A Prospective Multi-center Randomized Study on Total Hip Replacement With E1
Phase: NA
Conditions: Hip Osteoarthritis
Sponsor: Zimmer Biomet

 
 
 
 
 
 
 
 
 
 
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<A PROSPECTIVE MULTI-CENTER RANDOMIZED STUDY 
ON TOTAL HIP REPLACEMENT WITH E1> 
 
 
 
 
PROTOCOL NUMBER (Study ID): INT.CR.GH2 
 
PROTOCOL VERSION: v 1.0 (Feb. 29, 2012) 
 
NCT01883492 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
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Table of Contents 
 
1. INTRODUCTION 
 
1.1. BACKGROUND 
 
1.2. DEVICE DESIGN AND DESCRIPTION* 
 
1.3. RATIONALE FOR CURRENT STUDY 
 
1.4. STUDY PURPOSES 
 
2. STUDY DESIGN 
 
2.1. OVERALL DESIGN 
 
2.2. NUMBER OF SITES AND SUBJECTS/PROCEDURES 
 
2.3. PRIMARY AND SECONDARY ENDPOINTS 
 
2.4. ASSESSMENT PROCEDURE  
 
2.4.1. ASSESSMENT PARAMETERS AND METHODS 
 
2.4.2. ASSESSMENT TIMELINES/SCHEDULE (tabulated format preferred) 
 
2.4.3. ALLOWED WINDOW OF EACH SCHEDULE (tabulated format preferred) 
 
2.5. STUDY DURATION 
 
3. SELECTION AND WITHDRAWAL OF SUBJECTS 
 

 
 
 
 
 
 
 
 
 
 
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3.1. INCLUSION CRITERIA 
 
             3.2. EXCLUSION CRITERIA 
  
3.3. SUBJECT WITHDRAWAL 
 
4. ADVERSE EVENT MANAGEMENT AND REPORTING 
 
5. STATISTICAL ANALYSIS PLAN 
 
5.1. SAMPLE SIZE CALCULATION 
 
5.2. DATA ANALYSES 
 
5.2.1. INTERIM where appropriate 
5.2.2. FINAL 
 
6. DATA COLLECTION, HANDLING AND RETENTION 
 
6.1. SOURCE DOCUMENT REQUIREMENTS 
 
6.2. CASE REPORT FORMS 
 
6.3. ELECTRONIC DATA ENTRY 
 
7.  DATA REPORTING where appropriate 
 
7.1 INTERIM REPORT 
 
7.2 FINAL REPORT 
 
8. RISK ANALYSIS  

 
 
 
 
 
 
 
 
 
 
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9. MONITORING PLAN  
12.1 FREQUENCY 
12.2 SAMPLING PLAN 
12.3 MONITORING TASKS 
12.4 STUDY CLOSE-OUT  
 
10. ETHICAL AND REGULATORY REQUIREMENTS* 
 
10.1. CODE OF CONDUCT 
 
10.2. INSTITUTIONAL REVIEW BOARDS 
 
10.3. INFORMED CONSENT 
 
14.4. SUBJECT CONFIDENTIALITY 
 
11. APPENDICES 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
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STUDY SUMMARY 
 
 
TITLE A PROSPECTIVE MULTI-CENTER RANDOMIZED STUDY ON TOTAL 
HIP REPLACEMENT WITH E1 
DESIGN PROSPECTIVE, RANDOMIZED, MULTI-CENTER 
PURPOSE Evaluate E1 wear, clinical outcomes and quality of life on patients who 
received THA with E1 
POPULATION 160 hips 
DURATION EXPECTED DURATION OF THE PATIENT RECRUITMENT IS 1 YEAR. LAST 
FOLLOW-UP IS AT 10-YEAR AND THE EXPECTED COMPELETION DATE FOR 
THE LAST ENROLLED DATE IS 11 YEARS AFTER THE FIRST ENROLLMENT.  
 

 
 
 
 
 
 
 
 
 
 
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1. INTRODUCTION 
 
1.1. BACKGROUND 
Total hip arthroplasty (THA) is one of the most successful surgical procedures in general. Yet, a few 
problems remain unsolved, and aseptic loosening is probably the most important of them. One of the 
main reasons for aseptic loosening in THA is the foreign body reaction caused by the wear particles. Since 
the late 1990s, the orthopedic industry has been developing highly crosslinked polyethylene (HXLPE) 
materials to capitalize on the increased wear resistance. In 2007, E1® Antioxidant Infused Technology was 
developed to reduce wear rate, maintain mechanical properties and prevent oxidative degradation. In 
late 2010, E1® Acetabular Liners was introduced and has been used widely in Japan.  
Also alumina ceramic was introduced as a bearing surface in the 1971 as an alternative to the metal on-
polyethylene couplings. Since then, alumina ceramic has been used in THA successfully for more than 35 
years. BIOLOX®Delta is designed with improved fracture toughness, further reduces the risk of fracture 
and also extends the design flexibility of the material. 
However, there are a few clinical data collected on wear and performance of E1® Liners available for 
Caucasian population and no data for Japanese today. There is no clinical data of BIOLOX®Delta femoral 
head articulating against E1® Liner. Therefore, it is needed to collect clinical data to support marketing 
and validate design of E1® Liners in terms of its safety and efficacy. 
 
 
1.2. DEVICE DESIGN AND DESCRIPTION* 
All patients will receive the vitamin E treated polyethylene “E1® Liners”.  Short-term femoral head 
penetration and long-term steady state wear of the polyethylene will be measured using software.  
The investigational group, Ceramic-on-Polyethylene (CoP) total hip prosthesis, consists of BIOLOX® Delta 
ceramic modular femoral head articulating against E1® Liner. The ceramic femoral head is attached to a 
conventional femoral stem to complete the CoP total hip prosthesis device configuration.  
The control group, Metal-on-Polyethylene (MoP) hip prosthesis, consists of the commercially available 
cobalt chrome (CoCr) femoral head articulating against E1® Liner. The metal femoral head is attached to a 
conventional femoral stem to complete the MoP total hip prosthesis device configuration.  

 
 
 
 
 
 
 
 
 
 
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 
E1® Acetabular Liners: flat (MaxRom, MaxRom+) and hi-wall (Hi-Wall, Hi-wall+) style liner used for 
both the investigational (CoP) and control (MoP) cohorts. 
 28, 32 and 36mm inner diameters are available and 40mm will be available in mid CY 2012. 
 
 BIOLOX®Delta femoral heads: used for the investigational cohort. The BIOLOX® Delta ceramic 
femoral heads are manufactured from BIOLOX® delta, an alumina composite matrix. 
  28, 32, 36 and 40mm head diameters will be available in mid CY 2012. 
 
Biomet cobalt-chrome femoral heads used for the control cohort 
 28, 32, 36 and 40mm head diameters are available  
 
Any Biomet Femoral Component (Hip Stem) used for both the investigational and control cohorts  
 
RingLoc® PPS® or Ringloc+® Regenerex® Acetabular Shell System used for both the investigational 
and control cohorts. 
1.3. RATIONALE FOR CURRENT STUDY 
E1® Acetabular liners received approval in Japan in 2010. BIOLOX®Delta femoral heads has not been 
approved and estimated the approval in mid CY 2012.  Currently there is no clinical data on E1® 
Acetabular liners implanted in Japanese population. There is a need to collect clinical data to investigate 
how this hip system performs in Japanese population. 
 
1.4. PURPOSES 
The primary objectives of this pilot clinical study include: 
• Evaluate E1 Wear including early bedding-in process, clinical outcomes on patients who received THA 
with E1 
• Compare E1 wear used with CoCr and Biolox Delta heads 
 
2. STUDY DESIGN 
 
2.1. OVERALL DESIGN 
This study is a prospective, multi-center randomized controlled study and will be conducted in Japan at a 
maximum of 5 sites.  
The study will consist of two phases, over a period of 11 years. Phase 1 will collect data on penetration 
rate recognized as “early bedding-in” and patients will be followed at immediate post-op, 6 months and 1 

 
 
 
 
 
 
 
 
 
 
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year, 2 years, 3 years. Phase 2 will collect data on penetration rate recognized as “steady-state wear” after 
5 years, 7years and 10 years post-op. 
2.2. NUMBER OF SITES AND SUBJECTS/PROCEDURES 
 Total of 160 hips will be enrolled in the study.  
 
2.3. PRIMARY AND SECONDARY ENDPOINTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.4. ASSESSMENT PROCEDURE 
2.4.1. ASESSMENT PARAMETERS AND METHODS 
Medical History and Demographic Data 
Demographic information will be collected, a detailed medical history will be obtained and a physical 
examination will be performed (including height, weight).  
Clinical Assessments 
An operative record will be completed to record details of each operative procedure and of the used 
implants. 
PHASE 1:  Immediate post-op to 3 years 
Primary endpoints 
Early bedding in  
Secondary endpoints 
At all follow-up visits: 
Survivorship up to 3 years 
JOA 
Radiographic Assessment 
Complications including revisions 
PHASE 2: 5 to 10 years  
Primary endpoints 
Steady-state wear 
Secondary endpoints 
At all follow-up visits: 
Survivorship up to 10 years 
JOA 
Radiographic Assessment 
Complications including revisions 

 
 
 
 
 
 
 
 
 
 
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Data to determine the clinical and functional performance of the device will be collected. Pre-operative and 
post-operative analysis will be compared using recognized and validated systems (JOA Score). 
Radiographic Assessments (including Radiographic Assessment protocol) 
A radiographic assessments including polyethylene wear analysis and cup inclination angle will be 
completed at each follow-up period. 
The X-rays must be taken according to the Martell technique*, which requires an A/P pelvis view centered 
over the pubis. See attachment for radiographic technique. 
For the polyethylene wear analysis, all Radiographic images will be determined and the penetration rate will 
be measured by Hip Analysis Suite (software program, Dr. John Martel at Chicago University). 
 
 
2.4.2. ASEESMENT TIMELINES/SCHEDULE 
Example of Tabulated Assessment Schedule 
 
 
 
PHASE 1 
PHASE 2 
 
PRE-OP 
SURGERY 
IMMEDIATE 
POST-OP 
 6 
WK 
6 
MO 
1 
YR 
2 
YR 
3 
YR 
5 
YR 
7 
YR 
10 
YR 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographic and 
Historical Record 
X 
 
 
 
 
 
 
 
 
 
 
Operative Record 
 
X 
 
 
 
 
 
 
 
 
 
Radiographic 
Assessment 
 
 
X 
(X*) 
X 
X 
X 
X 
X 
X 
X 
JOA 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Complications 
including Revisions 
 
ANYTIME 
* Baseline for bedding in and total penetration rate 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
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2.4.3. ALLOWED WINDOW OF EACH SCHEDULE 
PHASE 
Evaluation Schedule 
 
Interval 
Follow-Up Window 
Months 
Post-Op Range 
PHASE 1 
Immediate Post-Op 
± 2 weeks 
Immediate post-op 
< 2 weeks 
6 weeks 
± 2 weeks 
4-8 weeks 
6 month follow-up 
± 1 month 
5-7 months 
1 year follow-up 
± 2 months 
10-14 months 
2 year follow-up 
± 3 months 
19-27 months 
3 year follow-up 
± 3 months 
33-39 months 
PHASE 2 
5 year follow-up 
± 3 months 
57-63 months 
7 year follow-up 
± 3 months 
81-87 months 
10 year follow-up 
± 3 months 
117 – 123 months 
 
 
2.5. Randomization 
Patients will be randomized to receive Delta Ceramic Head (investigational group), or CoCr Head (control 
group). Patients have an equal opportunity of being assigned to the investigational group or control group. 
Specifically: 
In case of unilateral patients, the affected side of hip will be randomized to one of two groups. In case of 
bilateral patients, both sides of hip will be randomized to the same device (Delta Ceramic or CoCr).  
The randomization will occur via a random number generator (manual or computer). Block randomization 
will be used. Blocks of K patients will be created where K = 4. 
The possible sequences are AABB, BBAA, ABAB and BABA.  Two sets of randomization blocks will be 
followed by unilateral and bilateral patients respectively.  
For unilateral patients, A or B represents the device assigned to affected side of the hip. For bilateral 
patients, A or B represents the device assigned to both affected sides of the hip. 

 
 
 
 
 
 
 
 
 
 
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The doctor or other health care professional does not choose the participants for each group. For Patients 
satisfying inclusion criteria, randomization will occur by retrieving the next randomly generated group 
assignment. 
 
2.6. DURATION OF THE STUDY 
Expected duration of recruitment period would be 1 year after the first case is enrolled. Each subject is to 
be followed-up to 3 years post-op for phase 1 and 10 years post-op for phase 2. 
 
3. SELECTION AND WITHDRAWAL OF SUBJECTS 
All subjects, regardless of sex, race, or geographic location, must fit into the scope of the Inclusion / 
Exclusion criteria to be eligible for the study. If required per applicable regulations, all participants must 
sign an Informed Consent to be enrolled into the study. 
 
3.1. INCLUSION CRITERIA 
In accordance with approved Indications for Use E1 liner and Delta Ceramic and CoCr femoral head hip 
system specifically: 
 
Patients suitable for primary Total Hip Replacement 
Patients with degenerative joint disease (inflammatory or non-inflammatory) or any of the composite 
diagnoses of: 
a. 
Osteoarthritis 
b. 
Avascular necrosis 
c. 
Legg Perthes 
d. 
Rheumatoid Arthritis 
e. 
Diastrophic variant 
f. 
Fracture of the pelvis 
g. 
Fused hip 
h. 
Slipped capital epiphysis 
i. 
Subcapital fractures 
j. 
Traumatic arthritis 
Patients aged over 20 
Patients with limited co-morbidity – ASA I – III 

 
 
 
 
 
 
 
 
 
 
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Patients must be able to understand instructions and be willing to return for follow-up 
 
 
 
3.2. EXCLUSION CRITERIA 
In accordance with approved Absolute and Relative Contraindications for use in participating countries for 
E1 liner and Delta Ceramic and CoCr femoral head hip system System. 
Absolute contraindications include: infection, sepsis, and osteomyelitis. 
Relative contraindications include:  
1) uncooperative patient or patient with neurologic disorders who are incapable of 
following directions,  
2) osteoporosis,  
3) metabolic disorders which may impair bone formation,  
4) osteomalacia,  
5) distant foci of infections which may spread to the implant site,  
6) rapid joint destruction, marked bone loss or bone resorption 
apparent on roentgenogram, and  
7) vascular insufficiency, muscular atrophy, or neuromuscular disease. 
8) pregnancy 
 
3.3. SUBJECT WITHDRAWAL  
It is recognized that the subject’s participation in this trial is entirely voluntary, and that she/he may 
refuse to participate and may withdraw from participation at any time without jeopardy to any future 
medical care.  It is also recognized that the investigator, at his/her discretion, may withdraw a subject 
from this study based upon his/her professional judgment.  In event of subject withdrawal, applicable 
local procedures should be followed. 
 
4. ADVERSE EVENT MANAGEMENT AND REPORTING 
A record of all adverse events relating to subjected device (see Risk Analysis Section) and 
operative procedure, including details of the nature, onset, duration, severity, will be made on the 

 
 
 
 
 
 
 
 
 
 
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relevant section(s) of the subject’s CRF. The subject will be questioned about any adverse 
event(s) at each subsequent follow-up assessment visit. 
 
 
 
5. STATISTICAL ANALYSIS PLAN 
 
5.1. Sample Size Calculation  
The study population is calculated based on the primary endpoint of Poly wear at 10 year postop. A total of 
160 hips will be recruited the study and randomly assigned to either CoCr or Ceramic head group. Each site 
is required to use the same stem and cup for both CoCr and Ceramic groups. 
 
Significance Level = 5 % (95% confidence) 
 
d = 0.5 mm 
Clinically significant difference in wear. 
 
ξ = 0.07 
 Estimate standard deviation of wear. 
 
N = 63 
 
Take into consideration of Lost-to-Follow-up Rate = 20%  for 10 year 
 
Final N = 80 hips per group 
 
 
5.1. Data Analyses 
 
5.1.1. INTERIM 
An interim data analyses will be conducted when all patients reach 1, 2, 3, 5 and 7 yr post-op follow-up.   
5.1.2. FINAL 
A final data analysis will be conducted upon study’s completion.   
 

 
 
 
 
 
 
 
 
 
 
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6. DATA COLLECTION, HANDLING AND RETENTION 
 
6.1.   SOURCE DOCUMENTATION REQUIREMENTS 
 
Source documentation for this study will be maintained to document the treatment and study course of a subject 
and to substantiate the integrity of the trial data submitted for review to the regulatory agencies. Source 
documentation will include, but not be limited to, worksheets, hospital and/or clinic or office records documenting 
subject visits including study and other treatments or procedures, medical history and physical examination 
information, laboratory and special assessments results, pharmacy records, device accountability records, and 
medical consultations (as applicable). 
 
6.2. CASE REPORT FORMS 
 
Data for this clinical trial will be collected and documented on the subject Case Report Forms (CRFs) provided, 
which may be in paper form or in an electronic form.  Authorized study site personnel will complete CRFs only. 
CRFs must be reviewed and signed by the Investigator or his/her designees.  
 
Since there is a potential for errors, inaccuracies, and misinterpretation in transcribing data onto the CRFs, the 
following documents must be available at all times for inspection and comparison to the CRFs by the study monitor 
where appropriate: 
• 
data query forms 
• 
originals and photocopies/certified copies of all relevant records and reports 
• 
copies of test results 
 
Sample CRFs to be used with this clinical trial are provided in Appendix 2. 
 
6.3. ELECTRONIC DATA ENTRY  
 
All sites will be required to complete and submit case report forms on Biomet’s online database, Joint Assist, in a 
timely manner.  Forms will be monitored for completeness and accuracy by Biomet Japan.  

 
 
 
 
 
 
 
 
 
 
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Further, it is imperative that the investigator answers all questions on the case report forms.  All data should be 
accurate, indelible and legible. 
 
7.  DATA REPORTING 
 
7.1.   INTERIM REPORT  
An interim report will be provided after each follow-up period. 
 
7.2.  FINAL REPORT 
Final report will be provided after 10 yr follow-up period. 
 
 
8. RISK ANALYSIS  
 
This clinical study is to collect data on the E1 liner and Delta Ceramic and CoCr femoral head hip system 
which is intended to help the participant gain mobility and decrease pain.  Risks associated with this Hip 
system include general surgical and Hip arthroplasty risks. Due to the investigational nature of the system, 
there are unknown risks. 
 
General Surgical Risks 
 
As with any surgical procedure, there are risks involved with total joint replacement surgery.  Potential 
adverse events include, but are not limited to: early or late infection perhaps necessitating device 
removal; component dislocation; damage to nerves and blood vessels; fracture of the bone or device; 
device loosening; allergic reactions to the metallic devices; phlebitis; long-term swelling; pulmonary 
embolization; and delayed wound healing. Other potential adverse effects include: prolonged illness; 
hematoma; wound dehiscence and/or drainage; the need for blood transfusions and/or further surgery; 
or permanent pain; deformity; and inconvenience. Risks associated with the anesthetic are those such as 
permanent brain damage, pneumonia, blood clots, and heart attack. Rarely some adverse events may be 

 
 
 
 
 
 
 
 
 
 
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fatal.  These possible adverse events are not unique to the 1 liner and Delta Ceramic and CoCr femoral 
head hip system and, as stated above, may occur with any total joint replacement surgery. 
 
As with any joint replacement post-operative activity, limitations may be imposed depending upon the 
participant’s age, general health, baseline (pre-operative) activity level and baseline (pre-operative) 
condition of the Hip and other joints. 
 
Potential Risks Associated with   E1 liner and Delta Ceramic and CoCr femoral head hip system 
 
As with all hip replacement systems, potential adverse effects include risk of infection, loosening of the 
components, breakage or bending of the components, or change in position of the components any of 
which can necessitate removal and/or revision surgery. There have been reports of sensitivity reactions to 
the components of Hip systems. Other potential adverse effects of Hip replacement surgery include 
neurovascular damage, dislocation, thromboembolic disease, and other less common adverse effects. 
 
1. Material sensitivity reactions. Implantation of foreign material in tissues can result in histological 
reactions involving various sizes of macrophages and fibroblasts. The clinical significance of this effect is 
uncertain, as similar changes may occur as a precursor to or during the healing process. Particulate wear 
debris and discoloration from metallic and polyethylene 
components of joint implants may be present in adjacent tissue or fluid. It has been reported 
that wear debris may initiate a cellular response resulting in osteolysis, or osteolysis may be 
a result of loosening of the implant. 
2. Early or late postoperative infection and allergic reaction. 
3. Intraoperative bone perforation or fracture may occur, particularly in the presence of poor bone stock 
caused by osteoporosis, bone defects from previous surgery, bone resorption, or while inserting the 
device. 
4. Loosening or migration of the implants can occur due to loss of fixation, trauma, malalignment, 
malposition, bone resorption or excessive, unusual and/or awkward movement and/ or activity. 
5. Periarticular calcification or ossification, with or without impediment of joint mobility. 
6. Inadequate range of motion due to improper selection or positioning of components. 

 
 
 
 
 
 
 
 
 
 
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7. Dislocation and subluxation due to inadequate fixation malalignment, malposition, excessive, unusual 
and/or awkward movement and/or activity, trauma, weight gain, or obesity. Muscle and fibrous tissue 
laxity can also contribute to these conditions. 
8. Fatigue fracture of component can occur as a result of loss of fixation, strenuous activity, mlalignment, 
trauma, non-union, or excessive weight. 
9. Fretting and crevice corrosion can occur at interfaces between components. 
10. Wear and/or deformation of articulating surfaces. 
11. Valgus-varus deformity. 
12. Patellar tendon rupture and ligamentous laxity. 
13. Interoperative or postoperative bone fracture and/or postoperative pain. 
 
Minimization of Risk 
It is believed that none of the previously mentioned adverse events will occur in significant numbers.  This 
study protocol has reduced the potential risk to the participant through the following methods: 
 
1. By defining a participant population that limits the exposure of the device to 
participants conforming to the proposed indications, exclusions, and age requirements 
2. The surgical technique has been developed to help eliminate potential operative 
difficulties. 
 
 
9. MONITORING PLAN  
 
Prior to commencing the study Biomet Japan will provide the investigators with the necessary information to 
enable him/her to carry out his responsibilities. This information includes but not limited to: 
 
• Investigator Brochure i.e. study protocol, investigator responsibilities, device information, etc. 
• Ethical Committee Approval Information. 
• Case Report Forms. 
• Patient Consent Forms 
• EDC user manual 
 

 
 
 
 
 
 
 
 
 
 
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The monitor of the evaluation periodically reviews the post-operative follow-up dates on all subjects for each 
evaluator.  A follow-up schedule is then sent to each investigator, which illustrates any follow-up, reports which 
are due or missing.  Every effort is made to assure that follow-up reports are completed in a timely manner, 
including contacting the evaluator by post, telephone or by personal visit when necessary.  Also, during the course 
of the evaluation, the monitor will conduct periodic discussions with the investigator or staff to ensure that the 
evaluation is being conducted in accordance with the protocol.  The monitor will maintain records of each visit or 
discussion.  
 
 
10. ETHICAL AND REGULATORY REQUIREMENTS 
 
10.1. CODE OF CONDUCT 
 
The Investigator will ensure that the clinical study is conducted in accordance with  
 
1. Protocol 
2. Regulatory and IRB/EC requirements  
3. ISO 14155, GCP, the Declaration of Helsinki  (optional) 
 
10.2. INSTITUTIONAL REVIEW BOARDS/ETHICS COMMITTEE 
 
The Investigator must obtain appropriate Independent Ethics Committee (IEC) approval before the study can be 
initiated.  A copy of the written approval from the IEC and a copy of the approved informed consent form should 
be sent to the Sponsor.  A list of the IEC members (including their Institution affiliations, gender makeup, and 
occupations); or a statement from the IEC specifying that the membership comply with applicable regulations is to 
be provided to the sponsor. 
 
Any changes to the protocol must be discussed and approved by the Sponsor in writing unless the change is made 
to assure the safety of the subject.  In the non-emergent setting, after agreement on the changes has been 
reached, an amendment to the protocol will be provided by the Sponsor for submission to the IEC for review and 
approval prior to initiation of the change. Any change made emergently must be documented in the subject's 

 
 
 
 
 
 
 
 
 
 
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medical record and reported to the Sponsor within the time period required by local SOPs and applicable 
regulations. 
 
The Investigator must immediately forward to the IEC any written safety reports or updates from the Sponsor. 
 
The Investigator must keep the IEC informed of the progress of the study as required by the IEC but at least 
annually. 
 
10.3.  INFORMED CONSENT 
 
Subjects (or the subject's legally authorized representative) will be provided with an informed consent and patient 
information sheet in order to give ample opportunity to review the consent and ask questions. The signed 
informed consent will be obtained before any study procedures begin. If the subject agrees to participate in the 
study, the subject/representative must sign the informed consent form.  The witness and the Investigator must 
also sign the informed consent form.  A copy of the informed consent form should be given to the 
subject/representative. All subjects who meet all of the entry criteria will be considered for inclusion in this trial. 
Any subject meeting any of the exclusion criteria will be excluded from the trial. 
The informed consent form must be approved by the institution’s IEC.  Subjects will be informed of new 
information learned during the study, which may affect the subject’s decision to continue participation in the study. 
 
An Informed Consent Log will be completed to document the existence of the signed informed consent form.  The 
log will contain: Subject ID, date informed consent form signed, and the version signed.  The monitor will initial and 
date the log once the executed informed consent form has been reviewed.  Signed informed consent forms (or 
copies) are to be maintained in the study file and must be available for verification by monitors or inspectors. 
 
10.4. SUBJECT CONFIDENTIALITY 
 
To ensure study patients’ privacy, all patients will be identified by unique identification numbers. All case report 
forms will only include patient IDs. It is the responsibility of the investigator to maintain a list of patient 
identification and Joint Assist. 
 

 
 
 
 
 
 
 
 
 
 
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Further the Joint Assist database is restricted, allowing a doctor to only view and enter data from his own patients.  
User authentication is required to view research data.  The data is transmitted to a centralized database through a 
secured (SSL) channel on the Internet.  Data in transit is in 128-bit encryption.  The access to the centralized 
database is limited to those who are responsible for maintaining the database. 
 
The Sponsor will maintain the confidentiality of the identity of subjects enrolled in the study and the information 
contained in their study records.  The Sponsor will also instruct the study investigators in the importance of 
maintaining the confidentiality of study records.  The records will be made available as required for review by 
governing regulatory agency such as FDA and a reviewing IEC/IRB, however to the extent possible, the subject’s 
identity will not be disclosed. 
 
 
11. APPENDICES 
 
Appendix 1 
Informed Consent and Patient Information Sheets 
 
Appendix 2 
Case Report Forms 
 
Appendix 3 
Investigator’s Brochure / Instructions for Use if applicable  
 
Appendix 4 
Declaration of Helsinki if applicable 
 
 
 
 
 
 
 
 
 
APPENDIX 4 
 

 
 
 
 
 
 
 
 
 
 
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WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53th WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 added) 
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added) 
59th WMA General Assembly, Seoul, October 2008 
 
A. INTRODUCTION 
 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of ethical 
principles for medical research involving human subjects, including research on identifiable human material and 
data. 
The Declaration is intended to be read as a whole and each of its constituent paragraphs should not be applied 
without consideration of all other relevant paragraphs. 
2. Although the Declaration is addressed primarily to physicians, the WMA encourages other participants in 
medical research involving human subjects to adopt these principles. 
3. It is the duty of the physician to promote and safeguard the health of patients, including those who are involved 
in medical research. The physician's knowledge and conscience are dedicated to the fulfilment of this duty. 
4. The Declaration of Geneva of the WMA binds the physician with the words, “The health of my patient will be my 
first consideration,” and the International Code of Medical Ethics declares that, “A physician shall act in the 
patient's best interest when providing medical care.” 
5. Medical progress is based on research that ultimately must include studies involving human subjects. 
Populations that are underrepresented in medical research should be provided appropriate access to participation 
in research. 
6. In medical research involving human subjects, the well-being of the individual research subject must take 
precedence over all other interests. 

 
 
 
 
 
 
 
 
 
 
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7. The primary purpose of medical research involving human subjects is to understand the causes, development 
and effects of diseases and improve preventive, diagnostic and therapeutic interventions (methods, procedures 
and treatments). Even the best current interventions must be evaluated continually through research for their 
safety, effectiveness, efficiency, accessibility and quality. 
8. In medical practice and in medical research, most interventions involve risks and burdens. 
9. Medical research is subject to ethical standards that promote respect for all human subjects and protect their 
health and rights. Some research populations are particularly vulnerable and need special protection. These 
include those who cannot give or refuse consent for themselves and those who may be vulnerable to coercion or 
undue influence. 
10. Physicians should consider the ethical, legal and regulatory norms and standards for research involving human 
subjects in their own countries as well as applicable international norms and standards. No national or 
international ethical, legal or regulatory requirement should reduce or eliminate any of the protections for 
research subjects set forth in this Declaration. 
 
B. PRINCIPLES FOR ALL MEDICAL RESEARCH 
 
11. It is the duty of physicians who participate in medical research to protect the life, health, dignity, integrity, right 
to self-determination, privacy, and confidentiality of personal information of research subjects. 
12. Medical research involving human subjects must conform to generally accepted scientific principles, be based 
on a thorough knowledge of the scientific literature, other relevant sources of information, and adequate 
laboratory and, as appropriate, animal experimentation. The welfare of animals used for research must be 
respected. 
13. Appropriate caution must be exercised in the conduct of medical research that may harm the environment. 
14. The design and performance of each research study involving human subjects must be clearly described in a 
research protocol. The protocol should contain a statement of the ethical considerations involved and should 
indicate how the principles in this Declaration have been addressed. The protocol should include information 
regarding funding, sponsors, institutional affiliations, other potential conflicts of interest, incentives for subjects 
and provisions for treating and/or compensating subjects who are harmed as a consequence of participation in the 
research study. The protocol should describe arrangements for post-study access by study subjects to 
interventions identified as beneficial in the study or access to other appropriate care or benefits. 
15. The research protocol must be submitted for consideration, comment, guidance and approval to a research 
ethics committee before the study begins. This committee must be independent of the researcher, the sponsor 

 
 
 
 
 
 
 
 
 
 
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and any other undue influence. It must take into consideration the laws and regulations of the country or countries 
in which the research is to be performed as well as applicable international norms and standards but these must 
not be allowed to reduce or eliminate any of the protections for research subjects set forth in this Declaration. The 
committee must have the right to monitor ongoing studies. The researcher must provide monitoring information 
to the committee, especially information about any serious adverse events. No change to the protocol may be 
made without consideration and approval by the committee. 
16. Medical research involving human subjects must be conducted only by individuals with 
the appropriate scientific training and qualifications. Research on patients or healthy volunteers requires the 
supervision of a competent and appropriately qualified physician or other health care professional. The 
responsibility for the protection of research subjects must always rest with the physician or other health care 
professional and never the research subjects, even though they have given consent. 
17. Medical research involving a disadvantaged or vulnerable population or community is only justified if the 
research is responsive to the health needs and priorities of this population or community and if there is a 
reasonable likelihood that this population or community stands to benefit from the results of the research. 
18. Every medical research study involving human subjects must be preceded by careful assessment of predictable 
risks and burdens to the individuals and communities involved in the research in comparison with foreseeable 
benefits to them and to other individuals or communities affected by the condition under investigation. 
19. Every clinical trial must be registered in a publicly accessible database before recruitment of the first subject. 
20. Physicians may not participate in a research study involving human subjects unless they are confident that the 
risks involved have been adequately assessed and can be satisfactorily managed. Physicians must immediately stop 
a study when the risks are found to outweigh the potential benefits or when there is conclusive proof of positive 
and beneficial results. 
21. Medical research involving human subjects may only be conducted if the importance of 
the objective outweighs the inherent risks and burdens to the research subjects. 
22. Participation by competent individuals as subjects in medical research must be voluntary. Although it may be 
appropriate to consult family members or community leaders, no competent individual may be enrolled in a 
research study unless he or she freely agrees. 
23. Every precaution must be taken to protect the privacy of research subjects and the confidentiality of their 
personal information and to minimize the impact of the study on their physical, mental and social integrity. 
24. In medical research involving competent human subjects, each potential subject must be adequately informed 
of the aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations of the 
researcher, the anticipated benefits and potential risks of the study and the discomfort it may entail, and any other 

 
 
 
 
 
 
 
 
 
 
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relevant aspects of the study. The potential subject must be informed of the right to refuse to participate in the 
study or to withdraw consent to participate at any time without reprisal. Special attention should be given to the 
specific information needs of individual potential subjects as well as to the methods used to deliver the 
information. After ensuring that the potential subject has understood the information, the physician or another 
appropriately qualified individual must then seek the potential subject’s freely-given informed consent, preferably 
in writing. If the consent cannot be expressed in writing, the non-written consent must be formally documented 
and witnessed. For medical research using identifiable human material or data, physicians must normally seek 
consent for the collection, analysis, storage and/or reuse. There may be situations where consent would be 
impossible or impractical to obtain for such research or would pose a threat to the validity of the research. In such 
situations the research may be done only after consideration and approval of a research ethics committee. 
26. When seeking informed consent for participation in a research study the physician should be particularly 
cautious if the potential subject is in a dependent relationship with the physician or may consent under duress. In 
such situations the informed consent should be sought by an appropriately qualified individual who is completely 
independent of this relationship. 
27. For a potential research subject who is incompetent, the physician must seek informed consent from the 
legally authorized representative. These individuals must not be included in a research study that has no likelihood 
of benefit for them unless it is intended to promote the health of the population represented by the potential 
subject, the research cannot instead be performed with competent persons, and the research entails only minimal 
risk and minimal burden. 
28. When a potential research subject who is deemed incompetent is able to give assent to decisions about 
participation in research, the physician must seek that assent in addition to the consent of the legally authorized 
representative. The potential subject’s dissent should be respected. 
29. Research involving subjects who are physically or mentally incapable of giving consent, for example, 
unconscious patients, may be done only if the physical or mental condition that prevents giving informed consent 
is a necessary characteristic of the research population. In such circumstances the physician should seek informed 
consent from the legally authorized representative. If no such representative is available and if the research cannot 
be delayed, the study may proceed without informed consent provided that the specific reasons for involving 
subjects with a condition that renders them unable to give informed consent have been stated in the research 
protocol and the study has been approved by a research ethics committee. Consent to remain in the research 
should be obtained as soon as possible from the subject or a legally authorized representative. 
30. Authors, editors and publishers all have ethical obligations with regard to the publication of the results of 
research. Authors have a duty to make publicly available the results of their research on human subjects and are 

 
 
 
 
 
 
 
 
 
 
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accountable for the completeness and accuracy of their reports. They should adhere to accepted guidelines for 
ethical reporting. Negative and inconclusive as well as positive results should be published or otherwise made 
publicly available. Sources of funding, institutional affiliations and conflicts of interest should be declared in the 
publication. Reports of research not in accordance with the principles of this Declaration should not be accepted 
for publication. 
 
ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE 
 
31. The physician may combine medical research with medical care only to the extent that the research is justified 
by its potential preventive, diagnostic or therapeutic value and if the physician has good reason to believe that 
participation in the research study will not adversely affect the health of the patients who serve as research 
subjects. 
32. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best 
current proven intervention, except in the following circumstances: 
• The use of placebo, or no treatment, is acceptable in studies where no current proven intervention exists; or 
• Where for compelling and scientifically sound methodological reasons the use of placebo is necessary to 
determine the efficacy or safety of an intervention and the patients who receive placebo or no treatment will not 
be subject to any risk of serious or irreversible harm. Extreme care must be taken to avoid abuse of this option. 
33. At the conclusion of the study, patients entered into the study are entitled to be informed about the outcome 
of the study and to share any benefits that result from it, for example, access to interventions identified as 
beneficial in the study or to other appropriate care or benefits. 
34. The physician must fully inform the patient which aspects of the care are related to the research. The refusal of 
a patient to participate in a study or the patient’s decision to withdraw from the study must never interfere with 
the patient-physician relationship. 
35. In the treatment of a patient, where proven interventions do not exist or have been ineffective, the physician, 
after seeking expert advice, with informed consent from the patient or a legally authorized representative, may 
use an unproven intervention if in the physician's judgement it offers hope of saving life, re-establishing health or 
alleviating suffering. Where possible, this intervention should be made the object of research, designed to evaluate 
its safety and efficacy. In all cases, new information should be recorded and, where appropriate, made publicly 
available. 
 

 
 
 
 
 
 
 
 
 
 
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REFERENCES 
1. 
Data on file at Biomet. Bench test results not necessarily indicative of clinical performance.