A Prospective, Randomized Study Comparing the Survival for X-3 Polyethylene to N2Vac Polyethylene When Used With the Triathlon Posterior Stabilized (PS) Total Knee System.
Phase: NA
Conditions: Arthroplasty, Replacement, Knee, Total Knee Replacement
Sponsor: Mayo Clinic

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PROTOCOL TITLE:  
A PROSPECTIVE, RANDOMIZED STUDY COMPARING THE 
SURVIVAL FOR X-3 POLYETHYLENE TO N2VAC POLYETHYLENE 
WHEN USED WITH THE TRIATHLON POSTERIOR STABILIZED (PS) 
TOTAL KNEE SYSTEM 
 
PRINCIPAL INVESTIGATOR: MATTHEW P. ABDEL, M.D. 
 
SUB-INVESTIGATORS : 
HAROLD I. SALMONS, M.D. 
 
 
 
 
DIRK R. LARSON, M.S. 
 
 
 
 
MICHAEL J. STUART, M.D. 
 
 
 
 
MARK W. PAGNANO, M.D. 
MARK J. SPANGEHL, MD 
HENRY D. CLARKE, MD 
CEDRIC J. ORTIGUERA M.D. 
 
 
INVESTIGATOR ADDRESS: 
MATTHEW P. ABDEL, M.D. 
 
 
 
 
MAYO CLINIC 
 
 
 
 
200 FIRST ST. SW 
 
 
 
 
ROCHESTER, MN  55905 

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SUMMARY 
A prospective, randomized, single-blinded clinical trial is proposed to compare Stryker 
Orthopaedics N2Vac Polyethylene to their X3 Polyethylene when used with the Triathlon 
Posterior Stabilized (PS) total knee system. This is a fixed-bearing knee intended for use 
in patients undergoing cemented total knee arthroplasty.  The devices to be used are both 
FDA approved via 510k clearance.  
A total of 572 cases (286 per group) will be entered.  Each patient will be assessed pre-
operatively and post-operatively at three months and two, five, seven and ten years. The 
primary endpoint will be the revision rate at ten years. This outcome will be evaluated 
using event rates analysis assuming a Poisson distribution. Additional endpoints, 
including the instance of mortality, revision surgery, deep vein thrombosis, pulmonary 
embolus, neurovascular complication, and infection will be evaluated in the same 
manner.  Other outcome measures incorporated in the Knee Society Clinical rating scale 
will undergo appropriate generalized linear regression for the type of outcome involved.   
PURPOSE 
The primary aim of the study is to compare the survivorship of two types of polyethylene 
(conventional N2Vac and highly cross-linked X3) used in a fixed-bearing total knee 
system in patients undergoing cemented total knee arthroplasty.  These results will be 
measured through radiographs at each post-operative interval with an independent 
radiograph review being performed after all patients have reached 7 and 10 year follow-
up. Secondary results will also be collected and will focus on disease-specific (Knee 
Society Scores), global (SF-12), and outcome measures.  Radiographic results consisting 

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of standing anteroposterior, lateral and Merchant views of the surgical knee will be 
recorded and analyzed.  Completion of the initial investigation will occur at the 10-year 
interval after the last enrolled patient. 
INTRODUCTION 
Pain, weakness, instability, and progressive dysfunction are the hallmarks of arthritis of 
the knee.  Total knee replacement may frequently be the only therapeutic intervention to 
provide adequate improvement in pain and function. Fixed bearing knees have a long 
track record of clinical success but the issue of polyethylene wear resulting in debris that 
leads to osteolysis has been the limitation of the survivorship of these implants. Highly 
cross-linked polyethylene has been used in hips for over 7 years with excellent clinical 
results. However the use of first-generation of highly cross-linked polyethylene in the 
knee has been avoided over concerns of the ability of highly cross-linked polyethylene to 
withstand shear forces across the tibia.  
 
METHODS AND MATERIALS 
Study Design 
This will be a prospective, single-blinded, randomized clinical trial.  A physician’s 
assistant will supervise the running of the study and evaluate the patients.   The 
randomization will be provided through a password-protected computer program 
developed by Mayo Clinic Division of Biostatistics personnel that can be accessed at any 
surgical computer terminal by the research assistant.  Patients will be blinded as to which 

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polyethylene tibial insert and patella they have received, provided they do not insist on 
being informed, or unless it becomes medically necessary to do so. 
Randomization of the Study Patients 
In order to assign patients to specific treatment groups in an unbiased manner, 
randomization will occur prior to surgery. After the patient has met the entrance criteria, 
and given full informed consent to participate in the study, they will be assigned to the 
treatment group.  The randomization will be stratified by variables with potential 
confounding effects on the outcomes of interest. Specifically, patients will be stratified by 
gender (male / female), Body Mass Index category (<25.0 / 25.0-29.9 / ≥30) and age 
group (21-55 / 56-85).  Within each stratum, subjects will be assigned to one of the two 
treatment groups using a computerized dynamic allocation program. Patient 
randomization will be performed just prior to surgery. 
Sample Size/Inclusion Criteria 
Five hundred seventy-two (572) patients will be recruited into the study; 286 receiving 
N2Vac polyethylene and 286 receiving X3 polyethylene.  
Surgical Technique 
All procedures will be performed by one of nine  knee arthroplasty surgeons (MEC, 
ADH, TMM, MWP, JSS, MJS, CJO, HDC, MJS).  The femoral, tibial and patellar 
components will be cemented. The patellar components will be all-polyethylene. 
Hospitalization 
Patients will be admitted to the hospital on the day of their surgery, unless medical 
problems dictate earlier admission.  Hospitalization of 3 to 5 days is routine for these 

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patients, although complications may prolong this.  These will be recorded on the data 
collection forms.  An extension splint will not be used following surgery and no pillows 
are to be used under the knee.  Continuous passive motion will be used according to the 
individual surgeon’s discretion as part of the postoperative management.  The patient will 
receive one preoperative dose and two postoperative doses of IV antibiotics separated by 
a 6 to 8 hour period.  All patients will receive appropriate anticoagulation for deep 
venous thrombosis prophylaxis at the individual surgeon’s discretion. 
Post-Op Physical Therapy 
Both treatment groups will have similar postoperative care.  Structural physical therapy 
will begin the day after surgery and continued during the hospitalization.  A home 
therapy program will be given to the patient. 
a. Initial Post-op Day 1, use of walker or personnel to assist with transfer from 
bed to chair. 
b. Active ROM to begin within first 24 hours postop. 
c. Weight bearing status and progression as tolerated. 
Progression 
• Progress ambulation from walker or crutches to a cane as tolerated 
• Post-Op Day 1 – commence ice and exercises as per exercise attached.  May 
include patellar mobilizations, massage to reduce swelling. 
• CPM initiated (at the individual surgeon’s discretion) on the day after surgery 
as tolerated and discontinued at dismissal from hospital. 

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• Patients should be encouraged to maximize independent ambulation and 
increase distance ambulated daily 
Discharge Criteria 
• Independent and safe using a walker or crutches for ambulation and 
satisfactory pain control. 
Radiographic Parameters 
Standing alignment, lateral, and Merchant (45 degrees of flexion) radiographs will be 
obtained preoperatively, immediately postoperatively, and three months, two years, five 
years, seven years, and ten years after surgery.  An independent reviewer will evaluate the 
radiographs for radiolucent lines, component position and alignment after all patients have 
completed the seven-year and ten-year visit. 
Study Procedures 
Data Collection (obtained via a blinded research assistant) 
Visit #1 
Preoperative:  Consent and initial data acquisition:  Knee Society Clinical 
Rating Score, SF-12, Radiographs of the knee (standing alignment, lateral 
and Merchant view at 45° of knee flexion) 
Visit #2 
Three months:  Radiographs of the knee (standing alignment, lateral and 
Merchant view at 45° of knee flexion); Knee Society Clinical Rating 
Score, SF-12.  These questionnaires can be obtained in-office, by phone or 
by mail.  While it is preferred that the visit occur in the clinic, if the 
participant is not returning they will still be asked to complete the study 
questionnaires.   

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Visit #3 
Two years:  As above #2.  . These questionnaires can be obtained in-
office, by phone or by mail.  While it is preferred that the visit occur in the 
clinic, if the participant is not returning they will still be asked to complete 
the study questionnaires. 
 
Visit #4 
Five years:  As above.  These questionnaires can be obtained in-office, by 
phone or by mail.  While it is preferred that the visit occur in the clinic, if 
the participant is not returning they will still be asked to complete the 
study questionnaires. 
 
Visit #5 
Seven years:  As above.  These questionnaires can be obtained in-office, 
by phone or by mail.  While it is preferred that the visit occur in the clinic, 
if the participant is not returning they will still be asked to complete the 
study questionnaires. 
 
Visit #7 
Ten years:  As above.  These questionnaires can be obtained in-office, by 
phone or by mail.  While it is preferred that the visit occur in the clinic, if 
the participant is not returning they will still be asked to complete the 
study questionnaires. 
 

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Measurement Tools 
Knee Society Clinical Rating Score 
This is a clinical standard for rating efficiency of total knee replacement.  It is a disease-
specific test, which has been validated and is widely used.  These questionnaires can be 
obtained in-office, by phone or by mail.  While it is preferred that the visit occur in the 
clinic, if the participant is not returning they will still be asked to complete the study 
questionnaires. 
SF-12 
This self-administered questionnaire has been validated for measuring and monitoring 
health status in large group studies.  These questionnaires can be obtained in-office, by 
phone or by mail.  While it is preferred that the visit occur in the clinic, if the participant 
is not returning they will still be asked to complete the study questionnaires. 
Complications/Lost to Follow-up Form 
Any serious complication, which occurs relating to the device, will be documented.  
Sepsis, embolism, failure of primary wound healing, hemorrhage, prosthesis loosening, 
skin necrosis, hematoma, device failure or fracture are possible complications.  If for any 
reason a patient is lost to follow-up (will not return for office visits or complete and 
return mailed study questionnaires) there must be a completed form to indicate this event. 
Financial Complications 
None 
Timetable 
The estimated time required to enroll 572 cases is three years. 

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Medical Device 
All study devices are FDA-approved. 
 
PARTICIPANT POPULATION 
Eligibility Criteria 
Inclusions: 
1. Subjects willing to sign the informed consent. 
2.  Subjects able to comply with follow-up requirements including post-
operative weight bearing restrictions and self-evaluations. 
3. Male and non-pregnant female subjects ages 21-85 years of age at the time 
of surgery. 
4. Subjects requiring a primary total knee replacement. 
5. Subjects with a diagnosis of osteoarthritis (OA), traumatic arthritis (TA), 
or avascular necrosis (AVN). 
6. Subjects with intact collateral ligaments as determined by the surgeon 
investigator. 
Exclusions: 
 
1. Subjects with inflammatory arthritis. 
2. Subjects with a history of total or unicompartmental reconstruction of the 
affected joint. 
3. Subjects that have had a high tibial osteotomy or femoral osteotomy. 

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4. Subjects with neuromuscular or neurosensory deficiency, which would 
limit the ability to assess the performance of the device. 
5. Subjects with a systemic or metabolic disorder leading to progressive bone 
deterioration. 
6. Subjects that are immunologically compromised, or receiving chronic 
steroids (>30 days). 
7. Subjects bone stock is compromised by disease or infection that cannot 
provide adequate support and/or fixation to the prosthesis. 
8. Subjects with knee fusion to the affected joint. 
9. Subjects with an active or suspected latent infection in or about the knee 
joint. 
10. Subjects that are prisoners.  
Recruitment 
The investigator or the research assistant will carry this out.  The study will be described to 
the patient in detail, and a consent form, clearly stating the background and reasoning, will be 
given to the patient.  A consent form will be signed by the patient and by a study person 
authorized to obtain consent.  One copy will be go with the participant as stated, a second 
copy will go into the patient's medical record, and the original consent will be kept in the 
patient's study folder.  
Competency 
Study participants must be able to give informed consent. 

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Gender and Racial/Ethnic Distribution 
No gender or racial/ethnic group will be intentionally excluded from this study. 
RISKS 
Participation in this study, involving FDA-approved devices, poses no increased risk to 
patients undergoing total knee replacement surgery.  With any knee replacement, there is 
a possibility that the prosthesis will need to be removed and replaced and that the 
procedure may involve unforeseeable risks.  Some of the known risks include:  failure to 
achieve firm attachment of the implant to the bone, fracture of bone during implantation, 
infection, deep vein thrombosis, neurovascular injury, wound problems, extensor 
mechanism problems, and anesthetic problems.  In a minority of cases, the knee 
prosthesis will loosen over years of use and pain and decreased mobility will occur.   
STATISTICAL METHODS AND REVIEW STATEMENT 
Primary Efficacy Parameters  
The primary efficacy parameter is the revision rate for total knee arthroplasty.  The key 
time point is ten years post-surgery.   
Secondary Efficacy Parameters 
The secondary efficacy parameters include: 
Active flexion, Passive flexion, Active extension, and Passive extension ROM at the 2, 5, 
7 and 10-year visits. 
KSS pain and motion scores at the 3 months, 2, 5, 7 and 10-year visit. 
SF-12 scores at the 3 months, 2, 5, 7 and 10-year visit. 
Radiographic success/failure at the 3 months, 2, 5, 7 and 10-year visits. 

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Radiographic failure is defined as a score of 10 or greater according to the Knee Society 
Rotenographic Scoring System, regardless of symptoms. A migrating or shifting 
prosthesis with or without the disappearance of radiolucent lines is also a failure 
regardless of the score. 
Primary Efficacy Hypothesis 
The primary efficacy hypothesis will be a joint superiority/non-inferiority hypothesis. 
The superiority hypothesis is that the relative risk of revision at 10 years post-surgery in 
the group of patients randomized to the Triathlon CR Total Knee System using the X3 
polyethylene relative to the group of patients randomized to the Triathlon CR Total Knee 
System using N2Vac will be less than 1.0.  
The non-inferiority hypothesis is that the relative risk of revision at 10 years post-surgery 
in the X3 polyethylene group relative to the N2Vac group will be less than 1.2. In other 
words, the X3 polyethylene group will demonstrate a relative increase in the 10-year 
revision rate no greater than 20% compared to the N2Vac group.  
Formally the superiority null and alternative hypotheses are: 
HS,O:  X3/N2Vac  1.0, and 
HS,A:  X3/N2Vac < 1.0, where X3 is the ten-year revision rate in the Triathlon CR 
Total Knee System group using the X3 polyethylene and N2Vac is the ten-year 
revision rate in the Triathlon CR Total Knee System group using the N2Vac. 
The non-inferiority null and alternative hypotheses are: 
HNI,O:  X3/N2Vac > 1.2, and 
HNI,A:  X3/N2Vac ≤ 1.2, where X3 and N2Vac are defined as above. 

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Secondary Efficacy Hypothesis 
For the secondary efficacy parameters (when data is available), a non-inferiority  
hypothesis will be tested at each scheduled follow-up visit, similar to the primary efficacy 
hypothesis. 
In addition, a comparison of the scores at each post-surgery visit with baseline (i.e., 
improvement scores) will be tested to see if any improvement is seen for each parameter 
and time point.  
For categorical secondary parameters (i.e., radiographic success/failure, subsidence and 
radiolucency), the non-inferiority alternative hypothesis is that the risk in the X3 
polyethylene group is not 0% worse relative to the N2Vac treated group within the 
period from surgery to the scheduled follow-up visit.  Formally the non-inferiority null 
and alternative hypotheses are: 
HNI,O:  X3/N2Vac > 0, and 
HNI,A:  X3/N2Vac < 0, where X3 is the rate in the Triathlon CR Total Knee 
System group using the X3 polyethylene, N2Vac is the rate in the Triathlon CR 
Total Knee System group using the N2Vac, and 0 is the equivalence limit 
difference (0).  
For continuous secondary parameters (i.e., ROM, KSS, SF12), the non-inferiority 
alternative hypothesis is that the mean using the X3 polyethylene is not 0 worse than the 
mean using the N2Vac treated group within ten years.  Formally the non-inferiority null 
and alternative hypotheses are: 
HNI,O:  X3  N2Vac + 0, and 

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HNI,A:  X3 < N2Vac + 0, where X3 is the mean in the Triathlon CR Total Knee 
System group using the X3 polyethylene, N2Vac is the mean in the Triathlon CR 
Total Knee System group using the N2Vac, and 0 is the equivalence limit 
difference (0).. 
 
The equivalence limit differences are as follows.: 
Parameter 
Equivalence Limit Difference (0)  
Range of Motion (ROM) 
10 degrees 
KSS pain and motion 
10% 
SF-12 
10% 
Radiographic success/failure 
No complete radiolucent lines 
Subsidence and Radiolucency 
No component subsidence 
 
In addition, for the continuous parameters, a comparison of the scores at each post-
surgery visit with baseline (i.e., improvement scores) will be tested to see if any 
improvement is seen for each parameter at each time point   That is, the formal 
hypothesis to be tested is that the difference is zero.  This is tested by: 
HI,O:  i,j – i,0 = 0, and 
HI,A:   i,j –  i,0  0, where  i,j is the parameter’s true mean at nominal visit j for 
treatment group i, where i is either X3 or N2Vac, and i,0 is the corresponding 
baseline parameter’s true mean for treatment group i. 
Safety 

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Primary Safety Parameters 
The primary safety parameter is the incidence of patellar fracture, dislocation, 
subluxation and wear. 
Secondary Safety parameters 
The secondary safety parameter is the incidence of all other device related adverse 
events. 
Primary Safety Hypothesis 
The incidence of patellar fracture, dislocation, subluxation and wear is the same in the 
Triathlon CR group as in other commercially available knees. 
Secondary Safety Hypothesis 
The incidence of all other device related adverse events is the same in the Triathlon CR 
group as in other commercially available knees. 
Missing Data 
Scores for missing SF-12 data will be imputed using the SF Health Outcomes Scoring Software.  
Both raw and imputed results will be reported.  The imputed values will be analyzed. 

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Statistical Methodology 
Data Summary 
All data entry and analysis will be done by the Mayo Clinic Division of Biostatistics.  
The following is a detailed proposal of statistical analyses planned for data collected 
during the study.  In general, data will be summarized by treatment group and nominal 
study visit, where applicable.   
For parameters represented by continuous variables (e.g., ROM), the summaries will 
consist of the mean, median, standard deviation, minimum, and maximum values.  Both 
the actual values at each nominal visit and the improvement from baseline at each post-
baseline visit for each treatment group and their difference will be presented with its 95% 
confidence intervals.  The improvement from baseline will also present the corresponding 
paired t-test p-values.   
For categorical variables (e.g., subsidence), the number of events, person-years of follow-
up, and the corresponding event rates with 95% confidence intervals will be presented.  
In addition, the rate ratios (relative risk) of the treatment groups along with 95% 
confidence intervals will be presented.   
Descriptive statistics and statistical comparisons for important demographic, efficacy, 
and safety variables will be provided in tables.  All data collected on the case report 
forms will be provided in data listings, which will be sorted by treatment group and 
patient number.   

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Documentation of statistical analyses will be provided in a statistical appendix.  All 
statistical analyses will be completed using SAS®, version 9 or higher (SAS Institute Inc, 
Cary, NC), and Splus, version 7 or higher (Insightful Corporation, Seattle, WA). 
All statistical tests will be two-sided and p-values less than 0.05 will be considered 
significant. 
Sample Size Justification 
Revision rates for total knee arthroplasty are approximately 0.5% per year over the life of 
the knee.  At ten years, this rate would be expected to be 5%.  Within the Triathlon PS, 
X3 has been shown to reduce wear over N2Vac by up to 68%.  Therefore, by assuming 
all revisions could be attributed to polyethylene debris the X3 can be assumed to have a 
revision rate of 1.6% at 10 years.  Assuming that the X3 knees have a 10-year revision 
rate of 1.6% and that the corresponding rate in the N2Vac knees is 5.0% yields a rate 
ratio of 0.32 (or 3.1 for N2Vac/X3).   In order to have 80% power to detect this rate ratio 
as being significantly different from 1.00 will require that 26 events (revisions) are 
observed during the 10-year follow-up period. Assuming the overall 10-year revision rate 
is 5%, the sample size required to observe 26 revisions is 26/0.05=520, or n=260 in each 
treatment group.   By factoring in a 10% lost to follow-up rate within the ten-year period, 
the total enrollment of about 572 subjects (286 in each group) will be needed.  
Interim Analyses and early Stopping Considerations 
No interim analysis is planned.  

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Efficacy Analyses 
Methods 
Primary Parameter:  The relative risk of revision (X3 relative to N2Vac) at ten years will 
be computed and a 95% confidence interval on the rate ratio computed, assuming a 
Poisson distribution. If the upper end of the confidence interval for the rate ratio is less 
than 1.0, then the superiority hypothesis will be supported.  Otherwise, if the upper end of 
the confidence interval is less than 1.2, then the non-inferiority hypothesis will be 
supported.  Secondary Parameters:  The categorical secondary efficacy parameters will be 
analyzed at each nominal visit by computing the 95% confidence interval for the rate 
ratio (relative risk) of the groups as above.  The clinically significant difference (0) is as 
presented on page 13 above.  The continuous secondary efficacy parameters will be 
analyzed at each nominal visit.  The 95% confidence interval on the difference between 
the two groups will be computed using the means, t-distribution and appropriate standard 
deviation.  The change from baseline will also be presented and their 95% confidence 
interval and p-value for the paired t-test using the baseline will be presented for each 
nominal visit and treatment group, along with the descriptive statistics. 
Patient Population  
Modified Intent to Treat  

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A Modified Intent-to-Treat (MITT) population will be used.  The analysis will include all 
subjects who received the Triathlon CR device.  All subjects with any data will be 
included where possible.   
Safety Analyses:  The analysis of the primary and secondary safety parameters will 
parallel the analysis of the categorical secondary parameters. 
Baseline and Demographic Analyses 
The baseline and demographic analyzes will be presented using descriptive statistics only. 
Potential Conflict of Interest for the Investigators 
There may be a conflict of interest for some investigators of this study.  All investigators who 
had financial interest were required to submit a Financial Disclosure form to the Conflict of 
Interest Board.  The board approved those investigators for the purpose of this study.