Anterior Cruciate Ligament Reconstruction Using Bone Patellar Bone or Quad Tendon Autograft With or Without Lateral Extra-Articular Tenodesis in Individuals Who Are at High Risk of Graft Failure (STABILITY 2)
Phase: NA
Conditions: Anterior Cruciate Ligament Injury, Anterior Cruciate Ligament Reconstruction, Joint Instability
Sponsor: University of Pittsburgh

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STABILITY 2: ACL Reconstruction +/- Lateral 
Tenodesis with Patellar vs. Quad Tendon 
Protocol Number: PRO19020231 
NCT: NCT03935750 
Principal Investigators: 
James Irrgang, PT PhD FAPTA 
Volker Musahl, MD 
Alan Getgood, MD 
Dianne Bryant, PhD 
Funding Agencies:  
Canadian Institute of Health Research (CIHR) 
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) 
Version Number:  1.4 
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STATEMENT OF COMPLIANCE 
The study will be conducted in accordance with the International Conference on 
Harmonization guidelines for Good Clinical Practice (ICH E6), the Code of Federal 
Regulations on the Protection of Human Subjects (45 CFR Part 46).  All personnel 
involved in the conduct of this study have completed human subjects protection training. 

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PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, 
including a description of the change and rationale. 
Version  Date 
Description of Change 
Brief Rationale 
1.4 
February 2, 
2021 
Administrative changes 
throughout. 
Updated version dates, add amendment history, 
etc. 
Updated section 3.1 to clarify 
definition of clinical failure 
To be consistent with section 4.1 
Updated section 4.1 with 
asymmetrical vs asymptomatic 
pivot shift 
Incorrect word was used to describe clinical 
failure definition. 
Added IKDC Subjective Knee 
Form items related to giving 
way of the knee during daily 
activity and sports. 
To further explore this relationship between 
instability and rotational laxity of the knee within 
the STABILITY 2 Trial we will administer the IKDC 
Subjective Knee Form items related to giving way 
of the knee during daily activity and sports.  
Furthermore, we will explore the number of 
individuals that meet the definition of ACL clinical 
failure that also have symptomatic knee instability 
as defined by the IKDC Subjective Knee Form 
items related to giving way of the knee. 
1.3 
November 
17, 2020 
Administrative changes 
throughout. 
Updated version dates, add amendment history, 
etc. 
Collection of demographics on 
eligible, non-consenting 
participants. 
Non-consenting, eligible patients will be asked if 
de-identified demographic data can be collected 
to accurately describe those that are eligible for 
participation in the study but otherwise do not 
consent for participation.  This information will be 
useful to more accurately describe the 
representativeness of the sample that participated 
in the study relative to the population of interest.   
Added new baseline visit if 
outside 6-week window. 
Collection of ROM and PROMs on day of surgery 
if baseline is outside of 6-week window.  
Collecting updated baseline information will allow 
us to more accurately describe the study 
participants’ status at the time of surgery and 
randomization. 
Removed symptomatic 
instability from definition of 
clinical failure. 
While instability of the knee is associated with 
ACL clinical failure, it is also associated with other 
conditions affecting the knee including pain, 
quadriceps weakness and patellofemoral pain. As 
such, the presence of symptomatic instability 

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(patient’s perception of knee giving way) it is not 
sufficient to make the determination of clinical 
failure.   
These changes in the operational definition of 
ACL clinical failure are consistent with the 
definition of ACL clinical failure reported in the 
STABILITY Study.  Using the same definition of 
ACL clinical failure in the STABILITY 2 Trial as 
was use in the STABILITY Study will enable us to 
compare the effects of use of a quadriceps or 
patellar tendon graft with or without a lateral 
extra-articular tenodesis to the effects of use of a 
hamstring graft with or without a lateral extra-
articular tenodesis, which is one of the planned 
comparisons in this project. 
Updated BTB femoral fixation. 
BTB Femoral fixation will be with either an 
interference screw or suspensory fixation to 
accommodate surgeon practice. 
Added collection of range of 
motion during examination 
under anesthesia.   
Prior to undergoing surgery, range of motion of 
the knee may be limited by pain and swelling.  To 
more accurately determine passive range of 
motion of the knee at the time of surgery, passive 
range of motion will be visually assessed and 
recorded by the surgeon as part of the 
examination under anesthesia.   
Removed active knee 
extension from 12 and 24-
month follow-ups 
Limited active knee extension is indicative of poor 
quadriceps muscle performance that is most likely 
observed within the first 6 months after surgery.   
More than 6 months after surgery it is unlikely that 
individuals will have a knee extensor lag as 
indicated by limited active knee extension and 
thus the range of active knee extension will 
provide little useful information beyond the 6-
month follow-up visit.   
Further, isometric strength of the quadriceps and 
hamstrings will be quantified with a crane gauge 
starting at 3 months after surgery.  
To measure isometric quadriceps and hamstring 
strength, we will utilize a crane gauge (also 
known as a crane scale) as opposed to a hand-
held dynamometer.  The crane gauge is a digital 
strain gauge that is rated to 300 kg, which far 
exceeds force output for the quadriceps and 
hamstrings.  To measure isometric quadriceps 
and hamstring strength, one end of the crane 
gauge will be securely attached to the participant 
using a padded ankle strap and the other end will 

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be attached to an unmovable object.  As the 
participant straightens or bends the knee, the 
device will record maximal force output in 
kilograms.  Use of the crane gauge will allow for 
enhanced stabilization during the test, which is 
necessary to reliably and accurately measure 
isometric quadriceps and hamstring strength.  
Additionally, purchase of a crane gauge will 
reduce the costs for purchase for the sites that do 
not already have an available method for 
quantifying isometric strength.  Reference to use 
of the crane gauge to measure isometric 
quadriceps and hamstring strength is made on 
pages 31 to 32 and 59 of the revised Clinical 
Protocol.  Additionally, the details for use of the 
crane gauge to measure isometric quadriceps 
and hamstring strength have been added to the 
Manual of Operations and Procedures.
Added manual pivot shift test at 
3m 
Performance of the manual pivot shift test will 
provide early information regarding the primary 
outcome of ACL clinical failure.  
Added PIVOT App test at 3m 
visit. 
Performance of the PIVOT App test will provide 
early information regarding the primary outcome 
of ACL clinical failure. 
Added PIVOT App test on the 
contralateral knee. 
Comparison of the PIVOT App test results 
obtained from the contralateral knee while under 
anesthesia with the PIVOT App test results of the 
test on ACL reconstructed knee at the 3, 6, 12 
and 24 month follow-up with the patient awake is 
not valid. As such both the ACLR and 
contralateral knees need to be quantified at each 
follow-up visit. 
Added isometric strength 
testing to the baseline visit. 
Pre-operative strength testing has been added to 
improve our understanding of the changes in 
muscle function after injury in both the ACL 
injured and contralateral normal knee. 
Additionally, this will benefit participants, as pre-
operative strength measures may be a better 
comparison than the contralateral limb for 
identifying post-operative strength deficits. This 
information can be used to guide rehabilitation.  
Added the measurement of 
muscle strength with a crane 
To measure thigh muscle strength using a crane 
scale (i.e. a strain gauge) was added to reduce 

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scale and removed handheld 
dynamometer. 
costs for sites that did not already have an 
available method for quantifying strength.  This is 
a reliable method, which is commonly used in 
clinical settings. 
1.2 
April 20, 
2020 
Administrative Changes 
throughout. 
Fix spelling errors, version dates, add amendment 
history, TOC updates, etc. 
Updated list of abbreviations. 
To include all abbreviations. 
Updated study title. 
To be consistent throughout all study documents. 
Updated aims. 
To clearly define study objectives. 
Defined failure in primary 
outcome as ACL Clinical 
Failure. 
The primary outcome is ACL clinical failure which 
will be a composite of rotational laxity defined as 
mild asymptomatic pivot shift (grade1) detected at 
two or more follow-up visits or moderate or severe 
(grade 2 or 3) asymmetric pivot shift at any visit, 
or graft rupture.   
Updated Participating Study 
Sites. 
Removed U of Missouri and added U of Michigan 
and U of Kentucky. 
Updated Screening and 
Baseline visits to 
Screening/Baseline Visit 
throughout. 
The screening and baseline visit ideally occur at 
the same time. 
Added PIVOT App data 
collection. 
The pivot shift will be further objectively assessed 
using an optical tracking software application 
validated to measure anterolateral subluxation 
during a standardized pivot shift test. 
The results of the Pivot App will be correlated with 
the blinded clinical examination findings. 
Test will be performed at Baseline/EUA, 6, 12 and 
24 months post-op. 
Added data collection on 
isometric quadriceps and 
hamstring strength utilizing a 
handheld dynamometer for all 
sites. 
Not all sites have access to an isokinetic 
dynamometer. Study funds will provide each site 
with a handheld dynamometer. 
Updated DVJ will be measured 
by using Microsoft Kinect V2 
and ACL-Gold software to 
Not all sites have access to a 3D optical marker 
based motion analysis system. 

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measure frontal plane 
kinematics.   
This technology has been shown to be a reliable 
method of calculating frontal plane moments and 
has been shown to have a very high correlation 
with 3D optical marker based motion analysis 
systems.  
Added Anterior Cruciate 
Ligament–Return to Sport after 
Injury (ACL-RSI) Scale as a 
PROM. 
To measure psychological readiness for return to 
sport at 6, 12 and 24 months. 
Added End of Study definition. 
End of study is defined when the last enrolled 
subject reaches the 24-month follow-up time point 
and close-out activities are complete. 
Added a definition for 
“competitive pivoting sport” 
Defined as sports that include cutting and pivoting 
activities such as basketball, American football, 
soccer, lacrosse, volleyball, tennis/squash, 
handball, downhill skiing etc.); 
Added definition of partial ACL 
injury. 
Defined as one bundle ACL tear requiring 
reconstruction/ augmentation of the torn bundle 
with no surgery required for the intact bundle. 
Added inflammatory 
arthropathy as an exclusion 
criteria. 
Inflammatory joint disease is not all that common 
and negatively affect the outcome of the 
procedure.
Added pregnancy as an 
exclusion criteria. 
Pregnancy will be confirmed as part of the 
standard of care for having surgery. Pregnancy 
post-operatively will not exclude individuals from 
continuing this research study. A pregnancy test 
will not be completed for research purposes. 
Updated Stability 1 data. 
Study is complete. Added published data. 
Added quarterly Participant 
Newsletter. 
To enhance participant retention. 
Added the requirement for 
participants to wear a tubigrip 
on both knees. 
To maintain blinding during the clinical 
examination and testing of range of motion, 
strength and performance-based functional tests. 
Added the requirement to take 
an arthroscopic picture of the 
tibial tunnel and upload into the 
To confirm the anatomic nature of the tunnel. 

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EmPower Data Management 
System.  
Added the requirement to 
measure the length and width 
of the tibial footprint using a 
flexible ruler intra-operatively. 
This is to assure individualized anatomic 
technique is being used, i.e. size of native ACL 
will be correlated to graft size retrospectively.
Added: For patients 
randomized to harvest of the 
quadriceps tendon (QT), either 
a soft tissue only or bone block 
technique may be utilized as 
per surgeon preference. 
There have been no differences observed 
between techniques in the literature. 
Added: Bone block technique. 
To maintain consistency across all surgeons who 
elect to use the bone block technique. 
Updated soft tissue only 
technique to include: 
The graft will be dissected off 
the patella with or without a 
strip of periosteum. 
Some people may take a strip of periosteum with 
the soft tissue graft to assist in the graft 
preparation.  This has no consequences in terms 
of donor site issues. 
Defined unscheduled visit. 
In the event of an unscheduled patient visit, the 
subject will undergo safety screening by 
completing the clinical assessment. Depending on 
the reason for the visit, the subject may be asked 
to have a radiograph or other standard of care 
tests. All adverse events reported by the subject 
or observed by the investigator will be 
documented and reported. Aside from adverse 
events, information gathered at these 
unscheduled visits will not be included in the 
statistical analysis. 
Added: Risk of falling and re-
injury to the knee. 
Risk of Falling and Re-Injury to the Knee: The 
performance-based measures of physical function 
may be associated with an increased risk of 
falling and/or re-injury to the ACL. However, these 
measures will not be performed until at least 6 
months after the surgical procedure and these 
risks are not greater than the ones encountered 
with typical rehabilitation activities or with 
participation in sports. 
Updated reportable events flow. 
NIAMS – one of our funding agencies requires to 
be notified within 48 hours of the PI becoming 

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aware of a Serious Adverse Event or 
Unanticipated Problem. 
Added comprehension quiz to 
the consent process. 
To determine the participant’s comprehension of 
the information that was discussed and 
understands their commitment. 
Added reconsent process when 
a minor turns age of majority 
during the trial. 
If the child turns 18 while enrolled in the study, 
they will sign the Consent for Continued Research 
Participation. This consent is an addendum form 
to the participant’s original informed consent form. 
Updated name of External 
Adverse Events Adjudication 
Committee. 
Removed the “Eligibility” from the committee 
name as this is not part of the committee’s role. 
Updated Rehabilitation 
Committee member – Andrew 
Lynch to Andrew Sprague. 
Andrew Lynch has a new position outside of the 
University of Pittsburgh and Andrew Sprague is 
his replacement. 
Sample size updated from 1200 
to 1236 patients. 
To account for cluster effect. 

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TABLE OF CONTENTS 
PAGE 
STATEMENT OF COMPLIANCE ................................................................................................ 2 
PROTOCOL AMENDMENT HISTORY ....................................................................................... 3 
TABLE OF CONTENTS ............................................................................................................ 10 
SIGNATURE PAGE .................................................................................................................. 13 
LIST OF ABBREVIATIONS ....................................................................................................... 15 
PROTOCOL SUMMARY ........................................................................................................... 17 
SCHEMATIC OF STUDY DESIGN ........................................................................................... 18 
1 
KEY ROLES AND CONTACT INFORMATION ................................................................. 19 
2 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ....... 22 
Background Information ........................................................................................ 22 
Overview of Anterior Cruciate Ligament Injuries and Reconstruction ........ 22 
Importance of the Anterolateral Complex .................................................. 23 
Importance of Graft Choice ....................................................................... 24 
Rationale .............................................................................................................. 27 
3 
OBJECTIVES ................................................................................................................... 28 
Primary Specific Aim ............................................................................................. 28 
Specific Aim 2 ....................................................................................................... 28 
Specific Aim 3 ....................................................................................................... 28 
Specific Aim 4 ....................................................................................................... 29 
4 
STUDY OUTCOME MEASURES ..................................................................................... 30 
Primary Outcome .................................................................................................. 30 
Secondary Outcomes ........................................................................................... 31 
Disease-Specific Patient Reported Outcomes ........................................... 32 
Knee-Specific Patient Reported Outcomes ............................................... 32 
Measures of Impaired Range of Motion and Muscle Function ................... 33 
Performance-Based Measures of Physical Function ................................. 34 
Return to Activity Measures ....................................................................... 35 
Donor Site and Adverse Events................................................................. 36 
Cost-Effectiveness Measures ............................................................................... 36 
5 
STUDY DESIGN .............................................................................................................. 38 
6 
STUDY ENROLLMENT .................................................................................................... 39 
Subject Inclusion Criteria ...................................................................................... 39 
Subject Exclusion Criteria ..................................................................................... 39 
Strategies for Recruitment and Retention ............................................................. 39 
Recruitment Process ................................................................................. 39 
Efforts to Maximize and Monitor Subject Recruitment ............................... 40 
Efforts to Maximize Subject Retention ....................................................... 41 
Randomization Procedures ....................................................................... 44 
Masking Procedures .................................................................................. 44 
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STUDY INTERVENTION .................................................................................................. 45 

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Surgical Intervention ............................................................................................. 45 
Anterior Cruciate Ligament Reconstruction ............................................... 47 
Graft Harvest ............................................................................................. 49 
Lateral Extra-articular Tenodesis ............................................................... 50 
Rationale for Specific Surgical Intervention ........................................................... 51 
Alternative Treatments .......................................................................................... 52 
Procedures for Training of Clinicians on Procedural Intervention .......................... 52 
Monitoring Fidelity in Delivering the Intervention ................................................... 52 
Rehabilitation ........................................................................................................ 53 
Tissue Protection Phase ........................................................................... 54 
Motor Control Phase ................................................................................. 55 
Functional Optimization Phase .................................................................. 56 
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STUDY PROCEDURES AND MATERIALS ...................................................................... 57 
Consent Process .................................................................................................. 57 
Screening ............................................................................................................. 57 
Randomization and Surgery .................................................................................. 58 
Rehabilitation ........................................................................................................ 59 
Clinical Follow-Up Appointments .......................................................................... 59 
Standard of Care Clinical Follow-Up Appointments ................................... 59 
Research Activities at Clinical Follow-Up Appointments ............................ 61 
Assessment of Outcomes ..................................................................................... 63 
Subject Payment ................................................................................................... 63 
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POTENTIAL RISKS AND BENEFITS ............................................................................... 65 
Potential Risks Associated with Study Interventions ............................................. 65 
Potential Risks Associated with Study Tests ......................................................... 66 
Potential Risks Associated with Privacy and Confidentiality .................................. 67 
Potential Benefits .................................................................................................. 68 
10 
ASSESSMENT OF SAFETY ............................................................................................ 69 
Definition of Adverse Events, Serious Adverse Events and Unanticipated 
Problems .............................................................................................................. 69 
Reportable Events ................................................................................................ 70 
11 
ETHICS/PROTECTION OF HUMAN SUBJECTS ............................................................. 73 
Ethical Standard ................................................................................................... 73 
Institutional/Ethics Review Board .......................................................................... 73 
Informed Consent Process ................................................................................... 73 
Subject Confidentiality .......................................................................................... 75 
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STUDY OVERSIGHT ....................................................................................................... 76 
Composition of the Data and Safety Monitoring Board .......................................... 76 
Study Committees ................................................................................................ 76 
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CLINICAL SITE MONITORING PLAN .............................................................................. 80 
Clinical Monitoring Communication Plan ............................................................... 80 
Scheduling of Visits .............................................................................................. 81 
Types of Visits and Monitoring Activities ............................................................... 81 

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Site Initiation Visit ...................................................................................... 81 
Interim Visits.............................................................................................. 84 
For-Cause Visits ........................................................................................ 85 
Close-Out Visit .......................................................................................... 85 
Ongoing Site Monitoring and Documents to be Monitored .................................... 86 
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STATISTICAL CONSIDERATIONS .................................................................................. 89 
Study Hypotheses ................................................................................................. 89 
Sample Size Considerations for Aim 1 .................................................................. 90 
For Sex-based Research Question ........................................................... 91 
Sample Size Considerations for Aim 2 .................................................................. 92 
Sample Size Considerations for Aim 3 .................................................................. 92 
Plan for Data Analysis ........................................................................................... 93 
Statistical Analysis for Aim 1 ..................................................................... 93 
Statistical Analysis for Aims 2 and 3 .......................................................... 94 
Statistical Analysis for Aim 4 ..................................................................... 95 
Handling Missing Data .......................................................................................... 97 
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SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS .................. 99 
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DATA MANAGEMENT PLAN ......................................................................................... 100 
Methods and Systems for Data Collection .......................................................... 100 
Methods and Systems to Ensure Data Confidentiality and Subject Privacy ......... 105 
Data Sharing Agreement .................................................................................... 106 
APPENDICES ......................................................................................................................... 116 
APPENDIX A: STUDY TIMELINE ........................................................................................... 117 
APPENDIX B: SCHEDULE OF EVENTS ................................................................................ 118 
APPENDIX C: STUDY FORMS .............................................................................................. 119 
APPENDIX D: DATA SAFETY AND MONITORING BOARD TABLES .................................... 120 

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SIGNATURE PAGE 
The signatures below constitute the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable Canadian and US 
federal regulations and ICH guidelines. 
We will ensure that all associates, colleagues, and employees assisting in the conduct 
of the study are informed about the obligations incurred by their contribution to the 
study. 
“STABILITY 2: ACL Reconstruction +/- Lateral Tenodesis with Patellar vs. Quad 
Tendon” 
Principal Investigator 
Signed: 
 
 
 
 
 
 
Date: February 2, 2021
Name: James Irrgang, PT PhD FAPTA 
Title: Professor and Chair, Department of Physical Therapy,  
University of Pittsburgh School of Health and Rehabilitation 
Sciences 
Co-Principal Investigators 
Signed: 
 
 
 
 
 
Date: February 2, 2021
Name:  Volker Musahl, MD 
Title: Blue Cross of Western Pennsylvania Professor and Chief, Division of 
Sports Medicine, Department of Orthopaedic Surgery, University of 
Pittsburgh School of Medicine 

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Signed: 
Date: February 2, 2021
Name: Alan Getgood, MD 
Title: Associate Professor,  
Western Ontario University Schulich School of Medicine & Dentistry 
Signed: 
Date: February 2, 2021
Name: Dianne Bryant, PhD 
Title: Associate Professor and Director of EmPower Health Research Inc 
Western University School of Physical Therapy 

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LIST OF ABBREVIATIONS 
ACL 
Anterior Cruciate Ligament 
ACLR 
Anterior Cruciate Ligament Reconstruction 
ACL-QOL 
Anterior Cruciate Ligament Quality of Life Questionnaire 
AE 
Adverse Event  
ALC 
Anterolateral Complex 
ALL 
Anterolateral Ligament 
BPTB 
Bone Patellar Tendon Bone 
CCC 
Clinical Coordinating Center 
Co-I 
Co-Investigator 
Co-PI 
Co-Principal Investigator 
CRA 
CRF 
Clinical Research Assistant 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCC 
Data Coordinating Center 
DSMB 
Data Safety and Monitoring Board 
DVJ 
Drop Vertical Jump 
EAEAC 
External Adverse Event Adjudication Committee 
eMonitor 
ESC 
Quality Control Clerk 
Executive Steering Committee 
EUA 
Examination Under Anesthesia 
FCL 
Fibular Collateral Ligament 
FCS 
Full Conditional Specification 
GCP 
Good Clinical Practice 
HT 
Hamstrings Tendon 
ICH 
International Conference on Harmonization 
ICMJE 
International Committee of Medical Journal Editors 
IKDC-SKF 
International Knee Documentation Committee Subjective Knee Form 
INB 
Incremental Net Benefit 
IRB 
Institutional Review Board 
ITB 
Iliotibial Band 
KOOS 
Knee Osteoarthritis Outcome Survey 
LET 
Lateral Extra-articular Tenodesis 
LSI 
Limb Symmetry Index 
MOOP 
Manual of Operating Procedures 

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OA 
Osteoarthritis 
OHRP 
Office for Human Research Protections 
OR 
Odds Ratio 
PASC 
Publications and Ancillary Studies Committee 
PC 
Project Coordinator 
PD 
PI 
Protocol Deviation 
Principal Investigator 
PRO 
Patient Reported Outcome 
PTOA 
Post-Traumatic Osteoarthritis 
QC 
Quality Control 
QCL 
Quality Control Lead 
QALYS 
Quality Adjusted Life Years 
QOL 
Quality of Life 
QT 
Quadriceps Tendon 
RC 
Research Coordinator 
ROM 
Range of Motion 
RRR 
Relative Risk Ratio 
SAE 
Serious Adverse Event  
SSL 
Scramble Word Format 
UP 
Unanticipated Problem 
 

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PROTOCOL SUMMARY 
Title: 
STABILITY 2: ACL Reconstruction +/- Lateral Tenodesis with 
Patellar vs. Quad Tendon  
Précis: 
STABILITY 2 is a 21-site multicenter, international, randomized 
clinical trial that will randomly assign 1236 individuals with an 
anterior cruciate ligament (ACL) deficient knee who are at high 
risk of re-injury to anatomic anterior cruciate ligament 
reconstruction (ACLR) using bone patellar tendon bone (BPTB) 
or quadriceps tendon (QT) autograft with or without a lateral 
extra-articular tenodesis (LET). 
Objectives: 
 
Aim 1: Determine if graft type (QT, BPTB or HT) with or without 
a LET affects the rate of ACL clinical failure at 2 years after 
ACLR. 
Aim 2:  Determine if graft type (QT, BPTB or HT) with or without 
a LET affects patient-reported symptoms, function & QOL, 
performance-based measures of function and return-to-sports 2 
years after ACLR. 
Aim 3: Determine if graft type (QT, BPTB or HT) with or without 
LET affects the rates of intervention-related donor site 
morbidity, complications and adverse outcomes 2 years after 
ACLR. 
Aim 4: Determine if use of a particular graft type (QT, BTPT or 
HT) with or without addition of LET is a more cost-effective 
approach to ACLR. 
Population: 
The study population will consist of 1236 young, active 
individuals from the United States, Canada and Europe. Eligible 
patients will have an ACL deficient knee, be skeletally mature 
but ≤25 years of age, and meet ≥2 of the following criteria: 
participate in a competitive pivoting sport; have a pivot shift of 
grade 2 or greater; have generalized ligamentous laxity 
(Beighton score of ≥4) and/or genu recurvatum >10 degrees. 
Phase: 
III 
Number of Sites: 
21 
Description of  
Intervention: 
All patients will undergo an anatomic ACLR using BTBP or QT 
autograft with or without LET. 
Study Duration: 
60 months 
Subject Participation 
Duration: 
24 months 
 
Estimated Time to 
Complete Enrollment: 
30 months 

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SCHEMATIC OF STUDY DESIGN 
 
 

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1 KEY ROLES AND CONTACT INFORMATION 
Principal Investigators 
 
James J. Irrgang, PhD, PT, ATC  
Study and Site Principal Investigator 
University of Pittsburgh 
Bridgeside Point 1  
100 Technology Drive, suite 210 
Pittsburgh, PA 15219  
Volker Musahl, MD 
Co-Principal Investigator 
University of Pittsburgh 
Rooney Sports Complex 
3200 South Water Street 
Pittsburgh, PA 15203 
 
 
Alan Getgood, MD 
Co-Principal Investigator 
Western University 
750 Base Line Road 
London, Ontario, Canada N6C 2R5 
 
 
Dianne Bryant 
Co-Principal Investigator 
Western University 
750 Base Line Road 
London, Ontario, Canada N6C 2R5 
 
Key Personnel at the Clinical and Data Coordinating Centers 
 
 
Alexandra Gil, PhD, PT 
Department of Physical Therapy 
University of Pittsburgh 
Bridgeside Point 1   
100 Technology Drive, Suite 210 
Pittsburgh, PA 15219 
 
Megan Dalzell 
University of Pittsburgh 
Rooney Sports Complex 
3200 South Water Street 
Pittsburgh, PA 15203 
M. Beatriz Catelani, PT, MS 
University of Pittsburgh 
Bridgeside Point 1 
100 Technology Drive, suite 210 
Pittsburgh, PA 15219 
Stacey Wanlin 
Western University 
3M Centre, Western University 
1151 Richmond Street 
London, Ontario, Canada N6A 3K7 
 
 
 
 
 
 
 
 

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USA Participating Sites 
 
University of Pittsburgh 
Bridgeside Point 1  
100 Technology Drive, suite 210 
Pittsburgh, PA 15219 
PI: James Irrgang, PhD, PT, ATC 
Co-PI: Volker Musahl, MD 
  
University of Minnesota 
450 McNamara Alumni Center 
200 Oak Street SE 
Minneapolis, MN 55455 
PI: Jeff Macalena, MD 
 
University of Virginia 
515 Ray C Hunt Drive 
Charlottesville, VA 22903 
PI: Brian Werner, MD 
  
Wake Forest University  
Department of Orthopaedic Surgery 
Medical Center Boulevard 
Winston-Salem, NC 27157 
PI: Brian Waterman, MD 
 
University of Michigan 
500 S State St,  
Ann Arbor, MI 48109 
PI: John Grant, MD 
 
University of Kentucky 
2195 Harrodsburg Rd,  
Lexington, KY 40504 
PI: Darren Johnson, MD 
 
 
Canadian Participating Sites 
 
University of Western Ontario d/b/a 
Lawson Health Research 
750 Base Line Road 
London, Ontario, Canada, N6C 2R5 
PI: Alan Getgood, MD 
Co-PI: Dianne Bryant 
 
Banff Sport Medicine 
#200-303 Lynx Street 
Banff Alberta, T1L 1B3, Canada 
PI: Mark Heard, MD 
  
Nova Scotia Health Authority  
Halifax Infirmary Building, 4th floor  
1796 Summer Street 
Halifax, Nova Scotia, Canada, B3H 3A6 
PI: Ivan Wong, MD 
 
Fraser Orthopaedic Institute 
Suite #400, 13450 102 Avenue  
Surrey, British Columbia, Canada 
PI: Dory Boyer, MD 
  
 
 

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McMaster University 
293 Wellington Street North, suite 120 
Hamilton, ON, L8L 8E7, Canada 
PI: Devin Peterson, MD 
PanAm Clinic Foundation 
75 Poseidon Bay 
Winnipeg, MB, R3M 3E4, Canada 
PI: Peter MacDonald, M 
 
Queen’s University 
78 Fifth Field Company Lane 
Kingston, On, K7L 3N6, Canada 
PI: David Bardana, MD 
 
 
St. Michael’s Hospital 
30 Bond Street 
Toronto, Ontario, M5B 1W8, Canada 
PI: Daniel Whelan, MD 
 
University of Calgary of Sport  
Medicine Centre 
2500 University Drive NW 
Calgary, AB T2N 1N4, Canada 
PI: Alex Resansoff, MD 
 
University of Ottawa 
725 Parkdale Avenue 
Ottawa, Ontario, K1Y 4E9, Canada 
PI: Allan Liew, MD 
 
European Participating Sites 
 
University Hospital Munster 
Albert-Schweitzer-Campus 1 
Gebaude W1 
48149 Munster, Germany  
PI: Elmar Herbst, MD 
University Hospitals Coventry and 
Warwickshire NHS 
UHCW NHS Trust 
Clifford Bridge Road 
Coventry, CV2 2DX, United Kingdom 
PI: Tim Spalding 
 
Karolinska Institutet 
Nobels vag 15a 
171 77 Stockholm, Sweden 
PI: Karl Eriksson 
 
University of Gothenburg 
Box 100, SE-405 30 
Gothenburg, Sweden 
PI: Kristian Samulesson 
Oslo University Hospital 
Lirkeveien 166 Tarnbygget 
0450 Oslo, Norway 
PI: Lars Engebretsen 
 
 
 
 

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2 INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE  
 
Background Information 
 
Overview of Anterior Cruciate Ligament Injuries and Reconstruction 
Anterior cruciate ligament (ACL) rupture is one of the most common musculoskeletal 
injuries in young individuals, particularly those that are active in sports. Age-specific 
patterns of ACL rupture differ in males and females, with a peak incidence (241.0 per 
100,000 person-years) between 19 and 25 years in males and a peak incidence (227.6 
per 100,000 person years) between 14 and 18 years in females.1 However, relative to 
the number of individuals playing sport, the incidence of ACL injury is 2 to 4 times 
higher in females.2-4 Epidemiological studies have shown that approximately 250,000 
patients undergo ACL reconstruction (ACLR) annually in the USA.5 Although surgery is 
recommended for those wishing to return to sport, several studies have demonstrated a 
significant reduction in quality of life (QOL) and subsequent socioeconomic burden as a 
result of ongoing knee instability,6 failure of the reconstruction, revision surgery, and the 
development of post traumatic osteoarthritis (PTOA) in the long-term.7 
Up to 30% of individuals under the age of 20 years suffer a re-injury to the ACL 
reconstructed knee.8,9 Revision ACLR has been associated with degeneration of the 
articular cartilage and increased rates of meniscal tears, increasing the risk of PTOA, 
additional surgical procedures and reduced physical function and QOL.10,11 As such, 
strategies to reduce ACLR failure, particularly in young active individuals, are critical to 
improving short and long-term outcomes after ACL rupture. 
Failure of ACLR is multifactorial, with four broad categories of factors associated with 
failure including traumatic re-injury, poor biological healing, insufficient rehabilitation 
(poor neuromuscular conditioning,12 proprioception and no sport-specific training), and 
surgical technique.13 The surgical method of reconstructing the injured ligamentous 
structures to re-establish knee stability can impact all of these risk factors and provides 
an opportunity to improve the likelihood of a favorable outcome.14 Two surgical 
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persistent rotational laxity and ACLR failure are the reconstruction of anterolateral 
complex and graft choice. 
 
Importance of the Anterolateral Complex 
The anterolateral complex (ALC) includes the iliotibial band (ITB), the anterolateral 
ligament (ALL) and the lateral meniscus.15 Anterolateral reconstruction, such as lateral 
extra-articular tenodesis (LET), may provide greater rotational stability,16 yet surgery-
induced lateral compartment OA is a concern given the potential for over-constraint of 
the joint.17 New evidence from the STABILITY 1 Study group members18-20 and others21-
23 have suggested that the ALC plays a key role in controlling knee stability and that 
ACLR may not be adequate to control rotation alone. Both the University of Pittsburgh 
and Western University in Canada, have been instrumental in determining the 
importance of the anterolateral complex to knee stability, importantly recognizing that 
high-grade rotatory laxity is not the result of an isolated ACL injury.24,25 Two anatomic 
studies from Western University26 and University of Pittsburgh,27 illustrated the 
characteristics of the anterolateral ligament and the iliotibial tract respectively. These 
studies were then followed by biomechanical studies in the respective laboratories. In a 
study at Western, Spencer et al.21 were the first to show that LET was superior to ALL 
reconstruction in controlling the pivot shift.  Rahnemai-Azar et al.28 showed that the 
anterolateral capsule was not as important as the iliotibial tract for providing knee 
stability, with Guenther et al.28 observing that the capsule acted more as a fibrous sheet 
than a distinct ligament. Further work at Western showed the importance of the other 
structures in the ALC in providing knee stability, including the lateral meniscus posterior 
root19 and the capsule-osseous layer of the ITB.21 This body of work demonstrates the 
importance of the ALC and the potential need for LET to aid in controlling pathologic 
rotatory laxity of the ACL reconstructed knee. 
Additionally, a systematic review, published by the team at Western University in 
Canada, showed that augmentation of ACLR with LET reduces the risk of rotational 
laxity of the knee.29 This review provided the basis for a 9-site randomized clinic trial  
lead by Co-PIs Getgood and Bryant that randomized 618 young patients (<25yrs) at 

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high risk of ACLR failure to compare hamstring tendon (HT) autograft ACLR with or 
without LET (STABILITY 1).30 The results of this study suggest that the addition of LET 
to ACLR reduces rotational laxity (RRR=0.38, 95%CI 0.21 to 0.52, p<0.0001) and ACL 
graft failure (RRR=0.67, 95%CI 0.36 to 0.83, p<0.001).31 
 
Importance of Graft Choice 
Surgeons in North America moved away from performing a LET when one study 
suggested that a well performed ACLR with a bone patella tendon bone (BPTB) 
autograft negated the need for additional anterolateral surgery.17 Unfortunately, this 
study was underpowered, poorly controlled, and a retrospective comparison. However, 
the idea that graft choice could overcome anterolateral biomechanical deficiencies has 
been the basis of significant study over the past 20 years. Numerous comparative 
studies and case series contributed to multiple meta-analyses comparing the results of 
different graft choices (see Table 1 for comparison and Figure 1 for graft choice of 
experts).32-39 The majority of studies fail to demonstrate a difference in patient-reported 
outcomes (PROs) between HT and BPTB grafts. Although most agree that BPTB has 
lower failure rates, less laxity, and limited loss of knee flexion compared to HT grafts.  In 
contrast, HT grafts are associated with less patellofemoral crepitance, kneeling pain, 
and loss of knee extension33.  In a 2016 study, Mohtadi et al. observed that rotational 
laxity, as measured by a positive pivot shift, resulted in a 22% prevalence of persistent 
abnormal rotational laxity in HT grafts compared to 16% in BPTB grafts.35 A randomized 
control trial by the same group comparing HT and BPTB autograft reconstructions40 
showed that HT grafts resulted in a higher rate of traumatic failure, with a greater 
number of patients presenting with persistent rotational laxity. Importantly, they found 
that patients under the age of 27 had a worse outcome in terms of failure and instability. 
However, with only 17 cumulative failures in the study, it was drastically underpowered.  
Few studies have thoroughly compared the effects of BPTB and HT graft harvest on 
functional performance of individuals, prior to return to sport. Successful return to sport 
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assessed by measuring quantity and quality of movement.41 Quantity of movement 
includes muscle strength and hop test performance.42 Quality of movement includes 
dynamic knee flexion and valgus when landing from a jump.43,44 Quantity and quality of 
movement are modifiable and may predict ACL re-injury45,46; however, a systematic 
review by Engelen-van Melick et al., indicates that few high level studies comparing HT 
vs. BPTB evaluate both quantity and quality of movement.47 Because only 63% of 
individuals after ACLR return to previous levels of activity,48 and re-injury rates can be 
as high as 30%, assessment of functional performance should be an integral 
component of future studies evaluating the risk of failure after ACLR. 
In addition to the paucity of information regarding functional performance with HT and 
BPTB grafts, quadriceps tendon grafts are becoming popular and there is some 
evidence supporting their use.49 In a recent editorial in the Journal of Arthroscopy 
entitled, “Quadriceps Tendon Autograft Is the Least Utilized Choice for ACL 
Reconstruction, But Use Is Expected to Increase”, the editor-in-chief stated several 
reasons for this trend including, but not limited to the following: HT has a higher 
infection rate and risk of re-rupture is greater in small diameter grafts, allografts are 
prone to re-rupture in young, active individuals, and quadriceps tendon grafts are larger 
and stronger than BPTB grafts.50  
Two comparative studies have recently been published investigating the merits of the 
QT graft. The first study by Cavaignac et al.51 compared QT to HT autograft in 95 
subjects undergoing ACLR.  At two years follow-up there were no differences in terms 
PROs, although there were reduced rates of rotational laxity in the QT group. In a small, 
non-randomized prospective study,52 Runer et al. compared QT to HT in 80 individuals 
after ACL rupture and reported no difference between the two groups in terms of PROs, 
stability, pain or function. Lastly, a recent meta-analysis of five retrospective studies 
comparing 452 BPTB grafts to 354 QT grafts demonstrated no differences in graft 
failure53; however, the small number of events (11 total) suggests this outcome was 
grossly underpowered. Stability rates and PROs were also similar, yet fewer patients 
with a QT graft complained of donor site issues. 

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Figure 1: Past and Current Trends in ACLR Autograft Selection, the International ACL 
Study Group 
 
 
Table 1: Summary of Pros, Cons, Unknowns for Surgical Strategies for Treatment of ACL 
Rupture 
Graft 
Type/Procedure 
Pro 
Con 
Unknowns 
Bone Patella 
Tendon Bone 
(BPTB) Autograft 
 Strong, stiff graft 
 Bone to bone healing 
 Good stability rates35 
 Lower rate of failure 
than HT54 
 Donor site morbidity35 
• Anterior knee pain 
• Anterior knee numbness 
• Kneeling pain 
• Risk of patella fracture 
• Risk of patella tendon 
rupture 
• Patellofemoral 
osteoarthritis 
• Range of motion extension 
deficit 
 No adequately powered study 
performed comparing BPTB to QT in 
young active patients at high risk of 
graft failure 
 Not known if the addition of LET is 
required to lower failure rates in 
young active patients at high risk of 
graft failure 
Quadriceps Tendon 
(QT) Autograft 
 Strong, stiff graft 
 Can harvest with or 
without bone from 
patella 
 
 Donor site morbidity53 
• Risk of patella fracture if 
bone harvested 
• Quadriceps weakness 
 
 Potential for reduced donor site 
issues compared to BPTB55 
 Possible similar failure rates to BPTB 
with lower failure rates compared to 
HT51 
 Potential for improved functional 
performance compared to BPTB and 
HT51 
 Not known if the addition of LET is 
required to lower failure rates in 
young active patients at high risk of 
graft failure 
Hamstring Tendon 
(HT) Autograft 
 Simple, easy 
technique 
 Satisfactory results in 
low demand patients 
 Higher failure rates in young 
active individuals54 
 Higher risk of infection than 
BPTB56 
 Donor site morbidity35 
• Muscle cramping 
• Anterolateral shin 
numbness due to nerve 
injury 
• Persistent hamstring 
weakness 
 
0
10
20
30
40
50
60
BPTB Auto
HT Auto
QT with Bone
QT without bone
% of ACLR Cases
Graft Trends within ACL Study Group 2018 Annual Meeting
Primary ACL 2017
2nd Choice Primary ACL
10 years from now

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Lateral Extra-
articular Tenodesis 
(LET) 
 Increased 
anterolateral 
stability20 
 Reduced failure rates 
when combined with 
HT ACLR (Stability I) 
 Reduced rotational 
laxity when combined 
with HT ACLR 29 
 Donor site morbidity29 
• Lateral knee pain 
• Hardware irritation 
• Haematoma 
 
 Concerns of lateral compartment over 
constraint57 and increased risk of OA 
(although this has not been shown to 
date)58 
 Unknown if the addition of LET to 
BPTB or QT ACLR will result in 
reduced failure rates in young active 
patients at high risk of graft failure 
 
 
Rationale 
The scientific premise for the proposed STABILITY 2 multicenter randomized clinical 
trial is that the rates of rotational laxity and ACL graft failure can be reduced by 
determining the optimal autograft choice for ACLR as well as the need for a LET. 
Furthermore, if successful, the results of this study will inform the optimal treatment of 
ACL rupture in young athletes, and women specifically, who are at risk for persistent 
rotational laxity/instability and graft re-rupture. Reducing the risk for graft failure will 
reduce the need for revision ACLR and the associated decreased QOL and 
socioeconomic burden that occurs because of ongoing knee instability and the 
increased risk for PTOA. 

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3 OBJECTIVES 
The overall primary objective of this 21-site international randomized trial is to determine 
if graft type (QT, BPTB or HT) with or without a LET will affect the rate of ACL clinical 
failure 2 years after surgery.  Secondary objectives will determine the effects of graft 
type and LET on patient-reported outcomes, performance-based measures of function, 
return to sports, intervention-related donor site morbidity, complications and adverse 
outcomes and cost effectiveness.  To achieve these objectives, we will randomize 1236 
participants with an ACL tear who are at high risk of failure to undergo ACL 
reconstruction with a QT or BPTB with or without a LET.  Study data will be combined 
with data from a prior trial that compared ACLR with HT grafts with or without a LET 
(STABILITY 1).   
The specific aims for the study are:  
 
Primary Specific Aim 
Determine if graft type (QT, BPTB or HT) with or without a LET affects the rate of ACL 
clinical failure at 2 years after ACLR. ACL clinical failure will be defined by “a composite 
of rotational laxity defined as mild asymmetric pivot shift (grade1) detected at two or 
more follow-up visits OR moderate or severe (grade 2 or 3) asymmetric pivot shift at 
any visit, OR graft rupture. 
 
Specific Aim 2 
Determine if graft type (QT, BPTB or HT) with or without a LET affects patient-reported 
symptoms, function and quality of life, performance-based measures of function and 
return-to-sports 2 years after ACLR. 
 
Specific Aim 3 
Determine if graft type (QT, BPTB or HT) with or without a LET affects the rates of 
intervention-related donor site morbidity, complications and adverse outcomes 2 years 
after ACLR. 

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Specific Aim 4 
Determine if the use of a particular graft type (QT, BPTB or HT) with or without LET is a 
more cost-effective approach to ACLR. 

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4 STUDY OUTCOME MEASURES 
 
Primary Outcome 
The primary outcome for this study is ACL clinical failure over the first two post-
operative years.  ACL clinical failure is operationally defined as a composite of rotational 
laxity defined as mild asymmetrical pivot shift (grade1) detected at two or more follow-
up visits OR moderate or severe (grade 2 or 3) asymmetric pivot shift at any visit, OR 
graft rupture. The pivot shift test has been reported by Scholten et al. as the most 
specific of all clinical ACL tests (with a specificity of 0.97-0.99 and sensitivity of 0.18-
0.48).59 Graft rupture is defined as a tear of the graft confirmed either by MRI or 
arthroscopic examination. Though the surgeon who performs the ACLR is not blind to 
participant’s group assignment, a second clinician, who is blinded, will conduct the 
physical examination and record the primary outcome. 
The pivot shift will be further objectively assessed using an optical tracking software 
application validated to measure anterolateral subluxation during a standardized pivot 
shift test.60,61 All patients will undergo pivot shift examination using the Pivot App on the 
provided tablets at the time of surgery under anesthesia and at 3, 6, 12 and 24 months 
post-operative AFTER the blinded assessment of the pivot shift. The results of the Pivot 
App will be correlated with the blinded clinical examination findings. 
While Kocher et al (AJSM 32:629-634, 2004) did not find any significant relationships 
between patient-reported knee instability with anterior laxity of the knee (Lachman or 
KT-1000 tests), they did find significant relationships between knee instability defined as 
partial (p=0.01) or full giving way (p=0.01) of the knee with the pivot shift test.  To further 
explore this relationship between instability and rotational laxity of the knee within the 
STABILITY 2 Trial we will administer the IKDC Subjective Knee Form items related to 
giving way of the knee during daily activity and sports (see below).  Furthermore, we will 
explore the number of individuals that meet the definition of ACL clinical failure that also 
have symptomatic knee instability as defined by the IKDC Subjective Knee Form items 
related to giving way of the knee. 

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Over the past week, to what degree have your daily activities (around the home 
and at work) been affected by the following symptoms in your involved knee? 
 
I Did Not 
Have the 
Symptom 
 
I Had the 
Symptom 
but it Did 
Not Affect 
my daily 
activity 
Affected 
my daily 
activity 
Slightly 
Affected my 
daily activity 
Moderately 
Affected 
my daily 
activity 
Severely 
Prevente
d ALL 
daily 
activity 
Giving way, buckling, 
or shifting of your 
knee  
 
 
 
 
 
 
Slipping or partial 
giving way of your 
knee  
 
 
 
 
 
 
Over the past week, to what degree have your sports, athletic, recreational, or 
performance activities been affected by the following symptoms in your involved 
knee? 
 
I Did Not 
Have the 
Symptom 
 
I Had the 
Symptom 
but it Did 
Not Affect 
my sport 
activity 
Affected 
my sport 
activity 
Slightly 
Affected my 
sport activity 
Moderately 
Affected 
my sport 
activity 
Severely 
Prevente
d ALL 
sport 
activity 
Giving way, buckling, 
or shifting of your 
knee  
 
 
 
 
 
 
Slipping or partial 
giving way of your 
knee  
 
 
 
 
 
 
 
 
Secondary Outcomes 
Secondary outcomes include PROs that assess symptoms, activity, participation and 
QOL, measures of impaired range of motion and muscle function (quadriceps & 

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hamstring strength), performance-based measures of physical function (hop tests, drop 
vertical jump), return to pre-injury sports, adverse outcomes, intervention-related donor 
site morbidity and complications. We will collect pre-operative data for all 
questionnaires, range of motion, muscle strength and the results of imaging procedures 
performed for clinical purposes (e.g. standing flexion radiographs and MRI results). 
Follow-up visits with the surgeon will occur at 6 weeks and 3, 6, 12 and 24 months after 
surgery, which is consistent with regular clinical practice patterns. Muscle strength and 
hop tests will be performed 6, 12, and 24 months post-operatively and the DVJ will be 
assessed 6 and 12 months post-operatively. 
Patient-reported outcomes will include a combination of disease- and region-specific 
measures of symptoms, activity, participation and QOL as follows:  
 
Disease-Specific Patient Reported Outcomes 
The ACL Quality of Life Questionnaire (ACL-QOL)62 assesses physical symptoms, 
occupational concerns, recreational activities, lifestyle, and social and emotional 
aspects of ACL injury.  Each item has a 100 mm visual analogue scale (VAS) response 
option, with labeled anchors at 0 mm (e.g. extremely difficult) and 100 mm (e.g. not 
difficult at all).  Scores are calculated by converting the average of each of the five 
domain scores to a total average score out of 100% where 100% represents the best 
possible score. 
 
Knee-Specific Patient Reported Outcomes 
The knee-specific PROs will include the International Knee Documentation Committee 
Subjective Knee Form (IKDC-SKF) and the Knee injury and Osteoarthritis Outcome 
Survey (KOOS).   
The IKDC-SKF is an 18-item questionnaire querying symptoms, function and sports 
activities.63 The items are summed and transformed to a score that ranges from 0 to 
100 with 100 representing no symptoms or limitations with function and sports activities. 

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The KOOS consists of 42 items in 5 domains that separately measure pain, other 
symptoms, function in daily living, function in sports/recreation and knee-related QOL.64 
Domain scores represent the sum of all items in the domain standardized to a score 
from 0 to 100 (worst to best).   
Both the IKDC-SKF and KOOS are being used because each is more familiar in 
different parts of the world and thus, including both will broaden the interpretability of the 
results. 
 
Measures of Impaired Range of Motion and Muscle Function 
A blinded assessor will measure passive and active knee extension and active-assisted 
knee flexion with a goniometer. For passive knee extension, the patient will lie supine 
on the examination table with a bolster under the heels with the quadriceps and 
hamstrings relaxed to assure full passive extension of the knee.  For active-assisted 
knee flexion, the patient will be seated on the examination table with both legs extended 
and instructed to perform active-assisted knee flexion by placing one hand under their 
thigh to initiate flexion and then clasp both hands just below the tibial tuberosity. The 
side to side difference in ROM will be determined and interpreted based on IKDC 
guidelines.65  
To assess quadriceps and hamstring strength bilaterally we will use a computerized 
isokinetic dynamometer using methods previously shown to be reliable and valid.66,67 
Briefly, the patient will wear a tubigrip sleeve on the operative limb to conceal group 
allocation.66 Isokinetic measurements will be performed at 90 degrees/sec because we 
are interested in peak torque and power measurements rather than endurance and 
fatigability.  To assess strength, quadriceps and hamstring indices will be calculated as 
the ratio of peak torque of the ACL reconstructed knee to peak torque of the 
contralateral normal knee multiplied times 100.  We will also calculate the hamstring to 
quadriceps ratio for the reconstructed and contralateral knees.  We will present these 
ratios by group by visit but expect that early between-group differences will reflect 
issues related to donor site morbidity that will resolve by 24 months postoperatively.  

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Not all sites have access to an isokinetic dynamometer therefore we will also collect 
isometric quadriceps and hamstring strength utilizing a crane scale (i.e. strain gauge) 
that has been shown to provide a reliable measure of muscle strength after ACL 
reconstruction.68  Additionally, isometric thigh strength will be collected prior to surgery 
on both the ACL-injured and contralateral normal knees. To measure isometric 
quadriceps and hamstring strength, one end of the crane gauge will be securely 
attached to the participant using a padded ankle strap and the other end will be 
attached to an unmovable object.  As the participant straightens or bends the knee, the 
device will record maximal force output in kilograms.  Use of the crane gauge will allow 
for enhanced stabilization during the test, which is necessary to reliably and accurately 
measure isometric quadriceps and hamstring strength.   
 
Performance-Based Measures of Physical Function 
Performance-based tests of the participant’s physical function will include hop tests69 
and the drop vertical jump test to assess dynamic knee flexion and valgus. The series of 
four hop tests (single hop for distance, triple hop for distance, triple cross over hop and 
timed 10-meter hop) are proxies for neuromuscular control, strength, and confidence in 
the limb. The hop tests are one of the most common functional outcomes used in ACL 
research.69-71  Participants will perform a series of four hop tests using methods 
previously shown to be reliable and valid following ACL reconstruction.69  The hop tests 
will be conducted by a trained physical therapist, kinesiologist or research assistant who 
is blinded to the operative procedures via tubigrip worn over the participant’s operative 
knee.  For each hop test, we will present results as a limb symmetry index (LSI),71 which 
expresses test performance of the operative limb as a percentage of the non-operative 
limb.  A higher LSI indicates a higher level of function for the operative limb. LSI for 
each hop test as well as the average LSI of the four hop tests will be used for data 
analysis.    
The DVJ test, which mimics the physical demands of competitive jumping sports like 
basketball or volleyball,72,73 will be used to access dynamic valgus collapse of the knee 
that is associated with risk of ACL injury.73-75 The test is particularly suitable for patients 

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who are preparing for return-to-sport after ACLR because it allows for a highly relevant 
evaluation of knee stability during sport specific movements. Recent studies have 
shown that measures of dynamic knee valgus during a DVJ test effectively 
demonstrates differences between healthy- and ACLR knees,76 and knees 
reconstructed with HT vs. BPTB grafts.41 The DVJ will be assessed on all participants 
using the Microsoft Kinect V2 and ACL-Gold software to measure frontal plane 
kinematics.  Dynamic valgus of the lower extremity is operationally defined as the ratio 
of the distance between the knees to the distance between the ankles.  This technology 
has been shown to be a reliable method of calculating frontal plane moments and has 
been shown to have a very high correlation with 3D optical marker based motion 
analysis systems.77,78 To perform the DVJ, participants will stand on a box 
approximately 30 cm in height with the balls of each foot off the edge of the box. A 
Microsoft Kinect V2 sensor is placed 3.4 meters away from the box, mounted on a 1 
meter high tripod. The Kinect sensor is connected to a Windows based computer with 
the ACL-Gold software. The participant drops off the box, landing on both feet and then 
performs a maximum vertical jump as quickly as possible, landing in the same spot as 
the initial landing. The participant then takes a few steps forward, which triggers the 
automated data collection.  The results are then automatically populated in a results 
screen in the system. The participant will perform 3 DVJs with the average 
measurement of dynamic valgus of the lower extremity calculated.  
 
Return to Activity Measures 
The Marx Activity Rating Scale will be used to measure return to activity. It is a four-item 
scale79 where individuals rate how often they are able to perform each activity (e.g. 
running, cutting, decelerating, and pivoting). One point is allocated for each response 
category to create a score that ranges from 4 to 16 points, with 16 representing the 
highest level of activity.   
Psychological readiness for return to sport will be measured using the Anterior Cruciate 
Ligament–Return to Sport after Injury (ACL-RSI) scale.80  The scale was developed to 
quantify psychological factors associated with return to sport (RTS). This scale includes 

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12 items measured on a 0 to 10 visual analogue scale (VAS) and was developed based 
on 3 components correlated to RTS in the literature: emotions, confidence in 
performance and risk appraisal. It has been shown to be a valid tool to assess 
psychological readiness for RTS, with studies showing that psychological and physical 
readiness are different constructs that may require different time frames for full 
recovery.81 
We will also record the primary sport and level of participation prior to injury and 
postoperatively to determine whether participant returns to his/her previous level of 
activity, and if not, why not. 
 
Donor Site and Adverse Events 
We will assess donor site morbidity by determining the presence of anterior kneeling 
pain and sensory disturbance secondary to the graft site skin incision. Anterior kneeling 
pain will be assessed by asking the participants to rate their pain using an 11-point 
numeric rating scale while they kneel on a hard floor. Sensory disturbance will be 
assessed via light touch to regions around the graft skin incision and anterolateral tibia 
and will be rated as absent, mild, moderate or severe.  
All complications (intra- and postoperative) will be recorded. Adverse events will be 
classified based on the standard medical terminology from the Common Terminology 
Criteria for Adverse Events.  Plain standing flexion AP radiographs will be obtained prior 
to and 2 years after surgery and will be used to assess lateral compartment joint space 
narrowing by a central reader blind to group and scan order. 
 
Cost-Effectiveness Measures 
Quality-adjusted life years (QALYs) will be measured using the European Quality of Life 
Scale (Euro-QoL).82 The EuroQoL comprises two sections, the EQ-5D index and the 
EQ-5D VAS. The EQ-5D index is a 5-item standardized generic measure of health-
related QOL (HRQOL) that includes the domains of mobility, self-care, usual activities, 
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response scale and each combination of response choices describes a health state 
(3125 unique health states). Each health state can be converted to a utility value from 0 
(worst) to 1.0 (best) using a scoring formula. The EQ-5D VAS is a 0 (worst) to 100 
(best) scale that assesses patient-perceived health status. We are including the EQ-5D 
as a measure of QALYs for an economic cost effectiveness analysis. 

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5 STUDY DESIGN 
The proposed study is a multicenter, international, randomized clinical trial that will 
include 21 sites across the USA, Canada, and Europe. Twelve hundred participants 
with an ACL deficient knee will be randomly assigned to ACLR with either quadriceps 
tendon (QT) or bone-patellar-tendon-bone (BPTB) autograft with or without lateral extra-
articular tenodesis (+/- LET). Randomization will be stratified by surgeon, sex and 
meniscal status (normal/repaired vs. meniscectomy). Patients will follow a standardized 
rehabilitation protocol. Outcomes will be assessed over two years postoperatively by a 
blinded evaluator. The primary outcome is ACL clinical failure, as defined by either graft 
rupture requiring revision ACLR surgery or persistent rotational laxity as measured by 
an asymmetrical positive pivot shift compared to the contralateral side (see section 4.1). 
Secondary outcomes will include PROs that assess symptoms, activity, participation 
and QOL (ACL-QOL, IKDC-SKF, KOOS, EQ5D), measures of impaired range of motion 
and muscle function (quadriceps & hamstring strength), performance-based measures 
of physical function (hop tests, DVJ), and return to pre-injury sports. Complications, 
adverse events, intervention-related donor site morbidity, lateral joint space narrowing 
on plain AP standing flexion radiographs and costs will also be recorded. End of study is 
defined when the last enrolled subject reaches the 24-month follow-up time point and close-out 
activities are complete. 

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6 STUDY ENROLLMENT 
 
Subject Inclusion Criteria 
Subjects deemed eligible for the study will have an ACL deficient knee, be 14-25 years 
old, skeletally mature (i.e. closed epiphyseal growth plates will be confirmed on 
standard of care knee radiographs for all study subjects), and have two or more of the 
following factors that are associated with a high risk of graft failure: participate in a 
competitive pivoting sport (defined as sports that include cutting and pivoting activities 
such as basketball, American football, soccer, lacrosse, volleyball, tennis/squash, 
handball, downhill skiing etc); or have a pivot shift of grade 2 or greater; generalized 
ligamentous laxity (Beighton score of ≥4) and/or genu recurvatum >10 degrees. 
 
Subject Exclusion Criteria 
Individuals will be excluded from the study if they have had previous ACLR on either 
knee, partial ACL injury (defined as one bundle ACL tear requiring reconstruction/ 
augmentation of the torn bundle with no surgery required for the intact bundle), multiple 
ligament injury (two or more ligaments requiring surgery), symptomatic articular 
cartilage defect requiring treatment other than debridement, >3 degrees of asymmetric 
varus, inflammatory arthropathy, pregnant or are unable to provide consent. 
Please note that pregnancy post-operatively will not exclude individuals from 
continuing this research study. Pregnancy will be confirmed as part of the standard 
of care for having surgery. A pregnancy test will not be completed for research 
purposes. 
 
 
Strategies for Recruitment and Retention 
 
Recruitment Process 
All consecutive patients with an ACL deficient knee presenting to a surgeon-investigator 
will be screened for eligibility. Eligible patients will have the study explained to them and 
if interested, they will be presented with a regulatory review board approved consent 
form. All patients will have an opportunity to ask questions about the study and all of the 

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study procedures prior to providing informed consent. All eligible patients who wish to 
participate in the study will review and sign the approved consent form.  Prior to signing 
the consent form, all questions will be answered to the satisfaction of the individual by 
the surgeon investigator and/or research staff. 
Non-consenting, eligible patients will be asked if de-identified demographic data can be 
collected to accurately describe this population in our manuscript. We will collect age, 
sex, type and level of sport, pivot shift test grade and Beighton score or hyperextension 
>10 degrees.  This information will be useful to more accurately describe the 
representativeness of the sample that participated in the study relative to the population 
of interest.   
Since the surgeons are also investigators in the study, we recognize that the surgeon 
may be conflicted in their attempts to recruit the individual into the study. During the 
recruitment and consent process, individuals will be informed of this potential conflict 
and offered the opportunity to discuss their care with another surgeon that is not 
associated with the study. Once informed consent has been obtained, screening 
procedures will be performed to confirm final eligibility for participation in the study. 
 
Efforts to Maximize and Monitor Subject Recruitment 
Several strategies will be used to ensure that we meet the recruitment targets. We will 
review all study procedures with an emphasis on successful recruitment methods at the 
first in-person Investigators’ Meeting as well as during the Site Initiation Visit.  
Recruitment materials, such as flyers, recruitment scripts and laminated reference cards 
that summarize eligibility criteria will be developed and distributed to the sites.  
As part of the Clinical Monitoring Plan, we will closely monitor monthly recruitment at 
each of the sites. Sites that achieve or exceed the recruitment goals will be permitted to 
recruit additional subjects beyond their targeted enrollment. For those sites that lag in 
recruitment, we will work closely with them to increase enrollment. Strategies to improve 
recruitment will vary based upon the barriers encountered by the site. If overall 

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recruitment for the study lags behind targeted enrollment, we will consider adding sites 
and will re-allocate financial support for additional sites from those sites that are not 
meeting recruitment projections or have been terminated from the study. 
 
Efforts to Maximize Subject Retention 
As with any longitudinal study, participants that are lost to follow-up are a concern. We 
recognize that keeping participants enrolled and active in this research study is 
important to the success and validity of the study. In our sample size calculation, we 
accounted for an attrition rate of 15% at the 2-year follow-up; however, as described 
below, we will make concerted efforts to minimize loss to follow-up rates. 
A total of 618 patients (297 males; 48%) with a mean age of 18.9 years (range, 14-25 
years) were randomized as part of STABILITY 1. There were 18 patients lost to follow-
up and 11 who withdrew (~5%), provides strong evidence that we are capable of 
successful retention in a study of this magnitude. In addition, the timing of follow-up 
assessments (6, 12 and 24 months postoperative) corresponds with regular standard of 
care visits to the surgeon following ACLR which will help minimize the attrition 
rate.STABILITY 2 will use the same measures used in STABILITY 1 to maximize 
completeness of follow-up. The following describe our data management and 
motivational strategies for the site and participant to maximizing retention.  
1. The clinical research assistant (CRA) will collect complete contact information 
from the participant and two individuals who do not reside with the participant but 
are likely to maintain contact should the individual relocate. This information will 
be collected at the time of enrollment in the study. Additionally, participants will 
be asked to update their contact information at each follow-up visit. 
2. The CRA will provide a regulatory institutional/ethics board approved consent 
form that details the purpose of the study, the importance of subject participation 
and attendance of follow-up visits. During the informed consent process, the 
surgeon and CRA will explain the time commitments required for participation, 

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and the participant will be given as much time as needed to read the consent 
form and ask questions, so that the participant fully understands their 
responsibility prior to signing the consent form. 
3. The CCC will provide the site PI and CRA with a quarterly newsletter to distribute 
to all English-speaking participants, with a message from the PIs. Sites will be 
asked during the SIV of translation requirements.   
4. The Project Coordinator (PC) and Quality Control Lead (QCL) at the data 
management company (EmPower Health Research) will proactively monitor 
participant retention using the web-based data management system. The 
EmPower data management software automatically generates reports of missing 
data. Missing data reports will be shared with the site CRA and principal 
investigator (PI) monthly for adjudication and resolution. In addition, site 
remuneration for data collection is dependent on complete and query-free CRFs 
per participant by visit. EmPower provides quarterly reports of visit completion 
and corresponding remuneration value to the site and to the lead institution 
responsible for issuing site payments. 
5. The data management software offers a participant tracker report that the CRA at 
each site can generate. The report provides a list of each participant by row and 
each column represents a visit. Each cell provides the status of the visit as 
complete, incomplete, overdue or missed. Upcoming visits display the date the 
visit window opens and the date the visit window closes. The report can be 
limited to those with an overdue visit or with a visit coming up within a defined 
number of days as specified by the CRA. This feature assists the site with 
planning and tracking participant visits. 
6. The EmPower data management software will send automatic email reminders to 
the CRA of an upcoming follow-up visit prior to the visit, on the date that the visit 
window opens, the ideal date, and a few days after the ideal date if the CRFs 
remain incomplete. The CRA and site PI are notified if the visit still remains 

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incomplete 7 days prior to the final visit window date. The PC and eMonitor are 
notified if the visit remains incomplete on the final day of the visit window. Since 
the analysis will use time as a random factor, visits that take place outside the 
specified window are not as problematic as when time is defined as a fixed 
factor. 
7. The EmPower data management software will send an automatic email or text 
message to participants (who have opted into this feature) regarding upcoming 
and overdue appointments. Multiple attempts to contact non-responders will be 
utilized. Participants will be contacted via email one week prior to the follow-up 
due date, at the due date, and up to three times after the due date. If the 
participant does not respond to the third contact to their preferred contact, phone 
calls will be made by the site RC until the participant completes the follow-up visit 
or withdraws their consent. Data collected up to the date of withdrawal will be 
retained for analysis. 
8. Participants may opt to complete the PROs by directly logging into the online 
EmPower data management software. Each participant is provided a secure 
login and login information. The EmPower data management software records 
the date, time and user information in the audit log so that the electronic 
information can serve as a primary data source. The audit log also tracks initial 
data values, updated data values and reasons for changes made to updated data 
values. Providing this option allows the research team to collect patient reported 
data when participants cannot physically attend a follow-up (e.g. vacation). 
9. Participants are remunerated $50 for completion of each of the 
screening/baseline, 6, 12, and 24-month postoperative visits and $20 for 
completion of each of the 6-week and 3-month postoperative visits.  Participants 
that complete all study visits will also be provided with an additional $50 
payment.   

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Randomization Procedures 
Randomization will be stratified by surgeon, participant sex, and meniscal status 
(normal/repaired v meniscectomy) in permuted block sizes to ensure that any 
differences in outcome attributable to these factors are equally dispersed between 
treatment groups. Each site will either use traditional or expertise-based randomization. 
Expertise-based randomization means that a surgeon with a preference or expertise for 
one intervention over the other (BPTB vs. QT) is paired with a surgeon at the same site 
who has a preference or expertise for the opposing intervention. Eligible and consenting 
patients are then randomly assigned to one of the surgeons who will perform their 
preferred intervention, reducing expertise bias. In this study, all surgeons will have the 
requisite expertise to perform an LET.  The potential for expertise bias exists with graft 
harvest and thus, for sites participating in expertise-based randomization, randomization 
to graft type will occur prior to surgery. Randomization to LET or no LET will take place 
in the operating room following diagnostic arthroscopy and final confirmation of eligibility 
criteria. At sites participating in traditional randomization, participants will be randomized 
to graft type and LET or no LET following diagnostic arthroscopy. All randomization will 
use the web-based application available through the EmPower data management 
center. This system requires entry of the patient’s date of birth, database ID and 
responses to all stratification questions prior to group allocation to ensure concealment 
of allocation is enforced. 
 
Masking Procedures 
Participants and their care provider (i.e. surgeon-investigator performing the surgery) 
will not be blinded to group assignment.  To account for this, a second blinded clinician 
will conduct the physical examination and record the primary outcome for the study.  To 
maintain blinding, study participants will wear tubigrip on the surgical knee during the 
clinical examination and testing of range of motion, strength and performance-based 
functional tests.  

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7 STUDY INTERVENTION 
 
Surgical Intervention 
All patients will undergo an anatomic ACLR, which will be performed in a similar manner 
across sites. Surgeons will use a BPTB or QT autograft as randomized, located in an 
anatomic position within the femoral and tibial insertion sites, with consistent graft 
fixation. 
All surgical findings and procedures will be documented on the Surgical Information 
CRF (see Appendix C).  As the quality control (QC) coordinators for the surgical 
intervention, Drs. Getgood and Musahl will be available to answer any questions from 
surgeons regarding a subject’s participation in 
the study. The surgical treatment will follow a 
standardized algorithm (Figure 2).  
Examination Under Anesthesia – All patients 
will have standard of care surgery performed 
under general or spinal anesthesia as per the 
discretion of the operating team. The patient 
will be placed in a supine position on the 
operating table and the operative leg set up in 
an appropriate position to allow for deep 
flexion during femoral tunnel drilling. An 
examination under anesthesia will be 
performed allowing documentation of baseline 
findings including range of motion, presence of 
effusion, Lachman, anterior/posterior drawer, 
pivot shift tests and varus/valgus stability. A 
tourniquet may be placed on the operative 
limb and inflated either before or during the 
Examination Under Anesthesia
Arthroscopy - ACL, Meniscus 
and Articular Cartilage Findings
Confirmation of Eligability and 
Randomization
Graft Harvest
Meniscus and Articular 
Cartilage Treatment
ACL Reconstruction
LET if Randomized
Figure 2. Surgical Algorithm 

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procedure, or not at all as per the discretion of the operating surgeon. The limb will then 
be prepped and draped in a sterile manner.  
Measurement of pivot shift using Pivot App – All patients will undergo pivot shift 
examination using the Pivot App on the provided tablets. Three yellow circular stickers 
will be placed on the lateral side of the knee.  One is placed over the lateral epicondyle, 
a second on Gerdy’s tubercle on the tibia, and a third placed 3 cm directly posterior to 
the second, in close proximity to the fibula head making a triangle on the lateral side of 
the knee (Figure 3).  A standardized pivot shift will be performed on both the operative 
and contralateral non-operative limb measured using the tablet and Pivot App. 
 
Figure 3: PIVOT App Subject Setup 
Arthroscopic Examination of the ACL, Meniscus, and Articular Cartilage; Final 
Confirmation of Eligibility and Randomization - For patients at a site using traditional 
randomization, arthroscopy will be performed to confirm eligibility prior to randomization. 
Confirmation of eligibility prior to randomization reduces the risk of selection bias.  
The arthroscopic examination will be done using the preferred portal placement of the 
operating surgeon that will facilitate anatomic graft placement via a transportal femoral 
tunnel drilling technique. The status of the menisci and cartilage will be assessed at this 
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to repair or debride the tissue at the discretion of the operating surgeon.  Treatment 
other than debridement of articular cartilage injuries will result in the patient being 
excluded from participation. Meniscus and cartilage findings and procedures will be 
documented on the Surgical Information CRF. The findings during the diagnostic 
arthroscopy will serve as final confirmation of patient eligibility, i.e. the patient must not 
have a partial ACL rupture where an ACLR is not performed, an articular cartilage lesion 
that requires any other surgical treatment apart from debridement, or require multiple 
ligament surgery (repair or reconstruction). Partial ACL injury is defined as a case were 
a the fibers of a specific bundle (anteromedial or posterolateral) is reconstructed, 
maintaining the integrity of the other bundle. Conversely, if a tissue 
preservation/remnant preservation surgical technique is utilized, creating an anatomic 
reconstruction, then this would be included. Participants from a site using traditional 
randomization who are confirmed eligible following examination under anesthetic will be 
randomized to graft type with or without LET. 
For patients in a site participating in expertise-based randomization, randomization to 
graft type (BPTB or QT) occurs prior to surgery. However, the operating surgeon will 
confirm eligibility by performing diagnostic arthroscopy. The criteria for determining 
eligibility is identical between the expertise-based and traditional randomization sites.  
Patients confirmed eligible will be randomized to the addition (or not) of a LET. 
Intraoperative Complications that occur during surgery will be documented on the 
Adverse Events CRF.  Intraoperative complications that are expected include nerve or 
vascular injury, loose hardware, and intraoperative fracture. Unexpected complications 
that occur will also be documented on the Adverse Events CRF. 
 
Anterior Cruciate Ligament Reconstruction 
A standardized transportal ACLR technique will be utilized for all patients.  Specifically, 
following treatment of the meniscal lesions and chondral surfaces the femoral tunnel will 
be prepared. The femoral footprint will be debrided and the position of the tunnel 
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Anatomic positioning of the femoral tunnel will be checked by viewing through the 
anteromedial portal, measurement of the femoral footprint and/or by fluoroscopic 
evaluation. With the knee in deep flexion, the guide pin will be drilled from the 
anteromedial portal following which the femoral tunnel socket will be prepared using an 
appropriately sized drill depending on the graft size. A passing suture will then be 
passed. An arthroscopic picture of the femoral tunnel will be taken from the medial 
portal to confirm the anatomic nature of the tunnel.  This arthroscopic picture will be 
uploaded to Empower.   
For the tibial tunnel, the position will be referenced off the tibial footprint of the ACL as 
well as the anterior root insertion of the lateral meniscus, aiming the guide pin position 
to be level with the posterior border of the anterior root of lateral meniscus, hugging the 
medial tibial spine. The length and width of the tibial footprint will be measured using a 
flexible ruler intra-operatively. A guide pin will be inserted from the anteromedial tibial 
cortex accessed via a separate skin incision using a 45-50 degree tibial guide 
depending upon graft length. Once the pin is in the desired location an arthroscopic 
picture of the tibial tunnel will be taken from the lateral portal to confirm anatomic nature 
of the tunnel.  This picture will be uploaded to Empower. An appropriately sized tibial 
drill will then be utilized to create the tunnel. The passing suture will be retrieved from 
the knee and the graft will be ready to pass.  
Graft passage will be performed from the tibial tunnel into the femoral tunnel. For the 
BPTB graft the bone block will be seated in the femoral tunnel and fixation will be with 
either interference screw or suspensory fixation. The knee will be cycled through the 
range of motion 15 times with tension applied to the graft. The knee will then be held at 
10 degrees of flexion and the tibial end fixed with a 7x25 mm interference screw.  
For the quadriceps tendon graft the femoral fixation will be similar to the BPTB graft if 
using a bone plug. For a soft tissue only graft, it will be advanced into the knee and 
pulled into the femoral tunnel. The suspensory fixation device will be flipped/deployed 
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will be performed using an interference screw 1 mm larger than the drill diameter with a 
screw post fixation utilized if cortical fixation is not achieved in instances where the graft 
is short. 
 
Graft Harvest 
The appropriate graft will be harvested as per randomization.  A standardized technique 
will be followed for each graft type. Specifically, for patients randomized to bone patella 
tendon bone (BPTB) harvest, a longitudinal skin incision will be made over the patellar 
tendon. The subcutaneous tissues will be dissected sharply down to the paratenon, 
which will be split longitudinally. The central one third of the patella tendon (measuring 
approximately 10 mm) will be marked with a sterile skin marker pen. A bone block 
corresponding to the central third of the tendon will then be harvested from both the 
distal pole of the patella and the tibial tubercle. For the patella a 9 mm wide, 20 mm long 
bone block will be marked. A central 2 mm drill hole will be placed following which the 
block will be cut using a small oscillating saw. On removal of the block a high strength 
suture (#5 ethibond suture or equivalent) will be placed through the 2 mm hole. The 
tendinous part of the graft will then be incised in line of the tendon fibers down to the 
tibial tubercle. A 10mm wide, 25 mm long bone block will then be marked and cut using 
the small oscillating saw. Two 2 mm holes will be drilled to facilitate the passage of two 
high strength sutures (#5 ethibond suture or equivalent). At the end of the procedure the 
patellar defect will be bone grafted using the excess bone removed from the blocks and 
from the tibial tunnel drill. 
For patients randomized to harvest of the quadriceps tendon (QT), either a soft tissue 
only or bone block technique may be utilized as per surgeon preference, as there have 
been no differences observed between techniques in the literature.83 
Both techniques will utilize a longitudinal skin incision made over the proximal pole of 
the patella and quadriceps tendon insertion. The paratenon will be split in the midline 
allowing access to the quadriceps. A 10 mm wide strip of tendon will be marked closer 
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medialis oblique. The tendon will be sharply dissected using a 15 blade and scissors. A 
minimum 5 mm thickness and 8 cm length of soft tissue graft will be harvested under 
direct visualization.  
For the bone block technique, a 10 mm wide, 20 mm long bone block will be marked. A 
central 2 mm drill hole will be placed following which the block will be cut using a small 
oscillating saw. On removal of the block a high strength suture (#5 ethibond suture or 
equivalent) will be placed through the 2 mm hole. A high strength suture (#5 Fiberwire 
suture or equivalent) will then be whip stitched to the other end of the graft. At the end 
of the procedure the patella defect will be bone grafted from the excess bone removed 
from the block and from the tibial tunnel drill. 
For the soft tissue only technique the graft will be dissected off the patella with or 
without a strip of periosteum.  It will then be passed to the back table in the operating 
room where a suspensory fixation loop (endobutton or equivalent) will be attached by 
either splitting the graft or utilizing a strip of patella periosteum to wrap over the loop. 
The loop will be secured in place using a high strength suture (#2 Fiberwire suture or 
equivalent). A high strength suture (#5 Fiberwire suture or equivalent) will then be whip 
stitched to the other end of the graft.  
For both techniques, the soft tissue graft diameter will be measured and recorded, 
looking to achieve between 8-9 mm of soft tissue. 
Once the grafts (BPTB or QT) are prepared, they will be left soaking in a vancomycin-
soaked sponge (5 mg/ml of saline) until implantation to reduce the risk of post-operative 
deep infection. 
 
Lateral Extra-articular Tenodesis 
In participants randomized to undergo the addition of a LET, the LET will be performed 
upon completion of the ACLR. Specifically, following final tensioning of the ACLR, a 
modified Lemaire procedure will be performed. A 6 cm curvilinear incision will be placed 
just posterior to the lateral femoral epicondyle. The posterior border of the ITB is 

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identified and freed of any fascial attachments to the level of Gerdy’s tubercle. An 8cm 
long x 1cm wide strip of ITB is harvested from the posterior half of the ITB, ensuring that 
the most posterior fibers of the capsulo-osseous layer remain intact. The strip of ITB is 
left attached distally at Gerdy’s tubercle, freed of any deep attachments to vastus 
lateralis, released proximally and a #1 vicryl whip stitch is placed in the free end of the 
graft. The fibular collateral ligament (FCL) is then identified. Small capsular incisions are 
made anterior and posterior to the proximal portion of the ligament and Metzenbaum 
scissors are placed deep to the FCL to bluntly dissect out a tract for graft passage. An 
attempt is made to remain extracapsular, while ensuring there is no iatrogenic damage 
to popliteus. The ITB graft is then passed beneath the FCL from distal to proximal. The 
lateral femoral supracondylar area is then cleared of the small fat pad found proximal to 
the lateral head of gastrocnemius using electrocautery to reduce risk of bleeding 
following damage to the lateral superior geniculate artery. The attachment site should 
be identified just anterior and proximal to the lateral gastrocnemius tendon. The 
periosteum is cleared using a cob on the metaphyseal flare of the lateral femoral 
condyle. Care is taken not to damage ACL femoral fixation as the suspensory loop 
button is often found close to this location. The graft is then held taught (<20 N) but not 
over tensioned, with the knee at 60-70 degrees flexion and the foot in neutral rotation to 
avoid lateral compartment over-constraint. 
The graft is secured using a small Richards staple (Smith and Nephew Inc.) and then 
folded back distally and sutured to itself using the #1 vicryl whip stitch. The wound is 
irrigated, hemostasis is confirmed, and closure is performed in layers. The posterior 
aspect of the ITB where the graft was harvested is closed up to the level of the 
transverse ligament to avoid over constraint of the patellofemoral joint. 
 
Rationale for Specific Surgical Intervention 
Failure of ACLR is multifactorial, with four broad categories of factors associated with 
failure: traumatic re-injury, poor biological healing, insufficient rehabilitation (poor 
neuromuscular conditioning,12 proprioception and no sport-specific training), and 
surgical technique.13 The surgical method of reconstructing the injured ligamentous 

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structures to re-establish knee stability can impact all of these risk factors and provides 
an opportunity to improve the likelihood of a favorable outcome.14 Two surgical 
strategies that continue to be a significant topic of interest for surgeons trying to address 
persistent rotational laxity and ACLR failure are the anterolateral complex and graft 
choice.  
 
Alternative Treatments 
Patients who do not wish to participate in the study may elect to undergo ACLR with 
one of the study interventions, BPTB or QT with or without LET as per their surgeon’s 
expertise or preference.  Patients may also choose to have ACLR with allograft tissue or 
hamstring autograft tissue. 
 
Procedures for Training of Clinicians on Procedural Intervention 
Surgeons will gather at an Investigators’ Meeting prior to trial commencement at a 
central location at which time the interventions will be reviewed in detail. All surgeons 
participating in the trial are experienced at performing the aforementioned interventions. 
The purpose of this meeting will therefore be to ensure that all surgeons perform the 
interventions in a standardized fashion to limit the degree of variability within and across 
study centers. To standardize the procedures for ACLR, we will review and demonstrate 
the procedures for harvest of the patellar and quadriceps tendon graft, anatomic 
placement of the femoral and tibial tunnels and methods of graft fixation. To standardize 
the procedures for the LET, we will review the procedures for harvesting the ITB, 
location of the femoral placement of the graft and methods of fixation. To ensure 
competency in terms of performing a LET, all surgeons who have not completed at least 
10 LETs will be required to complete at least 10 LET procedures prior to randomizing 
their first participant. 
 
Monitoring Fidelity in Delivering the Intervention 
Remote, electronic monitoring of the surgical interventions will be performed on 100% of 
the patients using the Surgical Information CRF (see Appendix C). The Surgical 

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Information CRF contains questions related to each procedure that alert the surgeon 
and the data monitoring team of protocol deviations(PD). The EmPower data 
management software automatically orders a PD CRF when a response is provided that 
signals that the surgical procedure did not follow the standardized plan. PDs  are 
regularly reviewed by the Executive Steering Committee (ESC) and DSMB and, as 
needed, an action plan will be developed, documented and implemented to improved 
fidelity with the surgical interventions. 
Remote, electronic monitoring of the fidelity of the rehabilitation intervention will be 
monitored for completeness for 100% of the participants using the Patients’ 
Experiences with Rehabilitation CRF (see Appendix C). 
 
Rehabilitation 
Regardless of group allocation, all patients’ physical therapists will be provided with the 
same postoperative rehabilitation protocol and a set of standardized instructions from 
the surgeon. Focus is placed upon early range of motion and weight bearing as 
tolerated.  
The rehabilitation protocol will require the physiotherapists to exercise professional 
judgement to determine how to integrate the protocol into an appropriate treatment plan. 
All exercises will be dependent on the equipment available at each facility. Due to the 
variability in subject’s progression, the protocol must be individualized for optimal return 
to activity. Variations may occur if limitations are imposed from additional associated 
injuries such as meniscal tears, articular cartilage trauma, bone bruises or other 
ligamentous injuries. 
The span of the rehabilitation protocol is 12 months, and it includes three criterion-
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Tissue Protection Phase 
The rehabilitation focuses on general range of motion, control of swelling, quadriceps 
activation, and a return to basic activities of daily living and lasts anywhere for 4 to 8 
weeks after surgery.  
The suggested progressions in this phase are as follows: 
• Patient education regarding:  
o Progressive increases in activity pending meeting criteria 
o Weight-bearing status and gently re-introducing loading to the knee; 
o Changes to rehab guidelines with concurrent pathologies (e.g. 
patellofemoral pain, meniscal repair, etc.) 
• Decrease inflammation 
o Pain should be well controlled (e.g. no more than 4/10) 
o Swelling should be a 1+  or less on the sweep test prior to weight bearing 
exercise 
• Increase range of motion & restore full extension* with the following goals: 
o Neutral Extension (0o) to 90o flexion by 2 weeks post-op 
o Hyperextension equal to the opposite limb to 120o flexion by 4 weeks 
post-op 
o Full motion compared to the non-involved limb by 6 weeks post-op 
• Quadriceps activation with the following goals: 
o Isolated quadriceps activation that produces a superior patellar glide by 
week 1 post-op 
o Straight leg raise with no quadriceps lag by 2 weeks post-op 
• Maintain flexibility of hamstrings, calves 
• Maintain cardiovascular fitness 
o Consider use of the upper body ergometer (arm bike) 
o Consider hydrotherapy when the incisions and portals have healed, and 
scabs have fallen off (~4 weeks) 

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• Normalize proprioception, balance, and neuromuscular control to normalize gait 
patterns, stair negotiation, and activities of daily living 
o Instruct in proper gait patterns with assistive devices  
o Progress to walking without assistive devices when the patient: 
 Has less than a 3o quadriceps lag 
 Can stand on the surgical limb for 10 seconds with good balance 
 Can walk with a normal gait pattern including direction changes 
o Normal transitions from sitting to standing and standing to sitting (e.g. no 
weight shift away from the surgical leg) 
o Normal reciprocal stair ascent and descent 
 
Motor Control Phase 
This phase promotes strength, neuromuscular, and cardiovascular re-training to prepare 
the patient to return to impact activities and lasts until at least 16 weeks after surgery. 
The goals and treatment progression during this phase are: 
• Range of Motion 
o Maintain full and pain free knee range of motion 
o Ensure normal hip joint motion (extension, rotation) and ankle joint motion 
o Address limitations in quadriceps, hamstrings, gastrocnemius flexibility 
• Quadriceps and Hamstrings strength equal to 80% of the opposite limb 
o Perform electromechanical dynamometry or 1-Repetition Maximum (RM) 
testing at 12 weeks post-surgery. 
o Address documented strength deficits with non-weight bearing isotonic 
exercises  
 Heavy resistance from 45o-95° 
 Light resistance from 90o to 0o 
o Isokinetic quadriceps strengthening should be performed from 90o to 45o 
at high and low velocity 
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meniscal or patellofemoral pathology 
• Continue strengthening gluteal muscle groups, specifically through 
full range of motion  
• Motor Control Phase ends when the patient meets all criteria to 
begin jogging: 
o Quadriceps Index of 80% or greater as measured with an 
electromechanical dynamometer or 1-RM knee extension test. 
o Able to walk 15 minutes at a fast pace without aberrant movements 
(limp), pain or swelling 
o Normal walking gait pattern has been achieved 
 
Functional Optimization Phase 
In the Functional Optimization Phase dynamic activities like running, jumping, agility 
training, and sport-specific training are introduced. The Functional Optimization Phase 
is the key to returning athletes to sport while minimizing the risk of injury. Athletes may 
be cleared to return to practice around 7 to 12 months after surgery, with full clearance 
as early as 9 months. The suggested progression during this phase is: 
• Progressively return the athlete to normal dynamic loading patterns with good 
control to minimize injury risk. 
• Implement evidence-based injury prevention techniques to reduce risk of second 
ACLR. 
• Ensure optimal lower extremity strength and flexibility to promote return to full 
activity. 
• Incorporate total body training to resume normal activity. 
• Practice sport-specific conditioning, drills, and movements in a safe environment. 
• Prepare the athlete to transition to training with coach, trainer, etc. 

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8 STUDY PROCEDURES AND MATERIALS 
 
Consent Process 
All patients with an ACL deficient knee will be assessed by a clinician to ensure they 
meet the eligibility criteria as specified on the Preoperative Screening Case Report 
Form (CRF). Eligible patients will have the study explained to them and informed 
consent will be obtained from those that are interested. All patients will have an 
opportunity to ask questions about the study and all of the study procedures prior to 
providing informed consent. All eligible patients who wish to participate in the study will 
review and sign a site-specific regulatory ethics board approved consent form. A 
detailed description of all possible randomization groups will be discussed with the 
patient during consent process. 
Non-consenting, eligible patients will be asked if de-ideintifed demographic data can be 
collected to accurately describe this population in our manuscript. We will collect age, 
sex, type and level of sport, pivot shift test grade and Beighton score or hyperextension 
>10 degrees. 
 
Screening 
After signing the consent form, and before surgery, patients will be registered in the 
web-based EmPower data management software, and they will be assigned a unique 
identifier called a database ID number. At each site, a list of participant names and 
contact information matched to the database ID will be kept separate from the study 
data and will not be shared outside the participant’s health care team.  
Once patients have been assigned a study ID, they will be asked to complete 
questionnaires on a tablet or on paper-based forms if requested. These questionnaires 
will ask about a patient's injury, pain, symptoms, activity level and quality of life 
regarding their ACL deficient knee. These questionnaires include the following: 
• Demographics 

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• International Knee Documentation Committee Subjective Knee Evaluation Form 
(IKDC-SKF) 
• Knee injury and Osteoarthritis Outcome Score (KOOS) 
• Anterior Cruciate Ligament Quality of Life (ACL-QOL) 
• EuroQol Visual Analog Scale (EQ5D VAS) 
• EQ5D Index 
• Marx Activity Rating Scale 
• Sports Participation Questionnaire 
Participants will be scheduled for surgery after signing the informed consent document 
and completing the standard of care pre-operative clinical examination (including 
imaging results) and isometric muscle strength testing. 
All patients will undergo Anatomic ACLR. Following a complete diagnostic arthroscopy, 
it will be determined if the patient can continue in the study as per the study eligibility 
criteria (i.e. they must not have a partial ACL rupture where an ACLR is not performed, 
an articular cartilage lesion that requires any other surgical treatment apart from 
debridement, or need for a multiple ligament reconstruction). The menisci will also be 
assessed and the findings and any surgical procedures for the meniscus will be 
recorded. At this time, eligible participants will be randomized to BPTB or QT with or 
without LET.   
 
Randomization and Surgery 
Randomization to graft type with or without LET will take place in the operating room 
after evaluation under anesthesia (EUA) and diagnostic arthroscopy to confirm 
eligibility. Prior to surgery, the surgeon investigator will discuss surgical options should 
the participant be deemed ineligible following the EUA and arthroscopy. Patients found 
to be ineligible following the EUA and diagnostic arthroscopy will proceed with the 
procedure established by the surgeon and the patient during the pre-operative exam for 
this instance. 
Possible randomization allocations (4) are as follows: 

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1. ACLR with Quad tendon 
2. ACLR with Quad tendon and LET 
3. ACLR with Bone-Patellar Tendon-Bone 
4. ACLR with Bone-Patellar Tendon-Bone and LET 
 
Rehabilitation 
Regardless of group allocation, all patients’ physical therapists will be provided with the 
same postoperative rehabilitation protocol and a set of standardized instructions from 
the surgeon. Focus is placed upon early range of motion and weight bearing as 
tolerated. Briefly, rehabilitation includes three criterion-based phases. In the Tissue 
Protection Phase, rehabilitation focuses on general range of motion, control of swelling, 
quadriceps activation, and a return to basic activities of daily living and lasts for 4 to 8 
weeks after surgery. The Motor Control Phase promotes strength, neuromuscular, and 
cardiovascular re-training to prepare the patient to return to impact activities and lasts 
until at least 16 weeks after surgery. The Functional Optimization Phase introduces 
dynamic activities like running, jumping, agility training, and sport-specific training. The 
Functional Optimization Phase is the key to returning athletes to sport while minimizing 
the risk of injury. Athletes may be cleared to return to the practice around 7 to 12 
months after surgery, with full clearance for return to sports as early as 9 months.  See 
section 7.6 for additional details related to the standardized post-operative rehabilitation.   
 
Clinical Follow-Up Appointments 
After surgery, the subjects will participate in the following standard of care and 
research activities: 
 
Standard of Care Clinical Follow-Up Appointments 
• Participants will attend regular clinical post-operative appointments with their 
surgeons at 6 weeks and 3, 6, 12 and 24 months. Data from these clinical visits will 
be collected and recorded for research purposes, including range of motion 
measurements and results of manual assessment of rotatory laxity (i.e. pivot shift 
test). Range of motion measures: a blinded assessor will measure passive and 

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active knee extension and active-assisted knee flexion with a goniometer. For 
passive knee extension, the patient will lie supine on the examination table with a 
bolster under the heels with the quadriceps and hamstrings relaxed to assure full 
passive extension of the knee. For active-assisted knee flexion, the patient will be 
seated on the examination table with both legs extended and instructed to perform 
active-assisted knee flexion by placing one hand under their thigh to initiate flexion 
and then clasp both hands just below the tibial tuberosity. The side to side difference 
in ROM will be determined and interpreted based on IKDC guidelines. 
• Pivot shift assessment: to perform this test, the examiner controls the patient’s leg 
with his ipsilateral hand at the level of the heel. The examiner lifts the patient’s leg 
off the table and gently abducts the hip. The leg is internally rotated with the 
ipsilateral hand. To control valgus stress, the examiners’ contralateral hand is placed 
with the thumb up at just below the level of the proximal tibia-fibula joint. A gentle 
valgus stress is applied. Knee flexion is initiated with the both hands. Internal 
rotation- and valgus stress are maintained until around 20 degrees of knee flexion. 
The rotational stress of the ipsilateral hand is released, and the proximal tibia is 
allowed to rotate externally. The reduction movement is felt at around 20-40 degrees 
of knee flexion. The pivot shift is graded as per the International Knee 
Documentation Committee (IKDC) Knee Ligament Rating guidelines as either equal 
(grade 0), a + glide (grade 1), a ++ clunk (grade 2) or +++ gross reduction (grade 
3).84 
The pivot shift assessment will be repeated at 3, 6, 12 and 24 months using the 
Pivot App. Three yellow circular stickers will be placed on the lateral side of the 
knee.  One is placed over the lateral epicondyle, a second on Gerdy’s tubercle on 
the tibia, and a third placed 3 cm directly posterior to the second, in close proximity 
to the fibula head making a triangle on the lateral side of the knee (Figure x).  A 
standardized pivot shift will be performed on both the operative and contralateral 
non-operative limb measured using the tablet and Pivot App. 
• Assessment of donor site morbidity: determined by the presence of anterior kneeling 
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pain will be assessed by asking the participant to rate his/her pain using an 11-point 
numeric rating scale while they kneel on a hard floor. Sensory disturbance will be 
assessed via light touch to regions around the graft skin incision and anterolateral 
tibia and will be rated as absent, mild, moderate or severe.  
In the event of an unscheduled patient visit, the subject will undergo safety screening by 
completing the clinical assessment. Depending on the reason for the visit, the 
subject may be asked to have a radiograph or other standard of care tests. All 
adverse events reported by the subject or observed by the investigator will be 
documented and reported. Aside from adverse events, information gathered at these 
unscheduled visits will not be included in the statistical analysis. 
 
Research Activities at Clinical Follow-Up Appointments 
• Completion of Patient Reported Outcome Measures: At each standard post-
operative clinical visit (6 weeks, 3, 6, 12, and 24 months), participants will complete 
the patient reported outcome measures as described in Section 4. 
• Muscle strength: To assess quadriceps and hamstring strength (bilaterally) at 6, 12 
and 24 months, we will use a computerized isokinetic dynamometer using methods 
previously shown to be reliable and valid. Briefly, the patient will wear a tubigrip 
sleeve on the operative limb to conceal group allocation. Isokinetic measurements 
will be performed at 90 degrees/sec. For sites without a computerized isokinetic 
dynamometer a crane scale will be used to measure isometric quadriceps and 
hamstring strength as described in section 4.2.3.   
• Functional Hop Series: At the 6, 12- and 24-month time points, participants will 
complete for hop tests as a research activity. The four hop tests mimic the demands 
of high-level sports, focusing on hopping on one leg for maximal distance while 
completing a stable landing and a test for maximal speed. These tests have been 
used to classify patients after ACL injury and measure functional recovery and 
determine readiness for return to sport after ACL reconstruction. The contralateral 
limb will be used as a within subject control, with symmetrical performance 
identifying satisfactory management. The four hop tests include the: 1) single hop for 

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distance; 2) straight triple hop for distance; 3) triple cross-over hop for distance in 
which the subject crosses over a 15 cm wide strip with each successive hop and 4) 
timed hop in which the subjects hops 6 m as fast as possible. Each subject will first 
perform 2 practice trials followed by 2 trials which will be averaged to create the hop 
test score for that limb. For each test, the results for the ACL-reconstructed leg will 
be expressed as a percentage of the contralateral normal leg to represent the limb 
symmetry index.  The hop tests will be administered by a trained tester (physical 
therapist, athletic trainer, kinesiologist, etc.) who is blind to the operative procedures 
via a tubigrip worn over the patient’s operative knee.  
• Drop Vertical Jump (DVJ): At the 6 and 12-month research visits, participants will 
complete a DVJ test as a research activity. The DVJ will be assessed on all 
participants using the Microsoft Kinect V2 and ACL-Gold software to measure frontal 
plane kinematics.  Dynamic valgus of the lower extremity is operationally defined as 
the ratio of the distance between the knees to the distance between the ankles.  To 
perform the DVJ, participants will stand on a box approximately 30 cm in height with 
the balls of each foot off the edge of the box. A Microsoft Kinect V2 sensor is placed 
3.4 meter away from the box, mounted on a 1 meter high tripod. The Kinect sensor 
is connected to a Windows based computer with the ACL-Gold software. The 
participant drops off the box, landing on both feet and then performs a maximum 
vertical jump as quickly as possible, landing in the same spot as the initial landing. 
The participant then takes a few steps forward, which terminates the automated data 
collection.  The results are then automatically populated in a results screen in the 
system.  The participant will perform 3 DVJs with the average angular measurement 
of dynamic valgus of the lower extremity calculated. 
• Standing Flexion Radiograph: Participants will undergo a standing flexion radiograph 
of the knee at 24 months to assess lateral compartment joint space narrowing by a 
central reader blind to surgical allocation. At the University of Pittsburgh, University 
of Virginia, University of British Columbia, McMaster University, PanAm Clinic, Oslo 
University Hospital, Sahlgrenska Institute and University Hospitals Coventry this is 
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procedure. Female participants may be given a urine pregnancy test as per standard 
of care. Any determination of pregnancy will exclude the participant from this 
research activity. 
 
Assessment of Outcomes 
The primary outcome is ACL clinical failure which will be a composite of rotational laxity 
defined as mild asymptomatic pivot shift (grade1) detected at two or more follow-up 
visits or moderate or severe (grade 2 or 3) asymmetric pivot shift at any visit, or graft 
rupture.  Individuals who experience a graft failure that results in revision ACLR will be 
asked to complete a healthcare utilization diary at the 2-year follow-up. The healthcare 
utilization diary will ask the participant to describe any direct costs (e.g. surgeries, 
number of rehabilitation sessions attended) and potential indirect costs (e.g. time 
missed from work). 
Secondary outcome measures will include PROs that assess symptoms, activity, 
participation and QOL, measures of impaired range of motion and muscle function 
(quadriceps & hamstring strength), performance-based measures of physical function 
(hop tests, DVJ), return to pre-injury sports, adverse outcomes, intervention-related 
donor site morbidity and complications. Complications include adverse events, donor 
site morbidity (kneeling pain, graft harvest site sensory disturbance), and lateral 
compartment joint space narrowing on standing flexion AP radiographs. 
 
Subject Payment 
Subjects will be compensated for participation in this study. The participating clinical 
sites will be responsible for payment of subjects enrolled at their site.  All subject 
payments will be processed by each site.  
Subjects who complete all research related activities, including isokinetic testing, will 
receive up to $290. 
Subject payment will be prorated as follows: 
• $25 for providing informed consent and completion of screening procedures. 

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• $25 for completion of all screening/baseline data collection forms. 
• $20 for completion of 6-week patient-reported outcome forms. 
• $20 for completion of 12-week patient-reported outcome forms. 
• $25 for completion of 6-month research visit that includes administration of PROs 
and performance of functional tests (hop tests and drop vertical jump tests). 
• $25 for completion of 6-month isokinetic strength testing of the quadriceps and 
hamstrings. 
• $25 for completion of 12-month research visit that includes administration of 
PROs and performance of functional tests (hop tests and drop vertical jump 
tests). 
• $25 for completion of 12-month isokinetic strength testing of the quadriceps and 
hamstrings. 
• $25 for completion of 24-month research visit that includes administration of 
PROs and performance of functional tests (hop tests and drop vertical jump 
tests). 
• $25 for completion of 24-month isokinetic strength testing of the quadriceps and 
hamstrings. 
• $50 incentive payment for completing the 6, 12 and 24-month research visits (all 
3 visits must be completed to qualify for incentive payment). 
 

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9 POTENTIAL RISKS AND BENEFITS 
Participants in this study will undergo ACL reconstruction surgery as part of their 
standard of care treatment. The surgery will be performed by surgeons who are 
experienced in reconstructing structures of the knee. The risks associated with the 
study including the risks of surgery, radiation exposure and temporary pain are no 
greater what would be expected if the individual did not participate in the study because 
the surgery, radiographs and clinical tests like the pivot shift test and measurement of 
range of motion are part of routine care for patients undergoing an ACLR. 
 
Potential Risks Associated with Study Interventions 
• Risks of Surgery: All subjects who agree to participate in this study have already 
elected to undergo ACL reconstruction. The risks associated with this surgery 
include complications related to anesthesia and those related specifically to the 
operation. Risks associated with an anesthesia include cerebrovascular accident, 
cardiac arrest, and death, all of which are extremely rare and not increased by 
participating in this study. 
• The expected effects after ACL reconstruction include temporary pain, swelling, 
limited range of motion, muscle atrophy and limited function. Adverse events related 
to ACL reconstruction include loss of motion/arthrofibrosis (5%), suture abscess, 
infection (<1%), nerve injury or paralysis (<0.5%), major vascular injury (<0.5%), 
deep vein thrombosis (<0.1%), pulmonary embolism (<0.1%) and graft failure (10-
15%). Harvest of the bone block (BPTB or QT) may result in a patellar fracture; 
however, this risk is rare (less than 1 in 100 cases). Because all subjects would be 
undergoing surgery regardless of whether or not they participate in this study, the 
risks associated with the surgery itself are no greater than the risks had the subject 
not participated in this study. 
• Risk of Autograft Harvest with Bone Block: The risk of patellar fracture associated 
with autograft harvest is up to 1.8% for BPTB, and up to 8.8 % for QT. Previous 
reports indicate that for QT autograft, about 5% of the patellar fracture cases are 
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• Risk of Donor Site Morbidity: For each procedure, there is a risk of pain or 
complications associated with harvesting the required tissue. For a bone patellar 
tendon bone (BPTB) autograft, tissue is harvested from the tendon that attaches the 
patella to the tibial tubercle. Harvesting this tendon can cause anterior knee pain or 
kneeling pain (10%). For a quadriceps tendon (QT) autograft, tissue is taken from 
the quadriceps. Harvesting this tendon can cause discomfort at the insertion to the 
patella as well as risk of patella fracture if a bone block is harvested. For both grafts, 
a screw is used to attach the graft to the tibia, which can cause some local 
discomfort (10%). For the LET, tissue is taken from the iliotibial band (ITB). The ITB 
is an important lateral knee structure responsible for maintaining coronal plane and 
rotational stability when weight bearing, thus it is possible that the patient may 
experience some discomfort or tightness following graft harvest. For this procedure, 
the graft is left attached to the tibia at Gerdy’s tubercle and reattached to the femur 
with a staple. Some patients complain of pain over the hardware used for the LET 
procedure (<5%). 
 
Potential Risks Associated with Study Tests 
• Risk of Radiation Exposure: Evidence of OA will be evaluated based on joint space 
narrowing on standing flexion AP radiographs obtained at screening/baseline and 2 
years after surgery as per usual clinical care.  For those sites at which 2-year 
radiographs are not standard of care, a research standing flexion AP radiographs 
will be obtained at the 24-month follow-up visit.  The x-ray dose delivered as part of 
this study is well within recommended guidelines and poses very low risk to the 
subjects.  
• Risk of Temporary Pain and/or Muscle Soreness: Some subjects may experience a 
temporary increase in pain during the pivot shift test to measure rotational laxity or 
during measurement of passive knee extension and active assisted knee flexion.  
However, this pain is expected to be short-lived, if it occurs at all. Further, the pivot 
shift test and measurement of range of motion are routinely performed as part of the 
standard of care for patients following ACLR. Therefore, the risks associated with 

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these measurements are no greater than what would be expected if the individual 
did not participate in the study.  
• Risks Associated with Isokinetic Measures of Impaired Quadriceps and Hamstring 
Strength: Isokinetic measurement of quadriceps and hamstring strength may be 
associated with knee pain and swelling and muscle soreness for 24 to 48 hours after 
testing.  This risk is no different than the risk of standard of care during rehabilitation 
treatment.   
• Risk of Injury to the Lower Extremity: The performance-based measures of physical 
function include a series of hop tests and the drop vertical jump (DVJ) test. There is 
a rare (less than 1%) risk of a temporary increase in pain or injury to the knee or 
other region of the lower extremity during these activities. However, these activities 
are routinely performed as part of rehabilitation beginning 4 to 6 months after 
surgery. Additionally, based on this study’s eligibility criteria, individuals included in 
this study will be accustomed to performing activities that require jumping and 
landing on one leg and are expected to be able to perform these activities after 
surgery and rehabilitation. 
• Risk of Falling and Re-Injury to the Knee: The performance-based measures of 
physical function may be associated with an increased risk of falling and/or re-injury 
to the ACL. However, these measures will not be performed until at least 6 months 
after the surgical procedure and these risks are not greater than the ones 
encountered with typical rehabilitation activities or with participation in sports. 
 
Potential Risks Associated with Privacy and Confidentiality 
• Hard Copy Case Report Forms: This study will collect data from or about the 
participant using paper-based forms. These paper-based forms will only include a 
participant’s unique database ID number. It will not include the participant’s name. 
The file that links the participant’s name with the unique database ID number is 
stored separate from the study data. All paper documents are kept in a locked filing 
cabinet in a locked room that is accessible only to individuals of the research team.   

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• Electronic data management: The study data is managed by a company called 
EmPower Health Research. All data is protected by a username and password. Data 
travels in a scrambled format (SSL) to an encrypted server that is secured by a 
professional company with extremely high standards of physical and virtual security. 
However, even with this high level of security, there is always a remote chance that 
study data could be accessed or “hacked”. The collection of sensitive information 
from the subjects is limited to the amount necessary to achieve the aims of the 
research. 
 
Potential Benefits 
Participants in this study may benefit from being followed more closely than usual 
clinical practice in terms of the effort research personnel will put into ensuring that 
participants complete follow-up visits and with respect to the battery of tests that are not 
formally part of standard care (e.g. strength, hop and DVJ tests). This may mean more 
timely identification and treatment of any complications (e.g., graft failure, meniscal 
pathology or hardware-related discomfort) associated with ACLR or LET.  
Because all subjects participating in this study would be undergoing surgery and 
standard of care follow-up regardless of whether they participate in this study, the 
associated risks of surgery, ACLR or rehabilitation are no greater than the risks had the 
subject not participated in this study. 
It is possible that there will be benefits to the medical and research community as a 
result of this study. Specifically, the results of this study may lead to improved surgical 
treatment of an ACL rupture, resulting in a reduced risk for re-injury which would reduce 
the number of individuals undergoing revision ACLR and the associated decreased 
QOL and socioeconomic burden that occurs because of ongoing knee instability and the 
increased risk for post-traumatic knee osteoarthritis. 

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10 ASSESSMENT OF SAFETY 
 
Definition of Adverse Events, Serious Adverse Events and 
Unanticipated Problems 
An adverse event (AE) is any untoward medical occurrence during a subject’s 
participation in the study that may or may not be related to the research procedures.  
Adverse events will include any new event not present during the pre-intervention 
period or events present during the pre-intervention period that have increased in 
severity. 
A serious adverse event (SAE) is an event that results in death, is life-threatening, 
requires or prolongs hospitalization, results in persistent or significant disability, 
incapacity, congenital anomaly or birth defect. An important medical event that is not 
life-threatening, does not result in death or require hospitalization may be considered a 
SAE when, based upon appropriate medical judgment, it may jeopardize the subject 
and require medical or surgical intervention to prevent one of the aforementioned 
outcomes. 
The Office for Human Research Protections (OHRP) and the IRB of Record consider 
unanticipated problems (UPs) that involve risks to subjects or others to be any incident, 
experience, or outcome that meets all of the following criteria: 
• Unexpected in terms of nature, severity, or frequency given the research procedures 
that are described in the IRB-approved research protocol and informed consent 
document; and the characteristics of the patient population being studied; 
• Related or possibly related to participation in the research (i.e., there is a reasonable 
possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and  
• Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized.  

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Based on the above definition, only a subset of AEs would be characterized as UPs 
involving risks to subjects or others. There are other types of incidents, experiences, 
and outcomes that are not considered AEs, but are characterized as UPs (e.g., breach 
of confidentiality or other incidents involving social or economic harm). 
 
Reportable Events 
The web-based data management software hosted by EmPower Health Research (Data 
Coordinating Center, DCC; www.secure.empowerhealthresearch.ca) will be responsible 
for the electronic monitoring of the quality of the data, generating missing data reports 
and creating queries to clarify nonsensical data. 
The site Clinical Research Assistant (CRA) will document withdrawals and AEs, SAEs 
or UPs into the electronic database within 48 hours of learning of the event. To do so 
the site CRA will enter the information pertaining to the event into the EmPower data 
management system by completing AE Forms and follow-up CRFs (Figure 4).  
When SAEs and UPs are reported, the DCC will automatically notify the site PI and 
CRA, KAI, and DCC/CCC Team by email notification.  The Clinical Coordinating Center 
(CCC) will review the event report form and follow-up with the CRAs at each site to 
ensure queries are resolved in a timely fashion and determine whether the event should 
be reported to the IRB of Record.  The CCC will notify KAI within 48 hours of the PI 
receiving notification of the event and KAI will notify NIAMS and the DSMB. The CCC 
will provide a report that includes a description of the event, as well as the investigator’s 
assessment of expectedness, relatedness, and other relevant information. The CCC will 
report any actions taken. 
. The timeline for reporting UPs to the IRB of Record is as follows: 
- 
All UPs that are SAEs will be reported within 24 hours from the time when the 
study team member learns about the event. 
- 
All UPs that are AEs will be reported within 5 working days from the time when 
the study team member learns about the event. 
- 
All other UPs will be reported within 10 working days form the time when the 
study team member learns about the event. 

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As described in Figure 4, all AEs will be presented to the PIs during the weekly research 
team meetings unless noted that the AE is also an UP. The AEs will be reviewed 
internally by the study team at the CCC and DCC on a weekly basis. 
A summary of AEs will be sent to members of the  External Adverse Event Adjudication 
Committee (EAEAC) every 2 months, with a convened meeting twice annually. A 
summary of AEs will be included in the biannual report to the DSMB. The site PI will 
determine the severity of AEs, SAEs and UPs and their relatedness to the study 
intervention, which will then be confirmed by the EAEAC. The EAEAC will provide an 
independent, external and systematic review of all participants excluded at the time of 
surgery as well as all adverse events reported during the conduct of the trial. The 
EAEAC will independently review the documentation of AEs, SAEs and UPs in terms of 
their classification, severity and relatedness to study procedures. The members of the 
EAEAC will be blinded to treatment allocation to ensure the committee’s 
recommendations are unbiased. 
The EAEAC will convene for a meeting at least twice annually to discuss the reported 
events approximately two months prior to the planned DSMB Meetings or as frequently 
as every 2 months to resolve disagreements Study participants will be identified by a 
study identification number only in all event reports to ensure participant confidentiality. 
In addition to the EAEAC, the ESC will monitor AEs in a blinded manner on a monthly 
basis. 
The PI will ensure participants’ safety by complying with reportable event timelines 
described above to the IRB of Record, the NIAMS, and the Data and Safety Monitoring 
Board (DSMB). 
The PI will record all reportable events with start dates occurring any time after informed 
consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day 
of study participation.  At each clinical visit and through the electronic surveys, the 
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related event since last contact.  Events will be followed for outcome information until 
resolution or stabilization. 
All AEs, regardless of their relatedness to the study intervention, will be recorded on the 
electronic AE form.  Hard coded checkboxes will be used when recording and 
classifying AEs. This standardization will allow sorting and grouping of like events, 
which will facilitate consistent documentation across all 21 sites as well as the 
calculation of the incidence of each AE. 
The data elements that will be recorded on the AE form include event term, event 
severity (mild, moderate, severe, life-threatening/disabling or death), start and end date, 
relatedness to study procedures (unrelated, unlikely, possible, probable or definite), 
action taken with study procedures (none, study procedure interrupted, discontinued or 
modified), other action taken (none, treatment given, discontinued from study or 
hospitalization), event status (recovered/resolved, resolved with sequelae, 
recovering/resolving, not recovered/resolved, fatal, unknown or lost to follow-up), and 
whether the event was an SAE. 
 
Figure 4. Flow Chart of Internal and External Adjudication of AEs 
 

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11 ETHICS/PROTECTION OF HUMAN SUBJECTS 
 
Ethical Standard 
The Principal Investigators will ensure that this study is conducted in full conformity with 
the principles set forth in The Belmont Report: Ethical Principles and Guidelines for the 
Protection of Human Subjects of Research, as drafted by the US National Commission 
for the Protection of Human Subjects of Biomedical and Behavioral Research (April 18, 
1979) and codified in 45 CFR Part 46 and/or the ICH E6 or another country’s ethical 
policy statement, whichever provides the most protection to human subjects. 
 
Institutional/Ethics Review Board 
The University of Pittsburgh Institutional Review Board (IRB) will serve as the IRB of 
Record for all clinical research sites in the US. To facilitate prompt IRB review and 
approval, the University of Pittsburgh will utilize the SMART IRB process to establish 
the reliance agreement with the other US clinical research sites.  A similar process will 
take place for the Canadian sites, as sites under the same province will be submitted 
with one regulatory ethics board serving as the regulatory board of record (i.e. Clinical 
Trials Ontario will serve as the regulatory ethics board whose approval applies to any 
site located in Ontario, Canada). For the Canadian sites outside of Ontario, the study 
protocol will be submitted to local ethics review board/institution for review and 
approval, as per their institutional requirements, prior to initiation of any study 
procedures. 
For the European sites, the study protocol will be submitted to local ethics review 
board/institution for review and approval, as per their institutional requirements, prior to 
initiation of any study procedures. 
 
Informed Consent Process 
For sites using traditional randomization, surgeons will describe the study to eligible 
patients including foreseeable risks. If interested, the CRA will provide the patient with 
the IRB approved consent form, further describe the study, including that randomization 

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to graft type and the possible addition of an LET will occur in the operating room, the 
required time commitments in terms of follow-up visits, and provide the opportunity for 
the patient to ask questions. If the patient is willing to participate in the study, prior to 
obtaining signature the CRA will quiz the participant by asking a series of 
comprehension questions to determine the participants comprehension of the 
information that was discussed.  Once the participant understands their commitment 
s/he will sign and date the consent form prior to participating in any research-related 
activities. The consent form will also signed be and dated by the investigator or their 
delegate who is responsible for obtaining informed consent. 
For sites using expertise-based randomization, patients referred to partnered surgeons 
will first meet with an independent clinician who will determine eligibility. Eligible patients 
will have the study described to them, including the random allocation to an expert 
surgeon and foreseeable risks of each procedure. If interested, the RC will provide the 
IRB approved consent form, further describe the study, that randomization to LET (or 
not) will occur in the operating room, the required time commitments in terms of follow-
up visits, and provide the opportunity for the patient to ask questions. If the patient is 
willing to participate in the study, s/he will sign and date the consent form prior to 
participating in any research-related activities. The consent form will also be signed and 
dated by the investigator or their delegate who is responsible for obtaining informed 
consent. 
For potential subjects that are younger than 18 years of age and depending on the legal 
age of consent as defined by the location of the site, the study will be explained to both 
the child and the child’s parent or legal authorized representative. If the child is willing to 
participate in the study, permission from the child’s parent or legal authorized guardian 
will be sought and documented on the informed consent form. Additionally, the child will 
be required to provide written assent to participate in the study. If the child turns 18 
while enrolled in the study, they will sign the Consent for Continued Research 
Participation. This consent is an addendum form to the participant’s original informed 
consent form. 

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All consent forms and study discussion will be presented in understandable language.  
 
Subject Confidentiality 
Participant confidentiality is strictly held in trust by the investigators, study staff, and the 
sponsor(s) and their agents.  This confidentiality is extended to cover any study 
information related to the participants. 
The study protocol, documentation, data, and all other information generated will be 
held in strict confidence.  No information concerning the study or data will be released to 
any unauthorized third party without prior written approval of the sponsor. 
Only authorized representatives of the sponsor may inspect all study documents and 
records required to be maintained by the investigator, including but not limited to, 
medical records (office, clinic, or hospital) for the study participants.  The clinical study 
site will permit access to such records. 
To ensure that the confidentiality of subject records is maintained, records associated 
with subject participation in this study will be indicated by a study identification number. 
Information linking these case numbers with subject identity will be accessible only to 
the investigators and their research team and will be stored in a locked file.  Any data or 
participant level information that is submitted for review to the DSMB, University of 
Pittsburgh Office of Research Conduct and Compliance, and the regulatory review 
boards, will be linked only to the participant’s case number and not the personal identity 
of the subject. 

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12 STUDY OVERSIGHT 
 
Composition of the Data and Safety Monitoring Board 
The DSMB will be created to review and monitor the safety of the study and act in an 
advisory capacity to the NIAMS. Prior to the start of recruitment, the DSMB will review 
the research protocol, informed consent documents and plans for data and safety 
monitoring and, if acceptable, approve the study to initiate enrollment. Afterwards, the 
DSMB will meet at least twice annually to monitor and evaluate the progress of the trial; 
consider factors external to the study that may have an impact on the safety of the 
participants or the ethics of the trial; review clinical research site performance; protect 
safety of study participants; report on safety and progress of trial; consider risk-benefit 
ratios; monitor confidentiality of the trial data; and make recommendations to the 
Principal Investigators and the NIAMS regarding  continuation, termination or other 
modifications of the trial. An emergency meeting of the DSMB may be called if there are 
any interim concerns. The DSMB Chair will write a report after each meeting, 
summarizing the study status and outlining any concerns. DSMB members will include 
experts in orthopaedic surgery, clinical epidemiology, and biostatistics. 
 
Study Committees 
The study will be governed by an ESC and five subcommittees. Each subcommittee will 
consist of investigators or individuals associated with the STABILITY 2 Trial, with the 
exception of the External Adverse Events Adjudication Committee. This external 
committee will consist of several qualified professionals who are not investigators or 
otherwise associated with STABILITY 2 Trial. 
Executive Steering Committee (ESC) 
The ESC will consist of James Irrgang (PI), Alan Getgood (co-PI), Volker Musahl (Co-
PI), Dianne Bryant (Co-PI, Director of DCC), Trevor Birmingham (Co-I), Alexandra Gil 
(Co-I and QCL), plus three additional surgeons to represent US, Canadian and 
European sites. The role of the ESC is to provide oversight of the trial. The ESC will 

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define the vision and the scientific goals of the STABILITY 2 Trial. Additionally, the ESC 
will review and approve the final study protocol and any proposed future modifications. 
Throughout the trial, the ESC will monitor the study progress including recruitment, 
retention, and site compliance with study procedures. The ESC will resolve any conflicts 
that arise among investigators as well as have the ultimate responsibility for terminating 
the trial. The ESC will review and issue final approval or recommend modification for all 
subcommittee decisions. The ESC will meet monthly via conference call. 
Publications and Ancillary Studies Committee (PASC) 
The PASC will consist of Alan Getgood (Chair), Volker Musahl (Co-Chair), James 
Irrgang (Ex Officio), Dianne Bryant (Ex Officio), Jacquelyn Marsh (Co-I, health 
economist), plus three additional surgeons to represent US, Canadian and European 
sites. The PASC has established the policies and procedures for assigning working 
groups and approving STABILITY 2 Trial-associated ancillary studies, secondary 
analyses of existing data and abstracts, presentations, and publications prior to their 
submission for dissemination. The PASC has also established guidelines for authorship 
for investigators following the guidelines specified by the International Committee of 
Medical Journal Editors85 for authors that have contributed to the scientific design and 
merit of the study. The investigators will pursue the publication of the results as soon as 
possible after the conclusion of the study. Each manuscript will include named authors 
and a study group name. Named authorship will be determined prior to writing the 
manuscript and will be based on the relative scientific contributions of the PIs and key 
personnel. All other participants will be listed under the group name, STABILITY 2 
Study Group. The PI will attempt to resolve any conflicts or disagreements among 
authors regarding publication of the results. If they cannot reach a mutually agreeable 
resolution, the procedures for conflict resolution as described in the Multi-Principal 
Investigator Leadership Plan will be followed.   
 
 

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Rehabilitation Committee 
The Rehabilitation Committee consists of several investigators and others rehabilitation 
professionals associated with the trial including James Irrgang (Chair), Trevor 
Birmingham (Co-Chair), Andrew Sprague (Co-I), Volker Musahl (Ex Officio), Alan 
Getgood (Ex Officio) plus additional three surgeons to represent US, Canadian and 
European sites. The Rehabilitation Committee has established the rehabilitation 
guidelines and protocols for subjects enrolled in the trial. The committee will ensure the 
training and standardization of the rehabilitation procedures at all study sites through 
the development of training materials and learning modules. The committee will also 
create materials for home exercise programs for participants. Throughout the trial, the 
Rehabilitation Committee will create procedures to monitor and maximize compliance 
with rehabilitation procedures at all sites. 
Quality Control Committee 
The Quality Control Committee will include of Alexandra Gil (Chair, Co-I and QCL), 
Dianne Bryant (Co-Chair), James Irrgang (Ex Officio), Alan Getgood (Ex Officio), Volker 
Musahl (Ex Officio), Stacey Wanlin (PC), plus an additional three surgeons to represent 
US, Canadian and European sites. The Quality Control Committee will review and affirm 
the quality of the conduct of the trial including implementation of the surgical 
interventions as randomized. The committee will oversee implementation of the study 
protocol and monitor the study data for completion of study procedures and for missing 
data. The committee will review the trial on an ongoing basis to review loss to follow-up 
and PDs in aggregate as well as by individual site. Additionally, the Quality Control 
Committee will be responsible for the oversight of site monitoring visits. 
Recruitment Committee 
The Recruitment Committee will consist of Volker Musahl (Chair), Alan Getgood (Co-
Chair), Dianne Bryant (Ex Officio), James Irrgang (Ex Officio) and at least three 
additional investigators representing the Canadian, US and European sites. The 

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Recruitment Committee will establish a plan and monitor recruitment throughout the 
duration of the trial. The committee will create recruitment materials to be used at the 
sites. Additionally, if a site struggles to meet recruitment targets, the committee will 
evaluate site factors and either provide recommendations to improve recruitment rates 
or terminate the site’s participation in the study. 
External Adverse Events Adjudication Committee (EAEAC) 
The EAEAC will consist of several qualified orthopaedic surgeons who are not 
associated with the STABILITY 2 Trial. They will provide an independent external and 
systematic review of all participants excluded at the time of surgery as well as all 
adverse events reported during the conduct of the trial. In addition, the committee will 
assign each adverse event a level of severity and will determine the relationship to the 
study intervention. Use of a similar committee in a clinical trial involving spine surgery 
found that more than one-third of the adverse events were reclassified and the majority 
of reclassifications lead to an upgrade in the level of severity or greater relatedness to 
the surgery or device.86 Therefore, we will assemble this committee to mitigate potential 
investigator bias and facilitate an accurate sampling and safety profile for the 
STABILITY 2 Trial. 
 
 

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13 CLINICAL SITE MONITORING PLAN 
The purpose of this Clinical Monitoring Plan (CMP) is to establish guidelines for 
conducting monitoring visits and related tasks to oversee the conduct and safety of the 
STABILITY 2 Trial.  The Clinical Coordinating Center (CCC) at the University of 
Pittsburgh in collaboration with Western University will be responsible for CMP under 
the co-leadership of Dr. Alexandra Gil and Stacey Wanlin, who will serve as Co- 
Investigator and Quality Control Lead (QCL) and Project Coordinator (PC) for this trial 
respectively. Drs. Irrgang (Principal Investigator), Getgood and Musahl (Co-Principal 
Investigators responsible for all aspects of surgery), Bryant (Co-Principal Investigator, 
Director of the Data Coordinating Center [DCC]) and the Project Coordinator from the 
Clinical Coordinating Center will also actively participate and contribute to the CMP.  Dr. 
Gil and the Project Coordinators from the CCC and DCC will serve as the Clinical Trial 
Monitors.   
The intent of the CMP is to ensure compliance with the research protocol, the 
International Conference on Harmonization (ICH) Good Clinical Practice Guidelines, 
national and local regulations, and institutional policies across all sites. The focus areas 
for the CMP include: 1) site assessment and staff training; 2) human subjects’ 
protection; 3) protocol compliance; 4) regulatory compliance; 5) quality assurance; 6) 
adverse event reporting; and 7) integrity of research data.  Implementation of the CMP 
will include regular communication with Clinical Research Assistants (CRA) (e.g. 
biweekly phone calls) as well as continuous year-round remote monitoring, such as 
review of electronic records using web-based software hosted by EmPower Health 
Research (www.secure.empowerhealthresearch.ca). 
 
Clinical Monitoring Communication Plan 
Communications for each monitoring visit will include a letter confirming the date and 
time of the site monitoring visit, agenda for the monitoring visit, post-monitoring visit 
debriefing, and a follow-up letter and/or visit report and Action Item Tracker.  All 

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documents will be sent via email to the study PI, Co-PIs for surgery, Co-PI and Director 
of the DCC, PC for the DCC, Co-I for rehabilitation as well as the site PI and CRA. 
 
Scheduling of Visits 
The Quality Control Lead or her designee will work with the site PI and CRA to schedule 
the remote monitoring visits. The study PI, Co-PIs for surgery, Co-PI and Director of the 
DCC, and PC for the DCC will be apprised of monitoring visits schedule. Prior to the 
visit, the site PI and CRA will receive a visit confirmation letter and agenda. The site PI 
and CRA will be expected to ensure they have the remote meeting software (Skype for 
Business, Go To Meeting or ZOOM) installed and determine that it is compatible with 
their computer system prior to the meeting time. The Clinical Trial Monitor will be 
available at the conclusion of the monitoring visit to discuss findings and answer 
questions from the study staff. The site PI and CRA are also expected to be available 
for a wrap-up meeting at the conclusion of the visit.  These expectations will be 
explained in the monitoring visit confirmation letter. 
 
Types of Visits and Monitoring Activities 
The CMP will include four types of monitoring visits for this study including a Site 
Initiation Visit, Interim Visits, For-Cause Visits and Study Close-Out Visit.  The CMP will 
also include ongoing monitoring of research records and documents. Site visits will be 
conducted remotely using Skype for Business, Go To Meeting or ZOOM.   
 Site Initiation Visit  
The site initiation visit will take place prior to site activation once IRB approval and all 
subcontracts and agreements are in place. Activities related to the site initiation visit will 
include:  
• Confirming the preparedness of the site to execute the research protocol; 
• Ensuring satisfactory facilities to support conduct of the study;  
• Clarifying applicable regulations and requirements as they relate to the protocol; 

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• Reviewing the process for implementing the protocol at the site and;  
• Conducting any necessary training prior to initiating site enrollment.  
Prior to the site initiation visit, the QCL and PC will develop an agenda and follow the 
communication plan to ensure that all relevant parties are informed of the meeting date 
and time commitment in advance. The agenda will contain a list of topics in the order of 
presentation, the expected duration of each discussion item and the name of individual 
who will lead the discussion.   
The following pre-requisites should be completed prior to the site initiation visit:   
• Protocol and consent have been reviewed and approved by the DSMB, site local 
regulatory review board, and IRB of Record;   
• All necessary site staff have been identified; and  
• All staff have completed training on the use of the EmPower database. 
The following list of activities will be used as a starting point for the agenda for the Site 
Initiation Visit: 
• Protocol Overview 
• Type of study 
• Study objectives 
• Enrollment goals 
• Recruitment plans 
• Informed consent discussion  
• Key inclusion/exclusion criteria 
• Completion of screening and eligibility scenarios 
• Study visit schedule/schedule of events 
• Study procedures 
• Safety: Definitions, Collection, and Reporting, Review of AEs, SAEs, and UPs  
• Completion of Reportable Events Scenarios 
• Review of timeline related to Reportable Events 

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• Queries resulting from the above 
• Site-specific study procedures 
• Review of site-specific study implementation 
• Review, creation and retention of source documentation 
• Review of procedures for data entry 
• Review of action items for reportable events 
• Discuss site-specific communication plan with participants, physical therapists, 
site PI, local regulatory review board and EmPower data management center.  
• Clinical monitoring 
o Contacts 
o Site responsibilities 
o Frequency 
o Close out procedures 
• Site Essential Documents File Review 
• Structure of the study binder as well as essential documents to include:  
o Regulatory review board approved documents;  
o Protocol;  
o Patient handouts; 
o Advertisements; 
o Consent document 
o Document updates 
• Summary/Review of Action Items 
A site can be activated only after all of the requirements on the Site Activation 
Requirements Checklist have been met (Table 2). 
 
 
 

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Table 2. Site Activation Requirements Check List 
Item 
Date 
1. Regulatory Review Board Approval Received for Protocol, Consent 
Form, and Other Applicable Documents  
 
2. Site Essential Document File Approved  
 
3. Study Materials on Site 
 
4. Site Initiation Visit Completed 
• Trained on protocol, study procedures (MOOP), EmPower 
electronic data management system. (Note this requirement 
includes re-training, if site activation is more than 8 weeks after 
the site initiation visit. The re-training will be conducted remotely 
via conference calls/webinars). 
 
5. Action Items from Site Initiation Visit Required for Site Activation 
Completed 
 
6. Study Specific Requirements Met 
 
 
 Interim Visits  
The first interim visit will be conducted remotely for each site after two or three 
participants have been enrolled and followed for three to four months. Subsequent 
interim visits will be conducted remotely annually. The objectives of interim visits are to 
confirm that: 
• The subjects’ rights are being protected;  
• The study is being conducted according to the protocol and applicable 
regulations; 
• Accurate reporting of interventions, subject safety data and study endpoints.  

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In addition, to ensure accuracy and completeness of the data, the QCL or her designee 
will review and match surgical source documentation (paper or electronic) and clinical 
follow-up visits source documentation to the respective Case Report Forms (CRFs). 
After each visit, a debriefing meeting will be conducted with the site PI, CRA and/or 
designee to review the findings and discuss key issues that may require follow up, and 
to share recommendations. This meeting will provide an opportunity for immediate 
dialogue, feedback, clarification and education. These items will also be summarized in 
an Action Item Tracker attached to the monitoring visit documentation. At a mutually 
agreed upon time (no later than four weeks after the interim monitoring visit), the QCL 
or designee and site research staff designee will meet via telephone conference to 
discuss resolved, in process, and pending action items. The need for, and frequency of, 
subsequent meetings will also be discussed. The follow-up letter, final monitoring visit 
report and Action Item Tracker will be sent within three weeks of the conclusion of the 
site visit. 
  For-Cause Visits 
For-Cause Visits will be conducted to address any unanticipated issues that arise that 
require training, remediation or other situations for which the site requires assistance.  
For-Cause Visits will be conducted remotely. 
 Close-Out Visit 
The Close-Out Visit will be conducted to ensure that all study data and other 
documentation is complete and accurate, and that all study records have been 
reconciled. Study closure activities may require several remote visits that will include 
conference calls and communication via email. Close-Out Visits may be conducted at 
study completion or earlier in the case of termination of the site’s participation in the 
study or termination of the study overall as determined by IRB, DSMB NIAMS or ESC. 
Study closeout procedures will begin when the last enrolled subject reaches the 24-
month follow-up time point. Closeout procedures will include: 

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• Verification that study procedures have been completed and all data have 
been collected and entered into EmPower; 
• Verification that all data queries have been resolved; 
• Ongoing maintenance of study records consistent with local and University of 
Pittsburgh policy for retention of research records (whichever is more 
stringent); 
• Maintenance of correspondence, study files and study participant files for 
future audits; 
• Notification of the local IRB and IRB of Record that the study has been 
completed. Once subject enrollment and follow-up is complete, the IRB status 
will be changed to “ongoing for data analysis purposes only”; 
• Preparation of a report summarizing the conduct of the study, which will be 
submitted to the IRB, DSMB and the NIAMS Program Officer; 
• Notification of the participants that the study has been completed; 
• Posting of final results on ClinicalTrials.gov website within one year of 2-year 
follow-up of the final enrolled participant. 
 
Ongoing Site Monitoring and Documents to be Monitored 
Remote monitoring of the site will also be done an ongoing basis.  The documents 
needed to support ongoing remote monitoring of the site will be uploaded to the 
EmPower database. Participant-specific documents (e.g. consent forms, source 
documentation for comparison to CRFs) will be de-identified and entered into separate 
folders for each participant.  Source documentation will be compared to the completed 
CRF of the first 10 patients enrolled in the study to identify any initial problems. 
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interim reports or ongoing data verification at the frequency specified summarized in 
Table 3.  
The ongoing monitoring process will be used to determine whether: 
• Informed consent was obtained and documented in accordance with IRB 
regulations; 
• Information recorded on EmPower forms is complete and accurate; 
• There are omissions in specific data fields; 
• Reasons for missing data are documented and;  
• Participant disposition when withdrawing from the study is accurately 
documented. 
A summary of the findings from the clinical monitoring process will be presented to the 
investigators at their monthly meetings. Corrective action plans will be developed, 
reviewed by PIs and study staff, and implemented as necessary. Ongoing monitoring 
will be performed to ensure resolution of any problems that are identified. Problems 
identified during the monitoring process may trigger a more thorough review, including 
scheduling of a for-cause visit, additional training, or review by the University of 
Pittsburgh Research Education and Compliance Office. PDs discovered in the quality 
review process will be documented and reported to the PIs, IRB, DSMB and the NIAMS 
Program Officer. 
 
 
 
 
 

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Table 3. Research Records and Documents to be Monitored  
Records and Documents to Be Monitored 
 
# 
Records 
Type 
of 
Monitoring 
Frequency 
Site Human Subject Protection Training 
Records  
100% 
Site Initiation Visit 
and Interim Visits 
Annually 
IRB Initial Approval and Annual Renewal 
Letters  
100% 
Site Initiation Visit 
and Interim Visits 
Annually 
Signed Informed Consent Forms 
100% 
Ongoing 
Monthly 
Eligibility Criteria 
100% 
Ongoing 
Monthly 
Surgical Source Documentation vs. CRFs 
100% 
Ongoing 
Quarterly 
Clinical Follow-up Visits Source 
Documentation vs. CRFs 
10% 
Ongoing 
Quarterly 
CRFs or Data Queries 
10% 
Ongoing 
Weekly 
Missed Visits and Missing Data 
100% 
Ongoing  
Monthly 
Documentation and Reporting of AEs, SAEs, 
PDs Documentation 
100% 
Ongoing 
Weekly 
Withdrawals and Dropouts Documentation 
100% 
Interim reports 
Biannually 
Site Regulatory Documents  
100% 
Site Initiation and 
Interim Visits  
Annually 
Close-out Visits 
Event Driven 

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14 STATISTICAL CONSIDERATIONS 
 
Study Hypotheses 
The overall primary objective of this 21-site international randomized trial is to determine 
if graft type (QT, BPTB or HT) with or without a LET will affect the rate of ACL clinical 
failure 2 years after surgery.  Secondary objectives will determine the effects of graft 
type and LET on patient-reported outcomes, performance-based measures of function, 
return to sports, intervention-related donor site morbidity, complications and adverse 
outcomes and cost effectiveness.   
To achieve these objectives, we will randomize 1236 participants with an ACL tear who 
are at high risk of failure to undergo ACL reconstruction with a QT or BPTB with or 
without a LET.  Study data will be combined with data from a prior trial that compared 
ACLR with HT grafts with or without a LET (STABILITY 1).   
 
Aim 1: Determine if graft type (QT, BPTB or HT) with or without a LET affects the rate 
of ACL clinical failure at 2 years after ACLR. ACL clinical failure will be defined by either 
graft rupture, symptomatic instability or persistent rotational laxity (asymmetrical positive 
pivot shift), at 2 years after ACLR. 
Our hypotheses for Aim 1 are: 
• The rate of clinical failure of ACLR performed with a QT, BPTB or HT graft will be 
reduced with the addition of a LET;  
• ACLR with BPTB without LET will result in a lower rate of ACL clinical failure 
compared to ACLR with HT and LET;  
• ACLR with QT without LET will result in a lower rate of ACL clinical failure 
compared to ACLR with HT and LET 
• ACLR with QT and LET will result in a lower rate of ACL clinical failure compared 
to ACLR with BPTB and LET. 
We also hypothesize that females who undergo ACLR and LET will have a lower ACL 
clinical failure rate. 

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Aim 2: Determine if graft type (QT, BPTB or HT) with or without a LET affects patient-
reported symptoms, function and quality of life, performance-based measures of 
function and return-to-sports 2 years after ACLR. 
Aim 3: Determine if graft type (QT, BPTB or HT) with or without a LET affects the rates 
of intervention-related donor site morbidity, complications and adverse outcomes 2 
years after ACLR.  
Aim 4: To determine if a particular graft type (QT, BTPT or HT) with or without addition 
of LET is a more cost-effective approach to ACLR. 
 
Sample Size Considerations for Aim 1 
The absolute risk of ACL clinical failure (as defined by either graft rupture/symptomatic 
instability requiring revision ACLR surgery or persistent rotational laxity as measured by 
an asymmetrical positive pivot shift compared to the contralateral side) is estimated to 
range from 25-35%.40,87,88 We consider a relative reduction in ACL clinical failure rate of 
at least 40% by 24 months after surgery to merit a change in practice (i.e. of sufficient 
magnitude to warrant the additional costs of adding a LET). Since, our primary interest 
is in determining the main effect of graft choice and whether the effect of LET varies by 
graft choice, the focus will be on the following comparisons: 1) HT+LET versus HT 
(already shown by STABILITY 1), 2) BPTB+LET versus BPTB, 3) QT+LET versus QT, 
4) BPTB versus HT+LET, 5) QT versus HT+LET, and 6) BPTP+LET versus QT+LET.  
With 210 patients per group and a type I error rate of 1%, we would have 80% power to 
detect a hazard ratio of 0.56 (i.e.  44% clinical failure risk reduction when comparing the 
LET v no LET condition) assuming the clinical failure rate is 33% (the average rate of 
failure in STABILITY 1). A small type I error rate of 1% was used to reduce the risk of a 
type I error due to the multiple comparisons based on the Bonferroni method to achieve 
an overall type I error rate of 5%. Even if there is an intra-cluster/surgeon correlation 
coefficient (ICC) as large as 0.02, 1) the average number of surgeons per site is 3 given 
the number of surgeons at each site ranges from 1 to 4, and 2) the average number of 
patients per surgeon is 22, we will need 281 patients per group to account for the 

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clustering effect. To reduce the risk of losing precision from patients withdrawn and lost 
to follow-up, an additional 10% of patients will be recruited (attrition was 5% from 
STABILITY 1), for a total of 309 participants per group or 1236 patients total (or 1853 
when STABILITY 1 and STABILITY 2 data are combined).  To appreciate the greatest 
statistical efficiency, each surgeon in a traditional randomization site (17 sites, 49 
surgeons) should recruit approximately 20 patients and each surgeon in an expertise-
based randomization site (3 sites, 6 surgeons) should recruit approximately 36 patients 
(given the ICC for trials using expertise-based randomization is usually slightly larger 
than the ICC for trials using non-expertise based randomization).  
 For Sex-based Research Question 
Preliminary results of STABILITY 1 suggested that HT+LET is superior to HT ACLR 
alone and is associated with an increased odds of failure compared to HT+LET for both 
males (odds ratio (OR) = 2.53, 95% confidence interval (CI) = 1.42, 4.51) and females 
(OR = 1.76, 95% CI = 1.05, 2.96).31 Given these results, and because females tend to 
be quadriceps dominant in their landing biomechanics compared to males, and use of a 
HT graft is currently the most common method of ACLR, we need to understand 
whether harvesting the HT (which may further contribute to quadriceps dominance) 
should ever be a first-line option for females. Thus, STABILITY 2 will compare failure 
between HT+LET and other graft options (BPTB or QT) for males and females 
separately.  
Among the 309 patients per group, we assume half will be female (51.5% of STABILITY 
1 participants were female). Thus, we expect to have 159 females in each of the 
HT+LET, BPTB, and QT groups. Given the failure rate of 29% for females when treated 
with HT+LET (based on the result from STABILITY 1), the minimum detectable OR will 
be 2.1 with a power of 80% at the significance level of 0.05. Given the failure rate of 
21% for males when treated with HT+LET (based on the result from STABILITY 1), we 
will be able to detect an OR of 2.4 with a power of 80% at the significance level of 0.05. 
According to the rule of thumb on magnitudes of effect sizes by Cohen,89 an OR of 2.1 
or 2.4 is considered to be as small (1.5) to medium (3.5) effect size, i.e. with the sample 

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size of 309 (159 females and 150 males) per group, we will have a power of 80% to 
detect a small to medium treatment effect for males and females separately at the 
significance level of 0.05. 
 
Sample Size Considerations for Aim 2 
All participants will complete data for the all PROs, ROM, hop and clinician-rated DVJ 
tests and Marx Activity Rating, however isokinetic testing can only be performed at 13 
sites (approximately 780  patients for this study or 929  including STABILITY 1 patients).  
The isokinetic tests are on a continuous metric and therefore do not require as large a 
sample size as the binary primary outcome.  By recruiting consecutive patients at each 
site, we will maintain a representative sample. In keeping with the planned comparisons 
outlined for the primary outcome, we will have 80% power (type I error of 1%) to detect 
a standardized effect size of 0.28, which is considered small (0.2) to medium (0.5) effect 
size according to Cohen89  for continuous outcomes measured for all participants (300 
per treatment group), which include the hop test, Kinect V2 DVJ test, patient-reported 
measures of symptoms, physical function and quality of life, EQ5D, range of motion, 
and the Marx Activity Rating Scale. For the isokinetic strength test, we only require a 
sample size of 75 per treatment group to have a power of 80% (type I error of 1%) to 
detect a standardized effect of 0.56. Our expected sample size for the isokinetic test 
data is approximately 195 per treatment group (13 sites x 60 participants per site).  
 
Sample Size Considerations for Aim 3 
For the adverse outcomes associated with donor site morbidity (presence of anterior 
kneeling pain and sensory disturbance secondary to graft site skin incision), adverse 
events associated with surgery (intra- and postoperative complications, lateral 
compartment joint space narrowing) and knee re-injury or new injury (graft re-tear, 
contralateral tear, meniscal re-tear, meniscal tear), which are all binary data, and 
measured for every patient, we will have 80% power (type I error of 1%) to detect a 
medium effect size (OR = 3.5) assuming an outcome event rate in ACLR is as low as 
10%. 

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Plan for Data Analysis 
The data collected through this study will be pooled with the data from STABILITY 1 for 
analysis (n=1853). We will provide a descriptive summary of participants in each 
treatment group at each visit using means and standard deviations for normally 
distributed data, median and interquartile range for continuous but not normally 
distributed data, and count and percentage for categorical data. 
 Statistical Analysis for Aim 1 
We will use a mixed-effects logistic regression using the primary composite outcome of 
failure measured over time as the dependent variable to estimate the effects for 
treatment group (HT+LET, HT, BPTB+LET, BPTB, QT+LET, and QT), time, and the 
time by treatment group interaction, with meniscal repair status, age, sex, surgeon (or 
surgeon pair for expertise-based sites) and tibial slope as time-independent covariates 
and contralateral injury, post ACLR meniscus tear/re-tear, ipsilateral limb exposure (in 
hours), time since returning to sport and time since discharge from physical therapy as 
time-dependent covariates and surgeon as a random effect.  Time to return to sport and 
to discharge from physical therapy are considered as covariates in the model since we 
expect that participants who return to sport earlier or cease to attend physical therapy 
earlier are more likely to experience the outcome. Both contralateral injury (yes/no) and 
meniscus tear/re-tear (yes/no) collected at each study visit will be included in the model 
as a time-varying covariate since the occurrence of contralateral injury and meniscus 
tear will alter (i.e. eliminate or reduce) the risk of experiencing graft failure over the next 
few months while the patient recovers. Following sufficient recovery time, the patient will 
resume activities and again be at risk of suffering the primary outcome (graft failure). 
Exposure time will be defined as the total number of hours spent playing sports since 
the surgery. The greater the exposure the greater the risk of graft failure. Since graft 
failure will occur only once during the follow-up period, the outcome data will be treated 
as missing after the failure occurs. Given these data are not missing at random, we will 
use the maximum conditional likelihood approach proposed by Skrondal and Rabe-
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will calculate the odds ratio, 95% confidence intervals, and p values for the six 
prespecified intergroup contrasts and for change in rate of failure within each group over 
time.  
As a second means to evaluate the primary outcome, we will conduct a time-to-event 
analysis to investigate the effects surgical procedures on the hazard of graft failure. The 
“survival” time is defined as the time from randomization to graft failure with data 
censored at the time of loss to follow-up or at the end of the study, whichever occurs 
first. We will use a multivariable Cox frailty model with random intercepts to account for 
site clustering, meniscal repair status, age, sex, surgeon as time-independent 
covariates, and contralateral injury, meniscus tear/re-tear, ipsilateral limb exposure, 
return to sport (yes/no), and discharge from physical therapy (yes/no) as time-
dependent covariates. Within this model, we will calculate the hazard ratio, 95% 
confidence intervals, and p values for the six prespecified between-group contrasts. 
To address the sex-based question, we will repeat the primary analysis for males and 
females separately and provide the odds of failure with a BPTB or QT graft compared to 
an HT+LET graft. 
 Statistical Analysis for Aims 2 and 3 
For secondary outcomes like return-to-activity and donor site adverse events, we will 
conduct an analysis similar to that described for the primary research question, as both 
are binary outcomes measured at ≥3 time points. For each continuous secondary 
outcome that is measured at ≥3 time points (PROs, hop test, return to activity measured 
using the Marx Activity Rating Scale, EQ5D, range of motion, and strength), linear 
mixed-effects models for measures will be used to obtain the effects for the six 
prespecified intergroup contrasts and for change of the outcome measure over time, 
with adjustment of the same covariates and covariance matrix as in the primary 
analysis.  

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For the evaluation of lateral compartment joint space narrowing, which is a continuous 
outcome measure, we will conduct linear regression where the 24 month measurement 
will serve as the dependent variable, treatment group will serve as an independent 
variable, and adjustment for the lateral compartment joint space at screening/baseline, 
age, sex, meniscal repair status, surgeon, time between surgery and return to sport, 
and time between surgery and final rehabilitation visit as covariates.  
For the Kinect V2 DVJ test, which is the secondary continuous outcome measured at 6 
and 12 months after the surgery, we will run two separate linear regression models with 
treatment groups as the independent variable and adjustment for age, sex, meniscal 
repair status, surgeon, return to sport (yes/no), and discharge from physical therapy 
(yes/no).  
For all linear and linear mixed-model analyses, we will examine distributions of residuals 
and use transformations of the outcome variables to achieve normality when necessary. 
 Statistical Analysis for Aim 4 
Healthcare Resource Use and Unit Costs: 
We will assign the average procedure cost for an ACLR surgery at each participating 
institution with the additional cost of the lateral extra-articular tenodesis for those 
patients randomized to the LET group. The main driver in cost difference is expected to 
be failure of the reconstruction requiring revision. Therefore, in addition to capturing the 
cost of the revision procedure, patients who have a failed ACLR will also be asked to 
complete a healthcare resource use diary to capture additional direct and indirect 
healthcare resources from the time of failure to the end of the study period. This will 
include any emergency room visits, hospitalizations, family doctor, specialist, healthcare 
professional or outpatient clinic visits, tests, procedures, prescription or over-the-counter 
medications and any miscellaneous costs related to their knee. We will also record 
employment status and time-off paid employment, homemaking or volunteer activities, 
for both patients and their caregivers, if applicable. 

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Consistent with recommended guidelines,91 we will incorporate multi-country costing 
and obtain unit cost prices that are jurisdiction specific to account for differences in 
relative or absolute price levels among participating centers. We will also report 
resource use separately from unit costs to increase the transparency of the analysis. 
We will obtain unit costs for surgical procedures using outpatient facility (hospital-based 
or ambulatory surgery center) fees and jurisdiction-specific professional reimbursement 
schedules. Patients will self-report productivity losses, out-of-pocket costs and 
healthcare resource use not covered by government or privately funded healthcare 
plans during the study period. We will use each nation’s average hourly wage to place a 
monetary figure on time off from paid employment, for both patients and their 
caregivers. We will use purchasing over power parity statistics to translate costs to a 
common currency ($USD). We will also report resource use separately from unit costs 
to increase the transparency of the analysis. 
We will use quality-adjusted life years (QALY) as our effectiveness outcome two years 
after surgery. QALYs incorporate both length of life and quality of life into a single 
measure and are the product of a patient’s utility score and the corresponding health 
state duration. Using each participants’ prospectively collected EQ-5D scores, we will 
assign the corresponding utility value according to published valuation sets for each 
participating center’s respective country. 
For our base case analysis, we will estimate the cost-effectiveness of ACLR + LET 
compared to ACLR from a societal perspective that includes all direct and indirect costs. 
We will also conduct sensitivity analyses using a healthcare payer perspective 
incorporating only government funded costs to reflect the cost-effectiveness in publicly 
funded healthcare systems. Presenting our results from both perspectives will enable 
interpretation for knowledge users in both publicly funded and private healthcare 
systems. 
We will report descriptive statistics to summarize country specific cost estimates (mean 
and standard deviation). 

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To analyze the cost-effectiveness data collected alongside multinational trials the 
recommended approach is hierarchical, multilevel modelling.92 Bayesian hierarchical 
models that use both patient and country-level information facilitate between-country 
generalizability of the study findings and allow decision makers in each respective 
country to interpret the results in context. Using a random effects model, we will obtain 
more appropriate estimates of the population average incremental cost effectiveness 
and associated standard errors and location-specific cost-effectiveness estimates to 
explore the between-location variability of the results.93 
We will calculate the incremental cost per QALY and estimate the incremental net 
benefit (INB) of ACLR + LET. To account for clustering among study sites as well as 
potential heterogeneity in costs and treatment effect across countries, we will use a 
random effects multilevel model where treatment group is a fixed effect and the treating 
institution and country are random effects. We will use Bayesian shrinkage estimation to 
derive a pooled, random effects estimate of incremental net benefit across all 
participating sites.94 We will consider ACLR + LET cost-effective if our estimate of INB is 
greater than 0. We will adjust for patient and country-level covariates (sex, age, 
previous or current meniscal excision, time between surgery and return to sport, time 
between surgery and final rehabilitation visit) in our model. To characterize the 
statistical uncertainty around our estimate of INB, we will use an extension of the 
standard net benefit regression framework95 using the hierarchical data to generate 
location-specific net benefit curves, and cost-effectiveness acceptability curves.96 These 
curves represent the probability that the intervention is cost-effective for a given level of 
decision maker maximum willingness to pay for additional unit of outcome. 
 
Handling Missing Data 
For missing data, (missing secondary outcomes or time-dependent covariates), we will 
evaluate whether data are missing completely at random by comparing the available 
data (especially at baseline) for those with and without missing data at follow-up. 
Multiple imputation using full conditional specification method (FCS) (also called the 
multivariate imputation by chained equations), which is widely applied for the arbitrary 

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missing pattern, will be used for imputing the missing data. In particular, FCS logistic 
regression method will be used for imputing binary data and FCS regression method will 
be used for imputing continuous data. We will set the maximum number of iterations as 
20 and generate 25 imputation datasets to ensure reliable inference.97 Complete case 
analysis will also be conducted as a sensitivity analysis to assess the impact of missing 
data on the estimation of intervention effect. For the primary outcome (i.e. graft failure), 
since graft failure will occur only once during the follow-up period, the outcome data will 
be treated as missing after the failure occurs. Given the data are missing not at random, 
we will use the maximum conditional likelihood approach to handle it as described 
above in the analysis for the primary research question. We will also conduct the time-
to-event analysis which does concern itself with data (either observed or missed) after 
the occurrence of graft failure. All the above analyses will be implemented using SAS 
9.4 (SAS Institute Inc., Cary, NC, USA). 

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15 SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
All initial screening/baseline, inclusion/exclusion, pre-operative PROs and baseline 
clinical visit forms will be collected and stored in EmPower Health Research Inc.  After 
randomization occurs, standard of care clinical visits and PROs will be completed 
remotely and managed through scheduled timepoints in EmPower. 
Medical record information that will be accessed for this study includes information 
related to surgical findings and procedures, radiographic findings and the clinical course 
of recovery following surgery including any complications that arise.  Radiographs and 
MRI that are obtained as the standard of care will also be reviewed to determine the 
nature and extent of injury (and healing) to the ligament, tendons, menisci, cartilage, 
nerves, blood vessels and bone. Study specific forms have been developed to collect 
this data and the information will be entered in EmPower. 
Each site CRA will review paper documents (i.e. signed consent forms) monthly and 
ensure the secure storage of the paper forms. All study questionnaires are designed to 
be completed out electronically, however if subjects elect to fill out paper forms, the data 
from the form will be entered by site staff and the paper form will be stored with their 
other paper documents.   
Dr. Bryant will delegate management of the EmPower database to the research staff 
that she supervises, and they will reconcile with each site any data discrepancies 
through routine audits (quarterly) of the database.    
Study staff will maintain appropriate medical and research records for this study, in 
compliance with ICH E6 and regulatory and institutional requirements for the protection 
of confidentiality of subjects.  Study staff will permit authorized representatives of the 
regulatory funding agencies to examine (and when required by applicable law, to copy) 
research records for the purposes of quality assurance reviews, audits, and evaluation 
of the study safety, progress and data validity.   
 

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16 DATA MANAGEMENT PLAN 
All study investigators are responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of all data that are collected and reported for this study.  All 
source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data.  The investigators will maintain adequate case histories of study 
subjects, including accurate case report forms (CRFs), and source documentation. 
 
Methods and Systems for Data Collection 
EmPower Health Research Inc (www.empowerhealthresearch.ca) will be responsible 
for the electronic monitoring of the quality of the data. This software has demonstrated 
compliance with privacy and security standards. To assist the CRA, the database 
automatically sends instructions to participants who wish to enter data directly using 
their own username and password and sends an email to the participant to set up a 
password. 
The EmPower data management software also generates several reports including 
Missing Data, Recruitment and Retention, Participant Tracker, AEs, Withdrawal, PD, 
Queries and Payout reports. 
The Missing Data Report specifies the site, visit, CRF and data elements that are 
missing and can be limited to exclude data that has already been acknowledged as 
missing, where the site is unable to collect that data point. 
The Recruitment and Retention Report provides a high-level report of the number of 
participants who are eligible and consenting, eligible after surgery, randomized, 
withdrawn and complete by site and overall. 
The Participant Tracker Report provides a participant by visit classification of the status 
of each participant’s visit. Participants are sorted by site; each participant is a row, each 
column is a visit. Cells provide each participant’s visit status as complete (all required 
data fields within all forms required for that visit are complete and query free), 

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incomplete, overdue with the visit start and end date provided (a visit is overdue if the 
date falls after the ideal date according to the date of surgery), missed (if a Missed 
Assessment CRF has been submitted to indicate that the site is unable to collect that 
data), or withdrawn. This report is limited by site for research assistants but inclusive of 
all sites for data quality personnel. The report can also be limited to exclude withdrawn 
participants or missed participant or to only include participants whose visit window start 
and end date include today’s date (date of query); features meant to add ease and 
efficiency to data management personnel at the site and DCC. 
The Adverse Event Report lists all AEs by site, by surgeon, and by participant and 
includes the visit within which the event was reported, whether the event was resolved 
within the visit (or not), and the name of the event (e.g. graft rupture, deep infection, 
etc). This report can also be generated to present a tally of each event type across the 
study (e.g. number of graft ruptures, number of deep infections, etc.). The EmPower 
data management system can also produce a report that lists participants by row and 
details the original adverse event report and the data regarding any subsequent follow-
ups for that specific adverse event. 
The Withdrawal Report lists all participants by site, by surgeon and by participant and 
lists the visit within which the participant was withdrawn and the reason for withdrawal. 
This report can also be generated to present a tally of each reason for withdrawal 
across the study (e.g. number of participants whose surgeon withdrew them, who 
withdrew themselves, deaths, lost-to-follow-up, etc.). 
The Protocol Deviation Report lists all participants by site and surgeon who have a PD. 
The report lists the visit where the deviation was reported and the description of the 
deviation. 
The Queries Report provides the date, visit, database ID, details of any queries created 
by the data quality personnel, whether a response has been submitted by the site CRA, 
the status of the query (resolved vs. outstanding), and any additional communication 
between the data quality personnel at the DCC and the site CRA. 

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The Payout Report generates an amount owed to each site based on the quality of data 
for each participant visit. Each visit must be complete and query free for the site to be 
reimbursed. A draft of the report is sent to the site within two weeks of finalization to 
provide them with sufficient time to complete data entry and cleaning tasks prior to 
finalizing the payout report. Once finalized, the report is sent to the Coordinating Center 
to administer payment and the EmPower data management system marks these visits 
as paid in the next Payout Report, automatically beginning its assessment of the 
amount owed from where it last paid out. 
The Monitoring Report provides an overall assessment of the status of each 
participant’s visit according to whether the visit has been electronically monitored, 
source data verified, whether there are outstanding queries and whether or not the 
participant’s file is locked. A participant’s file can only be locked once the participant has 
reached the final study visit, been withdrawn or suffered the primary outcome, each 
form has been reviewed by the monitor, and there are no outstanding queries. Locking 
a subject file means that regular users can no longer edit that participant’s data. 
The system can generate several logs including an Audit, Access and Communications 
Log. The Audit Log presents the username, date and time (EST) of initial data entry and 
any changes made to data with the reason for the change. The Access Log provides a 
list of the date and time that users login and logout and any form that they edited. The 
Communication Log presents the date, time, user, subject line and content of any email 
or text message sent by the system. 
Hard copy forms are available for participants who do not wish to enter data directly 
online, although with this age-group and our experience with STABILITY 1, the majority 
of participants are expected to enter their data online. The RC will enter data from 
paper-based case report forms directly into the online database the same day it is 
collected. 
The EmPower data management software will facilitate the generation of clean datasets 
by guiding individuals through the data collection process by only displaying questions 

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and screens that are appropriate for the particular participant, using within and between 
CRF logic to reduce the possibility of nonsensical data entries and the need for 
extensive recoding and cleaning by the statistician. 
The eMonitor in collaboration with the PC at the DCC will proactively monitor participant 
retention using the web-based EmPower data management system. Missing data 
reports will be shared with the site CRA and PI on a monthly basis for adjudication and 
resolution. In addition, site remuneration for data collection is dependent on complete 
and query-free CRFs per participant by visit. The eMonitor provides quarterly Payout 
Reports of visit completion and corresponding remuneration value to the site for 
verification. The verified quarterly reports summarizing the visit completion will be 
forwarded to the grants administrator at the University of Pittsburgh or Western 
University who will issue payments to the sites. 
The EmPower data management software will send automatic email or text message 
reminders to the CRA of an upcoming follow-up visit prior to the visit, on the date that 
the visit window opens, the ideal date, and a few days after the ideal date if the CRFs 
remain incomplete. The CRA, and site PI are notified if the visit still remains incomplete 
7 days prior to the final visit window date. The PC and eMonitor are notified if the visit 
remains incomplete on the final date of the visit window. Since the analysis will use time 
as a random factor, visits that take place outside the specified window are not as 
problematic as when time is defined as a fixed factor. 
The EmPower data management software will send an automatic email or text 
messages to participants (who have opted into this feature) regarding upcoming and 
overdue appointments. Participants will have the option to login using their unique 
username and password to complete patient reported outcomes directly online or to 
wait to complete these CRFs at the clinic. When participants log in, they only have 
access to CRFs that are meant for participants and that fall within the visit window 
according to that day’s date. 

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To maximize participant compliance with the protocol’s follow-up visit schedule, multiple 
attempts to contact non-responders will be utilized. Participants will be contacted via 
email one week prior to the follow-up due date, at the due date, and up to three times 
after the due date. If the participant does not respond to the third contact to their 
preferred contact, phone calls will be made by the site CRA until the participant 
completes the follow-up visit or withdraws their consent for continued participation in the 
study. Data collected up to the date of withdrawal will be retained for analysis. 
The PC and eMonitor will create reports for the investigators and the DSMB to chart 
progress of the study and identify potential problems with the data. The PC and 
eMonitor will generate reports for the DSMB on a semi-annual basis to allow for the 
early detection of problems.  
When withdrawals or AEs are reported, the system automatically notifies the Principal 
Investigators, QCL and PC via email. The ESC will meet monthly via teleconference 
(more frequently during start-up or as needed). Agenda items for meetings will include 
topics such as reports that document compliance patterns and quantify reasons why 
subjects were not enrolled; compare actual with targeted enrollment; determine whether 
recruitment targets for minority and both sexes are being met; assess completed and 
missed follow-up visits and rates of missing and incomplete data at each visit; list 
adverse events associated with the protocol; and chart the frequency and character of 
PDs. Action plans to resolve any problem will be developed and implemented. Ongoing 
follow-up reports will enable us to determine the effectiveness of any corrective actions 
that are taken. 
Data integrity and credibility of the study are dependent on strict adherence to the 
protocol, obtaining complete follow-up data from all participants and establishing and 
adhering to quality control measures to maintain high standards for data quality. The 
quality control procedures that have been developed and implemented for this study 
include following established procedures for the conduct of research and patient care at 

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the University of Pittsburgh, University of Pittsburgh Medical Center (UPMC) and 
respective study site as well as close monitoring of data and form completion. 
All study staff will receive initial and ongoing training related to all study procedures to 
maximize adherence to the protocol and achieve high quality data. Additionally, all study 
investigators and staff will complete training on research integrity, human subjects 
research and good clinical practice. 
 
Methods and Systems to Ensure Data Confidentiality and Subject 
Privacy 
All research procedures will take place in the privacy of an examination room at all sites. 
Only the participant and research staff will be in the room during data collection and 
doors will be kept closed throughout the testing or intervention. During surgery, drapes 
and other barriers will be utilized, as is the standard of care, to prevent undue exposure 
of the participant. The collection of sensitive information from the subjects will be limited 
to the amount necessary to achieve the aims of the research. 
Participant privacy and confidentiality will be maintained at all times. Consenting 
participants will be registered into the web-based EmPower Health Research data 
management software. EmPower has demonstrated compliance with privacy and 
security standards. To protect participant confidentiality, all participants will be assigned 
a unique database identification number. To ensure that the confidentiality of participant 
records is maintained, records associated with participation in this study will be 
indicated by only the case number. Information linking these case numbers with 
participant identity will be accessible only to the research team and will be stored in a 
locked file. Only the database ID number will be recorded on any paper forms or in 
electronic databases. Information collected for this study on any paper forms will be 
stored in a locked file cabinet and will be accessible only to the research staff involved 
in the study. Electronic data will be stored on a password protected secure network 
server. Access to computer-based files will only be made available to personnel 
involved in the study through the use of access permissions and passwords. Any data 
that is submitted for review to the DSMB, University of Pittsburgh Office of Research 

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Conduct and Compliance or the IRB will be linked only to the subject’s database ID 
number. Participants will not be identified in any publications or presentation of the 
research results. 
If a subject elects to withdraw from the study, any research data recorded for, or 
resulting from, participation in this research study prior to the date that he/she formally 
withdrew his/her data will continue to be used. 
 
Data Sharing Agreement 
After the last participant’s final follow-up assessment at 24 months, the online database 
will be locked to create the full analyzable data set. A copy of the data used for the 
analysis will be frozen and the analytic code will be stored to allow for the replication of 
the results in the future. 
The planned procedure on data access and sharing fulfills the requirements of the 
International Committee of Medical Journal Editors (ICMJE).98 The study database and 
all documentation will be maintained indefinitely at the DCC.  A public-use version of the 
dataset will be constructed by the DCC with contents to be determined jointly by the 
study PIs and the DCC Director. Copies of the public-use version of the dataset will be 
housed at the DCC on the DA secure server along with suitable documentation of this 
dataset. The public-use version of the dataset will be exported by CRF in one or more 
files in simple, widely-accessible formats, e.g., .xls, .csv, and/or SAS datasets.  
Documentation will be in .pdf files. Outside investigators wishing to conduct analyses 
using the data will submit a request with objectives, methods, and analysis plan to the 
PI and the Director of the DCC. Once the request is approved, the public-use version of 
the dataset, with documentation, will be sent by secure e-mail, ftp, or other mutually 
agreeable transmission method. The public-use version of the database will be made 
available two years after the study's main paper is published. Updates of the public-use 
version of the database will correct errors (if any) in the items included in earlier 
releases and will add new data items deemed to be locked since the previous version 
was released. 

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The ICMJE member journals have adopted a clinical trials registration policy as a 
condition for publication. The ICMJE defines a clinical trial as any research project that 
prospectively assigns human subjects to intervention or concurrent comparison or 
control groups to study the cause-and-effect relationship between a medical intervention 
and a health outcome. Medical interventions include drugs, surgical procedures, 
devices, behavioral treatments, process-of-care changes, and the like. Health outcomes 
include any biomedical or health-related measures obtained in patients or participants, 
including pharmacokinetic measures and adverse events. The ICMJE policy requires 
that all clinical trials be registered in a public trials registry such as ClinicalTrials.gov, 
which is sponsored by the National Library of Medicine. As such, the STABILITY 2 Trial 
will be registered with ClinicalTrials.gov prior to enrollment of the first participant.  The 
STABILITY 2 Trial results will be placed on the ClinicalTrials.gov website within one 
year of the last enrolled participants final follow-up visit. 

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17. 
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APPENDICES 
 

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APPENDIX A: STUDY TIMELINE 
Aim 1:  Determine if graft type (QT, BPTB or HT) with or without a LET affects the rate of ACL clinical failure at 2 years 
after ACLR.  ACL clinical failure will be defined by either graft rupture, symptomatic instability or persistent rotational laxity 
(asymmetrical positive pivot shift), at 2 years after ACLR. 
Aim 2: Determine if graft type (QT, BPTB or HT) with or without a LET affects patient-reported symptoms, function and 
quality of life, performance-based measures of function and return-to-sports 2 years after ACLR. 
Aim 3: Determine if graft type (QT, BPTB or HT) with or without a LET affects the rates of intervention-related donor site 
morbidity, complications and adverse outcomes 2 years after ACLR. 
Aim 4: Determine if the use of a particular graft type (QT, BPTB or HT) with or without LET is a more cost-effective 
approach to ACLR. 
Abbreviations: CCC = Clinical Coordinating Center; DCC = Data Coordinating Center; SS = Study Sites 
Major Tasks 
Sites involved 
Year 1 
Year 2 
Year 3 
Year 4 
Year 5 
Phase 1 
Phase 2 
1 
2 
3 
4 
5 
6 
7-12 
13-24 
25-30 
31-36 
37-48 
49-57 
58-60 
Study Start-up 
CCC, DCC, SS 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Subject Recruitment 
CCC, DCC, SS 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
Clinical Monitoring & 
Quality Control 
CCC, DCC 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Subject Follow-up 
CCC, SS 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Study Governance 
CCC, DCC, SS 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Analyze & 
Disseminate Results 
CCC, DCC, SS 
 
 
 
 
 
 
 
 
 
 
 
 
X 

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APPENDIX B: SCHEDULE OF EVENTS 
 
 
Baseline 
Surgery 
6 weeks 
3 months 
6 months 
12 
months 
24 
months 
Unscheduled 
PRN 
Visit Windows 
-6 weeks 
 
+/- 2 
weeks 
+/- 1 
month 
+/- 1 
month 
+/- 1 
month 
+/- 3 
months 
 
 
Consent 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Operative Screening 
 
X 
 
 
 
 
 
 
 
Group Allocation 
 
X 
 
 
 
 
 
 
 
Surgery Forms 
 
X 
 
 
 
 
 
 
 
PROs 
 
 
 
 
 
 
 
 
 
• 
ACL QOL 
X* 
 
X 
X 
X 
X 
X 
 
 
• 
KOOS 
X* 
 
X 
X 
X 
X 
X 
 
 
• 
IKDC-SKF 
X* 
 
X 
X 
X 
X 
X 
 
 
• 
Marx Activity 
X* 
 
X 
X 
X 
X 
X 
 
 
• 
EQ5D 
X* 
 
X 
X 
X 
X 
X 
 
 
• 
ACL - RSI 
 
 
 
 
X 
X 
X 
 
 
• 
Sport Participation 
X* 
 
 
 
 
 
 
 
 
• 
Return to Sport 
 
 
 
 
X 
X 
X 
 
 
• 
Patient Experiences 
During Rehabilitation       
 
 
X 
X 
X 
X 
 
 
 
Clinical Assessment 
X 
 
X 
X 
X 
X 
X 
X 
 
Pivot Shift Assessment (manual) 
X 
X 
 
X 
X 
X 
X 
X 
 
Pivot Shift Assessment (App) 
 
X 
 
X 
X 
X 
X 
X 
 
Donor Site Adverse Events 
 
 
X 
X 
X 
X 
X 
X 
 
Radiographs- PA Standing 
Flexion 
X 
 
 
 
 
 
X 
 
 
Radiographs- Lateral view 
X 
 
 
 
 
 
 
 
 
ROM & Muscle Function 
 
 
 
 
 
 
 
 
 
• 
Range of Motion (ROM) 
X* 
 
X 
X 
X 
X 
X 
 
 
• 
Strength Testing 
X 
 
 
 
X 
X 
X 
 
 
Performance Tests 
 
 
 
 
 
 
 
 
 
• 
Hop Test 
 
 
 
 
X 
X 
X 
 
 
• 
Kinect V2 Drop Vertical 
Jump 
 
 
 
 
X 
X 
 
 
 
As Needed 
 
 
 
 
 
 
 
 
 
• 
Adverse Event 
 
 
 
 
 
 
 
 
X 
• 
Withdrawal Form 
 
 
 
 
 
 
 
 
X 
• 
Cost Forms for failed 
ACLs 
 
 
X 
X 
X 
X 
X 
 
 

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Estimated time duration per visit 
2 hr 
5 hrs 
30 mins 
30 mins 
1.5 hrs 
1.5 hrs 
1.5 hrs 
.5 hrs 
 
*Repeat if more than 6 weeks between baseline measurement and surgery.  
 
APPENDIX C: STUDY FORMS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX D: DATA SAFETY AND MONITORING BOARD TABLES