STaR Trial: Multiple Ligament Knee Injuries

Background:

Multiple ligament knee injuries (MLKIs) represent a spectrum of injury ranging from
disruption of two ligaments to all four major ligaments of the knee. Concomitant injuries may
include fractures and injuries to vessels, nerves, tendons, menisci and/or articular
cartilage. As such, the treatment of MLKIs creates multiple complex problems fraught with
complications such as poor wound healing, arthrofibrosis, neurovascular injuries, persistent
pain and instability, and post-traumatic osteoarthritis. Following MLKI, individuals are
frequently limited with higher demand activities such as in military training, physical labor
and sports. Return to duty after combat-related MLKIs has been reported to be as low as 41%
and substantially lower than return to work reported for civilians.

There is controversy related to the optimal timing of surgery and post-operative
rehabilitation for the treatment of MLKIs. Early surgical intervention for MLKIs has been
advocated, however this may be associated with an increased risk for arthrofibrosis.
Conversely, delayed surgery may be associated with persistent instability. The best evidence
for timing of rehabilitation is based on evidence following ACL reconstruction, where early
post-operative rehabilitation is the current standard of care. However, because of the
frequency of soft tissue repair procedures, post-operative rehabilitation after surgery for a
MLKI typically involves a period of non-WB and delayed ROM exercises. Due to the lack of
evidence for the timing of surgery and post-operative rehabilitation, a large scale trial is
needed to optimize the outcomes for these potentially devastating injuries. Therefore, this
multicenter clinical trial will investigate the effects of timing of surgery and post-op
rehabilitation to optimize return to military duty, work and sports for military personnel
and civilians with a MLKI.

Objectives, Aims and Hypothesis:

The overall objective of this project is to investigate the effects of timing of surgery
(early vs. delayed) and timing of post-op rehabilitation (early vs. delayed) for treatment of
MLKIs. To achieve this objective, we will conduct two parallel randomized clinical trials.
The related aims and hypotheses are:

Specific Aim 1 and Hypothesis: Determine the effects of timing of surgery and post-op
rehabilitation on time to return to pre-injury level of military duty, work and sports and
patient-reported physical function. We hypothesize that early surgery, early rehabilitation
and the combination of early surgery with early rehabilitation will lead to an earlier and
more complete return to pre-injury military duty, work and sports and better patient-reported
physical function.

Specific Aim 2 and Hypothesis: For those individuals whose timing of surgery can not be
randomized, determine the effects of timing of rehabilitation on time to return pre-injury
level of military duty, work and sports and patient-reported physical function. We
hypothesize that early rehabilitation will lead to an earlier and more complete return to
pre-injury military duty, work and sports activity and better patient-reported physical
function.

Overview of Research Procedures:

Male and female military personnel and civilians between the ages of 16 and 55 with a MLKI
without a history of prior knee ligament reconstruction that do not have a vascular injury,
poly-trauma or a traumatic brain injury will be eligible to participate. After obtaining
informed consent, subjects will undergo a preoperative evaluation, including collection of
baseline demographics, activity level, and a physical examination.

To address Aim 1, 392 individuals with a MLKI that present within 6 weeks of injury will be
randomized to early (within 6 weeks of injury) or delayed (12 to 16 weeks after injury)
surgery and early (WB and unrestricted ROM exercises starting first week after surgery) vs.
delayed (knee brace locked in extension, no range of motion exercises and non-weightbearing
gait for the first 4 weeks after surgery). To address Aim 2, 298 individuals with a MLKI that
present greater than 6 weeks after injury, have an injury that precludes randomization to
early or delayed surgery as well as those that refuse surgical randomization will be eligible
to participate in the trial that compares only early vs. delayed rehabilitation.
Randomization will be stratified by study site and knee ligament injury pattern.

Collection of Baseline Demographics and Activity Level:

Following consent and screening, baseline demographic and pre-injury level of military duty,
work and sports participation will be recorded. The demographic information to be recorded
includes age, sex, weight, height, body mass index (BMI), marital status, education level,
pre-injury military duty, work and sports, smoking history and insurance status.

Military Duty - For military personnel, to measure military duty prior to injury we will
record the Military Occupational Specialty Physical Demand Classification and will ask three
questions from the Injury Surveillance Survey (ability to perform Annual Physical Fitness
Test; Deployability and Specific MOS Duties).

Work Activity - To measure work activity prior to injury, we will use the Cincinnati
Occupational Rating Scale. Additionally, we will record the individual's pre-injury
employment status (work regular duty full time, work regular duty part-time etc.) and
occupation.

Sports Activity and Participation - We will use the Marx Activity Rating Scale to measure the
subject's level of sports activity in the year prior to injury. To assess sports
participation, we will also record the type (very strenuous, strenuous etc.) and frequency
(4-7 times per week, 1-3 times per week etc.) of sports participation as well as the specific
sport(s) the individual participated in prior to injury.

Baseline Clinical Examination:

A standard of care baseline clinical examination will be performed by the individual's
attending orthopaedic surgery. The examination will include assessment of pain, range of
motion (ROM), ligament laxity, sensory and neurovascular status (pulses, sensory & motor
nerve function). Additionally, standard of care radiographs and MRI will be reviewed to
identify fractures and document the ligament injury. The information from the baseline
clinical examination will be used to confirm final eligibility in the surgical and
post-operative rehabilitation trial or the post-operative rehabilitation only trial.

Interventions:

Aim 1 - Randomization to Early vs. Delayed Surgery and Post-Operative Rehabilitation -
Subjects enrolled in the clinical trial for Aim 1 will be randomized to one of four groups:
early surgery/early rehabilitation, early surgery/delayed rehabilitation, delayed
surgery/early rehabilitation or delayed surgery/delayed rehabilitation.

Those randomized to early surgery will undergo surgery within six weeks of injury and those
that are randomized to delayed surgery will undergo surgery 12 to 16 weeks after injury. In
all cases, surgery will be in accordance with the principles of anatomic
repair/reconstruction of injured structures in a manner that will allow for early range of
motion. Surgical reconstruction with allograft or autograft will be performed for
mid-substance tears of the ACL and/or posterior cruciate ligament (PCL). Repair or
reconstruction will be performed for injury to the medial collateral ligament (MCL) and the
posterolateral corner (PLC) structures (fibular collateral ligament, popliteus tendon, and
popliteofibular ligament). Injuries to the biceps femoris tendon or iliotibial band will be
addressed as necessary. Medial and lateral meniscus tears will be repaired or debrided at the
time of surgery. Neuropraxic nerve injuries will not necessitate early intervention; however,
if a neurotmesis injury is discovered on MRI, then early intervention for primary repair,
grafting or benign neglect may be warranted. All surgical findings and procedures will be
documented on electronic surgical case report forms.

Two post-operative rehabilitation protocols have been created, differing only in the time to
begin weightbearing (WB) and ROM exercises. After surgery, all individuals will be placed in
a hinged brace that is locked in extension. Individuals randomized to early rehabilitation
will begin WB as tolerated (WBAT) with the brace locked in full extension and unrestricted
ROM approximately 1 week after surgery at the time of the first post-operative visit.
Individuals in this group will unlock the brace for ROM exercises, but will keep the brace
locked at all other times until the criteria to unlock the brace are met. Weightbearing will
be gradually progressed to full WB no earlier than 3 weeks after surgery pending achievement
of the criteria for doing so.

Those allocated to delayed rehabilitation will be placed in a knee brace locked in extension,
with no range of motion exercise and will utilize a non-weightbearing gait for the first 4
weeks after surgery.

Immediately after surgery both groups will begin isometric quadriceps exercises with the knee
in full extension (quad sets, straight leg raises) and high intensity neuromuscular
electrical stimulation (NMES) for the quadriceps will be utilized. Use of the post-op brace
will be discontinued no earlier than 6 weeks after surgery pending achievement of the
criteria to do so. In the Motor Control and Functional Optimization phases of rehabilitation,
progression to increasingly demanding activities will be time- and criterion-based to ensure
that the individual is advanced safely to reduce the risk of further injury.

Aim 2 - Randomization to only Early vs. Delayed Rehabilitation - Subjects enrolled in the
trial for Aim 2 will undergo anatomic surgical repair/reconstruction of the injured
structures as described above, however the timing of surgery will be determined by the
surgeon and patient after consideration of the individual's specific circumstances related to
the nature and extent of the MLKI, associated injuries and timing of presentation. Following
surgery, individuals will be randomized to undergo either early or delayed rehabilitation as
described above.

Clinical Follow-Up Visits:

Information gathered during standard of care clinical follow-up visits will be prospectively
collected at 1 week and 1, 3, 6 and 9 to 12 months after the date of surgery. This
information will be documented and will serve to provide additional outcomes related to
post-operative recovery. The information will include pain, pain medication usage, joint
effusion, wound and neurovascular status, ROM, WB status, use of a post-op rehabilitation
brace, imaging and/or laboratory tests ordered and completed, complications and adverse
events, additional surgical procedures and military duty, work and sports status. Knee laxity
will also be assessed 3, 6 and 9 to 12 months after surgery.

Research Follow-Up Visits:

Subjects in all studies will be followed for 24 months. The primary outcome will be time to
return to pre-injury military duty, work and sports. To precisely determine the time to
return to military duty, work and sports, we will administer a brief Return to Activity
Monitoring Survey on a monthly basis starting 6 months after randomization and continuing
through the 24-month follow-up. Patient-reported physical function as measured with the
Activity Limitation Scale of the Multiple Ligament Quality of Life (MLQoL) Questionnaire will
serve as a co-primary outcome and will be assessed 6, 12 and 24 months after randomization.
Secondary outcome measures will include additional knee-specific and general patient-reported
measures of physical function and health-related quality of life. We will also collect
measures of kinesiophobia, resiliency and functional comorbidities because these constructs
may affect return to military duty, work and sports.

For the clinical trials for both aims, male and female military personnel and civilians
between the ages of 16 and 55 with a MLKI (defined as a complete grade III injury of two or
more ligaments) will be eligible to participate. Individuals with a nerve injury or biceps
or popliteus tendon rupture or avulsion will not be excluded from participation in either
trial.

Individuals will be excluded from both trials if they:

1. Prior knee ligament surgery of the involved knee;

2. Torn or avulsed patellar or quadriceps tendon;

3. Periarticular or long bone fracture that is anticipated to preclude weight-bearing
after surgery;

4. Require use of an external fixator for greater than 10 days;

5. Planned staged surgical treatment;

6. Unable to weight bear on the contralateral uninjured leg;

7. Traumatic brain injury (TBI) that limits their ability to participate in their
post-operative care;

8. Surgical procedures that precludes early weight-bearing or range of motion.

9. Any condition that would preclude the ability to comply with post-operative
guidelines.

Additional Eligibility Criteria for Participation in Aim 1 - Randomization to Both Timing
of Surgery and Post-Operative Rehabilitation

To be eligible to participate in the study for Aim 1 individuals with a MLKI must present
to orthopaedic surgery in time to undergo definitive surgery within 6 weeks of injury if
randomized to the early surgery group.

Individuals will also be ineligible to participate in the study for Aim 1 if they have:

1. Vascular injury that dictates timing of surgery;

2. Poly trauma that precludes surgery within 6 weeks of injury;

3. Skin or soft tissue injury that precludes early surgery and rehabilitation.

Additional Eligibility Criteria for Participation in Aim 2 - Randomization to Only timing
of Post-operative Rehabilitation

Subjects with a MLKI that present to orthopaedic surgery at a time that precludes
randomization to early surgery or have an injury that precludes randomizing the timing of
surgery (such as a vascular injury) as well as those that refuse randomization to the
timing of surgery will be eligible to participate in the study for Aim 2 which randomizes
subjects to only early vs. delayed rehabilitation.

Individuals will also be excluded from the trial that randomizes only the timing
post-operative rehabilitation if they have:

1. Vascular surgery that precludes early rehabilitation;

2. Polytrauma that limits ability to participate in post-operative care;

3. Skin or soft tissue injury that precludes early rehabilitation