A Prospective, Multi-Center, Non-Randomized, Safety and Efficacy Clinical Study of the LEGION™ Primary Knee System for Primary Total Knee Replacement in Subject With Degenerative Knee Disease
Phase: NA
Conditions: Osteo Arthritis Knee, Total Knee Replacement
Sponsor: Smith & Nephew, Inc.

LEGION™ Primary Knee System (10-K300-95301) 
 
Version 3, 02/01/2011- 1 - 
 
 
 
 
 
 
 
 
 
 
A Prospective, Multi-Center, Non-Randomized, Safety and Efficacy Clinical 
Study of the LEGION™ Primary Knee System for Primary Total Knee 
Replacement in Subjects with Degenerative Knee Disease 
 
 
 
 
 
Protocol Number: 
10-K300-95301 
 
Protocol Date: 
February 1, 2011 
 
Study Product: 
LEGION™ Primary Knee System 
 
Sponsor: 
 
Smith & Nephew, Inc. 
 
 
 
7135 Goodlett Farms Parkway 
 
 
 
Cordova, TN  38016 
 
 
 
(901) 396-2121 
 
 
 
 
 
 
 
 
 
 
 
 
This document contains confidential information belonging to Smith & Nephew, Inc.  Except as may be 
otherwise agreed to in writing, by accepting or reviewing these materials, you agree to hold such 
information in confidence and not to disclose it to others (except where required by applicable law), nor 
use it for unauthorized purposes. 
 
™Trademark of Smith & Nephew, Inc. 

 
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STUDY CONTACTS 
 
Primary Smith & Nephew Study Manager:  
Cathy Newbill, CCRA 
Sr. Clinical Affairs Specialist 
Smith & Nephew, Inc. 
7135 Goodlett Farms Parkway 
Cordova, TN  38016 
USA 
 
Email: cathy.newbill@smith-nephew.com 
Phone: (901) 399-6422 
Fax:  (901) 399-1696 
 
 
Secondary Smith & Nephew Study Manager:   
Jason G. Jones, MS, CCRP 
Group Director, Clinical Affairs 
Smith & Nephew, Inc. 
7135 Goodlett Farms Parkway 
Cordova, TN  38016 
USA 
 
Email: jason.jones@smith-nephew.com 
Phone:  (901) 399-5583 
Fax:  (901) 399-1696 
 
 
Smith & Nephew Medical Advisor: 
Peter Heeckt, MD, PhD 
Chief Medical Officer 
7135 Goodlett Farms Parkway 
Cordova, TN 38016 
USA 
 
Phone: (901) 399-5766 
Fax:  (901) 399-1696 
 
 
 
 
 
 
 

 
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TABLE OF CONTENTS 
 
INTRODUCTION ........................................................................................................... 4 
I. 
STUDY OBJECTIVES .............................................................................................. 4 
A.  Efficacy Criteria ............................................................................................... 4 
B.  Safety Criteria ................................................................................................. 5 
C.  Health Economic Criteria .................................................................................. 5 
II. 
DEVICE DESCRIPTION AND PROCEDURES ............................................................... 5 
III. 
RISKS .................................................................................................................. 5 
IV. 
STUDY DESIGN .................................................................................................... 6 
V. 
STUDY POPULATION ............................................................................................ 7 
A.  Subject Selection Criteria ................................................................................. 7 
B.  Inclusion Criteria ............................................................................................. 7 
C.  Exclusion Criteria ............................................................................................ 7 
VI. 
STUDY PROCEDURES ............................................................................................ 8 
A.  Prior to Study Initiation ..................................................................................... 8 
B.  Subject Enrollment .......................................................................................... 8 
C.  Operative Procedures ..................................................................................... 8 
D.  Postoperative Procedures ................................................................................ 8 
E.  Follow-up Procedures ...................................................................................... 9 
F.  Radiographic Procedures ................................................................................. 9 
G.  Adverse Events .............................................................................................. 9 
H.  End of Study ................................................................................................. 10 
I. 
Schedule of Events ....................................................................................... 11 
VII. 
DATA COLLECTION ............................................................................................. 11 
A.  Case Report Forms........................................................................................ 11 
B.  Data Quality Assurance ................................................................................. 12 
VIII.  STATISTICAL METHODS ...................................................................................... 14 
A.  Literature Control .......................................................................................... 14 
B.  Non-inferiority Analysis ................................................................................. 14 
C.  Statistical Methods ....................................................................................... 15 
IX. 
STUDY SUPERVISION .......................................................................................... 16 
X. 
IRB/IEC & INFORMED CONSENT REQUIREMENTS ................................................... 17 
XI. 
DISCLOSURE OF DATA AND DATA-SECURITY ........................................................ 17 
A.  Disclosure .................................................................................................... 17 
B.  Data-Security and Confidentiality .................................................................... 18 
C.  Use of Information and Publication .................................................................. 19 
D.  Subject Drop-out/Withdrawal ......................................................................... 19 
XII.  COMPLETION OF STUDY ..................................................................................... 20 
XIII. INVESTIGATOR AGREEMENT ............................................................................... 20 
XIV.  REFERENCES ...................................................................................................... 21 
 
 
 

 
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INTRODUCTION 
 
As the incidence of joint disease continues to increase, an ever growing percentage of the 
affected population may choose to have total knee arthroplasty (TKA).1, 2, 3, 4  This recent upward 
trend appears to be directly related to the prevalence of certain health factors. Specifically, longer 
life spans, rising obesity rates, and increasing physical activity levels in relatively younger 
populations are all examples of health factors that may significantly contribute to knee 
degeneration.3, 5, 6  While strategies such as weight reduction, lifestyle change or drug therapy 
may offer temporary relief from the symptoms of knee degeneration, TKA remains the standard 
of care for subjects experiencing significant losses in quality of life due to advanced osteoarthritic 
disease.1, 3    
 
Contemporary advances in TKA are allowing for improved surgical techniques and implant 
designs. Given such a positive track record, surgeons have relatively high expectations for 
device safety and function. Moreover, both surgeons and subjects alike are placing increasing 
emphasis on the recovery of function postoperatively.8, 9, 10, 11 Therefore, once a device is 
introduced into a market, research focusing on clinical outcomes is essential in order to assess 
whether or not surgeon and subject expectations are being met. In addition, this data can be 
used to support the design rationale of future devices.  
 
Factors affecting clinical outcomes following TKA include subject age, subject activity level, 
preoperative range-of-motion, gender, anatomic variation, preoperative joint pathology and metal 
sensitivity.  Clinically successful devices must be versatile in order to address variation between 
cases.  
 
I. 
STUDY OBJECTIVES 
 
The objective of the current study is to establish the safety and efficacy of the LEGION™ 
Primary Total Knee System at each postoperative time point using the following 
parameters:  
 
A. 
Efficacy Criteria 
 
 
The Knee Society Clinical Rating System 15 (KSS) will provide separate measures of 
knee pain and subject function. The primary efficacy outcome measure will be 
passive flexion. Range of motion for the KSS score will be determined using a 
goniometer. 
 
The Knee Osteoarthritis Outcomes Score (KOOS) will be used as a self-
administered measure of subject health status.  Specifically, the KOOS score will 
allow for the assessment of pain, stiffness, and overall physical function. 
 
 
Serial radiographic follow-up of study subjects by the Clinical Investigator using 
the Knee Society Roentgenographic Evaluation and Scoring System. 16 The 
purpose of the radiograph evaluation at short-term follow-up is to assess baseline 
knee alignment. At mid-term follow-up and long-term follow-up, the focus of the 

 
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radiographic evaluations are to assess any evidence of loosening as indicated 
primarily by radiolucencies > 2mm; lack of evidence of surface wear or particulate 
debris generation as indicated by early osteolysis, implant migration, or other 
clinical or radiographic abnormalities. A flexed lateral radiograph will be taken and 
used to obtain the flexion angle.  
 
B. 
Safety Criteria 
 
 
Surgical and knee-related adverse events, including revision, will be reported 
during the conduct of this study.   
 
The frequency of revisions and knee related adverse events. 
 
C. 
Health Economic Criteria 
 
 
Intraoperative data, including operative time, blood loss and surgical related 
complications will be assessed. 
 
II. 
DEVICE DESCRIPTION AND PROCEDURES  
 
The LEGION™ Total Knee System is a comprehensive system designed to allow 
surgeons to address straightforward primary to complex knee arthroplasty.  The 
LEGION™ Total Knee System consists of oxidized zirconium or cobalt-chrome primary 
femoral components, titanium primary tibial components, and a polyethylene patella. In 
addition, conventional and cross linked polyethylene tibial inserts are available in both 
traditional and high flexion options. The resulting product is sufficient to accommodate 
a wide range of clinical applications.  
 
Various instruments are required that allow the surgeon to assemble the components and 
prepare the bones to accept the implants. These instruments are routinely utilized as part 
of the standard LEGION™ Total Knee System surgical procedure.  Instruments of the device 
system are typically manufactured from stainless steel meeting applicable American 
Society for Testing and Materials (ASTM) standards. Handles of some instruments are 
made of plastic or aluminum. Additionally, various general surgical instruments and bone 
shaping tools such as chisels, saws, knives, curets, drills, etc. may be used that are a 
generic component of any orthopaedic operative procedure.   
 
III. 
RISKS 
 
There are risks associated with any knee replacement procedure that may result from the 
surgery itself, the device that is implanted, or the instrumentation used to implant the 
device.  This study does not involve investigational products as all components have been 
cleared for use by the FDA and are commercially available.  Product labeling is available to 
outline product risks for this device.  The risk of this surgery should be explained to the 
subject as part of the consent for surgery.   

 
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Study assessment includes radiographic evaluation. Risks may be associated with 
radiographic evaluation as part of the routine care involving TKA procedures and exposure 
to more radiation due to the increased number of x-rays the subject will undergo in follow-
up. X-ray exposure risk is cumulative over a lifetime, and  total exposure should be kept as 
low as possible.  Additional risks associated with this study include the loss of 
confidentiality and the risks associated with blood collection. Blood collection procedures 
require that a sterile needle be placed into a vein. This may be associated with some 
discomfort as the needle is inserted into the vein. Other complications may occur such as 
blood or fluid leaking or collecting under the skin and forming a bruise, mild irritation of the 
skin or tissue in the area, and infection at the blood draw site. 
 
The risks associated with this study include: 
 Loss of confidentiality 
 Exposure to additional radiation due to the increased number of x-rays patient will 
undergo during follow-up visits. 
X-ray exposure risk is cumulative over a lifetime, and the total should be kept as low as 
possible. 
 
IV. STUDY DESIGN 
 
This is a prospective, consecutive series, multi-center clinical study of the LEGION™ Total 
Knee System. The study design was selected to assess the safety and effectiveness profile 
of the LEGION™ Total Knee System in subjects with degenerative knee disease requiring 
primary total knee replacement.   
 
Subjects meeting the entrance criteria specified in this protocol will be approached to 
participate in the study and enrolled sequentially.  Any consenting subjects meeting the 
inclusion criteria are not to be excluded unless they do not consent to participate. A 
nonrandomized, consecutive series of up to 138 subjects will be enrolled at a maximum of 
8 research sites, with an expectation of 18 subjects (up to a maximum of 28 subjects) to be 
enrolled at each site.  When 138 subjects are enrolled from all sites, enrollment will be 
stopped, regardless of the number contributed from each site.  Sites will be selected for 
participation in the study at the discretion of Smith & Nephew.   
 
Follow-up clinical assessments will be at Operative/Discharge, 3 months, 1 year, 2 years, 3 
years, 5 years, 7 years and 10 years. Each subject will receive a standard radiographic 
evaluation at discharge that will be used for baseline analysis.  Additional radiographic 
analysis will be performed at Operative/Discharge, 3 months, 1 year, 2 years, 3 years, 5 
years, 7 years and 10 years.  
 
The primary endpoint will be: 
 
Cumulative percent survival 

 
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The secondary endpoints will be: 
 
Surgical and device related adverse events 
 
Knee Society Score (KSS) 
 
Knee Osteoarthritis Outcome Score (KOOS) 
 
Radiographic evaluation 
 
V. 
STUDY POPULATION 
 
A. 
Subject Selection Criteria 
The subject population considered for this study is osteoarthritic subjects requiring a 
total knee replacement.  The following inclusion and exclusion criteria will be used to 
identify study candidates.  It is very important that every subject who meets these 
entry criteria be enrolled into the study and that no subjects be disregarded or 
omitted for other reasons. A method should be established upon beginning the study 
whereby all potential study candidates are given the opportunity to participate 
sequentially.  
 
B. 
Inclusion Criteria 
Subjects must meet all of the inclusion criteria: 
1. Subject is a candidate for the LEGION™ Primary  Knee System according to the 
instructions for use; 
2. Subject is of legal age and skeletally mature;  
3. Subject is willing to sign and date an ethics-approved consent form and 
participate in the study; 
4. Subject is willing to be available for ten-year follow-up postoperatively. 
 
C. 
Exclusion Criteria 
Subjects must not meet any of the exclusion criteria: 
1. Subject with immunosuppressive disorders; 
2. Subject has grossly insufficient femoral or tibial bone stock; 
3. Subject has an active localized or systemic infection; 
4. Subject is pregnant; 
5. Subject psychological or neurological conditions that would impair the subject’s 
ability or willingness to restrict activities or follow medical advice during the course 
of this study; 
6. Subject is a prisoner. 
 

 
LEGION™ Primary Knee System (10-K300-95301) 
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VI. 
STUDY PROCEDURES 
 
A. 
Prior to Study Initiation 
 
The following documents must be provided to Smith & Nephew prior to study 
initiation: 
1. Copies of the IRB approval letter and IRB approved informed consent for each 
institution used by the Investigator for the clinical study. 
2. A signed Statement of Investigator. 
3. A current, signed, dated CV and medical license for the Principal Investigator 
documenting the location where the study will be conducted. 
 
B. 
Subject Enrollment 
 
1. Screen Subject – All subjects who present with total knee osteoarthritis requiring 
joint replacement will be screened for eligibility in the study based on physical exam 
and radiographic evaluation of the joint.   
2. Informed Consent – If the subject meets all inclusion and exclusion criteria, a 
consent form is presented to the subject.  If the subject elects to participate in the 
study, the subject must sign the consent form prior to completing any study 
related activities. 
3. Preoperative Evaluation – After the subject meets the entrance criteria and signs the 
consent form, the appropriate preoperative study activities are to be completed.   
 
C. 
Operative Procedures 
 
1. Surgical Technique  
The medical device will be implanted using standard surgical technique(s), 
depending on the individual investigator’s standard procedure.  Instrumentation 
specific for the device will be used.  A surgical technique brochure for implanting 
the LEGION™ Total Knee System will be provided to each investigator. 
2. Operative Data  
Operative data and device information will be collected.  All operative adverse 
events will also be reported. 
 
D. 
Postoperative Procedures 
 
Adverse events occurring during the hospital stay will be reported.  Discharge 
information will also be captured. 
 

 
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E. 
Follow-up Procedures 
 
Subjects will be evaluated clinically at 3 months, 1 year, 2 years, 3 years, 5 years, 7 
years, and 10 years postoperative.  Please see Section I, “Schedule of Events” Table 
for details and visit windows.  
 
All radiographic observations are to be reported on the radiographic form.  
Postoperative device-related and surgical adverse events are to be reported.   
 
 
All reasonable efforts should be made to keep in contact with the subject for the 10 
year duration of this study. 
 
F. 
Radiographic Procedures 
 
The important aspects of successful joint arthroplasty are component position, joint 
alignment, and the prosthesis-bone interface or fixation.  
 
In order to assess the safety and efficacy of the current study device, radiographic 
evaluations will be performed during regular follow-up intervals up to the ten year 
postoperative visit.   
 
It is absolutely critical that positioning errors be minimized so that accurate and 
consistent measurements can be taken for all device components.  Radiographs are 
to be taken and reported Operative/Discharge, 3 months, 1 year, 2 years, 3 years, 5 
years, 7 years, and 10 years postoperatively.  The span of the bone-prosthesis 
interface obtained in these 3 views (AP/lateral/skyline) for each component is broken 
down into zone systems.  The scoring system for each of the three components is 
determined by measuring the radiolucent lines (in millimeters) for each of these 
zones. 
 
Any other radiograph views taken are at the discretion of the individual clinician.   
 
G. 
Adverse Events 
 
The following are definitions of adverse events: 
 
Adverse event - any undesirable clinical occurrence in a subject, regardless of the 
cause 
Device-related adverse event - an adverse event that is related to device use, e.g. 
component breakage  
Unanticipated adverse device effect (UADE)- an event that is not identified in 
nature, severity, or frequency in the current package label or informed consent 
Serious/severe adverse event - an event that is  

 
LEGION™ Primary Knee System (10-K300-95301) 
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1) Life threatening or fatal,  
 
 
2) Requires or prolongs hospitalization, 
  
 
3) Results in permanent impairment of a body function, or 
  
 
4) Results in permanent damage to a body structure. 
All postoperative device-related and surgery-related adverse events are to be 
reported. Specifically, all component removals (and/or revisions) whether device-
related or not must be recorded. Other adverse events not listed here may be 
classified as device-related (or non-device-related) depending on their frequency, 
medical 
significance, 
and 
circumstance. 
Device-related 
adverse 
events 
(complications) are defined as any of the following: 
 
 Any device implant component failure (e.g. breakage) 
 Device-wear particle-induced osteolysis, inflammation, etc. Wear debris may be 
metal, cement, and/or HA in composition. 
 Any device component experiencing dislocation, subluxation, subsidence, or 
migration. 
All serious adverse events, life-threatening problems, or deaths that occur during or 
following the use of the devices during the study should be fully documented in the 
research record by the Investigator including the onset date, complete description of 
the event, severity, duration, action taken, and outcome. The event should be 
documented on the appropriate interval and case report form. The investigator will be 
responsible for notifying the reviewing ethics committee or IRB of any unanticipated 
adverse events. The Investigator will record all non-serious, device-related adverse 
events on the appropriate case report form. All adverse events must be followed until 
they resolve, or are considered final. 
 
Adverse events that are serious, unanticipated and possibly device-related must be 
reported in detail by the Investigator to Smith & Nephew and the reviewing IRB as 
soon as possible, but in no event later than ten working days after the Investigator 
first learns of the event.  
 
H. 
End of Study 
 
Study completion status of the subject (e.g. completed per protocol, subject 
withdrawal, device removed, death, lost-to-follow-up, or other reason) is to be 
recorded.  A subject having a specified objection to continuing in the study will be 
withdrawn. Any subject who withdraws from the study postoperatively will be 
considered in the data analysis up until the time of their withdrawal.  Subjects lost to 
follow-up will be documented on the End of Study form. All reasonable efforts should 
be made to keep in contact with the subject for the 10 year duration of this study.  

 
LEGION™ Primary Knee System (10-K300-95301) 
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Subjects may be taken out of the study without their consent for the following 
reasons: 
 
 The Investigator decides that continuing the study would be harmful 
 Participants miss so many appointments that their data cannot be used in 
the study 
 The study Sponsor (Smith & Nephew, Inc.) decides to end the study 
 
If a subject is unwilling to return to the site for evaluation, available information may 
be collected on the subject’s condition via telephone or correspondence.  
Participation in this study is completely voluntary. If any subject chooses not to 
participate or removes their consent at any time, subject care must continue 
according to the physician’s standard of care. The site must document changes in 
subject enrollment via a de-identified summary and forward this information to the 
sponsor. All subjects who complete the study prematurely will be included in the data 
analysis up until the time of their study completion. 
 
I. 
Schedule of Events 
 
Study Activity 
Preop 
O/D 
3 mo 
(± 2 mo) 
1 yr 
(± 3 mo) 
2 yr 
(± 6 mo) 
3 yr 
(± 1 yr) 
5 yr 
(± 1 yr) 
7 yr 
(± 1 yr) 
10 yr 
(± 1 yr) 
Inclusion/exclusion Form 
X 
- 
- 
- 
- 
- 
- 
- 
- 
Informed Consent 
X 
- 
- 
- 
- 
- 
- 
- 
- 
Demographics/ 
Med History Form 
X 
- 
- 
- 
- 
- 
- 
- 
- 
Clinical KSS/KOOS 
X 
- 
X 
X 
X 
X 
X 
X 
X 
Operative/Discharge Form 
- 
X 
- 
- 
- 
- 
- 
- 
- 
Radiograph Analysis  
- 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Form 
- 
† 
† 
† 
† 
† 
† 
† 
† 
End of Study/Exit  Form  
- 
- 
† 
† 
† 
† 
† 
† 
† 
† This form should be completed when necessary. 
 
VII. DATA COLLECTION 
 
A. 
Case Report Forms 
 
Case report forms (CRF) will be used to collect the data obtained during this study. 
Data must be transcribed from source documentation to CRFs. Subject questionnaire 
data will be recorded directly onto the provided CRFs, and will not be transferred from 
source documentation.  

 
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The CRFs are a set of forms that include questions to record preoperative, operative, 
discharge, postoperative and x-ray information. A complete set of CRFs will be 
provided for each subject enrolled.    
 
Smith & Nephew, Inc. currently uses the DataFax data collection system.  It allows for 
case report forms to be faxed directly into the database system. Using this system will 
increase the speed and efficiency of data collection from the study sites, and will 
improve the quality of the study data through the use of automated missing data 
queries. DataFax will also track subject visits according to the scheduled intervals. 
Periodic due/overdue reports will be sent to the clinical site to help ensure subjects 
are evaluated at the appropriate intervals. 
 
Investigators are required to fax all completed CRFs to Smith & Nephew at (877) 515-
0213, at the appropriate intervals to ensure consistent, accurate analysis of study 
data.  Any parameters not collected may adversely impact the quality and validity of 
the final results of this study.  Special care should be taken to record any device-
related or surgical adverse event including a complete description of their relationship 
to the study device.   
 
Source Documents – Investigators are responsible for obtaining and maintaining 
complete subject health information in the medical record for each subject and each 
assessment (source documents). 
 
Source data includes all information in original records and certified copies of original 
records of clinic findings, observations or other activities in a clinical trial necessary 
for the reconstruction and evaluation of the trial.  Source data are contained in source 
documents (e.g., hospital records, clinic evaluation, transcriptions, operative notes, x-
rays, radiology reports, blood collection and shipment records, research subject files, 
etc.) 
 
Every data point that is found on the CRF and submitted to the Sponsor must have a 
corresponding source document in the subject record(s) that provides detailed 
evidence of the assessment.  The Sponsor and its agents will be provided direct 
access to source documents for the purpose of verifying the clinical data submitted to 
the Sponsor by the investigator on CRFs. 
 
B. 
Data Quality Assurance 
 
Quality assurance procedures are designed to ensure that complete, accurate and timely 
data are submitted, that protocol requirements are followed, and that complications or 
adverse reactions are immediately identified and addressed until closure. 
 

 
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The Clinical Affairs Department at Smith & Nephew, Inc. will promptly review all 
incoming case report forms and accompanying documentation to identify inconsistent or 
missing data and device-related complications.  Problems with these data will result in 
queries to the site that should be addressed within two weeks of receipt. It is incumbent 
upon the site to review all data recorded on each form prior to submission to Smith & 
Nephew, Inc. To ensure the confidentiality of data, Smith & Nephew, Inc. will maintain a 
secure study database.  
 
Protocol Deviation – Protocol deviation is defined as any non-adherence to the 
protocol or Investigational Plan.  Protocol deviations will be reported to Smith & 
Nephew on the appropriate Case Report Form.  The investigator must also report 
protocol deviations to the IRB as required. 
 
Modification of the Protocol – Neither the Investigator nor Sponsor will modify this 
protocol without mutual agreement.  After agreement to initiate the modification (in 
the form of a protocol amendment), the Investigator agrees not to institute this 
modification until instructed to do so by the Sponsor. It may  be necessary to obtain 
applicable regulatory authority and IRB/EC approval prior to implementation of any 
change in the protocol that may affect the scientific soundness or the rights, safety, or 
welfare of the subjects involved. 
 
Departure from Protocol for Individual Subject in Emergency – Only in an 
emergency where action is necessary to protect the life or physical well-being of the 
subject will a departure from the protocol for an individual subject be allowed, and the 
departure will be for that subject only.  The investigator or other physician in 
attendance in such circumstances will notify the IRB and contact the clinical study 
manager at Smith & Nephew immediately (within 48 hours) by telephone.  If the study 
manager is unavailable, contact the next available Smith & Nephew Clinical Affairs 
professional. 
 
Cathy Newbill, CCRA 
Telephone:  (901) 399-6422 
Email: cathy.newbill@smith-nephew.com 
Smith & Nephew, Inc.  
 
 
7135 Goodlett Farms Parkway 
Cordova, TN  38016 
 
A decision will be made by the investigator and Smith & Nephew about whether the 
subject (for whom the departure from protocol was affected) is to continue in the 
study.  Any departure from the protocol will be described in a written report by the 
investigator who will send the report to the IRB and Smith & Nephew along with the 
reasons for the departure, including relationship to the therapeutic use of the device. 
 

 
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VIII. STATISTICAL METHODS  
  
A. 
Literature Control 
 
For the current investigation, ahistorical control has been determined using the 
Australian Orthopedic Association National Joint Replacement Registry Annual Report 
2009 (See below).  
 
Survival Estimate of Primary Knee Replacement (Annual revision free rate * 
follow-up interval in years) 
 
 
F
For the current study, the revision free rate will be based on knowledge of parametric 
proportional hazards models. The survival times with an exponential distribution have 
a constant hazard function associated with exponential distributed survival time. 
Thus, for individuals sampled from this exponential survival distribution, the 
probability of surviving beyond time t=8 years is 0.95. The entire survival distribution 
can be defined by the same parameter value λ=0.0064 (nQuery Advisor 6.01).  
 
B. 
Non-inferiority Analysis 
 
As previously reported, an annual survival rate was extrapolated using equivalency of 
exponentially distributed survival times to determine 10 year survivorship.  As such, 
the current 10-year investigation will utilize a control survival rate of approximately 
93.7% (nQuery Advisor 6.01). 
 
All subjects implanted with the LEGION™ Primary Knee System, who meet the inclusion 
and exclusion criteria and who gave their voluntary consent to participate in the study 
will be included in the analysis. The analysis will include the description of subject 
demographics and baseline characteristics.  Accountability data will include the 
number of subjects enrolled and the followup data collected.  Data will be analyzed 
separately for changes from preoperative at 3 months, 1 year, 2 years, 3 years, 5 
years, 7 years, and  10 years(if required). Safety will be assessed by identifying and 
summarizing device-related adverse events throughout the study.  
 
The sample size is calculated based on the non-inferiority of the study device; the 
following hypotheses will be tested to test the difference in cumulative percent 
survival of the study device with the literature reference rate with a non-inferiority 
margin, >0: 
 
H0: 0 -   
Ha: 0 - <   
 
1 year 
3 year 
5 year 
7 year 
8 year 
Total Knee 
99.0% 
97.2% 
96.2% 
95.4% 
95.0% 

 
LEGION™ Primary Knee System (10-K300-95301) 
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Where  is the cumulative percent survival of study device and  0 is the reference 
rate, respectively. =0.07. For these hypotheses, rejection of the null hypotheses will 
imply non-inferiority of the study device compared to the reference rate. 
 
For the above hypotheses, the sample size for a specified α and power 100(1 – β)% is 
given by,  
 
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z
n
 
 
(Chow et al, 2003), where δ is the non-inferiority margin and nonnegative number. 
 
The cumulative percent survival for the study device is unknown for this population, 
but there is no reason to believe that it would be less than the reference rate. 
Therefore, a conservative success rate of 93.1% for the study device is used at 10 
years. The non-inferiority margin δ of 0.07 is chosen in the study (p13, Chow, Shao, 
and Wang, 2003). 96 subjects are required to achieve 100(1 – β) % =80% power to 
detect non-inferiority at the Significance level of α = 0.05. Based on the experience 
study, allowing 30% of the subjects lost to follow up by the end of 10 years, a sample 
size of at least 138 subjects are needed in this study. Therefore, a total of   138   
subjects will be enrolled into the study in up to 8 clinical sites. 
 
C. 
Statistical Methods 
 
Primary and secondary outcomes will be evaluated with the use of listings and 
summary statistics. 95% confidence intervals will be calculated for proportions and 
averages corresponding to the clinically significant outcomes. Improvement in pain 
and function will be analyzed using t-test or Wilcoxon Rank tests. Kaplan-Meier 
estimates will be used to analyze the survivorship of the prosthesis.  For survivorship 
analyses, revision will be defined as failure.  Adjustment of prognostic factors to the 
improvement in outcomes will be performed if needed using appropriate parametric 
or non-parametric statistical analysis.  All statistical analyses and calculation of 
confidence intervals will be performed using SAS or other appropriate statistical 
software. An alpha value of =0.05 will be used in all hypothesis testing. 
Experience from numerous studies has revealed that most of the missing data are 
usually due to lost to follow-up, revision, death and subject withdrawal. A complete 
accountability along with the explanation for lost-to-follow-up, death, revision, and 
withdrawn subjects will be provided in the final study report. The missing due to 
revision will be treated as device failure. A complete assessment of the 
informative/non-informative missing data will be performed using Kaplan-Meier (KM) 
method. The KM estimate of the success rate along with the 95% confidence interval 
of the estimate will be included in the final report. 

 
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IX. 
STUDY SUPERVISION  
A. 
Investigator Responsibilities 
 
The investigator is responsible for ensuring that the investigation is conducted 
according to the Statement of Investigator, this Protocol and applicable FDA 
regulations as required.  Investigator responsibilities are defined in Title 21 of the 
US Code of Federal Regulations Part 812, Subpart E and in ICH GCP guidelines. 
 
B. 
Sponsor Responsibilities 
 
Designated qualified personnel from the Clinical Affairs Departments at Smith & 
Nephew have been designated for study management and study monitoring. Smith & 
Nephew reserves the right to contract with qualified clinical research consultant(s) to 
manage the study and/or perform administrative duties.   
 
Responsibilities of the study manager include: 
 
 
conducting  site qualification visits (if applicable);  
 
receiving completed case report forms;  
 
monitoring the study to ensure that proper records are being kept, study 
procedures are being followed; and complete and accurate data are being 
collected 
 
For any questions regarding this study, please utilize the following study contact 
information: 
 
 
Study Manager: 
Cathy Newbill, CCRA 
Sr. Clinical Affairs Specialist 
7135 Goodlett Farms Parkway 
Cordova, TN  38016 
Tele:  (901) 399-6422 
FAX: (901) 399-1696 
Email: cathy.newbill@smith-nephew.com 
 
Secondary Sponsor 
Contact: 
Jason G. Jones, MS, CCRP 
Group Director, Clinical Affairs Manager 
7135 Goodlett Farms Parkway 
Cordova, TN 38016 
Tele:  (901) 399-5583 
FAX: (901) 399-1696 
Email: jason.jones@smith-nephew.com 
 

 
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A site qualification visit may be conducted before the study is initiated. Close contact will be 
maintained between the study manager and the investigational site to ensure that data 
regarding each subject is expeditiously sent to the Sponsor for review.  The adequacy of 
the facilities, the availability of the investigator, the potential number of study participants, 
and the provisions for support staff will also be assessed during any site visit. 
 
To ensure that the investigators and his/her staff understand and accept their defined 
responsibilities, the monitor or their representative will maintain regular correspondence 
and may perform periodic site visits during the course of the study to verify the continued 
acceptability of the facilities, compliance with the protocol, and the maintenance of 
complete records.  Monitoring will include review and resolution of missing or inconsistent 
data. The Sponsor currently uses the Chief Medical Officer as a Medical Advisor to advise 
on medical issues related to clinical studies (contact information for the Medical Advisor 
can be found on page 2).   
 
X. 
IRB/IEC & INFORMED CONSENT REQUIREMENTS 
 
Investigators are responsible for obtaining approval from the appropriate IRB/IEC committee 
prior to study initiation. A copy of IRB/IEC approval documents should be forwarded to the 
study manager at Smith & Nephew. The local hospital's IRB/IEC committee should give this 
approval, or should provide a waiver document for the investigator to use a central IRB/IEC.  
Typically the IRB/IEC approval consists of the protocol, the informed consent form, recruitment 
materials, and often the case report forms and associated documentation. A copy of the 
IRB/IEC approval documentation must be provided to sponsor prior to initiation of site, and 
receipt of subject study binders.   
 
As institutions vary, so do the requirements regarding medical device studies and the subject 
informed consent requirements. It is the Investigator’s responsibility to ensure that appropriate 
ethical oversight is obtained. Both the investigator and the Sponsor are responsible for 
ensuring that the study is conducted in compliance with the approved study protocol, Good 
Clinical Practice (GCP) guidelines, and all applicable regulatory requirements.  The Investigator 
is required to report withdrawal of IRB approval to Smith & Nephew within five days.  
  
XI. 
DISCLOSURE OF DATA AND DATA-SECURITY 
 
A. 
Disclosure 
 
Individual investigators may request summaries of their subject data by contacting 
the clinical study manager. However, if review of another Investigator’s data is 
requested for comparison purposes, the study manager must have confirmation of 
the involved Investigator’s authorization before release of their data can occur. Entire 
study summaries can be provided without such authorization(s), but the summary will 
not be stratified by individual surgeon or obtain surgeon identifiers. 
 

 
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B. 
Data-Security and Confidentiality 
 
The records of this study will be kept private.  In any sort of published report, there 
will be no identifying information. Records for this study may, however, be reviewed 
by representatives of the Institutional Review Board, which is the committee that 
oversees research, the United States Food and Drug Administration or other 
government agencies, and authorized representatives of the Sponsor or Investigator 
participating in this study may inspect and photocopy all medical records applicable 
to involvement in this study.  To that extent, confidentiality is not absolute.   
 
Surgeons will notify subjects as to any new information during the course of the study 
which may affect continued participation. 
 
Participating subjects will be asked to sign a consent form.  It allows the study 
Sponsor and the study investigator to collect, process and pass on to the Sponsor 
organizations any relevant personal de-identified health information collected from 
the subject, including billing records, during the study.  These are activities routinely 
carried out during all clinical studies. If the subject decides to take part in the study, 
and the Investigator cannot locate the subject, the site will attempt to make contact 
using all reasonable methods including use of Private Investigative services. The 
Private Investigator would only be given subject name, address, phone number, and 
date of birth as a means of location. 
 
De-identified personal information (including sensitive personal health information, 
such as medical history and racial / ethnic origin if relevant to the study) will be 
reviewed, collected on a computer database, stored in electronic or manual files, 
audited, and / or otherwise processed by: 
 
 the clinical study investigator and his associates 
 the study sponsor, Smith & Nephew, and / or its associate companies 
 regulatory or other governmental authorities of the United States and other 
countries 
 other persons authorized by the study sponsor 
 the investigator’s employees 
 Other persons or agencies as required by law or allowed by federal 
regulations 
 
Personal data will be collected and processed to: 
 
 check suitability to take part in the study 
 monitor treatment with the study device 
 compare and pool treatment results with those of other subjects in clinical 
studies 
 support the development of the study device 

 
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 support the licensing application for regulatory approval of the study device in 
the world 
 support the marketing, distribution, sale and use of the study device 
anywhere in the world 
 
Personal information may be processed within the US or elsewhere in the world.  The 
Sponsor, an associated company, or a carefully selected third party organization may 
transfer, process, store, or review personal information inside, or outside, the US.  
Subjects are free to refuse authorization to transfer personal information.  If the 
subject chooses not to agree to this authorization, the subject may be ineligible to 
participate in the study.  If the subject chooses not to sign the authorization, it will not 
harm relations with the surgeon. 
 
The subject has the right to inspect their medical records at any time.  Research 
records may be unavailable until the conclusion of the study.  At that point, it will be 
made available.  The subject may speak with the surgeon in order to access records. 
 
Whenever personal information is processed; it will be kept confidential and secure to 
the best of the Sponsor and Investigators ability.  It will be used only for the purpose 
for which it was collected.  
 
Retention of Records – The Investigator and Sponsor are required to maintain all 
study documentation for at least 3-5 years after the conclusion of the study. 
Thereafter, written permission is required from the study monitor in order to move or 
destroy any study document. If subjects wish to revoke authorization to use personal 
information, the subject shall inform their surgeon in writing.  Also, even after 
participation in the study ends, the Investigators and Sponsor may continue to use 
and disclose the de-identified health information obtained during the study, before 
the end of study participation. 
 
C. 
Use of Information and Publication 
 
Should the investigator wish to publish the results of this clinical investigation or the 
results of the activities in this clinical trial, the manuscript shall be submitted to Smith 
& Nephew for review prior to submitting the manuscript for publication.  
 
 
D. 
Subject Drop-out/Withdrawal 
 
Subjects may withdraw at any point during the study.  A final evaluation will be 
completed for all subjects who do not finish the study, and the reason for the 
withdrawal will be documented.  After withdrawing from the study, no effort will be 
made to follow the subject. The Investigator will sign an End of Study/Exit case report 
form stating the reason the subject withdrew from the study. However, some actively 
enrolled subjects will not return for follow-up exams due to a variety of reasons.  

 
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Often, actively enrolled subjects move during the course of the study without 
informing the study site.  The investigator/study site is committed to use every 
reasonable measure to obtain follow-up clinical data. The Sponsor reimburses sites 
for data collection activities associated with subject clinic follow-up.  The Sponsor 
reimburses reasonable examination and x-ray fees if not covered by subject’s 
insurance or are otherwise considered non-standard practice at a clinic or institution.   
Due to the long length of the study, sites will attempt to contact still active but non-
respondent subjects using phone calls, regular mail, e-mail, certified letters or other 
means to urge subjects to return for clinic follow-up or ascertain if a subject has 
moved, died, or otherwise become lost to follow-up.  These actions, along with any 
other options available to the site, should be followed to exhaust all reasonable 
means in locating lost subjects.  These actions should be documented in the 
subject’s records and may be performed concurrently or in parallel. 
 
XII. COMPLETION OF STUDY 
 
The Investigator is expected to complete enrollment and follow up per the clinical trial 
agreement.  Continuation of this study beyond the agreement must be mutually agreed 
upon in writing both by the investigator and by the sponsor.  It is agreed that either the 
investigator or the sponsor, may terminate this study before the above date, provided a 
written notice is submitted at a reasonable time in advance of intended termination.  After 
conclusion of the study,  the sponsor will prepare a clinical summary which will include 
tabulations of the data used to evaluate safely and efficacy. 
 
XIII. INVESTIGATOR AGREEMENT 
 
A fully-executed Statement of Investigator that includes the investigator and co-
investigators, must be in place prior to any study-related activities occurring.  
 

 
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XIV. REFERENCES 
 
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3. 
Chow, S.C., Shao, J., Wang, H. “Sample size calculations in Clinical Research” 
Publisher: Tayloy&Francis, New York, NY.pg.13, pg. 85-86.2003.  
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David Collett. “Modelling Survival Data in Medical Research”Chapman&Hall/CRC . 
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5. 
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Joint Surg A.  87: 1487-1497, 2005. 
 
6. 
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7. 
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Mokdad, AH, ES Ford, BA Bowman, WH Dietz, F Vinicor, VS Bales, JS Marks. 
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9. 
Laupacis, A, R. Bourne, and C Rorabeck. The effect of elective total hip replacement 
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13. Noble, PC, MJ Gordon, JM Weiss, RN Reddix, MA Conditt, KB Mathis. Does total knee 
replacement restore normal knee function? Clin Orthop Relat Res. 157-165, 2005. 
 

 
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14. Bourne, R, R Laskin, J Guerin. Ten-year results of the first 100 Genesis II total knee 
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16. Ishii, Y. Y Matsuda, S Sakata, N Onda, G Omori. Primary total knee arthroplasty using 
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17. Insall, J. N., Dorr, L. D., Scott, R. D., Scott, W. N. Rationale of the knee society clinical 
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18. Ewald, F. C. The Knee Society Total Knee Arthroplasty Roentgenographic Evaluation 
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