are responsible for oxidation [1-3]. 
Stabilization with vitamin E 
A solution to the problem of oxidative degradation is the addition of doping substances stabilizing 
against free radicals to UHMWPE. Stabilization of UHMWPE by the addition of vitamin E was 
introduced in 2005-2006 as an alternative method to annealing and re-melting, to provide greater 
resistance to oxidation without sacrificing the mechanical properties of UHMWPE. Vitamin E 
(alpha-Tocopherol) is in fact a natural molecule and is also present in our metabolism as an 
antioxidant agent. Vitamin E in its synthetic form is added in low concentrations to UHMWPE as a 
stabilizing agent against oxidative degradation. 
Vitamin E would have the advantage of maintaining the chemical and physical properties of the 
starting raw material over time, therefore prolonging the longevity of the joint component by 
reducing the risk of breakage, delamination and wear, a risk that increases exponentially with the 
increase in the degree of oxidation. 
The addition of low concentrations of Vitamin E has proven effective in protecting UHMWPE from 
oxidation in vitro. From research [4,5] it has been seen that a concentration of 0.05% by weight of 
vitamin E is already sufficient to protect UHMWPE from oxidation. 
UHMWPE with vitamin E added represents the latest generation of polyethylene for joint 
components, developed and introduced on the market in 2006 by Biomet, now Zimmer-Biomet 
(E1®). Polyethylene added with Vitamin E have recently been regulated through the ASTM F2695-
07 standard. On the market today there are many UHMWPEs added with vitamin E which however 
differ in the treatments they receive during the production process (Table 1). 
 

 
 
 
Page 7/20 
VITALECOQ2020 v01 protocol dated 09/18/2020 
Total knee arthroplasty with vitamin E polyethylene 
 
Commercial name 
Raw 
material 
Additive 
method 
Irradiation 
dose 
Irradiation 
method 
Sterilization 
method 
E1™ (Biomet) 
GUR 
1020/1050 
Infused 
100 kGy 
-Beam 
-Beam 
Vitamys® (Mathys) 
GUR 1020 
Blended 
100 kGy 
 -Beam 
Plasma gas 
Vivacit-E® (Zimmer) 
GUR 1020 
Blended 
100 kGy 
E-Beam 
Eto 
Vitelene® (Aesculap) 
GUR 1020 
Blended 
80 kGy 
E-Beam 
Eto 
Vital-XE® (Permedica) 
GUR 1020 
Blended 
60 kGy 
E-Beam 
Eto 
ECiMa™ (Corin) 
na 
Blended 
120 kGy 
Cold E-Beam 
na 
E-MAX™ (Renovis) 
GUR 1020 
Blended 
100 kGy 
-Beam 
Eto 
Table 1. Some of vitamin E-stabilized polyethylene brands for articular inserts for joint replacement 
in 2018. 
 
Vitamin E UHMWPE in the hip 
Numerous clinical studies are reported in the literature regarding primary total hip replacement with 
cross-linked polyethylene inserts added with vitamin E and the most recent ones show results up 
to 7 years of follow-up [6,7]. All studies report low linear wear, lower than conventional UHMWPE 
inserts and comparable to HXPE, and above all they show no signs of periprosthetic osteolysis. 
 
Vitamin E UHMWPE in the knee 
Numerous preclinical studies have shown the effective efficacy and safety of adding vitamin E to 
the polyethylene of joint inserts in total knee arthroplasty [8-11]. 
Simulator wear tests have shown excellent results with polyethylene inserts added with vitamin E 
[12-14]. 
 
However, in the literature there are few clinical studies published on total knee arthroplasty with 
polyethylene added with vitamin E and all concern short-term follow-up (maximum 3 years) and 
cross-linked polyethylene, infused with vitamin E by Zimmer Biomet (E1®), Table 2. To date, the 2 
retrospective case series studies confirm comparable short-term clinical, radiographic and survival 
results of prostheses with inserts with vitamin E compared to inserts without vitamin E [15,16]. A 
study on retrieved implants after an average in vivo period of 1.5 years reported less damage and 
less signs of wear and lower level of oxidation on Zimmer Biomet E1 inserts [17]. 
 
 
 
 

 
 
 
Page 8/20 
VITALECOQ2020 v01 protocol dated 09/18/2020 
Total knee arthroplasty with vitamin E polyethylene 
 
Ref. 
Study design No. 
cases 
FU 
Vit. E 
insert 
Prosthetics 
Main outcomes 
Conclusion 
Takemura, 
2019 [15] 
Comparative 
retrospective 
100 + 
100 
2 
E1 PS 
Biomet 
VanguardPS 
cemented 
ROM, KSS, 
radiological signs 
No differences 
Spece 2019 
[17] 
Retrievals 
103 + 
63 
1.5 
E1 PS vs 
Arcom PS 
VanguardPS 
cemented 
Signs of wear, 
oxidation 
Less oxidation in 
PE with vit. E 
Flament 
2016 [16] 
Case series 
163 
3.2 
E1 
Vanguard 
cemented 
Survival, ROM, 
KSS, radiological 
signs 
95% survival for 
any reason 
Barrack 
2013 [18] 
Case report 
1 
2.5 
E1 
Vanguard CR 
casehardened 
Insert breakage 
No oxidation 
 
Table 2. Literature review on total knee arthroplasty with vitamin E stabilized polyethylene. FU, 
mean follow-up in years. 
 
 
Study rationale 
The international scientific literature is still lacking in clinical studies reporting the safety, 
performance and effectiveness of the use of polyethylene added with vitamin E in joint inserts in 
primary total knee arthroplasty. There is therefore still no short-term clinical evidence on the clinical 
and radiographic results of these prosthetic implants. 
Furthermore, nothing has yet been published in the literature on mid-term results in primary total 
knee arthroplasty with polyethylene insert added with vitamin E. The maximum follow-up reported 
from clinical studies in total knee arthroplasty is in fact 3 years. 
A study that reports the medium-term results of a series of total knee arthroplasties using 
polyethylene with vitamin E and comparing them with those of an identical insert but made of 
conventional polyethylene is therefore considered scientifically valid and well-founded. 
The present study therefore aims to verify the survival, clinical and radiographic results of a 
consecutive series of patients undergoing first-time total knee arthroplasty with a polyethylene 
insert added with vitamin E, comparing them with an identical insert but made of polyethylene. 
standard, at a minimum follow-up of 7 years. 
 
 
3. Study design 
Observational, cross-sectional, comparative, monocentric clinical study with a retrospective cohort. 
The study is promoted and sponsored by Permedica S.p.A., Via Como 38, 23807 Merate (LC), 
Italy https://www.permedica.it/. The study centre is the Quadrante Orthopaedics Center (C.O.Q.) 
Hospital, placed in Lungolago Buozzi 25, 28887 Omegna (VB) - Italy. Study principal investigator 
(PI) will be Dr Marco Spezia. The study will be conducted by PI and other co-investigators, PI’s 
collaborators of the Orthopaedics Unit at C.O.Q. Hospital in Omegna and external collaborators of 
the CTO Hospital of Turin, coordinated by Prof. Alessandro Massè, Director of the Orthopaedics 
Unit and Traumatology 1, CTO Hospital of Turin. The study, being observational, will only concern 

 
 
 
Page 9/20 
VITALECOQ2020 v01 protocol dated 09/18/2020 
Total knee arthroplasty with vitamin E polyethylene 
 
the collection of data about the patient, his medical history and pathology, his surgery and 
prosthetic implant and the clinical and radiographic results. The patient will be contacted by 
telephone and invited to a follow-up visit. Clinical scores will be recorded by the patient and the 
investigators, radiographic signs will be recorded from preoperative and postoperative radiographs 
performed at the last follow-up. The study will therefore not require any additional diagnostic or 
therapeutic services compared to the standard clinical practice. The study will only take into 
consideration patients who have already undergone total knee arthroplasty at the C.O.Q. 
Orthopaedics Unit. 
 
4. Study objective 
The aim of the study is to verify the survival and mid-longterm clinical and radiographic results of a 
consecutive series of primary total knee arthroplasty performed using a cemented total knee 
prosthesis with a vitamin E polyethylene ultra-congruent mobile insert, in comparison to the same 
implant with a conventional polyethylene same design tibial insert. 
 
4.1 Primary endpoint 
The primary objective of the study is to verify that the survival of the prosthetic implant with vitamin 
E polyethylene is not inferior to the survival of the prosthetic implant with conventional 
polyethylene. The primary endpoint is therefore the cumulative implant survival, defining revision 
for aseptic loosening as the endpoint (or failure). 
 
4.2 Secondary endpoints 
The secondary objectives of the study are survival for any reason, clinical results and radiographic 
results, prevalence of complications. Secondary endpoints are therefore: 
• 
Survival of the prosthetic implant with vitamin E polyethylene and with conventional 
polyethylene, with revision for any reason as the end-point, 
• 
the American Knee Society Score (KSS) with Knee score and Function score, 
• 
the Forgotten Joint Score (FKS-12), 
• 
Number of reinterventions (without any component removal), non-surgical complications 
and adverse events, 
• 
Periprosthetic radiolucent lines and radiographic signs of periprosthetic osteolysis. 
 
5. Prosthetic device 
The medical device under investigation is a cemented bicompartmental knee prosthesis with a 
rotating tibial plateau, the GKS Prime Flex Mobile Bioloy® by Permedica S.p.A.  (Figure 1). The 
femoral and tibial components are both coated with a titanium-niobium nitride (TiNbN) ceramic 
coating with 4.5 ± 1.5 microns thickness (Bioloy®). The femoral and tibial component are both 
cemented. The rotating tibial insert has an ultra-congruent articular surface and is made with 

 
 
 
Page 10/20 
VITALECOQ2020 v01 protocol dated 09/18/2020 
Total knee arthroplasty with vitamin E polyethylene 
 
UHMWPE blended with vitamin E (0.1% alpha-Tocopherol), non-cross-linked and sterilized by 
ethylene oxide (VitalE®), or with conventional non-cross-linked UHMWPE (Figure 2).  
 
 
Figure 1. Cemented mobile-bearing total knee prosthesis with TiNbN coating, GKS Prime Flex 
Mobile Bioloy® by Permedica S.p.A. 
 
 
Figure 2. A: UHMWPE blended with 0.1% vitamin E, non-cross-linked and ethylene oxide 
sterilized (VitalE®) ultra-congruent rotating insert. B: Conventional, non-cross-linked, E-beam 
sterilized UHMWPE ultra-congruent rotating insert with same desing. 
 
6. Study population 
The study will concern a consecutive series of patients who underwent primary total knee 
arthroplasty with the same knee prosthesis at the C.O.Q. hospital in Omegna (VB), Italy, from 
January 2011 to December 2015 and who will meet all eligibility criteria. 

 
 
 
Page 11/20 
VITALECOQ2020 v01 protocol dated 09/18/2020 
Total knee arthroplasty with vitamin E polyethylene 
 
6.1 Study group 
At least 152 knees with GKS Prime Flex Mobile Bioloy prosthesis from Permedica with rotating 
mobile insert with vitamin E polyethylene (VitalE®). 
6.2 Control group 
At least 152 knees with Permedica GKS Prime Flex Mobile Bioloy prosthesis with rotating mobile 
insert with conventional polyethylene without vitamin E. 
6.3 Eligibility criteria 
Inclusion criteria: 
• 
Patient underwent primary implant total knee arthroplasty surgery cemented with GKS Prime 
Flex Mobile Bioloy prosthesis with mobile insert by Permedica. 
• 
Patient with minimum follow-up of 7 years. 
• 
Patient aged ≥ 18 years and < 85 years. 
• 
Patients who signed the informed consent. 
 
Exclusion criteria: 
• 
Patient with knee prosthesis other than Permedica's GKS Prime Flex Mobile Bioloy. 
• 
Patients already included in other clinical investigations. 
• 
Patients who do not sign the informed consent. 
 
7. Study procedure 
The study can start only upon the approval of this protocol by the competent Ethics Committee of 
the study centre and after formal communication of the study centre. 
7.1 
Screening 
All patients who underwent primary total knee arthroplasty from January 2011 to December 2015 
at the Orthopaedics Unit of the C.O.Q. Hospital in Omegna will be identified through hospital 
database. If deemed eligible according to the inclusion/exclusion criteria, patients will be contacted 
by telephone by the principal investigator or one of his representatives and invited to take part in 
the study. If possible, the patient information sheet, the patient's informed consent form and the 
information on the processing of personal data will be sent by ordinary post or e-mail. The 
investigator will invite each patient eligible for the study to present themselves at the C.O.Q. 
Orthopaedics Unit for a follow-up and will be invited to present themselves with all the radiographic 
documentation in their possession. 
7.2 
Enrolment 
The principal investigator, or one of his representatives, will explain to the patient the reasons and 
methods for carrying out the study and provide all the necessary information before enrolment. The 
patient will be given the Patient Informed Consent form, the Consent to the Processing of Personal 
Data form. Furthermore, the investigator will be available to provide an adequate response to any 
questions or concerns expressed by the patient. The investigator will advise the patient to carefully 
and calmly read the Patient Informed Consent and Consent to the Processing of Personal Data 
forms and to discuss their contents with their family, friends and doctor before making any decision 

 
 
 
Page 12/20 
VITALECOQ2020 v01 protocol dated 09/18/2020 
Total knee arthroplasty with vitamin E polyethylene 
 
in this regard. The patient will give his informed consent by completing and signing the printed 
Patient Informed Consent and Consent to the Processing of Personal Data forms. From this point 
on the patient will be considered enrolled in the study. 
7.3 
Follow-up visit 
At the follow-up visit, an objective evaluation of the operated knee will be carried out, questions will 
be asked about the patient's current state of health, as well as a radiographic follow-up evaluation 
will be carried out assessing the last anterior-posterior and lateral knee radiographs compared with 
the first postoperative radiograph. 
If the patient has signed the Informed Consent and the Consent to the Processing of Personal 
Data, the information requested in the case report forms described below will be recorded. 
7.4 
End of the study 
To complete the individual patient study, the recording of all information required in all case report 
forms must be complete. These forms must also be completed in the event of spontaneous 
withdrawal from the study, loss of follow-up, failure and surgical revision of the implant. If some 
information is not available, the blank fields must be crossed out. The study is considered 
completed once all case report forms have been completed for all patients deemed eligible for the 
study. 
 
8. Data recording and management 
8.1 
Case Report Forms (CRF) 
For data recording according to this protocol, specific data collection forms, or case report forms 
(CRF), are prepared. The information reported in anonymous fashion on the CRFs must be 
recorded for each patient included in the study. Patients will be identified through their 
name/surname initials following a progressive number. Only the principal investigator will know the 
1:1 association between patient and his ID. The CRFs, annexed to this protocol, are the following: 
1. Medical history. General data of the patient, age, weight, height, diagnosis, medical history, 
previous medical history, known allergies, osteoporosis. 
2. Intervention. Prosthetic implant information, the operation date, tibial insert material, whether 
conventional polyethylene without vitamin E or vitamin E polyethylene (respectively, control 
group or treatment group), are recorded. 
3. AKSS. Knee-specific clinical evaluation score that the investigator completes at the last follow-
up during the patient's follow-up visit [19]. 
4. FJS-12. Clinical evaluation score on the patient's awareness on his prosthesis, to be filled by 
the patient himself at the last follow-up [20]. 
5. Radiographic evaluation. Form that the investigators complete by evaluating and comparing 
the first postoperative radiograph taken after surgery and the anterior-posterior and lateral knee 
radiographs taken at the last follow-up. The radiographic signs showing the presence of any 
periprosthetic radiolucency lines or areas of periprosthetic osteolysis, signs of prosthetic 
loosening and component position will be recorded for each periprosthetic zone according to 
the “Modern Knee Society Radiographic Evaluation System and Methodology for Total Knee 
Arthroplasty”. 

 
 
 
Page 13/20 
VITALECOQ2020 v01 protocol dated 09/18/2020 
Total knee arthroplasty with vitamin E polyethylene 
 
6. Complications. Form to be completed in case of presence of one or more intraoperative or 
postoperative complications recorded through assessment of the patient’s medical records, or 
at the first telephone contact or during the follow-up visit. 
7. Implant outcome. Form to be completed to establish whether the patient has been contacted 
and/or visited, lost to follow-up, or deceased. Furthermore, the outcome of the prosthetic 
implant, i.e. whether it is still in place and well functioning, whether and when it was failed and 
surgically removed (revised) or whether it was failed with reoperation but not surgical removed, 
is recorded. By completing this form, it will be possible to complete the study flowchart like the 
following shown in Figure 3 to describe the outcome of the entire study population.  
 
Figure 3. Descriptive flowchart of the study population. 
 
8.2 
CRFs completion 
The information requested on CRFs are to be recorded by writing with pen on paper printed CRFs. 
• 
The principal investigator is responsible for the completeness and accuracy of the 
information transcribed on the printed CRF forms. 
• 
No field will be left incomplete without a reason. 
8.3 
Data entry, analysis and storage 
All printed CRFs number 1-7, fully completed and signed in original, must be grouped together in 
one folder per patient. The original completed CRFs will be stored by the principal investigator in a 
specific study file, for a period of 15 years at the study centre. A copy of the completed CRFs will 
be stored by the sponsor in a specific study file, for a period of 15 years at the sponsor facility. 
Principal investigator and sponsor have the responsibility for data management. The CRF data will 
be entered by the sponsor into a single electronic database protected by password, which will 
undergo periodic back-up after each new data entry. The sponsor will have the responsibility for 
data analysis. At the end of the study, a PDF/A copy of the database file will be stored at the 
sponsor server and, moreover, will be saved on CD and other external memory and stored at the 
sponsor facility. 

 
 
 
Page 14/20 
VITALECOQ2020 v01 protocol dated 09/18/2020 
Total knee arthroplasty with vitamin E polyethylene 
 
 
9. Duration of the study 
The study will begin following the Ethics Committee approval and after the authorization from the 
C.O.Q. Management to start the study. A duration of approximately 12 months is estimated for 
patient screening, telephone contact, follow-up visits and data recording. The study will end with 
the completion of all the forms required for all enrolled patients. The duration of data entry from the 
paper CRF format to the electronic database is approximately 1 week but can be carried out at the 
same time as data collection. An additional 2 months are estimated for data analysis and drafting 
of the study report. 
 
10. Statistical analysis 
10.1 Sample size 
In order to calculate the sample size of the study group and the control group, a non-inferiority 
study is chosen as the most suitable type. Since in the medium term (5-7 years of follow-up), there 
is reasonably no expectation of significantly better survival results when using a vitamin E 
polyethylene articular insert compared to a standard polyethylene insert, but rather comparable 
results. Therefore, we choose to calculate the sample size of the groups using a statistical test of 
non-inferiority for binary variables (failed implant vs survived implant) of 2 paired groups. 
From the prosthetic joint replacement registries of Australia and UK, reports of 2019 and 2018 
respectively, the cumulative percentage of revision in total knee arthroplasty with mobile insert is 
reported as 2.77% at 5 years of follow-up [NJR Report 2018] and 2.8% for HXPE polyethylene 
inserts at 5 years of follow-up [AUS Report 2019]. The Australian registry also reports 2.3% as the 
cumulative revision rate for total knee arthroplasty with an insert supplemented with vitamin E at 5 
years of follow-up. A difference of at least 4% is considered clinically relevant between survival 
rates of different knee implants. 
Using these failure/survival rates for the control group and the treatment (vitamin E) group, 
choosing a significance level (alpha) of 5%, a power of 80%, a survival rate of 97.2% for the control 
and 97.7% for the vitamin E group and with 4% as margin of non-inferiority between both groups, 
the calculation provides 152 implants per group. 
https://www.sealedenvelope.com/power/binary-noninferior/ 
 
10.2 Outcome analysis 
Cumulative survival is calculated according to the Kaplan-Meier method [21], indicating the 95% 
confidence interval. Descriptive analysis to summarize the data and study results will be carried out 
by calculating mean, standard deviation and range of minimum and maximum values for 
continuous variables and by number and percentage for dichotomous variables. Data distribution 
was tested for normality with Shapiro-Wilk and D’Agostino Pearson tests. 

 
 
 
Page 15/20 
VITALECOQ2020 v01 protocol dated 09/18/2020 
Total knee arthroplasty with vitamin E polyethylene 
 
The analysis of survival rates with 95% confidence intervals of study group versus control group 
will be performed with logarithmic rank test placing statistical significance at a p-value < 0.05. 
The analysis of the differences between the 2 groups regarding the continuous variables will be 
carried out with Student's t test, while Mann-Whitney U test was used when distribution resulted 
not normal. The analysis of differences in dichotomous variables will be carried out with Chi-
Square or Fisher's Exact tests if at least one of the variables has a value≤5. 
The analysis will be carried out with one of the most used statistical software for this type of 
analysis (GraphPad Prism 10.1.0 Software, Boston, MA, USA). 
 
11. Ethical and regulatory considerations 
This clinical investigation is conducted in compliance with the ethical principles set out in the 
Declaration of Helsinki [22]. 
11.1 Regulations 
The clinical investigation described in this protocol is conducted in compliance with international 
standards [23], international guidelines, EU MDR 2017/745 [24] and Italian laws currently in force, 
listed below. The use of personal information collected during this study will take place in 
accordance with Legislative Decree No. 196, 30 June 2003 and with the European Data Protection 
Regulation GDPR 2016/679 [25]. 
11.2 Ethical considerations on the patient 
The study aims to verify the survival, results, safety and reliability of a particular prosthetic device 
used in total knee arthroplasty. This is a cross-sectional study with a retrospective cohort and it will 
not involve any additional treatment for the patient. The patient has already undergone primary 
total knee arthroplasty with the investigational device according to the standard procedures 
provided by the C.O.Q. Orthopaedics Unit. The patient will only be contacted in order to receive his 
consent to participate in the study, for the compilation of a subjective evaluation form and for the 
collection of his clinical and radiographic data from visits and radiographic follow-ups normally 
carried out during normal clinical practice. 
11.3 Ethics Committee 
This protocol will be presented to the relevant Ethics Committee (EC) for the necessary approval to 
start the study. The Principal Investigator will communicate to the EC: 
a) Request for any deviations from the Study Protocol and reports of deviations from the 
Protocol, only if the deviation adversely affects the rights, health and well-being of the 
patient or the scientific integrity of the study; 
b) Amendments to any document already approved by the EC; 
c) If applicable, any suspension or premature termination of the study; 
d) If applicable, justified request to resume the study after its suspension; 
e) Final report of the study or its summary. 

 
 
 
Page 16/20 
VITALECOQ2020 v01 protocol dated 09/18/2020 
Total knee arthroplasty with vitamin E polyethylene 
 
11.4 Insurance coverage 
It is not necessary to take out an insurance policy for the type of study. No additional interventional 
or diagnostic treatment will be performed on the patient that is not already part of usual clinical 
practice. The study is observational. 
11.5 Confidentiality and protection of patients' personal data 
The personal and sensitive data of the patient included in the study will be used exclusively for the 
purposes of scientific research within the limits and in the manner established by the GDPR EU 
2016/679 and by the national regulations that regulate the matter. The personal and sensitive data 
of the patients enrolled in the study will not be disclosed outside the study centre nor will they be 
processed by third parties but will be processed only by the Data Processor and by the healthcare 
personnel appointed by the Data Controller and made available anonymous according to statistical 
analysis in order to protect the privacy and identity of every single patient involved in the study. 
 
12. Publication Policy 
The study promoter/sponsor undertakes to make the results of the trial public in a timely manner, 
whatever they may be, in accordance with GDPR and privacy legislation. It is in the interest of all 
the investigators to achieve a peer-reviewed scientific publication of the present study in a journal 
indexed on PubMed/MEDLINE. Therefore, all the investigators will collaborate in order to draft a 
scientific original article to be submitted to a selected journal. All information and results related to 
the present study will be object of possible presentations at congresses before any publication. 
Ownership of the data generated from the study will be upon the promoter/sponsor. 
 
13. Costs 
The additional costs deriving from the conduct of the Study, such as identification and screening of 
patients, telephone contact of patients, follow-up visits and recording of study data will be covered 
by financial coverage provided by the study sponsor, Permedica S.p.A., as according to the study 
economic agreement. The EC submission fee for study protocol approval is supported by the 
Sponsor. 
 
14. Amendments to the protocol 
All amendments to the protocol following its approval by the EC must be agreed with the principal 
investigator together with his co-investigators and afterwards will be notified to the EC for their 
approval by means of a written letter that justify such amendments. Any suspension or early 
termination of the study will be communicated to the EC. 
 
 
15. ANNEX 
CRFs 1-7 

 
 
 
Page 17/20 
VITALECOQ2020 v01 protocol dated 09/18/2020 
Total knee arthroplasty with vitamin E polyethylene 
 
16. References 
1. Costa L, Luda MP, Trossarelli L, Brach del Prever EM, Crova M, Gallinaro P.In vivo 
UHMWPE biodegradation of retrieved prosthesis.Biomaterials. 1998 Aug;19(15):1371-85. 
 
2. Brach Del Prever EM,Bistolfi A,Bracco P,Costa L. UHMWPE for arthroplasty: past or 
future?J Orthop Traumatol.2009 Mar;10(1):1-8. Epub 2008 Dec 24. 
 
3. Gómez-Barrena E,Medel F,Puértolas JA. Polyethylene oxidation in total hip arthroplasty: 
evolution and new advances.Open Orthop J.2009 Dec 24;3:115-20. 
 
4. Kurtz SM, Dumbleton J, Siskey RS, Wang A, Manley M.Trace concentrations of vitamin E 
protect radiation crosslinked UHMWPE from oxidative degradation.J Biomed Mater Res A. 
2009 Aug;90(2):549-63. 
 
5. Oral E, Greenbaum ES, Malhi AS, Harris WH, Muratoglu OK. Characterization of irradiated 
blends of alpha-tocopherol and UHMWPE. Biomaterials. 2005 Nov;26(33):6657-63. 
 
6. Galea VP, Rojanasopondist P, Laursen M, Muratoglu OK, Malchau H, Bragdon C. 
Evaluation of vitamin E-diffused highly crosslinked polyethylene wear and porous titanium-
coated shell stability: a seven-year randomized control trial using radiostereometric 
analysis. Bone Joint J. 2019 Jul;101-B(7):760-767. 
 
7. Snijders TE, Halma JJ, Massier JRA, van Gaalen SM, de Gast A. The Survivorship of the 
Uncemented Iso-Elastic Monoblock Acetabular Component at a Mean of 6-Year Follow-up. 
HSS J. 2020;16(1):15-22. doi:10.1007/s11420-018-09658-8. 
 
8. Puppulin L, Leto A, Hasegawa M, Pezzotti G. A comparative microstructural study of 
vitamin-E blended and infused highly crosslinked UHMWPE for total knee arthroplasty. J 
Mech Behav Biomed Mater. 2014;39:247-256. doi:10.1016/j.jmbbm.2014.07.029 
 
9. Turner A, Okubo Y, Teramura S, et al. The antioxidant and non-antioxidant contributions of 
vitamin E in vitamin E blended ultra-high molecular weight polyethylene for total knee 
replacement. J Mech Behav Biomed Mater. 2014;31:21-30. 
doi:10.1016/j.jmbbm.2012.12.006 
 
10. Haider H, Weisenburger JN, Kurtz SM, et al. Does vitamin E-stabilized ultrahigh-molecular-
weight polyethylene address concerns of cross-linked polyethylene in total knee 
arthroplasty?. J Arthroplasty. 2012;27(3):461-469. doi:10.1016/j.arth.2011.03.024 
 
11. Wernle JD, Mimnaugh KD, Rufner AS, Popoola OO, Argenson JN, Kelly M. Grafted 
Vitamin-E UHMWPE may increase the durability of posterior stabilized and constrained 
condylar total knee replacements. J Biomed Mater Res B Appl Biomater. 
2017;105(7):1789-1798. doi:10.1002/jbm.b.33710 
 
12. Micheli BR, Wannomae KK, Lozynsky AJ, Christensen SD, Muratoglu OK. Knee simulator 
wear of vitamin E stabilized irradiated ultrahigh molecular weight polyethylene. J 
Arthroplasty. 2012;27(1):95-104. doi:10.1016/j.arth.2011.03.006 
 
13. Schwiesau J, Fritz B, Kutzner I, Bergmann G, Grupp TM. CR TKA UHMWPE wear tested 
after artificial aging of the vitamin E treated gliding component by simulating daily patient 
activities. Biomed Res Int. 2014;2014:567374. doi:10.1155/2014/567374 
 

 
 
 
Page 18/20 
VITALECOQ2020 v01 protocol dated 09/18/2020 
Total knee arthroplasty with vitamin E polyethylene 
 
14. Grupp TM, Fritz B, Kutzner I, Schilling C, Bergmann G, Schwiesau J. Vitamin E stabilized 
polyethylene for total knee arthroplasty evaluated under highly demanding activities wear 
simulation. Acta Biomater. 2017;48:415-422. doi:10.1016/j.actbio.2016.10.031 
 
15. Takemura S, Minoda Y, Sugama R, et al. Comparison of a vitamin E-infused highly 
crosslinked polyethylene insert and a conventional polyethylene insert for primary total 
knee arthroplasty at two years postoperatively. Bone Joint J. 2019;101-B(5):559-564. 
doi:10.1302/0301-620X.101B5.BJJ-2018-1355.R1 
 
16. Flament EM, Berend KR, Hurst JM, Morris MJ, Adams JB, Lombardi AV Jr. Early 
Experience with Vitamin E Antioxidant-Infused Highly Cross-Linked Polyethylene Inserts in 
Primary Total Knee Arthroplasty. Surg Technol Int. 2016;29:334-340. 
 
17. Spece H, Schachtner JT, MacDonald DW, et al. Reasons for Revision, Oxidation, and 
Damage Mechanisms of Retrieved Vitamin E-Stabilized Highly Crosslinked Polyethylene in 
Total Knee Arthroplasty. J Arthroplasty. 2019;34(12):3088-3093. 
doi:10.1016/j.arth.2019.07.018 
 
18. Barrack RL. Retrieval Analysis of an Early Fracture of a Vitamin E-Stabilized Tibial Liner in 
Total Knee Arthroplasty: A Case Report. JBJS Case Connect. 2013;3(2 Suppl 2):1-6. 
doi:10.2106/JBJS.CC.L.00276. 
 
19. Insall JN, Dorr LD, Scott RD, Scott WN. Rationale of the Knee Society clinical rating 
system. Clin Orthop Relat Res. 1989 Nov;(248):13-4. 
 
20. Behrend H, Giesinger K, Giesinger JM, Kuster MS. The "forgotten joint" as the ultimate goal 
in joint arthroplasty: validation of a new patient-reported outcome measure. J Arthroplasty. 
2012 Mar;27(3):430-436.e1. 
 
21. Kaplan EL, Meier P. Nonparametric Estimation from Incomplete Observations. J Am Stat 
Assoc. 1958;53(282):457. doi:10.2307/2281868. 
 
22. 59th WMA General Assembly, Seoul. WORLD MEDICAL ASSOCIATION DECLARATION 
OF HELSINKI, Ethical Principles for Medical Research Involving Human Subjects. 2008 
 
23. ISO 14155 
 
24. EU MDR 2017/745 
 
25. EU GDPR 2016/679 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
Page 19/20 
VITALECOQ2020 v01 protocol dated 09/18/2020 
Total knee arthroplasty with vitamin E polyethylene 
 
17. PROTOCOL APPROVAL  
 
The Investigators, through their signature and date on this page: 
- 
approve this study protocol; 
 
- 
declare that the study will be conducted in accordance with what is reported in this protocol. 
 
Name and surname 
of the investigator 
(*principal) 
Position 
Signature 
Date 
Marco Spezia* 
Head of the 
Management of the 
Surgical Unit and 
Director of the 
C.O.Q. Orthopedic 
Unit of Omegna 
 
 
Alessandro Masse' 
Director of 
Complex Unit 1 
Orthopaedics and 
Traumatology CTO 
of Turin. 
 
 
Lorenzo Banci 
Head of Clinical 
Research 
Permedica SpA of 
Merate. 
 
 
 
 
 
 
 
 
 

 
 
 
Page 20/20 
VITALECOQ2020 v01 protocol dated 09/18/2020 
Total knee arthroplasty with vitamin E polyethylene