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LISS Protocol

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					Prospective Randomized Clinical Study To Evaluate
The Effects Of Less Invasive Stabilization System
(LISS) Plating Techniques In Distal Femoral
Fractures

Lead Site Investigators:       Dr. Ross K. Leighton
                               Dr. Mike Dunbar
                               Dr. Dave Petrie
                               Dr. Kevin Deluzio
                               QEII Health Sciences Centre &
                               Dalhousie University
                               Halifax, Nova Scotia, Canada


Participation Sites have been chosen as they are members of the Canadian
Orthopedic Trauma Society (C.O.T.S.)—a Canadian Multicenter Study Group:


   1. Peter O’Brien
      Vancouver General Hospital            5. Trauma Group—ED Harvey
      Vancouver British Columbia               MUHC
                                               Montreal Quebec
   2. Richard Buckley and Jim Powell
      Foothills Hospital                    6. Trauma Group—Dave Sanders
      Calgary, Alberta                         UWO
                                               London Ontario
   3. Mike McKee and Emil Schemitsch
      St Michael’s Hospital                 7. Bob McCormack and Graham Pate
      Toronto, Ontario                         Royal Columbian Hospital
                                               Vancouver, B.C.
   4. Dave Stephen and Hans Kreder
      Sunnybrook Hosp
      Toronto Ontario
                                                            Table of Contents
1.0   BACKGROUND, RATIONALE, AND STATEMENT OF RESEARCH QUESTIONS ................................1
2.0   SUBJECT SELECTION ....................................................................................................................................2
      2.1    Inclusion Criteria ...................................................................................................................................2
      2.2    Exclusion Criteria ..................................................................................................................................3
      2.3    Concomitant Medications ......................................................................................................................4
3.0   RESEARCH PLAN ...........................................................................................................................................4
      3.1    Study Sites .............................................................................................................................................4
      3.2    Allocation of Study Device ....................................................................................................................5
      3.3    Control Group ........................................................................................................................................5
      3.4    Baseline Evaluation ...............................................................................................................................5
      3.5    Intra-operative Procedure ......................................................................................................................6
      3.6    Post-operative Procedure .......................................................................................................................6
        3.6.1       Clinical Examination .....................................................................................................................6
        3.6.2       Radiograph Examination ...............................................................................................................7
      3.7    Time Schedule .......................................................................................................................................7
      3.8    Study Completion ..................................................................................................................................9
        3.8.1       Study Success Criteria ...................................................................................................................9
        3.8.2       Study Failure Criteria .....................................................................................................................9
      3.9    Adverse Experiences............................................................................................................................ 10
        3.9.1       Definition ..................................................................................................................................... 10
        3.9.2       Reporting Serious Adverse Experiences ...................................................................................... 11
        3.9.3       Documenting Adverse Experiences ............................................................................................. 11
      3.10 Data Collection .................................................................................................................................... 11
      3.11 Protocol Deviations.............................................................................................................................. 12
      3.12 Amendments ........................................................................................................................................ 12
      3.13 Informed Consent from Patients .......................................................................................................... 12
      3.14 Institutional Review Board (IRB) ........................................................................................................ 13
      3.15 Data Ownership ................................................................................................................................... 13
      3.16 Case Report Forms .............................................................................................................................. 13
4.0   ANALYSIS OF DATA ................................................................................................................................... 14
      4.1    Primary Study Hypothesis ................................................................................................................... 14
      4.2    Efficacy Endpoints ............................................................................................................................... 14
      4.3    Sample Size Determination.................................................................................................................. 14
      4.4    Study Populations ................................................................................................................................ 15
        4.4.1       Safety Population ......................................................................................................................... 15
        4.4.2       Efficacy Population ...................................................................................................................... 15
      4.5    Interim Analysis................................................................................................................................... 15
      4.6    Baseline Characteristics ....................................................................................................................... 15
      4.7    Study Completion ................................................................................................................................ 15
      4.8    Efficacy ................................................................................................................................................ 15
      4.9    Safety ................................................................................................................................................... 16
5.0   RISKS .............................................................................................................................................................. 16
      5.1    Risks Associated with the LISS Device ............................................................................................... 16
      5.2    Complications Associated with Fractures ............................................................................................ 17
6.0   BENEFITS....................................................................................................................................................... 17
7.0   LIABILITY ..................................................................................................................................................... 17
8.0   DISCLOSURE OF ANY FINANCIAL COMPENSATION .......................................................................... 17
9.0   BIBLIOGRAPHY............................................................................................................................................ 17
1.0     BACKGROUND, RATIONALE, AND STATEMENT OF
        RESEARCH QUESTIONS
The purpose of this clinical study is to determine whether the rate of fracture healing and
fracture union, repaired with this LISS device, will be as good as or better than the usual
fracture fixation systems. Outcomes associated with distal femoral fracture types will be
investigated to determine whether there is a benefit to using the Less Invasive
Stabilization System (LISS) to assist in fracture repair. These fractures are frequently
associated with comminution and consequently bone defects exist following fracture
reduction. In addition, the difficult surgery often results in complications such as wound
problems, infection, malunion, and nonunion. These complications can result from
inadequate fracture reduction and stabilization, soft tissue damage from insertion of the
fixation device, and disruption of blood supply to the healing bone.

The LISS is designed to improve on these problems (see attached information on this
system, Appendix C). The key features of the LISS are: 1) locking screws, which
improve load transfer to the plate and minimize bone-plate contact; 2) percutaneous, self-
drilling, unicondylar screws that minimize soft tissue disruption; and 3) submuscular
plate placement, which reduces soft tissue dissection and preserves bone blood supply.

This product may therefore reduce the proportion of patients experiencing post-operative
malunions, delayed unions, or nonunions of repaired fractures, while perhaps improving
bone healing. A prospective, multi-center, randomized trial has been designed to
investigate this system.

Two primary endpoints are planned for this clinical trial. The first is to determine
whether the LISS reduces the time to radiological and clinical union. The second is to
determine whether the LISS can reduce delayed unions and/or nonunions. Assessment of
the remodeling and healing process will also be followed over the study duration.
Secondary endpoints include, but are not limited to, physical function self assessment and
adverse event frequency.

In all of the involved institutions, the standard treatment for distal femoral fractures is
open reduction and internal fixation with a fixed angle device, such as a Dynamic
Condylar Screw (DCS), or a Condylar Buttress Plate (CBP). AO fracture types A, B,
and C will be included in a prospective consecutive randomized process.

Comparisons are planned between patients treated with the LISS and patients treated with
either 1) a dynamic condylar screw in Type A, B, and C fractures, where possible; or 2) a
condylar buttress plate in Type C fractures with coronal splits when a fixed angled device
would not be possible. Randomization will be done in a consecutive fashion. A total
enrollment of 110 patients in group one (55 of each device) and 40 patients in group two
(20 of each device) is planned at eight participating centers. Patients will be followed


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postoperatively at hospital discharge, 6 weeks, 3 months, 6 months, and 12 months. The
technique utilized should be as described in the technique guide enclosed (Appendix D).


The surgical treatment of the fracture is to occur while fresh and must occur within
fourteen days of the injury. Efficacy will be assessed by the clinical and radiographic
healing of the fracture. The primary efficacy study objective is the secondary
displacement or collapse at the fracture site. This will be assessed for each patient using
x-rays. The second primary objective is the percent of patients clinically and
radiographically healed by 6 months as determined by the investigator. Clinical healing is
defined as full weight bearing without external support with no greater than moderate
pain at the fracture site. Clinical and radiographic healing will be assessed by the
investigator at each follow-up visit. Radiographic healing is defined as bridging the gap
between the cortical surfaces of the fracture and or defect with cortical and/ or trabecular
bone.

To analyze for possible surgeon bias, the radiographs will also be reviewed by an
independent surgeon or radiologist at the lead site.

As a secondary endpoint, functional impairment in this clinical study will be evaluated by
a patient function questionnaire, the Lower Extremity Measure (LEM), to be completed
while in hospital, at 6 months, and at one year. A SF-36 will be used at 6 months and one
year. Both the SF-36 and the LEM have been validated. Recent studies on fractured hip
patients show the SF-36 is valid to assess fracture patients. The LEM has recently been
validated as a lower extremity measurement tool in the Journal of Bone and Joint Surgery
(JBJS) issue 82A, vol. 7, pages 955—962, 2000.

The therapeutic management of the patients will be carried out as per standard medical
practice for the specific indication. It should be noted that Less Invasive Stabilization
System is an approved device in Canada for uses as described in this proposal.


2.0      SUBJECT SELECTION

One hundred and fifty patients will be treated with open reduction and internal fixation at
eight sites in Canada. To be enrolled in the study, patients must meet the following
inclusion and exclusion criteria.

2.1      Inclusion Criteria

      1. Patients must present with a distal femoral fracture for which the surgeon deems
         use of internal fixation necessary within fourteen days from the date of injury.




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                                                                                 Study Number


      2. The fracture must be fresh (surgical treatment must occur not more than 14 days
         from injury).

      3. Fixation must be done with a LISS or Dynamic Condylar Screw (DCS) in group
         one; a LISS or Condylar Buttress Plate (CBP) in group two. A second medial
         plate may be used to prevent varus collapse.

      4. Patient’s growth plates must be closed.

      5. Patients must undergo the consent procedure and sign the informed consent
         document.

2.2      Exclusion Criteria

      1. Superficial or deep infection or osteomyelitis at the operative site.

      2. Healing potential may not be compromised. The patient must not have diabetes,
         alcoholism, or substance abuse.
      3. Pre-existing severe vascular or neurological disease, or significant vascular
         impairment to operative site.

      4. The presence of a significant metabolic disorder or bone disease (e.g. Paget’s
         disease or osteomalacia) requiring care/treatment by a physician.

      5. Concurrent use of systemic steroids (may affect bone healing).

      6. Immunosuppressive therapy or immunocompromised status.

      7. Malignant (tumor) disease.

      8. Inability to participate in follow-up and/or functional tests during follow-up
         (including inability due to substance abuse, geographic location, etc.).

      9. Participation in another clinical study within past 30 days.

      10. Legal or limited legal incapacity.

All screened patients will be followed to healing of the fracture with particular attention
to the maintenance of the post operative reduction.




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2.3      Concomitant Medications

Concomitant medications given intraoperatively or postoperatively are not prohibited
unless they fall under those listed in the exclusion criteria. Patients who are receiving or
will receive chemotherapeutic agents or immunosuppression, which may affect bone
healing, will be excluded from the study. Should any of these medications be necessary
postoperatively, the patient will continue to be followed as intent to treat but will not be
included in the final analysis of the per protocol group. Any pain medications which the
patient continues to take at 6 months and 12 months should also be recorded on the case
report form.

3.0      RESEARCH PLAN

3.1      Study Sites

Eight Canadian sites will participate in the study. Proposed Investigators and Study
Centers are:

      1. Ross Leighton, Dave Petrie, Mike Dunbar, and Kevin Deluzio
         QEII Health Sciences Centre &
         Dalhousie University
         Halifax, Nova Scotia, Canada

      2. Peter O’Brien
         Vancouver General Hospital
         Vancouver British Columbia

      3. Richard Buckley and Jim Powell
         Foothills Hospital
         Calgary, Alberta

      4. Mike McKee and Emil Schemitsch
         St Michael’s Hospital
         Toronto, Ontario

      5. Dave Stephen and Hans Kreder
         Sunnybrook Hosp
         Toronto Ontario

      6. Trauma Group—ED Harvey and Greg Berry
         MUHC
         Montreal Quebec




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      7. Trauma Group—Dave Sanders
         UWO
         London Ontario

      8. Bob McCormack and Graham Pate
         Royal Columbian Hospital
         Vancouver, B.C.

3.2     Allocation of Study Device

Patients who meet the eligibility criteria and sign the informed consent form will be
randomized at 1:1 to receive either the LISS system or the usual fixation device of the
involved surgeon based on the fracture type and the choices of devices noted above on
any one fracture.

3.3     Control Group

The treatment group randomized to receive the other devices (DCS or CBP) will be used
as a control group to evaluate the safety and efficacy of the LISS device. The percent
healed clinically and radiographically by 6 months will be calculated for each treatment
group. The same data points will be collected for both treatment groups. Radiographic
evaluation will also measure the amount of secondary collapse, as is the usual on all
radiographic reports.

3.4     Baseline Evaluation

The patient will be evaluated relative to the inclusion and exclusion criteria at the initial
visit to determine eligibility. If the patient satisfies the eligibility criteria and signs an
informed consent form, the investigator or designee will enroll the patient in the study,
assign the next patient study number and randomize the patient into a treatment group.
The randomization scheme will be stratified by site. A centralized, computerized
randomization process will be used to accomplish the randomization at each site.

Baseline information to be collected from each patient includes date of birth, height,
weight, race, sex, smoking history, and medical history. The patient diagnosis case report
form will collect the following data: date of injury, date of hospitalization, location of
fracture, description of fracture, and randomized treatment group. Occupation, WCB
status, type of work and grade of work (heavy, moderate, light or sedentary) will also be
collected. Pre-operative radiographs will be taken to determine the injury and fracture
type. In addition the patient will complete the patient function questionnaire (LEM)
during the initial hospital stay, based on the patient’s function prior to the injury. A SF36
will be done at 6 months and 12 months.




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3.5     Intra-operative Procedure

The patients are operatively treated as per standard medical procedure. The patient will
be treated with the chosen internal fixation as done by the attending surgeon with plates
and screws.

3.6     Post-operative Procedure

All patients will be followed postoperatively at hospital discharge, 6 weeks ± 2 weeks, 3
months ± 2 weeks, 6 months ± 4 weeks, and 12 months ± 4 weeks. During each follow-
up the patient will be evaluated for clinical and radiographic healing. Radiographs in at
least two views will be taken at each follow-up, as per standard treatment. The date of
hospital discharge should be recorded on the case report form. The Lower Extremity
Measure (LEM) will be done during the hospital stay, at 6 months, and at 1 year. SF36
questionnaires will be done at 6 months and 1 year.

3.6.1 Clinical Examination

Clinical healing is defined as full weight bearing without external support with no greater
than moderate pain at the fracture site. It will be evaluated as follows:
 Weight bearing on one leg
 Pain at the fracture site recorded by patient using a visual analog scale

Function will be evaluated by:
 Patient questionnaire (LEM) for lower extremity impairment (at discharge, 6 months
   and 12 months)
 SF-36 at 6 months and 12 months

The clinical examination must be performed by the investigator (or designee) post-
operatively and at each follow-up visit. The examination shall include an assessment of
the following variables to be recorded on the case report forms:
 Date of follow-up visit and follow-up visit period
 Time to return to work
 Presence of local symptoms including: pain at rest, tenderness, swelling, induration,
    calor, rubor, hyperthermia, skin necrosis, wound dehiscence, seroma, hematoma, and
    signs of compartment syndrome
 Pain at fracture site
 Wound condition at fracture site
 Modification of wound treatment at fracture site
 Stability
 Range of motion of the involved joint
 Need for surgical intervention
 Conformance to rehabilitation protocol


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3.6.2 Radiograph Examination

Radiographic healing has been defined in this study as bridging the gap between the
cortical surfaces of the defect within cortical or trabecular bone. According to standard
care procedures, radiographs taken from at least two standard views providing
unobstructed detail of the fracture will be evaluated at each follow-up visit for evidence
of healing at the defect site.

If evidence of healing cannot be determined by standard views, oblique views may be
used to elucidate defect changes. The data to be collected and recorded on the case report
form are as follows:

     Date radiograph taken
     Comparison to baseline radiograph of the following:
              Gap between the cortical surfaces
              Migration of the implant from the defect site
              Fracture of metal fixation
              Dislocation of metal fixation
     Any additional comments may also be recorded on the case report form.

The radiographs will be assessed by the study investigator and also by an independent
reviewer. The original radiographs will be digitized where and when possible and
forwarded to the QEII HSC, Halifax (Kelly Collier, Research Coordinator).

3.7      Time Schedule

After the eligibility criteria have been satisfied and patient consent signed, the patient
may be enrolled in the study, assigned a patient number, and randomized into a treatment
group.

Prior to surgery (baseline):

     inclusion/exclusion criteria evaluation
     randomization
     medical history
     patient questionnaire
     clinical evaluation
     radiographic examination
     labs-CBC, metabolic profile, urinalysis (only if standard trauma protocol)


Intraoperative:
 Use of the fixation device of choice


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                                                                                      Study Number


Postoperative:
       Hospital discharge
                  clinical examination
                  radiograph examination
                  patient questionnaire ( LEM)

        6 weeks ± 2 weeks
                   clinical examination
                   radiograph examination

        3 months ± 2 weeks
                  clinical examination
                  assessment of weight-bearing for the affected lower limb
                  radiographic evaluation

        6 months ± 4 weeks
                  clinical examination
                  assessment of weight-bearing for the affected lower limb
                  radiograph examination
                  patient questionnaire (LEM and SF-36)

        12 months ± 4 weeks
                  clinical examination
                  radiograph examination including CT scan
                  assessment of weight-bearing for the affected lower limb
                  patient questionnaire (LEM and SF-36)
                  end of study case report form

Study Schedule         Preop     Intraop      Discharge        week   month   month      month
                                                                6       3       6         12
Medical History           X
ORIF (LISS or                        X
alternative)
Clinical Exam             X                        X             X     X       X           X
Labs                      X
Radiographs               X                        X             X     X       X           X
Concomitant               X          X             X             X     X       X           X
Medication
Adverse Events                       X             X             X     X       X           X
SF-36                                                                          X           X
LEM                       X                                                    X           X




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                                                                                 Study Number


3.8      Study Completion

Patients will have completed the clinical study at the 12-month follow-up visit. The End
of Study case report form should be completed in addition to the usual follow-up case
report forms. Patients who withdraw from the study at any other time point should
complete the end of study case report form and specify the reason(s) why the study was
prematurely ended.

Reasons for premature end of study are:
 withdrawal of patient consent
 occurrence of exclusion criterion
 occurrence of adverse events (withdrawal if desired or considered necessary by
   investigator or patient)
 unplanned surgical intervention (i.e. nonunion)
 fixation failure prior to healing
 patient lost to follow-up

3.8.1 Study Success Criteria

Successes are defined as those patients who are determined by the investigator to be both
clinically and radiographically healed at 6 months. Nonunion or delayed union or failure
of the fixation device would be considered a treatment failure. Removal of fixation after
clinical and radiographic healing has been achieved is considered a planned surgical
intervention and would not alter a study success. This will not be considered an adverse
experience or a study failure.
     Clinical healing is defined as: 1) full weight bearing with no external support and no
      greater than moderate pain at the fracture site.
     Radiographic healing is defined as bridging the gap between the cortical surfaces of
      the defect with cortical or trabecular bone

3.8.2 Study Failure Criteria

Patients who have not radiographically or clinically healed at 6 months will be
considered study failures. If an unplanned surgical intervention for replacement of
fixation occurs the patient will be considered a study failure at the time of the reoperation
procedure, discontinued from the study, and followed for safety. Removal of internal or
external fixation after clinical and radiographic healing has been achieved is considered a
planned surgical intervention and will not alter a study success. This will not be
considered an adverse experience or a study failure, but will be documented.




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3.9     Adverse Experiences

3.9.1 Definition

An adverse experience is any adverse change from the subject’s baseline and usual (pre-
treatment) condition, whether or not it is believed related or unrelated to the experimental
intervention. A pre-existing condition that recurs with an increased frequency or
intensity is also an adverse experience.

A serious adverse experience is any untoward medical occurrence, whether considered
implant-related or not, that is (1) fatal, (2) results in cancer, (3) is life-threatening,
meaning that the subject was at risk of death at the time of the event (this does not refer
to an event which might have caused death if it had occurred in a more severe form), (4)
requires in-patient hospitalization or prolongs the existing hospitalization, (5) is
permanently disabling or incapacitating, (6) is a congenital anomaly or birth defect, or (7)
is an overdose.

Removal of internal fixation after clinical and radiographic healing has been achieved is
considered a planned surgical intervention and will not be considered an adverse
experience.

Medical judgment should be exercised in deciding whether other experiences may be
considered serious. Important medical events, which may not be immediately life
threatening or result in death or hospitalization but may jeopardize the patient or require
intervention to prevent one of the other outcomes meeting the definition of serious,
should be considered serious.

At each study visit, and after the subject has had the opportunity to spontaneously report
complaints, the investigator or designee should inquire about the incidence of adverse
experiences by asking general and non-leading questions such as ―Have you noted any
medical problems since your last visit?‖ or ―Have you needed a medical evaluation since
the last visit?‖ The incidence of an adverse event will be based on changes in the
subject’s physical examination, laboratory evaluation, and/or clinical signs and
symptoms. The investigator or designee should instruct the subject to call immediately if
any signs or symptoms of concern or of a serious nature occur.

All adverse experiences must be medically monitored until resolution, until the condition
is determined to be chronic and stable, or until a satisfactory explanation for the test
result or symptom has been found.




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                                                                                Study Number


3.9.2 Reporting Serious Adverse Experiences

Any adverse experience meeting the definition of serious as described above that has
occurred during the course of the study must be reported to R. K. Leighton or Kelly
Collier (QEII HSC, Halifax) within 24 hours of the site learning of the experience, even
if only preliminary information is known at the time. The investigator will report serious
adverse experiences to the Institutional Review Board according to the IRB’s
requirements.

3.9.3 Documenting Adverse Experiences

All clinical adverse experiences, regardless of intensity, causality, or seriousness must be
promptly recorded and sufficiently documented by the investigator or designee in the
source record and case report form. The investigator or designee must determine the
intensity of the adverse experience according to the following definitions:

    Mild – mild symptoms that are easily tolerated and transient in nature with minimal
     or no impairment of normal activity

    Moderate – moderate symptoms that are poorly tolerated, sustained and interfere
     with normal activity

   Severe – severe symptoms that are sustained, intolerable, incapacitating, life-
    threatening, fatal, permanently disabling, result in congenital abnormalities, cancer or
    an overdose

An assessment of causality of the event by the investigational agent must also be
provided according to the following definitions:

   Related – experience follows a reasonable temporal association with the use of the
    LISS device.

   Unrelated – there is no relationship between the experience and exposure to the LISS
    fixation.

3.10    Data Collection

The investigator or designee must prepare and maintain accurate and complete study
documentation. The lead site will provide case report forms specific to this protocol to
the clinical site. Case report forms are to be completed in a clear and legible manner
using black ink. When corrections are made, a single line should be used to cross out the
error, the correct data should be written in and the correction initialed and dated.




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                                                                                 Study Number


A copy of the protocol and case report forms, as well as medical records, original test
result reports, investigational agent accountability and dispensing logs, correspondences,
record of informed consent and other documents pertaining to the conduct of this study
must be retained by the investigator for at least five years after the completion of study.
No study document shall be destroyed without prior written agreement between the lead
site and investigator. Should the investigator wish to assign the study record to another
party or move them to another location, the lead site must be notified in writing.

Sample case report forms are provided in Appendix B.

3.11    Protocol Deviations

Deviations from the protocol that eliminate an apparent immediate hazard to subjects do
not require pre-approval by the IRB, but must be reported in writing to the IRB within 5
days of implementation. If appropriate, changes will be incorporated into the protocol to
reflect the necessary deviation as soon as possible by the way of a formal amendment. If
the deviation is specific to a given subject, and not viewed as an appropriate amendment
to the protocol, the investigator must document the deviation in a memo to the study files
and provide this information to the IRB as per usual. The memo shall be maintained as
an official study record.

3.12    Amendments

Protocol modifications to ongoing studies may be made only after agreement with the
lead site. Changes which may affect the relative safety of subjects, the scope of the
investigation, the scientific quality of the study, the experimental design, the duration of
therapy, the assessment variables, the number of subjects treated, or any of the subject
selection criteria require formal protocol amendments. Amendments may only be
generated by the lead site (QEII) and require review and approval by the investigator’s
local IRB.

3.13    Informed Consent from Patients

It is the responsibility of the investigator or designee to obtain informed written consent
from each subject participating in the study, according to the local IRB requirements.
Consent must be obtained prior to the initiation of study-related procedures and should
include an adequate explanation of the aims, methods, anticipated benefits and potential
hazards of the study. The investigator or designee must also explain that the subjects are
completely free to refuse to enter the study or to withdraw from it at any time.

Each prospective study subject must be informed of the purpose of the study, the nature
of the study, its possible hazards, and their right to withdraw at any time from the study
without prejudice to further treatment. Each subject must agree to cooperate in all
aspects of the study and must give written informed consent to the Investigator prior to


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                                                                                 Study Number


initial assessment for the study in order to participate. Since all devices used in this study
are approved for use in Canada, the consent is an agreement to comply with follow-up
procedures, not a consent for surgery. Signed subject consent forms must be retained and
be available for review by a lead site representative.

3.14    Institutional Review Board (IRB)

The protocol, informed consent form, and Investigator’s Brochure will be submitted to
the appropriate IRB for review and approval, as required by current regulations. In
addition, any amendments to the protocol or informed consent form will be reviewed and
approved (if necessary) by the IRB. A letter documenting the IRB approval must be
received by the Lead site prior to the initiation of the study.

The principal investigator is also responsible for informing the IRB of the progress of the
study and for obtaining annual IRB renewal. The IRB must be informed at the time of
completion of the study and should be provided with a summary of the results of the
study by the principal investigator. The principal investigator must notify the IRB in
writing of any significant adverse experiences. The IRB must operate in accordance with
current federal regulations. The lead site must have on file, prior to study initiation, a
record that the board is duly constituted.

3.15    Data Ownership

The data is the express property of the individual investigators and the principal
investigator in the lead site (QEII). It can be presented or published at any time by the
lead investigator or co-investigators, BUT the lead site has the right to review but NOT
alter the data prior to presentation or publication. The lead site must be given a minimum
of 6 weeks to review and respond prior to the release of this data.

3.16    Case Report Forms

The following will be completed within 10 days of the surgery date. They will be
submitted within 4 to 6 weeks to Halifax, the lead site.

   Study admission checklist
   Informed patient consent
   Patient historical profile
   Operative detail form

The LEM will be done at the time of the surgery, based on the patient’s function prior to
the injury, again at 6 months and 1 year (i.e. three times for each patient). No post-
operative SF-36 would be needed except as noted above (i.e. 6 months and 1 year).




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                                                                               Study Number


Radiographs, digitized if possible, will be sent to Halifax for independent reading every 3
to 4 months.

Complications and withdrawals are to be noted within 1 week of the event. Specifics
should be available within 3 to 4 weeks.

4.0     ANALYSIS OF DATA
4.1     Primary Study Hypothesis

The null hypothesis is that the percent of LISS patients with clinical and radiographic
healing at 6 months will be greater than those with the other systems. The alternative
hypothesis is that the percent of LISS patients with clinical and radiographic healing by 6
months will be no more than 8% greater than those with other fixation methods. By
disproving the null hypothesis the alternative hypothesis will be accepted. A one-sided
hypothesis test will be used.

4.2     Efficacy Endpoints

The primary endpoint will be delayed union or nonunion of the distal femur. A secondary
endpoint will be the percent of each patient population with radiographic healing by six
months. Secondary data (all non-primary data recorded on the CRFs) collection and
analysis includes, but is not limited to the following:
       a.      Time to clinical healing
       b.      Function as assessed by patient
       d.      Frequency of adverse events
       e.      Range of motion

All secondary data will be displayed and analyzed by treatment modality.

4.3     Sample Size Determination

The standard formula by Blackwelder and Chang for a two-sample population was used
for computation of sample size for a two-sample comparison. This compares the LISS to
the standard fixation for the presenting fracture. The calculations are based on the null
hypothesis of a 93% clinical and radiographic healing at 6 months. The Type I error is
5% and the power is 80% for the one-sided hypothesis test. The total sample size is 150
patients using a 1:1 randomization and allowing for a 15% dropout rate.




Clinical Study Evaluating the L.I.S.S. for Distal Femoral Fractures                         14
                                                                                Study Number


4.4     Study Populations

4.4.1 Safety Population

All patients receiving any study therapy will be included in the safety population.

4.4.2 Efficacy Population

The per-protocol analysis, which will be the primary study analysis, will exclude
ineligible patients as well as those patients who did not follow the protocol; however, all
patients screened will be followed to fracture healing and any surgery needed will be
noted.

4.5     Interim Analysis

No interim analysis will be performed.

4.6     Baseline Characteristics

Study groups will be assessed for balance at baseline for the following covariates:
fracture location and time from injury to study therapy. The volume required and type of
fixation used will also be assessed. Age, sex, race, and study site will also be presented
for all groups.

4.7     Study Completion

The percents failing to complete the study, losses to follow-up, times lost to follow-up,
reasons for discontinuation, and patients requiring additional treatments (including
revisions) will be presented.

4.8     Efficacy

Intent to treat and per-protocol analyses will be performed for all study endpoints. The
per-protocol analysis will be the primary analysis. An exit analysis will be performed
using the last valid, post-baseline, on-study observation for patients who withdraw early.

Secondary study data will be assessed in a similar manner. The percents with
radiographic healing will be analyzed in the same manner as the percents with clinical
healing. The concordance (kappa) will also be computed between the clinical and
radiographic healing outcomes. This analysis will be performed using patients with both
clinical and radiographic data available at the same observation times. The time to
clinical and the time to radiological healing will be displayed using a Kaplan-Meier
lifetable. Cox proportional hazards models will be run parallel to the logistic regression
models performed for the healed percents. In addition, results will be displayed by


Clinical Study Evaluating the L.I.S.S. for Distal Femoral Fractures                           15
                                                                                 Study Number


treatment modality for all secondary data including, but not limited to, clinical function
performance, fixation removal, drain removal, and need for surgical intervention.

4.9     Safety

Safety parameters to be displayed include the incidence of any local symptoms (pain,
tenderness, swelling, skin necrosis) as well as complications (wound infection,
osteomyelitis, wound dehiscence, delayed wound healing, loss of reduction, refracture,
hematoma).

The number of events and incidence of adverse events by first occurrence, maximum
severity, and device relationship will also be displayed. The incidence and relationship
of serious adverse events to study therapy will also be assessed.

95% upper confidence bounds will be computed for the incidence of adverse events and
complications. No adjustment will be made for repeated confidence interval calculations.

All statistical tests for significance will be performed at the 0.05 significance level using
one-sided tests. No p-value adjustments are anticipated since the primary efficacy
endpoint has been pre-defined and the month 12 visit (or study exit) is to be the key
analysis time.


5.0     RISKS
In the study under consideration in this plan, all patients entering the study will have a
significant fracture. The minimum treatment that all patients would undergo in any event
would be reduction and fixation of the fracture, with periodic follow-up including clinical
examination and radiographs as noted in this study. Most routine follow-ups go out to
two years. The follow-up scheme for this study is based on the current standard of
clinical care, and includes radiographs at each time point. As with any surgical procedure,
there are risks of infection and additional trauma associated with surgical intervention.

5.1     Risks Associated with the LISS Device

Disadvantages of the LISS device may include decreased range of motion secondary to
early, significant callus formation and proximal screw pullout due to poor positioning of
the plate on the bone (a difficulty of the closed reduction technique). A decrease in range
of motion can occur in these fractures regardless of fixation type and it is not known
whether the LISS increases the chances of this occurring. If difficulty positioning the
plate is encountered intraoperatively, the surgeon can widen the incision to properly place
the plate. Because only patients whose fracture typically would be treated with an ORIF
will be recruited for this study, there is believed to be no increased risk from the surgery



Clinical Study Evaluating the L.I.S.S. for Distal Femoral Fractures                             16
                                                                                 Study Number


due to participation in this study. The LISS is in current use in all the study centers across
Canada.


5.2      Complications Associated with Fractures

Complications associated with surgically treated fractures include infection, wound
slough, compartment syndrome, loss of reduction, nonunion, post-traumatic arthritis, and
fixation failure (including, but not limited to, screw loosening and angulation of the
implant). Infection is the most common and devastating complication resulting from
wound problems. The use of the LISS device is NOT expected to result in an increase in
the complications associated with these fractures.

6.0      BENEFITS
As discussed previously, the favourable features of the LISS device are its anatomical
shape, unicondylar locking screws, percutaneous screw insertion, submuscular ―sliding‖
plate placement, and minimal bone contact. These result in smaller incisions, less soft
tissue dissection, better and more stable alignment, and preservation of osseous
vascularity. Possible clinical benefits include lower infection rate, decreased need for
bone grafting, higher and faster union rate, and maintenance of fixation, which may
reduce the need for reoperation.

7.0      LIABILITY
The patient’s rights are not waived by participating in this study. The principal
investigator, research doctor, and involved institution are not released from their legal or
professional responsibilities.


8.0      DISCLOSURE OF ANY FINANCIAL COMPENSATION
Patients will not be compensated for their participation in this study.


9.0      BIBLIOGRAPHY
      1. Babst R, Hehli M, Regazzoni P. LISS Tractor. Combination of the ―Less Invasive
         Stabilization System‖ (LISS) with the AO Distractor for Distal Femur and
         Proximal Tibial Fractures. (Article in German) Unfallchirurg 2001 Jun; 104(6):
         530-5.




Clinical Study Evaluating the L.I.S.S. for Distal Femoral Fractures                            17
                                                                              Study Number


    2. Bong MR, Egol KA, Koval KJ, Kummer FJ, Su ET, Iesaka K, Bayer J, Di Cesare
       PE. Comparison of the LISS and a retrograde-inserted supracondylar
       intramedullary nail for fixation of a periprosthetic distal femur fracture proximal
       to a total knee arthroplasty. J Arthroplasty 2002 Oct;17(7):876-81.

    3. Fankhauser, Marti, et al; A Comparative Biomechanical Evaluation of Three
       Systems for the Internal Fixation of Distal Femur Fractures; ORS poster
       presentation; Anaheim, CA; 1999.

    4. Haas, NP et al. LISS – Less Invasive Stabilization System—ein neuer Fixateur
       Intern für distale Femurfraturen. OP Journal, Dec. 1997;3.

    5. Henry, Stephen and Philip Kregor; Supracondylar Femur Fractures. Operative
       Techniques in Orthopaedics vol. 9, no. 3; 1999.

    6. Könemann B, Schandelmaier P, Partenheimer A, Krettek C. Stabilisierung enier
       distalen Femurfraktur mit dem ―Less Invasive Stabilization System‖ LISS.
       Trauma 2000. Hannover, Germany. September 2000.

    7. Kregor et al. Prospective Clinical Trial of the Less Invasive Stabilization System
       (L.I.S.S.) for Supracondylar Femur Fractures. OTA paper present #33, Charlotte,
       NC; 1999.

    8. Kregor et al. Prospective Clinical Trial of the Less Invasive Stabilization System
       (L.I.S.S.) for Supracondylar Femur Fractures. AAOS paper present #42, Orlando,
       FL; 2000.

    9. Kregor et al. Limited Invasive Stabilization System for the Distal Femur. Injury
       Vol. 32 Supplement 3, 2001.

    10. Krettek C, Schandelmaier P, Richter M, Tscherne H. Distal Femoral Fractures.
        (Article in German) Swiss Surg 1998;(6):263-78.

    11. Marti et al; Biomechanical Evaluation of the Less Invasive Stabilization System
        for the Internal Fixation of Distal Femur Fractures. J Orthop Trauma 2001, Sep-
        Oct; 15(7): 482-7.

    12. Partenheimer A, Marti A, Koenemann B, Fankhauser C, Stephan C,
        Schandelmaier P. LISS und retrograde Marknagelung im biomechanischen
        Vergleich. Trauma 2000. Hannover, Germany. September 2000.

    13. Schandelmaier P, Blauth M, Krettek, C. new technique: Internal Fixation of
        Distal Femur Fractures with the Less Invasive Stabilizing System (LISS).
        Orthopedics and Traumatology. Vol 9, Iss 3, 2001, pp 166-184.


Clinical Study Evaluating the L.I.S.S. for Distal Femoral Fractures                       18
                                                                             Study Number




    14. Schandelmaier P, et al. LISS—Osteosynthese von distalen Femurfrakturen.
        Trauma und Berufskrankheit. 1999; 1(4).

    15. Schandelmaier P, Stephan C, Krettek C, Tscherne H. Distal Fractures of the
        Femur. (Article in German) Der Unfallchirurg 2000 Jun; 103(6): 428-36.

    16. Schandelmaier P, Stephan C, Krettek C. bewegungsapparat: Less-invasive-
        stabilizing-System (LISS). Trauma und Berufskrankheit Vol. 3 Issue 8, 2001, pp
        S439-S446.

    17. Schandelmaier, Peter, et al; Results of 32 Distal Femoral Fractures with the LISS
        System. OTA poster #50; Charlotte, NC; 1999.

    18. Schavan, Robert, et al; LISS—The Less Invasive Stabilization System for
        Metaphyseal Fractures of Femur and Tibia. OTA poster #1; Vancouver, BC;
        1998.

    19. Schutz M, Haas NP. LISS—Internal Plate Fixator. (article in German).
        Kongressbd Dtsch Ges Chir Kongr 2001; 118:375-9.

    20. Zlowodski et al; Biomechanical Evaluation of the Less Invasive Stabilization
        System (LISS), Angled Blade Plate, and Retrograde Intramedullary Nail for the
        Fixation of Distal Femur Fractures: An Osteoporotic Cadaveric Model; OTA
        2002.




Clinical Study Evaluating the L.I.S.S. for Distal Femoral Fractures                      19
                                                                               Study Number


APPENDIX A:               ADVERSE EXPERIENCES

Definition:    An adverse experience is any adverse change from the subject’s baseline
and usual (pre-treatment) condition, whether or not it is believed related or unrelated to
the experimental intervention. A pre-existing condition that recurs with an increased
frequency or intensity is also an adverse experience.

A serious adverse experience is any untoward medical occurrence, which is (1) fatal or 2)
limb-threatening, meaning that the subject was at risk of death or limb loss at the time of
the event.

Removal of internal fixation after clinical and radiographic healing has been achieved is
considered a planned surgical intervention and will not be considered an adverse
experience. Pin exchange or wire removal is also considered a planned intervention and
not an adverse experience.

Medical judgment should be exercised in deciding whether other experiences may be
considered serious. Important medical events which may not be immediately life or
limb-threatening or result in death or hospitalization which may jeopardize the patient or
require intervention to prevent one of the other outcomes meeting the definition of
serious should be considered serious.

Reporting Serious Adverse Experiences:
Any adverse experience meeting the definition of serious as described above that has
occurred during the course of the study must be reported to the IRB within seven working
days of the site learning of the experience even if only preliminary information is known
at the time. The investigator will provide the IRB and lead site, if necessary, with
medical records as needed to document the adverse experience and will keep the IRB
informed of the subject’s condition as per usual IRB protocol.

The investigator will report serious adverse experiences to the Institutional Review Board
according to the IRB’s requirements.

An assessment of causality of the event by the investigational agent must also be
provided by the investigator according to the following definitions:

   Related – experience follows a reasonable temporal association with the use of the
    LISS plate
   Unrelated – there is no relationship between the experience and exposure to the
    investigational agent




Clinical Study Evaluating the L.I.S.S. for Distal Femoral Fractures
                                                                      Study Number


APPENDIX B:               SAMPLE CASE REPORT FORMS



       Study Admission Checklist
       Patient Medical History
       Operative Form
       Radiographic Evaluation
       Clinical Evaluation
       Event/Complication/Withdrawal Form
       Lower Extremity Measure (LEM)
       SF-36
       End of Study Form




Clinical Study Evaluating the L.I.S.S. for Distal Femoral Fractures
                                                                             Study Number




APPENDIX C:               DEVELOPMENT OF THE LISS




The Development of the Distal Femur Less Invasive Stabilization System (LISS)

R. Frigg, A. Appenzeller, R. Christensen, A. Frenk, S. Gilbert, R. Schavan

Injury, Int. J. Care Injured (2001) 32 S: C24-C31.




Clinical Study Evaluating the L.I.S.S. for Distal Femoral Fractures
                                                                      Study Number




APPENDIX D:               LISS TECHNIQUE GUIDE




Clinical Study Evaluating the L.I.S.S. for Distal Femoral Fractures

				
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