STaR (Surgical Timing and Rehabilitation) Trial for Multiple Ligament Knee Injuries
Phase: NA
Conditions: Knee Dislocations, Multiple Ligament Knee Injuries
Sponsor: University of Pittsburgh

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Surgical Timing and Rehabilitation for Multiple 
Ligament Knee Injuries: A Multicenter Integrated 
Clinical Trial 
Protocol Number: PRO16090503 
 
 
Principal Investigators: 
 
James Irrgang, PT PhD FAPTA 
Volker Musahl, MD 
DoD Program Official: 
Jessica Clement MS, Science Officer 
Sponsor: Department of Defense (DoD) 
DoD Contract Number: WB81XWH-17-2-0073 
 
Version Number:  1.0 
 
 May 2018 
 
 

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STATEMENT OF COMPLIANCE 
The study will be conducted in accordance with the International Conference on 
Harmonisation guidelines for Good Clinical Practice (ICH E6), the Code of Federal 
Regulations on the Protection of Human Subjects (45 CFR Part 46), and the Terms and 
Conditions US Army Medical Research Acquisition Activity (USAMRAA).  All personnel 
involved in the conduct of this study have completed human subjects protection training. 

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TABLE OF CONTENTS 
PAGE 
STATEMENT OF COMPLIANCE ................................................................................................ 2 
TABLE OF CONTENTS .............................................................................................................. 3 
SIGNATURE PAGE .................................................................................................................... 7 
LIST OF ABBREVIATIONS ......................................................................................................... 8 
PROTOCOL SUMMARY ........................................................................................................... 11 
1 
KEY ROLES AND CONTACT INFORMATION ................................................................. 14 
2 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ....... 19 
 
Background Information ........................................................................................ 19 
 
Overview of Multiple Ligament Knee Injuries ............................................. 19 
 
Impact of Multiple Ligament Knee Injuries on Military Duty, Work, and 
Sports........................................................................................................ 20 
 
Association Between Multiple Ligament Knee Injuries and Premature 
Development of Arthritis ............................................................................ 21 
 
Controversies in Surgical Management of Multiple Ligament Knee 
Injuries ...................................................................................................... 22 
 
Postoperative Rehabilitation of Multiple Ligament Knee Injuries ................ 22 
 
Rationale .............................................................................................................. 23 
 
Rational for Early vs. Delayed Post-Operative Rehabilitation for Multiple 
Ligament Knee Injuries .............................................................................. 24 
 
Potential Risks and Benefits ................................................................................. 25 
 
Potential Risks .......................................................................................... 25 
 
Potential Benefits ...................................................................................... 27 
3 
OBJECTIVES ................................................................................................................... 28 
 
Study Objectives ................................................................................................... 28 
 
Specific Aim 1 ........................................................................................... 28 
3.1.2 
Specific Aim 2 ........................................................................................... 28 
 
Study Outcome Measures .................................................................................... 28 
 
Primary Outcome ...................................................................................... 29 
 
Co-Primary Outcome – Patient Reported Physical Function ...................... 30 
 
Secondary Outcomes ................................................................................ 31 
4 
STUDY DESIGN .............................................................................................................. 34 
5 
STUDY ENROLLMENT AND WITHDRAWAL .................................................................. 36 
 
Subject Inclusion Criteria ...................................................................................... 36 
 
Inclusion Criteria for Participants Enrolled Aims 1 and 2 ........................... 36 
 
Inclusion Criteria for Participants Enrolled in Aim 1 - Randomization to 
Both Timing of Surgery and Post-Operative Rehabilitation ........................ 36 
 
Inclusion Criteria for Aim 2 - Randomization to Only Timing or Post-
Operative Rehabilitation ............................................................................ 36 
 
Subject Exclusion Criteria ..................................................................................... 36 

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Exclusion Criteria for Enrollment of Participants in Trials for Either Aims 
1 or 2 ......................................................................................................... 36 
 
Exclusion of Participants in Trial for Aim 1 - Randomization to Both 
Timing of Surgery and Post-Operative Rehabilitation ................................ 37 
 
Exclusion of Participants in Trial for Aim 2 – Randomization to Only 
Post-Operative Rehabilitation .................................................................... 37 
 
Strategies for Recruitment and Retention ............................................................. 39 
 
Recruitment of Participants for the Trial for Aim 1 that Randomizes Both 
the Timing of Surgery and Rehabilitation ................................................... 39 
 
Recruitment of Participants for the Trial for Aim 2 that Randomizes 
Timing of Rehabilitation ............................................................................. 39 
 
Recruitment Process ................................................................................. 40 
 
Efforts to Monitor and Maximize Subject Recruitment ............................... 41 
 
Subject Payment ....................................................................................... 42 
 
Efforts to Maximize Subject Retention ....................................................... 43 
 
Treatment Assignment Procedures ....................................................................... 44 
 
Randomization Procedures ....................................................................... 45 
 
Masking Procedures .................................................................................. 46 
 
Subject Withdrawal.................................................................................... 46 
 
Reasons for Withdrawal ............................................................................ 47 
 
Handling of Subject Withdrawals or Subject Discontinuation of Study 
Intervention ............................................................................................... 47 
 
Premature Termination or Suspension of Study .................................................... 48 
6 
STUDY INTERVENTION .................................................................................................. 49 
 
Description of Study Procedural Intervention(s) .................................................... 49 
 
Early vs. Delayed Surgery for MLKI ........................................................... 49 
 
Early vs. Delayed Rehabilitation after Surgery for MLKI ............................ 51 
 
Procedures for Training of Clinicians on Procedural Intervention .......................... 57 
 
Procedures for Training Surgeons on Surgical Intervention ....................... 57 
 
Procedures for Training Physical Therapists on Rehabilitation 
Interventions.............................................................................................. 58 
 
Assessment of Clinician and/or Subject Compliance with Study Procedural 
Intervention ........................................................................................................... 60 
 
Assessment of Surgeon Adherence to Timing of Surgery as 
Randomized .............................................................................................. 60 
 
Assessment of Participant Adherence with Rehabilitation as 
Randomized in the first Month after Surgery.............................................. 60 
 
Assessment of Patient Reported Adherence to Rehabilitation as 
Prescribed after the First Month after Surgery ........................................... 61 
7 
STUDY SCHEDULE ......................................................................................................... 62 
 
Subject Identification, Prescreening, and Informed Consent Processes ................ 62 
 
Screening ............................................................................................................. 63 
 
Baseline Visit ........................................................................................................ 63 

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Randomization and Scheduling and Completion of Surgery.................................. 63 
 
Standard of Care Clinical Follow-Up Visits ............................................................ 65 
 
Research Follow-Ups ............................................................................................ 66 
8 
STUDY PROCEDURES /EVALUATIONS ........................................................................ 67 
 
Study Procedures/Evaluations .............................................................................. 67 
 
Consent Process ....................................................................................... 67 
 
Screening .................................................................................................. 67 
 
Baseline Visit ............................................................................................. 71 
 
Study Interventions.................................................................................... 72 
 
Post-Operative Clinical Visits .................................................................... 74 
 
Research Follow-Up Visits ........................................................................ 76 
 
Assessment of Outcomes.......................................................................... 77 
 
Other Patient-Reported Measures ............................................................. 85 
9 
ASSESSMENT OF SAFETY ............................................................................................ 87 
 
Specification of Safety Parameters ....................................................................... 87 
 
Unanticipated Problems ............................................................................ 87 
 
Adverse Events ......................................................................................... 88 
 
Serious Adverse Events ............................................................................ 89 
 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 89 
 
Characteristics of an Adverse Event ..................................................................... 90 
 
Relationship to Study Intervention ............................................................. 90 
 
Expectedness of SAEs .............................................................................. 90 
 
Severity of Event ....................................................................................... 90 
 
Internal and External Review and Adjudication of AE and SAE documentation..... 91 
 
Reporting Procedures ........................................................................................... 93 
 
Unanticipated Problem Reporting to IRB and HRPO ................................. 93 
 
Adverse Event and Serious Adverse Event Reporting to IRB and HRPO .. 94 
 
Criteria for Intervention Discontinuation ................................................................ 94 
10 
STUDY OVERSIGHT ....................................................................................................... 95 
 
Composition of the Data and Safety Monitoring Board .......................................... 95 
 
Roles and Function of the DSMB .......................................................................... 97 
 
Independent Research Monitor ............................................................................. 98 
 
Study Committees ................................................................................................ 99 
11 
CLINICAL SITE MONITORING PLAN ............................................................................ 104 
 
Clinical Monitoring Communication Plan ............................................................. 104 
 
Scheduling of Visits ............................................................................................ 105 
 
Types of Visits and Monitoring Activities ............................................................. 105 
 Site Initiation Visit .................................................................................... 105 
 Interim Visits............................................................................................ 108 
 For-Cause Visits ...................................................................................... 109 
 Close-Out Visit ........................................................................................ 109 
 
Research Records and Documents to be Monitored ........................................... 109 
12 
STATISTICAL CONSIDERATIONS ................................................................................ 111 

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Study Hypotheses ............................................................................................... 111 
 
Sample Size Considerations ............................................................................... 111 
 
Safety Review ..................................................................................................... 113 
 
Final Analysis Plan ............................................................................................. 113 
 Statistical Analysis for Specific Aim 1 (Randomization to Early vs. 
Delayed Surgery and Post-Operative Rehabilitation) ............................... 114 
 Statistical Analysis for Specific Aim 2 (Randomization to Only Early vs. 
Delayed Post-Operative Rehabilitation) ................................................... 116 
13 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ................ 117 
14 
QUALITY CONTROL AND QUALITY ASSURANCE ...................................................... 120 
 
Quality Management ........................................................................................... 120 
15 
ETHICS/PROTECTION OF HUMAN SUBJECTS ........................................................... 128 
 
Ethical Standard ................................................................................................. 128 
 
Institutional Review Board .................................................................................. 128 
 
Informed Consent Process ................................................................................. 129 
 
Subject Confidentiality ........................................................................................ 131 
16 
DATA HANDLING AND RECORD KEEPING ................................................................. 132 
 
Data Management Responsibilities ..................................................................... 132 
 
Data Capture Methods ........................................................................................ 132 
 
Identifiers ............................................................................................................ 133 
 
Confidentiality ..................................................................................................... 133 
 
Data Capture, Verification and Disposition .......................................................... 134 
 
Data Reporting.................................................................................................... 138 
 
Study Records Retention .................................................................................... 140 
 
Protocol Deviations ............................................................................................. 140 
17 
PUBLICATION/DATA SHARING POLICY ...................................................................... 142 
18 
LITERATURE REFERENCES ........................................................................................ 143 
APPENDICES ......................................................................................................................... 150 
APPENDIX A: STUDY TIMELINE ........................................................................................... 151 
APPENDIX B: SCHEDULE OF EVENTS ................................................................................ 153 
APPENDIX C: STUDY FORMS .............................................................................................. 155 
APPENDIX D: DATA SAFETY AND MONITORING BOARD TABLES .................................... 156 
 
 
 

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SIGNATURE PAGE 
The signature below constitutes 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 US federal 
regulations and ICH guidelines.  
I 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. 
 
“Surgical Timing and Rehabilitation for Multiple Ligament Knee Injuries: A 
Multicenter Integrated Clinical Trial” 
 
Principal Investigator 
Signed: 
 
Date:  
 
 
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 Investigator 
 
Signed: 
 
 
 
 
Date:  
 
 
Name: Volker Musahl, MD 
 
Title: Associate Professor and Chief, Division of Sports Medicine, 
Department of Orthopaedic Surgery, University of Pittsburgh School of 
Medicine 
 

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LIST OF ABBREVIATIONS 
ACL 
Anterior Cruciate Ligament 
ADL 
Activities of Daily Living 
AE 
Adverse Event  
AEAC 
Adverse Event Adjudication Committee 
CAT 
Computerized Adaptive Test 
CCC 
Clinical Coordinating Center 
Co-I 
Co-Investigator 
CMP 
Clinical Monitoring Plan 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTSI 
Clinical and Translational Science Institute 
CSOC 
Clinical Study Oversight Committee 
DCC 
Data Coordinating Center 
DoD 
Department of Defense 
DMP 
Data Management Plan 
DSMB 
Data Safety and Monitoring Board 
DSMP 
Data Safety and Monitoring Plan 
EHR 
Electronic Health Record 
ES 
Effect Size 
ESC 
Executive Steering Committee 
FCI 
Functional Comorbidity Index 
GCP 
Good Clinical Practice 
GRC 
Global Rating of Change 
HRPO 
Human Resources Protection Office 
ICH 
International Conference on Harmonization 
ICMJE 
International Committee of Medical Journal Editors 
IKDC 
International Knee Documentation Committee 
IKDC-SKF 
International Knee Documentation Committee Subjective Knee Form 
IRB 
Institutional Review Board 
ITB 
Iliotibial Band 
LCL 
Lateral Collateral Ligament 
MCL 
Medial Collateral Ligament 
MLKI 
Multiple Ligament Knee Injury 

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MLQoL 
Multiple Ligament Quality of Life Questionnaire 
MOP 
Manual of Operating Procedures 
MOS 
Military Occupational Specialty 
NMES 
Neuromuscular Electrical Stimulation 
NPRS 
Numeric Pain Rating Scale 
NWB 
Non-Weight Bearing 
OA 
Osteoarthritis 
ORP 
Office of Research Protections 
PASC 
Publications and Ancillary Studies Committee 
PASS 
Patient Acceptable Symptom State 
PCL 
Posterior Cruciate Ligament 
PF 
Physical Function 
PFL 
Popliteofibular Ligament 
PEB 
Physical Evaluation Board 
PI 
Principal Investigator 
PLC 
Posterolateral Corner  
POL 
Posterior Oblique Ligament 
PRO 
Patient Reported Outcome 
PROMIS 
Patient Reported Outcome Measurement Information System 
PTOA 
Post-Traumatic Osteoarthritis 
PWB 
Partial Weight-Bearing 
QA 
Quality Assurance 
QC 
Quality Control 
QCC 
Quality Control Coordinators 
QCI 
Qualified Clinical Investigator 
QM 
Quality Management 
RC 
Research Coordinator 
ROM 
Range of Motion 
SAE 
Serious Adverse Event  
SID 
Study Identification Number 
TBI 
Traumatic Brain Injury 
TSK 
Tampa Scale for Kinesiophobia 
TTWB 
Toe-Touch Weight-Bearing 
UP 
Unanticipated Problem 

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US 
United States 
USAMRMC 
United States Army Medical Research and Materiel Command 
WBAT 
Weight-Bearing As Tolerated 
 

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PROTOCOL SUMMARY 
Title: 
Surgical Timing and Rehabilitation for Multiple Ligament Knee 
Injuries: A Multicenter Integrated Clinical Trial 
Précis: 
Military personnel and civilians between the ages of 16 and 55 
with a multiple ligament knee injury (MLKI) without a history of 
prior knee ligament reconstruction that do not have a peri-
articular fracture, vascular injury, poly-trauma or a traumatic 
brain injury will be eligible to participate in this multicenter 
randomized clinical trial. Participants will be randomly assigned 
to timing of surgery (early – within 6 weeks of injury vs. 
delayed – surgery 3 to 4 months after injury) and timing of 
post-operative rehabilitation (early – weightbearing as tolerated 
[WBAT] gait and unrestricted range of motion [ROM] exercises 
starting within one week of surgery or delayed – non-
weightbearing [NWB] gait and limited ROM for four weeks). 
Subjects that cannot be randomized to timing of surgery will be 
randomized to only timing of rehabilitation in a separate 
parallel trial.  Participants return to pre-injury military duty, work 
and sports participation and patient-reported physical function 
will be monitored over 24 months follow-up.     
Objectives: 
 
To investigate the effects of timing of surgery (early vs. 
delayed) and timing of post-op rehabilitation (early vs. delayed) 
for the treatment of military personnel and civilians that have 
sustained a MLKI on time to return to pre-injury level of military 
duty, work and sports participation and patient reported 
physical function. Secondary outcome measures will include 
additional knee-specific and general patient-reported measures 
of physical function and health related quality of life, recovery 
of range of motion (ROM), arthrofibrosis, residual laxity, 
complications/adverse events, re-injury and additional surgical 
procedures.  The specific aims are: 
Aim 1: Determine the effects of timing of surgery and post-
operative rehabilitation on time to return to pre-injury level 
of military duty, work and sports and patient-reported 
physical function.  We hypothesize that early surgery, early 
rehabilitation and the combination of early surgery with early 
rehabilitation will lead to an earlier and more complete return to 
pre-injury military duty, work and sports and better patient-
reported physical function.   
Aim 2: Determine the effects of timing of rehabilitation on 
time to return pre-injury level of military duty, work and 

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sports and patient-reported physical function.  We 
hypothesize that early rehabilitation will lead to an earlier and 
more complete return to pre-injury military duty, work and 
sports activity and better patient-reported physical function.   
Population: 
A total of 690 (392 for Aim 1 and 298 for Aim 2) male and 
female military personnel and civilians between the ages of 16 
and 55 with a MLKI (complete grade III injury of two or more 
ligaments) without a history of prior knee ligament 
reconstruction will be eligible to participate in the clinical trials.  
Individuals with a torn or avulsed patellar or quadriceps 
tendon, fracture that precludes adherence to post-operative 
care guidelines or use of an external fixator to maintain 
reduction of the knee for greater than 10 days, that are unable 
to WB on the contralateral uninjured leg or have a traumatic 
brain injury (TBI) that limits their ability to participate in their 
post-operative care will be excluded from participation in these 
studies.   
Phase: 
III 
Number of Sites: 
25 
Description of  
Intervention: 
To address Aim 1, individuals with a MLKI that present within 6 
weeks of injury will be randomized to early (within 6 weeks of 
injury) or delayed (12 to 16 weeks after injury) surgery and 
early (WB and unrestricted ROM exercises starting first week 
after surgery) vs. delayed (non-WB and knee locked in 
extension for the first four post-op weeks) rehabilitation.  To 
address Aim 2, individuals with a MLKI that present greater 
than 6 weeks after injury, have an injury that precludes 
randomization to early or delayed surgery as well as those that 
refuse surgical randomization will be eligible to participate in 
the trial that compares only early vs. delayed rehabilitation. 
Study Duration: 
48 months 
Subject 
Participation 
Duration: 
24 months 
 
Estimated Time to 
Complete 
Enrollment: 
21 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 
Phone: (412) 383-9865 
E-Mail: jirrgang@pitt.edu  
Volker Musahl, MD 
Co-Principal Investigator 
Qualified Investigator for Surgery 
University of Pittsburgh 
Rooney Sports Complex 
3200 South Water Street 
Pittsburgh, PA 15203 
Phone (412) 432-3618 
E-Mail: musahlv@upmc.edu  
 
 
Co-Investigators 
 
Andrew Lynch, PhD, PT 
 
 
 
Qualified Investigator for Rehabilitation  
Department of Physical Therapy  
 
University of Pittsburgh 
 
 
 
Bridgeside Point 1  
 
 
  
100 Technology Drive, Suite 210  
 
Pittsburgh, PA 15219 
 
 
 
Phone: (412) 383-6632 
 
 
 
E-Mail: adl45@pitt.edu  
 
Charity G. (Moore) Patterson, PhD, MSPH 
Director of Data Coordinating Center 
Department of Physical Therapy 
University of Pittsburgh 
Bridgeside Point 1   
100 Technology Drive, Suite 210 
Pittsburgh, PA 15219 
Phone: (412) 383-4812 
E-mail: cgp22@pitt.edu 
 
Alexandra Gil, PhD, PT 
 
 
Quality Control Coordinator 
 
 
Department of Physical Therapy   
University of Pittsburgh 
 
  
Bridgeside Point 1   
 
 
100 Technology Drive, suite 210  
Pittsburgh, PA 15219 
 
 
Phone: (412) 383-6714  
 
 
E-mail: agil@pitt.edu 
Bryson Lesniak, MD 
Site Co-Investigator 
Department of Orthopaedic Surgery 
University of Pittsburgh 
Rooney Sports Complex 
3200 South Water Street 
Pittsburgh, PA 15203 
Phone: (412) 432-3721 
E-mail: lesniakbp@upmc.edu 
 
 
 
 
 
 
 

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Peter Siska, MD 
 
 
 
Site Co-Investigator 
Department of Orthopaedic Surgery 
University of Pittsburgh 
 
 
Suite 911, Kaufman Building 
 
3471 Fifth Avenue  
 
 
Pittsburgh, PA 15213 
 
 
Phone: (412) 687-3900 
 
 
 
E-mail: siskpa@upmc.edu  
Ivan Tarkin, MD 
Site Co-Investigator 
Department of Orthopaedic Surgery  
University of Pittsburgh 
Suite 911, Kaufman Building 
3471 Fifth Avenue 
Pittsburgh, PA 15213 
Phone: (412) 432-3252 
E-mail: tarkinis@upmc.edu 
 
Research Coordinator – Pittsburgh Site 
 
M. Beatriz Catelani, PT, MS 
 
University of Pittsburgh  
 
 
Bridgeside Point 1  
 
 
100 Technology Drive, suite 210  
Pittsburgh, PA 15219  
 
 
Phone: (412) 383-6762  
 
 
E-mail: mcc68@pitt.edu 
 
 
 
Participating Sites 
 
University of Pittsburgh 
Bridgeside Point 1  
100 Technology Drive, suite 210 
Pittsburgh, PA 15219 
PI: James Irrgang, PhD, PT, ATC 
Phone: (412) 383-9865 
E-mail: jirrgang@pitt.edu  
 
Rhode Island/Brown University 
593 Eddy Street 
Providence, RI 02903 
PI: Brett Owens, MD 
Phone: (401) 330-1434 
E-mail: owensbrett@gmail.com  
Health Partners Institute for Education 
and Research 
8170 33rd Avenue South 
P.O. Box 1524  
Minneapolis, MN 55440 
PI: Jonathan Cooper, DO 
Phone: 651-254-2005 
Email: 
jonathan.m.cooper@healthpartners.com  
Hospital for Special Surgery 
535 East 70th Street  
New York, NY 10021 
PI: Anil Ranawat, MD 
Phone: 646-797-8708 
Email: ranawatanil@hss.edu  

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Keller Community Army Hospital 
900 Washington Road 
West Point, NY 10996 
PI: Matthew Posner, MD 
Phone: 845-938-6612 
Email: matthew.a.posner.mil@mail.mil  
Mayo Clinic 
200 First Street SW 
Rochester, MN 55905 
PI: Bruce Levy, MD 
Phone: 507-284-9214 
Email: levy.bruce@mayo.edu  
 
     
Nova Scotia Health Authority  
Queen Elizabeth Health Sciences Center 
Halifax Infirmary Building, 4th floor  
1796 Summer Street 
Halifax, Nova Scotia, Canada, B3H 3A6 
PI: Cathy Coady, MD 
Phone: 902-473-2575 
Email: Cathy.Coady@dal.ca  
 
 
San Antonio Military Medical Center  
3551 Roger Brooke Drive 
Fort Sam Houston, TX 78234 
PI: Travis Burns, MD 
Phone: 210-916-3400 
Email: travis.c.burns.mil@mail.mil  
St. Michael’s Hospital 
30 Bond Street 
Toronto, Ontario, Canada, M5B 1W8 
PI: Daniel Whelan, MD 
Phone: 416-864-6002 
Email: wheland@smh.ca  
 
TRIA Orthopaedic Center  
8100 Northland Drive  
Bloomington, MN 55431 
PI: Bradley Nelson, MD 
Phone: 612-273-8058 
Email: nels5101@umn.edu  
 
Tripler Army Medical Center  
1 Jarrett White Road 
Honolulu, HI 96859 
PI: Craig Bottoni, MD 
Phone: 808-433-5969 
Email: craig.r.bottoni.civ@mail.mil  
University of Cincinnati 
Surgery University of Cincinnati 
Academic Health Center 
PO Box: 670212 
Cincinnati, OH 45267 
PI: Brian Grawe 
Phone: (513) 558-4516 
E-mail: grawebn@ucmail.uc.edu  
 
 
University of Connecticut 
263 Farmington Avenue 
Farmington, CT 06030-5456 
PI: Robert Arciero, MD 
Phone: (860) 679-2460 
E-mail: arciero@uchc.edu  
University of Kentucky Research 
Foundation 
800 Rose Street 
Lexington, KY 40536 
PI: Darren Johnson, MD 
Phone: 859-218-3054 
Email: dljohns@uky.edu  
 

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University of Michigan  
3003 S. State Street 
Ann Arbor, MI 48109 
PI: John Grant, MD 
Phone: 734-232-9604 
Email: johngran@med.umich.edu  
University of Minnesota 
450 McNamara Alumni Center 
200 Oak Street SE 
Minneapolis, MN 55455 
PI: Jeff Macalena, MD 
Phone: 612-273-8059 
Email: Maca0049@umn.edu  
 
 
University of New Mexico Health 
Sciences Center 
1 University of New Mexico 
Albuquerque, NM 87131 
PI: Robert Schenck Jr, MD 
Phone: 505-272-1350 
Email: rschenck@salud.unm.edu  
University of Texas Health Sciences 
Center at Houston 
6400 Fannin Street Suite 1700 
Houston, TX 77088 
PI: Christopher Harner, MD 
Phone: 713-486-5525  
Email: christopher.harner@uth.tmc.edu  
 
 
University of Virginia 
515 Ray C Hunt Drive 
Charlottesville, VA 22903 
PI: Mark Miller, MD 
Phone: 434-243-0278 
Email: mdm3p@hscmail.mcc.virginia.edu  
University of Washington 
4333 Brooklyn Avenue NE 
Box 359472  
Seattle, WA 98195 
PI: Albert Gee, MD 
Phone: 206-543-3690  
Email: ag112@uw.edu  
 
 
 
University of Western Ontario d/b/a 
Lawson Health Research 
750 Base Line Road 
London, Ontario, Canada, N6C 2R5 
PI: Alan Getgood, MD 
Phone: 519-661-4003  
Email: alan.getgood@uwo.ca  
 
 
Wake Forest University  
Department of Orthopaedic Surgery 
Medical Center Boulevard   
Winston-Salem, NC 27157 
PI: Brian Waterman, MD 
Phone: 336- 716-2130 
Email: brian.r.waterman@gmail.com  
Walter Reed National Military Medical 
Center  
8901 Wisconsin Avenue 
Bethesda, MD 20889 
PI: Jeffrey Giuliani, MD 
Phone: 301-512-5551 
E-mail: jeffrey.r.giuliani.mil@mail.mil  
Washington University 
Campus Box 1054  
One Brookings Drive  
St. Louis, MO 63130 
PI: Matthew Matava, MD 
Phone: 314-514-3569 
Email: matavam@wudosis.wustl.edu  

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William Beaumont Army Medical Center  
5005 N. Piedras Street 
El Paso, TX 79920 
PI: Mark Pallis, MD 
Phone: 915-742-4588 
E-mail: mark.p.pallis.mil@mail.mil  
 
 
 

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2 INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE  
 
Background Information 
 
Overview of Multiple Ligament Knee Injuries 
Multiple ligament knee injuries, including knee dislocations, represent a spectrum of 
injury from disruption of two ligaments (one cruciate ligament and one collateral 
ligament) to all four ligaments (both cruciates and both collateral ligaments).  These 
injuries are potentially devastating and are often associated with significant injury to 
multiple structures of the knee including the capsule, tendons, menisci, chondral 
surfaces, bone, nerves and blood vessels.  Concomitant injuries may include those to 
the popliteal artery,1 tibial nerve, peroneal nerve,1,2 joint capsule, patellar, quadriceps, 
biceps and/or popliteus tendons, iliotibial band, medial or lateral menisci and/or 
fractures.3  Because of the extensive nature of injury, treatment for MLKIs creates 
multiple complex problems fraught with complications4-6  As such, MLKIs often have 
adverse effects on the long-term health of the knee7,8and frequently lead to restricted 
participation in military duty, work and sports.9,10 and early separation from the military.  
While multiple studies have reported treatment algorithms and outcomes for MLKIs, 
many of these studies are retrospective in nature with small sample sizes.  Only a few 
prospective studies have been published and to date there are no randomized 
controlled studies that have investigated optimal treatment methods for these complex 
knee injuries.   
The lack of high-level evidence related to treatment of MLKIs is due to both the 
heterogeneity of the injury and the relatively low incidence of MLKIs compared to 
isolated ligament injury.  A precise estimate of the number of knee dislocations has not 
been determined, however it has been estimated that for every 1400 orthopaedic 
injuries there is one knee dislocation.11  Furthermore, the incidence of MLKIs is likely 
under-estimated because many of the knee dislocations spontaneously reduce and are 
misdiagnosed.  Because of the physical demands in the military and the 10 fold greater 
risk of ACL injuries in the military compared to civilian population,12 the risk of a knee 

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dislocation or MLKI in the military population is likely greater than the risk in the civilian 
population.    
Despite their relatively low incidence, MLKIs and knee dislocations are associated with 
a high rate of adverse outcomes due to poor wound healing, arthrofibrosis, 
neurovascular injuries, persistent pain and instability and PTOA, resulting in residual 
disability and high direct and indirect health care costs.  Functionally, patients have few 
limitations with activities of daily living but are frequently limited with higher demand 
activities such as those associated with military training, physical labor and sports.9  
 
Impact of Multiple Ligament Knee Injuries on Military Duty, Work, and 
Sports  
Multiple ligament knee injuries result in significant time lost from military duty, work and 
sports.9,13-15  In many cases, patients are unable to return to their pre-injury military duty, 
work, or sports.  In fact, the return to duty rate after combat-related MLKIs has been 
reported as low as 41% 13to 50%9 and is substantially lower than the average reported 
civilian return to work rate of  81%.10,16,17  The most commonly cited reasons for 
individuals not being able to return to work after a MLKI are knee pain (53%), instability 
(26%) and concurrent injuries (26%).16  While these studies indicate the majority of 
civilians with a MLKI return to work, neither the influence of the physical work demands 
or the precise time for return to work have been considered, which are both needed to 
fully understand the economic and societal costs of these devastating injuries.   
Reported return to sports rates after MLKI are generally lower than return to work rates, 
ranging from 17% to 81%, with a mean of 50%.10  For competitive athletes, only 22% 
were able to return to the same level of competitive sports.18  A similarly low return to 
sports rate of 17% was observed among military service members after MLKI.9  The 
ability to return to sports after a MLKI appears to depend on the pre-injury level of sports 
in which the individual participates.  A greater percentage of individuals with a low level 
of pre-injury activity were able to return to a similar level of activity compared to patients 
with a higher pre-injury activity level.18  Factors associated with the inability to return to 

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sports include pain (55%), instability (19%), concurrent injuries (14%) and swelling 
(12%).16   
While studies have reported the rates of return to military duty, work, and sports, 
relatively few have provided information regarding the time from surgery to return to 
activity. Furthermore, the majority of the studies are retrospective in nature with limited 
sample sizes and none have prospectively determined the time required to return to 
pre-injury military duty, work and sports, which from the military’s perspective is of 
primary interest and highly relevant to unit readiness and return to duty capabilities. 
 
Association Between Multiple Ligament Knee Injuries and Premature 
Development of Arthritis 
Post-traumatic osteoarthritis arthritis (PTOA) is the most common long-term 
complication of a MLKI.8,19  At a minimum of two years follow-up, 87% of knees with a 
MLKI had grade 2 or worse Kellgren & Lawrence arthritic changes on radiographs, in 
contrast to only 35% of uninjured knees.8  Richter et al. reported similar rates of arthritis 
(68% Grade 2 or worse) at a mean of 8-years follow-up, and perhaps most importantly 
found an inverse relationship between PTOA and knee stability at follow-up, suggesting 
that surgical restoration of native knee stability may decrease the risk of PTOA.  
The robust link between MLKI and premature development of knee osteoarthritis (OA) is 
especially pertinent for the military population.  Knee OA represents an exceptionally 
large occupational burden for military personnel,7 and affects military service members 
at higher rates than their civilian counterparts.20,21  The overall rate of arthritis in military 
service members has been rising, and the incidence of PTOA in the military has risen 
100% since 2005.7  A recent review of U.S. Physical Evaluation Board (PEB) data for 
1566 combat-injured service members reported that 100% of battlefield knee injuries 
resulted in PTOA.21  The implications of this rising incidence are staggering considering 
that the most common reason for disability-related medical separation for military 
service members is OA.21,22 
The development of PTOA following a MLKI is at least in part due to the inability to 
restore normal structure and function of the knee.  Joint contracture, residual instability, 

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muscle weakness and/or poor neuromuscular control may all contribute to abnormal 
knee kinematics leading to altered loading of the knee with subsequent development of 
PTOA in the long term.  We believe that determining the optimal time for surgery and 
initiation of post-op rehabilitation may reduce residual knee impairments that contribute 
to development of PTOA.  Because of the extended time to develop PTOA, PTOA as an 
outcome measure will not be included in this study, however we will consider follow-on 
studies to assess long-term outcomes, including PTOA, of the subjects that participate 
in this study.   Rivera et al. 21 provided a fitting summary for this study by stating that 
“PTOA is common in the battlefield population,” and recommended that future studies 
should focus on “identification of clear treatment-related factors” that contribute to the 
development of PTOA, including “timing of surgery for intra-articular injuries” and 
“optimum rehabilitation strategies.”  
 
Controversies in Surgical Management of Multiple Ligament Knee 
Injuries 
While there are a number of controversies related to treatment of MKLIs, the literature 
has consistently demonstrated that operative management is superior to non-operative 
management of MLKIs.10,16,23,24  Patients treated surgically were significantly more likely 
to return to work25,26and sports.16,26,27  Furthermore, patients who underwent operative 
treatment for MLKI have shown lower rates of endstage arthritis and higher patient-
reported outcomes (PROs) scores than those who underwent non-operative 
management for the same types of injury.16  However, the optimal timing of surgery is 
less well understood and remains the subject of intense debate.  
 
Postoperative Rehabilitation of Multiple Ligament Knee Injuries 
The timing of rehabilitation after surgery for a MLKI has not been investigated.  The 
best available evidence for the timing of post-operative rehabilitation for knee ligament 
surgery is based on evidence from the ACL literature.  Early (accelerated) rehabilitation 
(immediate WB, ROM, quadriceps exercises) after ACL reconstruction is the current 
standard of care.28  Early (accelerated) rehabilitation has been found to reduce post-
operative stiffness,29 and is either superior or equivalent to delayed rehabilitation in 

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terms of PROs and resolution of ROM and strength deficits without adversely affecting 
knee joint laxity.30-32 
Post-operative rehabilitation after surgery for a MLKI typically involves a period of non-
weightbearing and delayed initiation of ROM exercises to protect the 
repaired/reconstructed structures33,34 however these guidelines are based on Level V 
expert opinion and have not been tested in a trial. 
 
 
Rationale 
The timing of surgical intervention is a crucial consideration for treatment of MLKIs, and 
the ideal timing for surgery has yet to be conclusively determined.  While certain 
circumstances require early intervention (irreducible knee dislocation, vascular injury, 
etc.), the majority of MLKIs create a treatment conundrum.  Recently, authors have 
suggested early surgical intervention within 3 to 6 weeks of injury, because within this 
time period tissue planes are more easily identifiable, tissue quality is sufficient to hold 
sutures for repair, and retraction of tissues such as ruptured tendons is minimized.24  
However, other authors have agreed with the conventional wisdom that delayed surgery 
for MLKI can decrease perioperative risks, such as compartment syndrome (from 
capsular fluid extravasation during surgery) and arthrofibrosis.35-37  Although several 
studies have compared the results of early vs. delayed surgery for MLKIs, the 
overwhelming majority of these studies were retrospective.3,38-42 Notably, no Level I 
prospective randomized trials have compared outcomes of early vs. delayed surgery for 
MLKI, and results from existing studies vary widely. 
A systematic review of 12 retrospective studies found no difference in outcomes based 
on the International Knee Documentation Committee (IKDC) Knee Ligament grade 
between early (58.4% good/excellent) and delayed (45.5% good/excellent) surgical 
management of KD-III injuries.36  However, the authors pooled results across studies 
that did not directly compare early vs. delayed surgery.   A second systematic review of 
24 Level III and IV retrospective studies that compared early vs. delayed surgery found 
increased post-op anterior laxity and more frequent flexion deficits in those undergoing 

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early surgery for a MLKI, but no difference in posterior, varus or valgus instability, 
average ROM, or patient reported outcomes.  There were a greater number of patients 
ultimately needing manipulation under anesthesia for post-op stiffness in the early 
compared to delayed surgery group.43 A third systematic review of five retrospective 
studies involving 130 patients that underwent early (within 3 weeks of injury) or delayed 
surgery for a MLKI found that that early surgery resulted in higher Lysholm scores (90 
versus 82) and a greater percentage of “excellent/good” IKDC results (47% verus 31%).  
No differences in ROM between the early and delayed surgery groups were found.24     
In summary, there is a trend in published studies toward improved patient-reported 
outcomes and laxity in early compared to delayed surgery, but there is an increased risk 
of postoperative stiffness.  However, non-randomized and retrospective studies that 
have investigated the timing of surgery for MLKIs are inherently limited because 
patients were selected for early versus delayed surgery based on the time of 
presentation and the expected or perceived soft tissue quality.  As such, it is not 
possible to directly compare the early vs. delayed surgery and inferences from the data 
must be made with caution.  Furthermore, none of the studies that examined early vs. 
delayed surgery precisely measured time to return to military duty, work and sports as 
an outcome, which of paramount importance from the perspective of unit readiness and 
the social and economic impact of these injuries.  Due to the conflicting evidence 
regarding early versus delayed surgical management of MLKIs, there is a need for a 
large randomized controlled trial to determine the optimal timing of surgery for these 
devastating injuries that can only be achieved in a large multicenter trial. 
 
Rational for Early vs. Delayed Post-Operative Rehabilitation for 
Multiple Ligament Knee Injuries  
Mook and colleagues systematically reviewed the available literature through 2008 
concerning the timing of post-operative rehabilitation.  In individuals treated with early 
surgery and immediate motion compared to immobilization, there were fewer instances 
of posterior, varus and valgus laxity, loss of flexion >10º, loss of extension >5o, and poor 
outcome scores.43  These results are specific only to the mobility component of 

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rehabilitation – early mobility was defined as allowing greater than 30o motion prior to 3 
weeks after surgery.  It should be noted that all of the studies included in the review by 
Mook et al were non-randomized comparative or single cohort retrospective studies.  
Currently there are no randomized trials comparing early vs. delayed motion.   
Mook and colleagues43 did not review the effects of weight bearing status.  Many 
published rehabilitation protocols for MLKIs call for an extended period of non-weight 
bearing (NWB) ranging from 4 weeks to 6 weeks.33,44-50  Very few protocols recommend 
weight bearing as tolerated (WBAT)51 and some recommend early partial weight 
bearing (PWB)3,8,16,34,40,52,53 or toe-touch weight bearing (TTWB).54-56  Considering the 
variability with the current expert recommendations for weight bearing (ranging from 
NWB, TTWD, PWB tor WBAT) and the lack of established outcomes after MLKI 
surgery, there is little evidence to support the need for non-weight bearing status.  
Conversely, controlled weight bearing benefits cartilage and meniscus nutrition,57 can 
provide beneficial proprioceptive input to the knee joint, and promote muscle activity.  
Given the variability in weight bearing after MLKI surgery and its potential benefits, we 
will test a method to dose early weight bearing for the reconstructed knee based on the 
cardinal signs of inflammation (effusion, pain, warmth & redness).   
Therefore, given the above information, we have designed this study to determine if 
early controlled WB and ROM exercises within the first week after surgery will allow for 
restoration of normal ROM of the knee with no increased risk of laxity or instability, 
leading to an earlier and more complete return to military duty, work and sports.  We 
hypothesize that early WB and ROM exercises initiated within the first week after 
surgery will shorten the time to return to pre-injury level of military duty, work and sports. 
 
 
Potential Risks and Benefits 
 
Potential Risks 
Participants in this study will undergo multiple knee ligament 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 of surgery will be 

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discussed during the clinical surgery consent process. The risks of surgery include the 
risks associated with anesthesia as well as post-operative pain and swelling, loss of 
motion or joint stiffness, recurrent laxity and instability, infection, deep vein thrombosis 
and injury to neurovascular structures. Because subjects participating in this study 
would be undergoing surgery regardless of whether 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. 
While the current standard of care for MLKIs includes early or delayed surgery and early 
or delayed post-operative rehabilitation, there is no definitive evidence of the risks 
associated with these methods of treatment. However, randomization to these standard 
of care methods for surgical treatment and rehabilitation of MLKIs may carry associated 
risks that are currently unknown. These may include the risk of joint stiffness and 
contracture for those in the early surgery and/or delayed rehabilitation groups as well as 
increased joint laxity and instability of the knee for those undergoing delayed surgery 
and/or early rehabilitation. To mitigate these risks, we will closely monitor post-operative 
recovery of the individual and will intervene as necessary. This could include additional 
surgery and/or physical therapy to address arthrofibrosis or instability.  
Follow-up activities involved with this study include the completion of patient-reported 
outcome measures and evaluation of return to activity by subjects at multiple intervals 
throughout the duration of the study. These follow-up activities will be completed by the 
subjects remotely via Internet-based data collection methods. Although data security 
measures will be implemented, there is a risk of breach of confidentiality. 
Subjects will complete several instruments (PROMIS Global 10 Health Scale and the 
Emotional Impairments Scale of the Multiple Ligament Quality of Life Questionnaire) 
that inquire about behavioral health status. While these instruments are not direct 
measures of emotional distress (depression, anxiety etc.), responses to some of these 
questions could indicate the participant is in emotional distress.  On the PROMIS Global 
10 Health Scale, this includes questions 4 (In general, how would you rate your mental 
health, including your mood and ability to think?) and 8 (How often have you been 

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bothered by emotional problems such as feeling anxious, depressed or irritable?) and 
question 34 (How often are you depressed or sad due to knee pain or nerve pain?) on 
the Emotional Impairment Scale of the Multiple Ligament Quality of Life Questionnaire.  
Responses of "poor" to question 4 or "always" to question 8 on the PROMIS Global 10 
Health Scale or a response of "always" to question 34 on the Emotional Impairment 
Scale of the Multiple Ligament Quality of Life Questionnaire could indicate that the 
participant is in emotional distress.  The responses to these questions will be monitored 
and will provide feedback to the participant regarding appropriate intervention, if needed 
and if the situation affects the immediate safety of the subject, we will communicate this 
to the research team who will assist in facilitating immediate evaluation at the 
Emergency Department or through a crisis center. 
 
Potential Benefits 
Participants in this study may benefit from being followed more closely during the 
conduct of the study. This would allow for more timely progression of the post-operative 
recovery process as well as more timely identification and treatment of any 
complications associated with multiple ligament knee injuries. This study also has the 
potential to improve the surgical and rehabilitation care for future patients undergoing 
treatment of a multiple ligament knee injury. 

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3 OBJECTIVES 
 
Study Objectives 
The overall objective of this project is to investigate the effects of timing of surgery 
(early vs. delayed) and timing of post-op rehabilitation (early vs. delayed) for the 
treatment of military personnel and civilians that have sustained a MLKI. To achieve this 
objective, we will conduct two parallel randomized, controlled trials. The aims and 
hypotheses for these trials are: 
 
Specific Aim 1 
To determine the effects of timing of surgery and post-op rehabilitation on time to return 
to pre-injury level of military duty, work and sports and patient-reported physical 
function. We hypothesize that early surgery, early rehabilitation and the combination of 
early surgery with early rehabilitation will lead to an earlier and more complete return to 
pre-injury military duty, work and sports and better patient-reported physical function. 
3.1.2 
Specific Aim 2 
To determine the effects of timing of rehabilitation on time to return pre-injury level of 
military duty, work and sports and patient-reported physical function.  We hypothesize 
that early rehabilitation will lead to an earlier and more complete return to pre-injury 
military duty, work and sports activity and better patient-reported physical function. 
 
 
Study Outcome Measures 
The primary outcome will be time return to full pre-injury military duty, work and sports. 
Patient-reported physical function as measured with the Activities Limitation Scale of the 
Multiple Ligament Quality of Life (MLQoL) Questionnaire will be assessed as a co-
primary outcome 6, 12 and 24 months after randomization. Secondary outcome 
measures will include additional knee-specific and general patient-reported measures of 
physical function and health related quality of life, recovery of range of motion (ROM), 

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arthrofibrosis, residual laxity, complications/adverse events, re-injury and additional 
surgical procedures. 
 
Primary Outcome 
The primary outcome will be time return to full pre-injury military duty, work and sports.  
For military personnel, to assess return to duty we will ask three questions from the 
Injury Surveillance Survey (ability to perform Annual Physical Fitness Test; 
deployability, ability to perform specific military occupational specialty [MOS] duties). 
Additionally, we will record the military subject’s MOS physical demand classification.  
The physical demands of work and sports activity will be assessed using the Cincinnati 
Occupational Rating58 and Marx Activity Scales,59 respectively.  To further assess return 
to work, we will also record the individual’s current employment status and specific 
occupation. To assess sports participation, we will record the type (very strenuous, 
strenuous etc.) and frequency (4-7 times per week, 1-3 times per week etc.) of sports. 
Because of the expected heterogeneity of pre-injury activity level of individuals that 
sustain a MLKI we will combine return to pre-injury military duty, work and sports into an 
overall Return to Activity and Participation variable.  Individuals will be classified as 
having returned to activity if and when they have returned to their pre-injury level of 
military duty, work and sports.  Successful return to activity will be assessed using the 
patient-reported measures of military duty, work and sports and will be compared to the 
individual’s pre-injury level of military duty, work and sports.   
Individuals in the military will achieve a “Full Return to Activity and Participation” 
designation if and when they indicate they have returned to full pre-injury level of 
military duty, work and sports without any restrictions based on their: 
• Reported ability to pass an Annual Physical Fitness Test at a level similar to pre-
injury and are as deployable and mission capable as they were prior to injury (per 
the ISS); 
• Achievement of the same or better score on the Cincinnati Occupational Rating 
Scale and;  

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• Achievement of the same or better score on the Marx Activity Rating Scale and 
participation in the same type and frequency of sports as prior to injury. 
Individuals who are not in the military will achieve a “Full Return to Activity and 
Participation” designation if and when they have returned full pre-injury work and sports 
without any restrictions based on their:  
• Achievement of the same or better score on the Cincinnati Occupational Rating 
Scale and;  
• Achievement of the same or better score on the Marx Activity Rating Scale and 
participation in the same type and frequency of sports as prior to injury. 
Any individual who does not meet all of these criteria will be designated as having “Not 
Returned to Full Activity and Participation”.  Participants reporting that they have 
returned to military duty, work and sports in a limited or modified role will be considered 
as having “Not Returned to Full Activity and Participation”.   
 
Co-Primary Outcome – Patient Reported Physical Function 
The Multiple Ligament Quality of Life (MLQoL) Questionnaire60 is a condition-specific 
patient-reported outcome measure for individuals that have sustained a MLKI.  It was 
developed with stakeholder input from patients with a MLKI and clinicians that treat 
those patients to address the limitations of existing knee-specific patient-reported 
outcome measures that do not represent the full spectrum of content that is pertinent to 
individuals with a MLKI.  The MLQoL questionnaire consists of 52 items that are divided 
into 4 domains: physical impairment (19 items), emotional impairment (15 items), 
activity limitations (12 items) and social involvement (6 items).  Lower scores represent 
the best outcomes for each subscale.     
To measure physical function, we selected the Activity Limitation scale of the MLQoL 
Questionnaire as the primary outcome based on input from patients with a MLKI that 
indicated items contained in this scale were most important and relevant over the long-
term.60  Psychometric testing of the Activity Limitation scale in individuals with a MLKI 

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found no floor or ceiling effects, internal consistency (Cronbach’s Alpha) was 0.94 and 
test re-test reliability (intra-class correlation coefficient[ICC]) was 0.91.  Furthermore, the 
Activity Limitations scale demonstrated construct validity as evidenced by satisfying 
seven of eight a priori hypotheses. 
 
 
Secondary Outcomes 
3.2.3.1 Secondary Knee-Specific Patient-Reported Outcome Measures 
The MLQoL Questionnaire Physical Impairment, Emotional Impairment and Social 
Involvement Scales will serve as MLKI-specific secondary measures of patient-reported 
outcome.  These scales contain content that is relevant for individuals with a MLKI, 
have no floor or ceiling effects and acceptable levels of internal consistency 
(Cronbach’s Alpha 0.94, 0.93 and 0.91 respectively), test re-test reliability (ICC 0.89, 
0.86 and 0.88 respectively) and construct validity.60 
International Knee Documentation Committee Subjective Knee Form (IKDC-SKF) is an 
18-item knee-specific patient-reported measure of symptoms, function and sports 
activities for individuals with a variety of knee conditions, including MLKIs.  The IKDC-
SKF has undergone extensive psychometric testing.61-63 and normative data in a 
representative sample of the United States population has been determined.64  Test re-
test reliability was high (ICC 0.94) with a standard error of measurement of 4.6.  The 
IKDC-SKF is related to concurrent measures of physical function (r=.47 to .66) but not 
emotional function (r=.16 to .26).  A change score of 11.5 was found to distinguish 
between those who were improved and those who were not over an average of 19 
months follow-up.62  Most recently, the threshold for the patient acceptable symptom 
state (PASS) for the IKDC-SKF for individuals 1 to 5 years after ACL reconstruction has 
been established.65   

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3.2.3.2 General Measures of Patient-Reported Physical Function 
The Patient Reported Outcome Measurement Information System (PROMIS) Physical 
Function (PF) Scale was developed by the PROMIS Network, which was an NIH 
Roadmap Initiative, to assess physical function regardless of the health condition 
present.  The PROMIS PF item bank has been shown to be well suited to assess 
patient-reported outcomes in those with a variety of orthopaedic disorders.  PROMIS PF 
CATs have been used for patients with foot and ankle disorders,66 following ACL 
reconstruction67, osteoarthritis,68 knee osteoarthritis69 and have demonstrated adequate 
internal consistency,66 test re-test reliability,68 decreased ceiling and floor effects,66 and 
shorter completion times.66,67  As part of an NIAMS-funded study, we recently 
demonstrated the PROMIS PF CAT had moderate test re-test reliability (ICCs 0.55 to 
0.68) over 1 and 3 month time periods in a stable cohort of individuals 2 or more years 
after ACL reconstruction and large effect sizes (ES) from before to 12 (ES 1.85 ) and 24 
months (ES 1.80 ) after ACL reconstruction.  To minimize response burden we will 
administer the PROMIS PF scale as a CAT that is offered through the REDCap library.      
3.2.3.3  Patient-Reported Multi-Dimensional Quality of Life 
The PROMIS Global 10 scale is a 10-item patient-reported measure of physical and 
emotional health.70  Exploratory and confirmatory analyses indicated the global health 
items fit a two factor model that included global physical and global mental health.  The 
scales had an internal consistency of 0.81 and 0.86 respectively and the global physical 
health scale was more strongly correlated (r=0.76) with the EQ-5D then was the global 
mental health scale (r=.59).  We are including the PROMIS Global 10 as a measure of 
global health because global health items are predictive of future health care utilization 
and mortality. 
3.2.3.4 Additional Secondary Outcomes from Clinical Follow-Up Visits 
Information gathered during standard of care clinical follow-up visits will be 
prospectively collected at 1, 3, 6 and 9 to 12 months after the date of surgery.  This 
information will be documented on a Clinical Visit Form and will serve to provide 

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additional secondary outcomes related to post-operative recovery.  The information will 
include pain, pain medication usage, joint effusion, wound and neurovascular status, 
ROM, WB status, use of a post-operative rehabilitation brace, imaging and/or laboratory 
tests ordered and completed, complications and adverse events, additional surgical 
procedures and military duty, work and sports status.  Knee laxity will also be assessed 
at the final clinical follow-up 9 to 12 months after surgery.   

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4 STUDY DESIGN 
To address the controversies and lack of evidence related to the timing of surgery and 
post-operative rehabilitation for treatment of individuals with a MLKI we will conduct two 
parallel phase 3 unblinded multicenter randomized clinical trials (Figure 1). In the first 
trial, we will randomize 392 individuals to four groups (98 per group): early surgery/early 
rehabilitation, early surgery/delayed rehabilitation, delayed surgery/early rehabilitation 
and delayed surgery/delayed rehabilitation.  In the second trial, which will be conducted 
concurrently with the first trial, we will randomize 298 individuals (149 per group) with a 
MLKI whose surgery cannot be randomized due to presentation greater than 6 weeks 
after injury or vascular or other injury requiring immediate surgery as well as those that 
refuse randomization to surgery to either early or delayed post-operative rehabilitation.   
Participants will be recruited at 25 clinical sites, including 5 United States (US) military 
sites and 3 Canadian and 17 US civilian sites.  Randomization will be done using 
permuted blocks with random block sizes stratified by site and injury pattern.  
Randomization will be concealed to those responsible for recruitment and determining 
subject eligibility.  Recruitment is expected to occur over 21 months and participants will 
be followed for 24 months. 
Early surgery will be defined as surgical treatment of the MLKI within 6 weeks of injury 
and delayed surgery will be performed 12 to 16 weeks after injury.  Early post-operative 
rehabilitation will consist of WBAT gait and unrestricted ROM exercises starting within 1 
week after surgery.  For delayed post-operative rehabilitation, participants will use a 
NWB gait and the knee brace locked in extension for the first 4 weeks after surgery 
followed by progressive WB and ROM exercises.      
The primary outcome will be the time to return to pre-injury military duty, work and 
sports, which will be assessed monthly starting 6 months after randomization through 
24 months.  The Activity Limitations Scale of the Multi-Ligament Quality of Life Scale 
which is a knee-specific patient-reported measure of physical function, will serve as a 
co-primary outcome and other knee-specific and general health related quality of life 
PROs that will serve as secondary outcomes will be collected at the time of 

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randomization and at 6, 12 and 24 months after randomization.  Return to pre-injury 
activity and patient-reported outcome will be collected electronically through surveys 
administered by the Data Coordinating Center at the University of Pittsburgh.   
Additional secondary outcomes, including recovery of ROM, arthrofibrosis, residual 
laxity, complications/adverse events, re-injury and additional surgical procedures, will be 
determined through standardized, structured usual-care clinical follow-up visits 1, 3, 6 
and 9 to 12 months after surgery.  These data will be recorded on electronic Clinical 
Visit Forms completed by the clinical and research staff at each participating clinical 
site. 
 
 
Figure 1 - Subject Presentation, Eligibility, and Randomization. Blue boxes are associated with 
Aim 1. Yellow boxes are associated with Aim 2. 

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5 STUDY ENROLLMENT AND WITHDRAWAL 
 
Subject Inclusion Criteria 
 
Inclusion Criteria for Participants Enrolled Aims 1 and 2 
Male and female military personnel and civilians between the ages of 16 and 55 with a 
MLKI (defined as a complete grade III injury of two or more ligaments) without a history 
of prior knee ligament reconstructions will be eligible to participate in the clinical trials for 
Aim 1 or 2.  Individuals with a nerve injury or biceps or popliteus tendon rupture/avulsion 
will not be excluded from participation in either trial (Table 1). 
 
Inclusion Criteria for Participants Enrolled in Aim 1 - Randomization to 
Both Timing of Surgery and Post-Operative Rehabilitation 
To be eligible to participate in the trial that randomizes individuals to both the timing of 
surgery and timing of post-operative rehabilitation, individuals with a MLKI must present 
to the orthopaedic surgeon in time to undergo definitive surgery within 6 weeks of injury 
if randomized to the early surgery group. 
 
Inclusion Criteria for Aim 2 - Randomization to Only Timing or Post-
Operative Rehabilitation 
Subjects with a MLKI that present to orthopaedic surgery at a time that precludes 
randomization to early surgery or have an injury that precludes randomizing the timing 
of surgery (such as a vascular injury) as well as those that refuse randomization to the 
timing of surgery will be eligible to participate in the study for Aim 2 which randomizes 
subjects to only early vs. delayed rehabilitation. 
 
 
Subject Exclusion Criteria 
 
Exclusion Criteria for Enrollment of Participants in Trials for Either 
Aims 1 or 2 
Individuals will be excluded from both trials if they: 
1. Have a history of prior knee ligament surgery of the involved knee: 

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2. Have a torn or avulsed patellar or quadriceps tendon; 
3. Have a periarticular or long bone fracture that is anticipated to preclude weight 
bearing after surgery;  
4. Require use of an external fixator to maintain reduction of the knee or soft 
tissue/open wound management for greater than 10 days;  
5. Planned staged surgical treatment for MLKI; 
6. Are unable to WB on the contralateral uninjured leg; 
7. Have a traumatic brain injury (TBI) that limits their ability to participate in their 
post-operative care or any condition that would preclude the ability to comply with 
post-operative guidelines; 
8. Skin or soft tissue injury that precludes early surgery and/or early rehabilitation; 
9. Surgical procedure that precludes early WB & ROM (i.e. surgery for extensor 
mechanism rupture or avulsion, vascular graft surgery).  
10. Have multiple trauma that limits ability to participate in early rehabilitation; 
 
 
Exclusion of Participants in Trial for Aim 1 - Randomization to Both 
Timing of Surgery and Post-Operative Rehabilitation 
Individuals will be excluded from the trial that randomizes both the timing of surgery and 
post-operative rehabilitation if they: 
1. Have a vascular injury that dictates the timing of surgery; 
2. Have multiple trauma that precludes surgery within 6 weeks of injury; 
 
Exclusion of Participants in Trial for Aim 2 – Randomization to Only 
Post-Operative Rehabilitation 
Individuals will be excluded from the trial that randomizes only the timing post-operative 
rehabilitation if they: 
1. Have vascular surgery that precludes early rehabilitation; 
2. Have a skin or soft tissue injury that precludes early weightbearing or range of 
motion. 
 

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Table 1: Summary of Eligibility Criteria for Each Clinical Trial 
Specific Aim 1 – Randomize Timing of 
Surgery & Post-Operative Rehabilitation 
Specific Aim 2 – Randomize Timing 
of Post-Operative Rehabilitation 
Inclusion Criteria 
Inclusion Criteria 
• Male and female military personnel & 
civilians with MLKI (grade III injury of 2 or 
more ligaments) 
• Male and female military personnel 
& civilians with MLKI (grade III 
injury of 2 or more ligaments) 
• 16 to 55 years of age 
• 16 to 55 years of age 
• Present for treatment in time to be 
randomized to early surgery (within 6 
weeks of injury) 
 
Exclusion Criteria 
Exclusion Criteria 
• Prior ligament reconstruction of 
ipsilateral knee 
• Prior ligament reconstruction of 
ipsilateral knee 
• Torn or avulsed patellar or quadriceps 
tendon 
• Torn or avulsed patellar or 
quadriceps tendon 
• Have a periarticular or long bone fracture 
that is anticipated to preclude weight 
bearing after surgery 
• Have a periarticular or long bone 
fracture that is anticipated to 
preclude weight bearing after 
surgery 
• External fixator for greater than 10 days 
• External fixator for greater than 10 
days 
• Planned staged surgical treatment 
• Planned staged surgical treatment 
• Inability to WB on contralateral leg 
• Inability to WB on contralateral leg 
• Traumatic brain injury that limits ability to 
participate in post-op care 
• Traumatic brain injury that limits 
ability to participate in post-op care 
• Vascular injury that dictates timing of 
surgery 
• Vascular surgery that precludes 
early rehabilitation 
• Polytrauma that precludes surgery 
within 6 weeks of injury 
• Polytrauma that limits ability to 
participate in post-op care 
• Skin or soft tissue injury that 
precludes early surgery and 
rehabilitation 
• Skin or soft tissue injury that 
precludes early rehabilitation 
• Surgical procedure that precludes early 
WB & ROM 
• Surgical procedure that precludes 
early WB & ROM 

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Strategies for Recruitment and Retention 
 
Recruitment of Participants for the Trial for Aim 1 that Randomizes 
Both the Timing of Surgery and Rehabilitation 
Based on our preliminary retrospective study, we estimate that across 25 clinical sites 
there will be 1213 MLKIs over a 2-year recruitment period.  Additionally, based upon the 
preliminary retrospective study we expect that approximately 78% of the patients will 
present to orthopaedics within 6 weeks of injury, making it possible to randomize the 
individual to early surgery, defined as surgery within 6 weeks of injury.  We utilized the 
prevalence of polytrauma; soft tissue and skin, vascular and quadriceps and patellar 
tendon injuries and use of an external fixator to estimate the number of individuals we 
would expect to meet our eligibility criteria for Aim 1.  In doing so, we estimated that 
50% of the individuals with polytrauma would be able to undergo surgery within six 
weeks of injury if randomized to early surgery.  After these exclusions, we estimated 
that there will be approximately 650 eligible individuals with a MLKI that present to 
orthopaedic surgery in time to make it possible to perform surgery within 6 weeks if 
randomized to early surgery. If approximately 60% of the eligible subjects agree to 
participate in the study, this would provide a total sample size of 392 (n= 98 per cell). 
Assuming 10% lost to follow-up over two years, we expect to have 352 subjects (n=88 
per cell) for the final analysis. To achieve the required sample size for the trial that 
randomizes both timing of surgery and post-operative rehabilitation, with 25 clinical 
sites, we expect that each site will recruit and randomize approximately 16 subjects.    
 
Recruitment of Participants for the Trial for Aim 2 that Randomizes 
Timing of Rehabilitation 
After accounting for those included in the trial that randomizes surgery and rehabilitation 
and applying the exclusions described above we estimate that approximately 440 
individuals with a MLKI will be eligible for participation in the trial that randomizes only 
timing of post-op rehabilitation.  If approximately 68% of the eligible subjects agree to 
participate in the study that randomizes only timing of post-operative rehabilitation, this 

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would provide a total sample size of 298 (n= 149 per cell). Assuming 10% lost to follow-
up over two years, we expect to have 268 subjects (n=134 per cell) for the final 
analysis. To achieve the required sample size for the trial that randomizes only the 
timing of post-operative rehabilitation, with 25 clinical sites, we expect that each site will 
recruit and randomize approximately 12 subjects.  
 
Recruitment Process 
Potentially eligible patients will be informed of the study by their orthopaedic surgeon or 
the surgeon’s clinical designee, either during an office visit or in the Emergency 
Department.  To identify potentially eligible individuals that present to the Emergency 
Department, the study team will work closely with the orthopaedic residents and 
orthopaedic trauma attending surgeons and fellows to identify and inform individuals 
with a MLKI that are eligible for the study.  Individuals with a MLKI interested in learning 
more about the study will be introduced to a research coordinator who together with the 
surgeon-investigator will explain the study details to the participant.  If the individual is 
willing to participate in the study, he/she will review and sign the consent form, which 
will also be signed by the surgeon-investigator.  The participant will be given as much 
time as necessary to review the consent form and ask questions.  Prior to signing the 
consent form, all questions will be answered to the satisfaction of the individual by 
research coordinator and/or surgeon-investigator.   
For active duty military personnel, no individuals in the participant’s chain of command 
will be involved in the recruitment process.  Because the surgeon is also an investigator 
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, subjects 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 trial for Aim 1 or 2. 
 
 

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Efforts to Monitor and Maximize Subject Recruitment 
A number of strategies have been and 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 to 
the Research Coordinator 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.  To keep all study personnel 
engaged we will produce and distribute a quarterly newsletter that highlights study 
successes, provides recruitment tips and lists the recruitment results for each site.   
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 encouraged 
to recruit additional subjects beyond their targeted enrollment and will be rewarded 
accordingly based on the budget model that reimburses sites based on the number of 
subjects enrolled and followed.   
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.  Site participation in the study will be reconsidered if 
recruitment drops below 50% of site target enrollment after 3 quarters of recruitment 
(i.e. enrolled less than 6 subjects by the end of year 1).  If overall 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. 
A Recruitment Committee has been established and consists of investigators and 
research coordinators from the Coordinating Center and the collaborating clinical 
research sites.  The Recruitment Committee will establish a plan for and monitor 
recruitment throughout the duration of the trial. The committee will review and approve 
recruitment materials, such as cards with eligibility criteria, posters that can be used at 
the sites.  The Committee will also encourage each site to do a presentation related to 
MLKIs and the STaR Trial at the site’s Grand Rounds.   Additionally, should a site be 

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recruiting fewer subjects than recommended, the Recruitment Committee will evaluate 
the site and make recommendations to improve recruitment.  If recruitment fails to 
improve, the Recruitment Committee will make a recommendation to the Executive 
Committee to terminate the site. 
 
 
Subject Payment 
Individuals will be compensated for participation in the study.  The participating clinical 
sites will be responsible for payment of subjects enrolled by the site.  All participant 
payments will be processed by each site. 
5.3.5.1 Pro-Rated Payments for Subjects Recruited at Civilian Research Site 
If individuals participate and complete all research-related activities, they will receive up 
to $400.  Payment for partial participation in the study will be pro-rated as follows: 
• Participants will be paid by the site at which they were enrolled $50 for informed 
consent and $55 for completion of the baseline patient-reported forms;  
The Coordinating Center at the University of Pittsburgh will assume responsibility for 
collecting all patient-reported outcomes data.  Participant payment for completion of 
follow-up patient-reported outcomes data will be prorated as follows:  
• Completion of 6-month return to activity & patient-reported outcome measures - 
$35; 
• Completion of 12 month return to activity & patient-reported outcome measures - 
$35; 
• Completion of 24 month return to activity & patient-reported outcome measures - 
$35; 
• Participant assessment of rehabilitation activities at post-operative months 1, 3 
and 6 - $10/month up to $30; 
• Participant completion of brief return to activity measure at post-operative months 
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5.3.5.2 Payment of Participant from Military Treatment Centers 
No payments will be provided to active military personnel that are recruited to 
participate in this study. Dependents of active military personnel and retired military 
personnel will be paid for participation in the study as described above for civilians. 
 
 
Efforts to Maximize Subject Retention 
5.3.6.1 Research Follow-ups 
For US Sites, all research follow-ups starting 6 months after randomization will be 
initiated by the Coordinating Center at the University of Pittsburgh utilizing text and/or e-
mail messages.  Contact information, including the participant’s primary and secondary 
e-mail accounts and home and cell phone numbers will be obtained at the time of 
enrollment in the study.  Individuals will also indicate their preferred method for 
communicating with the study investigators (i.e. e-mail, text messaging, phone).  
Additionally, we will ask participants to identify and provide contact information for two 
family members or close friends that do not live with the participant but know and will 
most likely always know how to contact the participant. Access to identifiable 
information will be limited to the site local research team and to research team at the 
Coordinating Center. 
Canadian sites will enter de-identified clinical data including screening, baseline clinical 
examination, surgical findings and procedures and information from all clinical follow-up 
visits into the University of Pittsburgh electronic data capture system (REDCap). 
Contact information for each participant (email and/or phone number) is needed for the 
research follow-ups; however due to Canadian privacy laws that information for 
Canadian participants cannot be maintained on the University of Pittsburgh servers.  
Therefore, a copy of the REDCap project structure for the surveys involving patient 
reported outcomes will be sent to each Canadian site so that they can create their own 
survey project in the REDCap instance at their institution. Once the surveys have been 
administered, each Canadian site will be responsible for regularly exporting de-identified 
survey data and sending it to the STaR Trial DCC. The DCC will send reports back to 

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each Canadian site pertaining to missed follow-ups, potential adverse events and 
emotional health problems, and data quality. 
Multiple attempts to contact non-responders will be utilized.  Generally, participants will 
be contacted by their preferred method (either via e-mail or text messaging) 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 Coordinating Center and/or by the site research staff.   
5.3.6.2 Clinical Visit Follow-Ups 
Standard of care clinical follow-up of participants will occur approximately 1 week and 1, 
3, 6, and 9 to 12 months after surgery.  This follow-up will make use of a standardized 
clinical examination and will be documented on the Clinical Visit Form.  Sites will be 
paid upon completion and submission of the clinical forms.  The electronic data capture 
system will generate regular reports of missing forms and missing data points.  These 
reports will be shared with the site research coordinator for adjudication and resolution.  
Should participants move or not attend follow up visits, efforts will be made by the 
research team to access the electronic health records to collect data from the follow-up 
clinical visits to complete the Clinical Follow-Up Visit form.  The collection and use of 
clinical information from the medical record for research purposes is included in the IRB 
protocol and study participants agree to this in the informed consent process. 
 
 
Treatment Assignment Procedures 
To address Aim 1, 392 individuals with a MLKI that present within 6 weeks of injury will 
be randomized to early (within 6 weeks of injury) or delayed (12 to 16 weeks after injury) 
surgery and early (WB as tolerated and unrestricted ROM exercises starting first week 
after surgery) vs. delayed (non-WB and limited ROM exercises for the first four post-op 
weeks) rehabilitation. To address Aim 2, 298 individuals with a MLKI that present 
greater than 6 weeks after injury, have an injury that precludes randomization to early or 

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delayed surgery as well as those that refuse randomization to surgery will be eligible to 
participate in the trial that randomizes only early vs. delayed rehabilitation. 
Subjects will be randomized in 1:1 allocation for both factors (timing of surgery and 
timing of rehabilitation) in the two by two trial (Aim 1) and for timing of rehabilitation in 
the two-arm trial (Aim 2).  Therefore, participants will have an equal chance of being 
randomized to one of four groups in the trial that randomizes timing of surgery and 
timing of post-operative rehabilitation and to one of two groups for the trial that 
randomizes only timing of post-operative rehabilitation.     
For those enrolled in the trial for Specific Aim 1, randomization to early versus delayed 
surgery will occur after the informed consent process in individuals who are eligible for 
randomization to early surgery and agree to be randomized.  To prevent the allocated 
rehabilitation intervention from influencing the surgical intervention, allocation to early 
vs. delayed rehabilitation will not be disclosed to the participant until after surgery. 
Randomization for the rehabilitation only trial (Aim 2) will remain pending until the 
participant has undergone surgery and eligibility criteria are re-confirmed. The allocated 
rehabilitation protocol will be communicated to the physical therapist by the surgeon 
and/or research coordinator at the time when the subject is referred to physical therapy 
one week after surgery. 
 
Randomization Procedures 
Randomization will occur at the subject level. The randomization schedule will be 
created by the Data Coordinating Center (DCC) statisticians using permuted blocks with 
random block sizes stratified by site and injury pattern (KD I, KD II-KDIV, KD-V). The 
randomization lists will be created using SAS version 9.4 using a random number 
generator and fixed seed. The lists will be uploaded into the REDCap randomization 
module. This module permits allocation concealment such that the allocation to the 
treatment arm is only viewed once all eligibility criteria are entered and confirmed to be 
met. Once the study coordinator has obtained and entered all screening information, 

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he/she can request a randomization assignment by clicking on the ‘Randomize’ field 
which will then provide the allocation for only that subject. 
The SAS program used to generate the randomization schedule will be stored in the 
DCC STaR network folder which is only accessible by DCC staff. 
 
Masking Procedures 
These are unblinded trials as the participants and care providers will know when they 
are receiving surgery and when they are receiving rehabilitation.  Both interventions 
being tested (early versus delayed surgery, early versus delayed rehabilitation) cannot 
be masked to the site coordinators because of these individuals are responsible for 
scheduling (or assisting with scheduling). The rehabilitation assignment will only be 
communicated to the surgeon after the surgery so as not to influence surgery. The 
dates of the surgery and rehabilitation are collected as part of the standard of care and 
will be available to the surgeons during follow-up. The primary outcome and most of the 
secondary outcomes are patient self-report, therefore, the health providers and 
research team have no influence on the response.  Given that our interventions are 
either early or delayed surgery and/or rehabilitation, it is difficult for us to estimate the 
direction of potential bias (if any) that could come from the unblinded nature of this 
study. 
 
Subject Withdrawal 
Subjects may withdraw, at any time, their consent for participation in this research 
study. Any identifiable research or medical information recorded for, or resulting from, 
their participation in this research study prior to the date that they formally withdraw their 
consent may continue to be used and disclosed by the investigators for the purposes of 
the research study.   
To formally withdraw consent for participation in this research study each subject should 
inform their decision the research team at the contact information provided on the first 
page of the informed consent document.  

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A subject’s decision to withdraw their consent for participation in this research study will 
have no effect on their current or future relationship with the institution at which they 
were recruited.  Their decision to withdraw their consent for participation in this research 
study will have no effect on their current or future medical care at the institution or with 
an affiliated health care provider.  
It is possible that subject’s may also be removed from the research study by the 
researchers.  Subjects may be withdrawn if they do not comply with study procedures.  
 
Reasons for Withdrawal 
Patients will be discontinued from the study if, for example, they are unable to be 
compliant with the study follow-up procedures.  The following is a list of examples of 
reasons for withdrawal:  
1. Participant is deemed ineligible after signing consent; 
2. Participant is unable or unwilling to travel to study center; 
3. Participant finds the frequency of full follow-up visits burdensome; 
4. Investigator determination, specify: ____________________________ 
5. Participant has withdrawn consent, not otherwise specified 
6. Lost to follow-up 
7. Participant Death __/__/____ (date of death) 
Other: (specify) ______________________________________________ 
 
Handling of Subject Withdrawals or Subject Discontinuation of Study 
Intervention 
As specified in the local Data and Safety Monitoring Plan, subject withdrawals and 
deviations from allocated interventions will be reviewed during regularly scheduled data 
and safety monitoring meetings. The local Data and Safety Monitoring Plan (DSMP) will 
be implemented by the site PI and Co-Investigators.   

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Premature Termination or Suspension of Study 
This study may be suspended or prematurely terminated if there is sufficient reasonable 
cause.  Suspension or termination may be imposed by the Principal Investigators, 
Research Monitor, Data and Safety Monitoring Board, IRB and/or HRPO.  Written 
notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to Drs. James Irrgang and Volker 
Musahl, the site principal investigators and Ms. Jessica Clement, the DoD Scientific 
Officer.  If the study is prematurely terminated or suspended, the principal investigator 
will promptly inform and provide the reason(s) for termination or suspension to the IRB 
and the DoD HRPO.  
Circumstances that may warrant termination include, but are not limited to: 
1. Determination of unexpected, significant, or unacceptable risk to subjects; 
2. Failure to meet recruitment targets; 
3. Insufficient adherence to protocol requirements; 
4. Data that are not sufficiently complete and/or evaluable;  
5. Determination of futility; 
6. Non-compliance with the terms and conditions of the award from the DoD. 

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6 STUDY INTERVENTION 
 
Description of Study Procedural Intervention(s) 
 
Early vs. Delayed Surgery for MLKI 
For the clinical trial that is performed for Specific Aim 1, we have operationally defined 
early definitive surgery to be surgery within 6 weeks of injury to repair and/or reconstruct 
the torn structures.  Delayed surgery to has been operationally defined as repair and/or 
reconstruction of the torn structures 12 and 16 weeks after injury.  Although early 
surgery is defined as within 6 weeks, every effort will be made to perform surgery as 
soon as possible, if randomized to early surgery.  Staged surgery will not be considered 
an option for surgical treatment of MLKIs in this study and will render a potential 
participant ineligible.  
All surgical findings and procedures will be documented on electronic surgical case 
report forms.  As the QC for Surgery, Dr. Musahl will be available to answer any 
questions from surgeons regarding a subject’s participation in the study. 
Definitive surgical treatment of soft tissue injuries will 
follow a standardized algorithm (Figure 2) comprising 
primary repair and/or reconstruction.  Surgery will be 
performed in accordance with the principles of anatomic 
repair and/or reconstruction of injured structures in a 
manner that will allow for early range of motion.  Graft 
choice for reconstruction of injured tissues will be at the 
discretion of the operating surgeon and will not be 
standardized; however, graft choice will be recorded on 
the surgical case report form.     
Examination Under Anesthesia – A complete 
assessment of knee function will be performed after 
anesthesia has been induced. The surgeon will assess 
Examination Under 
Anesthesia
Meniscus Findings and 
Procedures
Cartilage Findings and 
Procedures
Ligament Findings and 
Procedures
Peroneal Nerve Findings 
and Procedures
Figure 2. Surgical Algorithm 

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range of motion of the knee joint as well as the function of the cruciate ligaments, 
collateral ligaments, and the posterolateral corner. 
Meniscus and Cartilage - The status of the menisci and cartilage will be assessed 
arthroscopically.  Injuries to the menisci or cartilage may be left in situ, or surgery may 
be performed to repair or debride the tissue at the discretion of the operating surgeon.  
Meniscus and cartilage findings and procedures will be documented on form. 
Cruciate Ligaments - Primary suture repair may be performed in cases of complete soft 
tissue avulsions or bony avulsions of either the ACL and/or posterior cruciate ligament 
(PCL). These injuries may also be reconstructed or augmented with an autograft or 
allograft. Anatomic single- or double-bundle reconstruction will be used for mid-
substance disruptions of the ACL and/or PCL.  Tunnels will be created in the footprints 
of the ACL and PCL on the femur and tibia using standard arthroscopic equipment, drill 
guides, and reamers.  Grafts will be anchored either within the tunnels using 
interference screws or outside the tunnels using cortical suspensory buttons or suture 
post screws.  For reconstruction of PCL injuries, PCL fixation will be performed with the 
tibia reduced at 90 degrees of knee flexion.  Fixation of grafts for ACL reconstruction will 
be performed near extension. 
Medial Injuries – Open approaches will be used for repair and/or reconstruction of the 
medial collateral ligament (MCL) and posteromedial corner.  Soft tissue planes will be 
separated to facilitate layer-by-layer repair of the sartorius facia, superficial MCL and 
posterior oblique ligament (POL), as well as deep MCL and capsular structures.  Suture 
anchors will be used as indicated for soft tissue or bony avulsions.  Reconstruction of 
the medial structures will be performed as necessary depending on soft tissue quality 
and size of the zone of injury. Grafts will be placed into the MCL footprints on the femur 
and tibia. Fixation will be performed at 30° of knee flexion under varus stress following 
ACL and/or PCL fixation as described above. 
Lateral Injuries – Open approaches will be used for repair and/or reconstruction of the 
lateral collateral ligament (LCL) and posterolateral corner structures [popliteus tendon 
and popliteofibular ligament (PFL)].  Injuries to the biceps femoris tendon or iliotibial 

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band will be addressed as necessary.  Soft tissue planes will be separated to facilitate 
layer-by-layer repair of the iliotibial band (ITB) and biceps; LCL, PFL, and popliteus 
tendon; as well as the posterolateral and anterolateral capsule complex as indicated.  
Suture anchors will be used as indicated for soft tissue or bony avulsions.  
Reconstruction with grafts will be performed as necessary depending on soft tissue 
quality and size of the zone of injury. Grafts will be placed into the anatomic footprints of 
the LCL, PFL, and popliteus on femur/fibula, tibia/fibula, and femur/tibia, respectively.  
Fixation will be performed at 30° of knee flexion under valgus stress following ACL 
and/or PCL fixation as described above.  
Peroneal Nerve Injury – During open lateral surgery, the peroneal nerve will be 
identified and protected from further injury.  In cases of existing injury, the type of injury 
and any treatment provided will be documented. 
Complications – Complications that occur during surgery will be documented.  
Intraoperative complications that are expected include nerve or vascular injury, loose 
hardware, and intraoperative fracture. Other unexpected complications that occur will 
also be documented. 
At the conclusion of surgery, a hinged, long-leg brace will be placed on the participant’s 
leg.  This brace will be locked in extension (anatomic 0o) until the first post-operative 
visit with the surgeon.  The brace will be worn for a minimum of 6 weeks and will be 
unlocked based on the rehabilitation program to which the participant was randomized. 
Medication for pain control, anti-coagulation/deep vein thrombosis prophylaxis, and 
antibiotics will be prescribed at the discretion of the operating surgeon.  The decision to 
discharge the patient to home or to admit to the hospital for monitoring will also be 
made at this time.  Each of these decisions will be documented at the first post-
operative visit.   
 
Early vs. Delayed Rehabilitation after Surgery for MLKI 
We will investigate the effects of early vs. delayed post-operative rehabilitation after 
surgery for a MLKI in the randomized trials for Aims 1 and 2.  Delayed rehabilitation will 

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be characterized by not allowing knee motion and use of a non-weight bearing gait for 
four weeks after surgery.  Early rehabilitation will be characterized by weight bearing 
and unrestricted motion starting after the first post-operative visit with the orthopaedic 
surgeon.   
After introduction of weight bearing and unrestricted ROM, all trial participants will follow 
the same criterion-based rehabilitation progression with three phases – Tissue 
Protection, Restoration of Motor Control, and Optimization of Function (Figure 3).  The 
randomized intervention is nested inside of the Tissue Protection Phase; however, the 
Motor Control and Optimization of Function phases are the same for both groups. 
The goals of the criterion-based rehabilitation progression are to return individuals to:  
1. Normal activities of daily living, and  
2. Work, military duty, and sports activities at the same level of participation as prior to 
injury. 
6.1.2.1 Tissue Protection Phase 
The Tissue Protection Phase begins immediately after surgery with a focus on restoring 
function while not disrupting the tissues addressed during surgery.  The study 
rehabilitation interventions are nested in the Tissue Protection Phase; therefore, each 
group will have a different experience during this phase. Both groups will be managed 
identically between surgery and the first post-operative visit with the surgeon. 
Generally, the Tissue Protection Phase ends when the participant meets the criteria to 
discharge all post-operative assistive devices for ambulation.  In cases where 
hamstrings exercise must be limited, the Tissue Protection Phase ends when the 
participant meets the criteria to initiate non-resisted hamstrings exercise. 
6.1.2.2 Immediate Post-Operative Rehabilitation   
The brace will be locked in extension for the first week after surgery and participants will 
be non-weight bearing.  Until the first post-operative appointment with the surgeon, all 

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participants will be instructed to perform isometric quadriceps exercises (quad sets, 
straight leg raises) and self-patellar mobilization.   
During the first post-operative office appointment with the surgeon, the participant will 
be informed of the rehabilitation program to which he or she was randomized.  The 
participant will be referred for standard of care physical therapy, with the instructions for 
WB and ROM as randomized.  The physical therapist will be provided with the criterion-
based protocol to advance gait and exercise activity as indicated by performance. 
6.1.2.3 Delayed Rehabilitation Intervention 
Participants randomized to the delayed rehabilitation treatment arm will be instructed 
not to bear any weight on the surgical limb for 4 weeks after surgery. For ambulation, 
the brace will be locked in extension.  Participants will keep the brace locked in 
extension for four weeks and will continue the exercise program described in Section 
6.1.2.2. After four weeks, the brace will be unlocked per the rehabilitation guidelines for 
gait and exercise.  At this time, participants will also transition to a weight bearing as 
tolerated (WBAT) gait for ambulation. Four weeks after surgery, the participant’s 
exercise and ambulation will be advanced based on the tissue response to treatment in 
a fashion that is identical to the progression of participants in the early rehabilitation 
treatment group. 
6.1.2.4 Early Rehabilitation Intervention 
Participants randomized to the early rehabilitation treatment group will be instructed to 
bear weight on the surgical limb as tolerated in the post-operative rehabilitation brace 
beginning one-week after surgery at the first post-operative visit with the orthopaedic 
surgeon.   Participants will be able to perform unrestricted ROM exercise in the post-
operative brace both in rehabilitation and at home. 
The early rehabilitation intervention will not be confused with “accelerated” rehabilitation 
after anterior cruciate ligament reconstruction, in which range of motion is targeted 
aggressively after surgery and is generally the current standard of care. 28,71  The post-
operative rehabilitation for the early rehabilitation group was developed to promote 

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gradual recovery of motion an weight bearing based on participant tolerance – no end 
range stretching or over-pressure is used and painful weight bearing is to be avoided. 
6.1.2.5 Tissue-Specific Considerations During Tissue Protection Phase 
The variety of injury patterns and surgical interventions to treat those injuries contribute 
to the variety of rehabilitation recommendations after MLKI. During the tissue protection 
phase, some tissues need significant protection to prevent disruption of the surgical 
repair or reconstruction.  These protections are described in Table 2. 
Table 2 Tissue Specific Considerations 
Tissue 
Involved 
Rehabilitation Modifications 
ACL 
Prevent resisted NWB knee extension between 10° and 60° 
PCL 
Prevent posterior translation of the tibia for 6 weeks 
No active or resisted hamstrings contraction 
PLC/LCL 
Range of knee extension limited to 0o (no hyperextension) 
Prevent posterior translation of the tibia for 6 weeks 
Avoid excessive varus forces on knee joint 
No active or resisted hamstrings contractions 
MCL 
ROM exercises with foot internally rotated 
Avoid excessive valgus forces on knee joint 
Meniscus 
Repair (root or 
body repair) 
Brace locked in extension for 4 weeks for ambulation, WBAT (if 
randomized to early rehabilitation) 
Avoid WB flexion in any range 
Flexion ROM limited to 90 degrees for 4 weeks (perform in non-
weight bearing only) 
No active or resisted hamstrings contractions 
 
 

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6.1.2.6 Activity Progression during the Tissue Protection Phase 
Progression of Weight Bearing 
For this study, we have operationally defined “weight bearing as tolerated” as the 
amount of weight bearing that the participant can tolerate without evidence of increased 
inflammation of the knee (i.e. without pain, warmth, redness or effusion).  
The time for initiation of weight bearing on the surgical knee will be based on the 
allocated rehabilitation group (early – starting at the first post-operative appointment 
with the physician; delayed – starting 4 weeks after surgery). 
When initiating weight bearing, participants will be instructed to bear weight on their 
surgical limb as tolerated.  Tolerance is defined as the amount of weight bearing that 
does not appreciably increase knee joint pain, effusion, or warmth.   
Initially, weight bearing will be performed with an assistive device in a locked, double 
upright knee brace to prevent excessive sagittal or frontal plane motion.  When 
participants can bear full weight on the leg without signs of increased inflammation and 
can demonstrate appropriate control of the knee when walking with the brace unlocked, 
gait training with a less restrictive assistive device (i.e. single crutch or cane) and with 
the brace unlocked brace will be initiated, and progressed as safely tolerated.   
Progression of Exercise Activities 
The immediate goal of exercise is to restore quadriceps activity and increase and/or 
maintain range of motion within the post-operative guidelines.  Exercises progress from 
non-weight bearing quadriceps exercise through bilateral and unilateral weight bearing 
exercises.  Weight bearing exercise recommendations and gait activity 
recommendations follow similar trajectories and complement each other.   
All participants will begin exercises to restore quadriceps function immediately after 
surgery (e.g. quadriceps sets, straight leg raises). 

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All exercise recommendations 
are based on achievement of 
criteria as outlined in Figure 3.  
The criteria are identical 
between rehabilitation groups 
with the exception of time after 
surgery. 
In the delayed rehabilitation 
intervention, non-weight bearing 
exercise, basic weight bearing 
exercise on two legs (e.g. 
squats and wall sits to 45O), and 
simple unilateral exercises (e.g. 
step ups and single leg balance) 
may begin no sooner than four 
weeks after surgery. 
In the early rehabilitation 
intervention, non-weight bearing 
exercise and basic weight 
bearing exercise on two legs 
(e.g. squats and wall sits to 45O) 
may begin within two weeks of 
surgery.  Simple unilateral 
exercises (e.g. step ups and 
single leg balance) may begin 
no sooner than three weeks 
after surgery.   
Week 6 
Week 6 
Week 8 
Week 8 
Week 10 
Week 10 
Week 12 
Week 12 
Week 16 
Week 16 
Week 18 
Week 18 
Week 20 
Week 20 
Tissue Protection Phase 
Delayed 
Rehab 
Group 
Early 
Rehab 
Group 
Gait Progression 
NWB  
locked brace 
bilateral crutches 
WBAT 
locked brace  
bilateral crutches 
WBAT  
unlocked brace 
bilateral crutches 
WBAT 
unlocked brace  
no crutches 
Unrestricted Gait 
Walking Program 
Exercise 
Progression 
Immediate Post-
Op Exercises 
NWB Quadriceps 
Exercise 
Basic Bilateral WB 
Exercise 
Basic Unilateral 
WB Exercise 
Advanced WB 
Exercise 
Hamstrings Progression 
Optimization of Function Phase  
Stationary Cycling for 
Conditioning 
Elliptical Trainer for 
Conditioning 
Free Weight Training 
Walk-Jog Progression 
Agility & Jumping Drills 
Hopping, Cutting/Pivoting, 
& Sport-Specific Drills 
Week 0 
Week 1 
Week 3 
Week 0 
Week 4 
Motor Control Phase  
Figure 3. Rehabilitation Schema 

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Advanced weight bearing exercise (e.g. squats up to 90o, step down exercises) may 
begin no sooner than six weeks after surgery in either group. 
6.1.2.7 Motor Control Phase 
In the case of a PCL, PLC, or meniscus repair, hamstrings exercises are prohibited for 8 
weeks and protected for 12 weeks.  After 8 weeks, active contraction of the hamstrings 
without external resistance may begin.  After 12 weeks, resistive exercises for the 
hamstrings may be initiated.   
Because of the relatively long period of low-intensity cardiovascular training that allows 
the tissues to recover, conditioning exercises are important to initiate when safe cycling 
for aerobic conditioning can be initiated – 10 weeks after surgery, and when the 
individual has the necessary range of motion and control of the lower extremity to 
initiate and safely stop cycling.  This is a direct progression from cycling for range of 
motion.  
6.1.2.8  Optimization of Function Phase 
Advanced training for general conditioning, lower extremity strength, and military, work 
and/or athletic movements is progressed from as early as 12 weeks after surgery 
through discharge from physical therapy.  Progression is based on time from surgery, 
the inflammatory response of the knee joint, and mastery of more basic skills (e.g. the 
patient must master jumping on two legs before beginning hopping on one leg).  This 
progression follows standard approaches after anterior cruciate ligament reconstruction. 
 
 
Procedures for Training of Clinicians on Procedural Intervention 
 
Procedures for Training Surgeons on Surgical Intervention 
6.2.1.1 Investigator’s Study Kickoff Meeting – February 10, 2018 
To review study procedures, discuss preliminary recruitment issues, and re-orient the 
site investigators to the study, we hosted a Study Kickoff Meeting in Pittsburgh, PA in 

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February 2018.  Discussion topics included study organization, clinical equipoise, 
inclusion and exclusion criteria, study design, assessment of safety, data management 
and quality control. The audio recording of the meeting and annotated meeting minutes 
are available in a shared folder with the investigators and research coordinators in the 
STaR Trial Meeting Repository.  
6.2.1.2 Informational Investigator’s Conference Calls 
Informational conference calls with the study investigators are held on a monthly basis.   
The purpose of these calls is to relay important, study related information to site PI’s 
and Co-I’s.  The calls are conducted via Skype for Business and are preceded by an 
electronic meeting invitation and updated with an agenda.  Skype for Business allows 
for screen sharing capabilities and recording of the conference call.  There is potential 
for attendee participation via both audio and text-based interaction.  All audio and 
screen presentations of the calls will be recorded and archived.  Annotated meeting 
minutes and recordings will be made available via a public web folder through the 
University of Pittsburgh for individuals who cannot attend the live meeting.  No patient-
specific or identifiable information will be discussed during a conference call.     
 
Procedures for Training Physical Therapists on Rehabilitation 
Interventions 
6.2.2.1 Rehabilitation Protocol and Written Guidelines 
Because of the multi-centered nature of this project, as well as the participant’s choice 
of physical therapist for their standard of care post-operative rehabilitation, we have 
established procedures to standardize and minimize variability in the allocated post-
operative rehabilitation program.  The Rehabilitation Committee created the 
standardized rehabilitation program for the early and delayed rehabilitation groups with 
clearly specified time- and criterion-based standards for progression of activity and 
exercise for each group. To standardize implementation of the rehabilitation program, 
we have also developed group-specific (early and delayed rehabilitation) written 
guidelines describing the post-operative rehabilitation program that will be provided to 

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the participant and the participant’s physical therapist. These include Executive 
Summary Reference Sheets for the Physical Therapist. 
6.2.2.2 Training Webinars via MedBridgeEducation.com 
We have recorded training webinars that describe the following topics: 
• Study Introduction, Overview, and Purpose 
• Overview of Rehabilitation Program; Early and Delayed Rehabilitation Programs; 
Tissue Specific Protections  
• Criterion-Based Activity Progression  
• Potential Poor Outcomes and Indications for Contacting the Surgeon 
• Your role as a physical therapist treating a patient in this study 
The instructional videos will be made available to all physical therapists who provide 
post-operative rehabilitation to participants enrolled in the study.  We have partnered 
with a third-party rehabilitation education company, Medbridge Education, to host the 
training videos.  Medbridge will make the videos available to any physical therapist that 
treats a study participant, free of charge. We will include the information about the 
training videos in the introductory letter to the physical therapist from the surgeon-
investigator.  Medbridge will collect basic demographic data about the physical therapist 
when the physical therapist registers with the Medbridge system.  This demographic 
information will allow us to identify the therapists and learn about their experiences.  
Additionally, Medbridge will be able to tell us how many of the physical therapists 
accessed and completed the videos. 
6.2.2.3 On-going Interaction 
As the Qualified Collaborator for Rehabilitation, Dr. Lynch will be available at all times to 
answer any questions from physical therapists regarding an individual’s participation in 
the study. 

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Assessment of Clinician and/or Subject Compliance with Study 
Procedural Intervention 
 
Assessment of Surgeon Adherence to Timing of Surgery as 
Randomized 
To determine whether the surgery was performed as randomized, the date of surgery 
will be compared to the date of injury.  In cases where the surgery was performed 
outside of the time window that corresponds with randomization, a protocol deviation 
will be filed, and the case will be flagged as non-adherent to timing of surgery. 
All surgeons will follow the same general procedures for anatomic repair or 
reconstruction of torn structures; however, due to the variability of injury patterns in 
MLKIs, it is not possible to strictly standardize the surgical protocol for all participants.  
Rather, we will use surgical CRFs to thoroughly document the surgical findings and 
procedures. 
 
Assessment of Participant Adherence with Rehabilitation as 
Randomized in the first Month after Surgery 
To determine whether the participant was adherent to the allocated rehabilitation 
program, we will utilize a three-part monitoring process in the first month after surgery.  
We will consider participant self-report and the opinions and conclusions of the 
orthopedic surgeon and physical therapist. (See Figure 4) At the one-month post-
operative clinical visit with 
the surgeon, the participant 
will complete a brief survey 
(Patient Reported 
Rehabilitation Activities 
Form) asking about his/her 
activity over the last month.  
Items include an estimate of 
how much weight the 
participant put on their 
Patient Self-Report
Surgeon 
Assessment of 
Patient Adherence
Physical Therapist 
Assessment of 
Patient Adherence
Figure 4. Triangulation of Adherence to Rehabilitation as Randomized 

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lower extremity on a regular basis and how restrictive the participant was with knee joint 
motion.  To improve reporting, we have implemented a picture-based reporting 
mechanism to accompany written descriptions. 
In the one-month Clinical Visit Form and one-month Physical Therapy Case Report 
Form, the surgeon and physical therapist, respectively will be asked to comment on the 
participant’s WB and ROM status.  By obtaining information from the participant, 
surgeon, and physical therapist, we will be able to determine with reasonable certainty 
the participant’s adherence with the allocated rehabilitation program. 
In cases of agreement among all three data sources, there is a clear indication of 
adherence.  In cases of discord between the three parties, the general rule is to take the 
opinion of the majority (i.e. 2 of 3 reports results in determination of adherence). 
However, if the participant self-reports that he/she was not adherent to 
recommendations, we will designate the participant as non-adherent.   
 
Assessment of Patient Reported Adherence to Rehabilitation as 
Prescribed after the First Month after Surgery 
Using the 3-month and 6-month Patient Reported Rehabilitation Activities Forms, we 
will determine how participants progressed through rehabilitation activities after surgery.  
We will compare this to the suggested beginning times for activities in the rehabilitation 
protocol.  Specifically, we want to know how often participants begin impact activities 
(e.g. running, jumping, or cutting/pivoting) and advanced training prior to 3 months after 
surgery.  The rehabilitation program delays initiation of these activities in an effort to 
promote appropriate healing of surgical procedures, however, the impact of these 
activities on healing and outcome is unknown.   
We will also identify participants that have demonstrated poor progression of activity 
and have not initiated advanced training by 6 months after surgery.  We will assess for 
predictors of individuals who have not returned to advanced training to identify those 
who may need more intensive rehabilitation or closer monitoring. 

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7 STUDY SCHEDULE 
 
Subject Identification, Prescreening, and Informed Consent Processes 
We expect to recruit and randomize 690 military personnel and civilians (392 for 
Specific Aim 1 and 298 for Specific Aim 2) with a MLKI from 5 military and 20 civilian 
(17 US and 3 Canadian) centers of excellence for treatment of MLKIs. 
Patients presenting with a MLKI to a surgeon-investigator’s office or Emergency 
Department at a participating clinical study site will undergo pre-screening that will 
consist of review of the medical record to determine if the individual is potentially eligible 
to participate in the study.  This review will be performed by members of the clinical care 
team that would otherwise have access to the medical record information that is being 
reviewed.  The identification and pre-screening of potential study participants could 
occur in either in the surgeon’s office or in the Emergency Department in consultation 
with the orthopaedic trauma service.   
If the pre-screening process reveals that the patient is potentially eligible for 
participation in the study, he/she will be approached by a member of the clinical care 
team to ask the patient if he/she would be interested in learning more about the study.  
At that point if the individual is interested in learning more about the study, the surgeon-
investigator and/or the research coordinator will provide additional information regarding 
participation in the study.   
If the pre-screening indicates that the patient is not potentially eligible for participation, 
no interaction between the study team and the patient will occur, however the results of 
the pre-screening process, including the reason(s) why the patient was not eligible for 
participation will be stored in a separate, de-identified table in the REDCap database. 
For the individuals that are potentially eligible and interested in learning more about the 
study, the surgeon-investigator and/or the research coordinator will provide detailed 
information regarding the study.  This will include a discussion of the reason for the 
study, research procedures, risks and benefits of participation and compensation.  Prior 
to providing informed consent, all of the potential subject’s questions will be answered 

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by the surgeon-investigator and/or research coordinator.  If the individual agrees to 
participate in the study, the participant will review and sign the informed consent form, 
which will also be signed by the surgeon-investigator.  For individuals that are 16 or 17 
years of age, written signed informed consent will be obtained from the individual’s 
parent or legal representative and the participant will provide attestation.  A copy of the 
signed informed consent form will be given to the participant and the original copy will 
be stored by the research team.  Additionally, a copy of the signed informed consent for 
will be included in the electronic health record. 
 
 
Screening 
Patients with MLKI that have provided informed consent will undergo further screening 
to determine eligibility for participation in the study.  Screening procedures for the study 
entail collection of demographics and participant information, review of medical records 
and the baseline clinical examination performed by the surgeon-investigator.  At the 
conclusion of the screening process, subjects will be informed as to whether or not they 
are eligible for participation in the study. 
 
 
Baseline Visit 
Participants deemed eligible for the study will complete baseline patient-reported 
outcomes (see Section 8) prior to randomization, to minimize missing baseline data and 
to avoid selection bias. Eligible participants will complete a list of patient-reported 
outcomes using the REDCap system. 
 
 
Randomization and Scheduling and Completion of Surgery 
Subjects will be randomized in 1:1 allocation for both factors (timing of surgery and 
timing of rehabilitation) in the two by two trial (Aim 1) and for timing of post-operative 
rehabilitation in the one arm trial (Aim 2). Randomization will be conducted by the DCC 

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statisticians using permuted blocks with random block sizes stratified by site and injury 
pattern. The randomization lists will be created using SAS Enterprise Guide version 6.1 
and uploaded using the REDCap randomization module. This module permits allocation 
concealment such that the allocation to the treatment arm is only viewed once certain 
criteria are entered into the system. The same approach will be used for the randomized 
trial of early versus delayed post-operative rehabilitation. Once the study coordinator 
has obtained and entered all screening information, he/she can request a randomization 
assignment by clicking on the ‘Randomize’ field which will then provide the allocation for 
only that participant. 
For those individuals participating in the trial for Aim 1, randomization will be performed 
after final confirmed eligibility and collection of baseline patient-reported outcomes. The 
surgery will be scheduled based on the allocation for timing of surgery. Those assigned 
to early surgery will undergo surgical procedure for MLKI within 6 weeks of injury, and 
for those assigned to delayed surgery, the surgical procedure will be performed 
between 12 to 16 weeks after injury. To prevent the allocated rehabilitation intervention 
from influencing the surgical intervention, allocation of early vs. delayed rehabilitation 
will be disclosed at the completion of the surgical intervention, and it will be shared with 
the participant during his/hers first post-operative clinical follow-up visit.  
Participants that cannot or refuse to be randomized to timing of surgery will only by 
randomized to timing of rehabilitation.  For those individuals, surgery will be scheduled 
and performed at the discretion of the surgeon.  Randomization to early vs. delayed 
rehabilitation will be performed after surgery to ensure that the individual is still eligible 
to participate in the study and to avoid any bias in the performance of surgery based 
knowledge of the assigned post-operative rehabilitation. 
For individuals that undergo surgery greater than 4 weeks after collection of the 
baseline patient-reported forms, the patient-reported outcome measures (i.e. the 
MLQoL, IKDC-SKF and PROMIS PF) will be re-administered within 1 week of the date 
surgery, either during a pre-operative clinical visit or on the day of surgery in the pre-
operative holding area.  These pre-operative patient-reported outcome measures will 

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serve as the baseline outcome measures for those enrolled in the trial that randomizes 
only post-operative rehabilitation (Aim 2).  The pre-operative patient-reported outcome 
measures for those in the trial for Aim 1 will not replace the baseline outcome measures 
that were collected at the time of enrollment in the study and will be used only for 
descriptive purposes. 
At the time of surgery, the surgeon will perform a standard of care examination under 
anesthesia and diagnostic arthroscopy and will perform surgery in accordance with the 
principles of anatomic repair or reconstruction of all injuries in the knee.  During or 
immediately after completion of surgery, all surgical findings and procedures will be 
documented on the following forms as outlined in Section 8.  
For both trials, the research coordinator will only inform the surgeon and participant of 
individual’s group assignment for post-operative rehabilitation after the surgery has 
been completed. 
 
Standard of Care Clinical Follow-Up Visits 
Clinical visits with the surgeon-investigator and his/her clinical staff will be performed as 
part of the standard of care after knee surgery.  The clinical follow-up visits will occur 
approximately 1 week and 1-, 3-, 6- and 9 to 12 months after surgery.  The results of 
the clinical follow-up visits will be documented on the Clinical Visit, Additional Surgeries 
– Clinical, Concomitant Medications, and Complication Reporting forms.  Patient-
reported rehabilitation activities will also be collected at each of the clinical follow-up 
visits.  Sites will not be compensated for these standard of care clinical visits, however 
they will receive $75 per participant for their effort to complete the case report forms to 
summarize these clinical visits. 
If participants have other standard of care clinical visits, the results of these clinical 
visits will be recorded as Interim Visits into REDCap. 
 

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Research Follow-Ups 
Research follow-up assessments will assess the participant’s current military duty, work 
participation, and sports participation on a monthly basis. This will begin 6 months after 
randomization and continue through 24 months from randomization. Additionally, we 
will collect knee-related physical function and health related quality of life patient-
reported outcome measures 6, 12, and 24 months after randomization.      
The research follow-ups will be conducted remotely by the Data Coordinating Center. 
Participants will be asked to complete follow-up surveys electronically using a REDCap 
link (with instructions to access the surveys) that will be sent to their preferred method 
of contact method (via e-mail and/or text message). Multiple contact attempts to 
complete the patient-reported measures will be sent to maximize response rate. If the 
participant does not respond to the first two automated e-mail/messages, a member of 
the research staff will call the participant to remind them to complete the surveys. Each 
participant will receive at most three phone calls from the research staff to remind them 
to complete the surveys.  The research coordinator from the site at which the participant 
was recruited will be enlisted to assist with participant contact as necessary for 
participants who do not respond to requests from the Coordinating Center. 
Completion of the patient-reported measures of knee-specific and general measures of 
physical function and health-related quality of life will take approximately 30 minutes 
(estimated time). Participants will also be compensated $35 for their time to complete 
the measures at 6, 12 and 24 months. 
 

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8 STUDY PROCEDURES /EVALUATIONS 
 
Study Procedures/Evaluations 
 
Consent Process  
Potential patients that present to surgeon’s office or in the Emergency Department with 
a MLKI will be informed of the study. Patients with MLKI who are interested in 
participating in the study will be introduced to the research staff for detailed information 
about the study. This will include a discussion of the reason for the study, research 
procedures, risks and benefits of participation and compensation.  Prior to providing 
informed consent, all patient’s questions related to the study procedures will be 
answered by the surgeon-investigator and/or research coordinator. If the individual 
agrees to participate in the study, the participant will review and sign the informed 
consent form, which will also be signed by the surgeon-investigator.  For individuals that 
are 16 or 17 years of age, written signed informed consent will be obtained from the 
individual’s parent or legal representative and the participant will provide attestation.  A 
copy of the signed informed consent form will be given to the participant and the original 
copy will be stored by the research team.  Additionally, a copy of the signed informed 
consent for will be included in the electronic health record. 
For active military personnel, no individuals in the participant’s chain of command will be 
involved in the recruitment process. 
 
Screening 
Screening of patients will occur at surgeon-investigator’s office after signing informed 
consent, and the process consists of demographics, history and physical examination 
performed by the orthopaedic surgeon and imaging to determine if individual has a 
MLKI.  
Final eligibility for the individuals participation in the study will be determined at the 
conclusion of the screening activities.  Participants will not be able to be randomized 
until final eligibility for participation in the study has been determined. Data elements 
from the screening process will be entered into the REDCap database and will auto-

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populate the Inclusion/Exclusion Criteria form and will determine individual’s eligibility to 
participate in the study. 
8.1.2.1 Demographics and Participant Information 
Demographics and participant information, including primary and secondary contact 
information will be collected.  Access to any the participant’s identifiable information will 
be limited to the local research team and to the research personnel at the Data 
Coordinating Center (except for the Canadian sites). Demographic information will 
include age, sex, weight, height, marital status, educational level, pre-injury military 
duty, work activity, and sports activity, smoking history and insurance status. 
Further screening to determine eligibility for the study will entail the surgeon-investigator 
(or his/her designee) documenting the results of the standard of care initial examination 
on the Baseline Clinical Visit form. 
8.1.2.2 Pre-injury activity measures 
• Military Duty 
To measure military duty prior to injury we will record the physical demand classification 
of the military occupational specialty (MOS) 72 and will ask three questions from the 
Injury Surveillance Survey (ability to perform Annual Physical Fitness Test; Deployability 
and Specific MOS Duties).  These questions were developed based on input from 
members of a working group at the Office of the Surgeon General and are being 
incorporated in the Medical Readiness Assessment Tool (MRAT).  Additionally, the 
questions are also scheduled to be added to the new DoD/VA electronic medical record 
that is to be released in 2016.73  These questions have also been included as an 
outcome measure in a prospective study to develop predictive models for spine and 
lower extremity injury after discharge from rehabilitation (see 
https://clinicaltrials.gov/ct2/show/NCT02776930).   
• Work Activity 
To measure work activity prior to injury, we will use the Cincinnati Occupational Rating 
Scale, which has demonstrated high test-retest reliability in both patients (ICC=.97) and 

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uninjured individuals (ICC=.87).58  Additionally we will record the individual’s pre-injury 
employment status (work regular duty full time, work regular duty part-time etc.) and 
occupation.  
• Sports Activity and Participation 
We will use the Marx Activity Rating Scale59 to measure the participant’s level of sports 
activity in the year prior to injury.  Test re-test reliability for this scale over a two-week 
period was high (ICC=.97) and it had moderately strong correlations with the Cincinnati 
and Lyhsolm scores.59  To assess sports participation, we will also record the type (very 
strenuous, strenuous etc.) and frequency (4-7 times per week, 1-3 times per week etc.) 
of sports participation as well as the specific sport(s) the individual participated in prior 
to injury. 
8.1.2.3 Baseline Clinical Examination  
A standard of care history and clinical examination and review of standard of care 
imaging studies will be performed by the surgeon-investigator to confirm the diagnosis 
of a MLKI and determine eligibility for inclusion in the study. This information will be 
documented on a Baseline Clinical Visit Form.  Data that will be collected on the 
Baseline Clinical Visit form will include current level of pain, ROM, imaging and/or 
laboratory tests ordered and completed, knee ligament testing, neurovascular status, 
and plan for pre-operative management. 
• Pain 
Pain intensity will be recorded utilizing an 11-point numeric pain rating scale (NPRS) 
that ranges from 0 (no pain) to 10 (worst imaginable pain).  Pain ratings of 4 to 6 
represent moderate pain. Current pain intensity will be recorded.  The minimal clinically 
important difference for a change that is deemed quite a bit better is 2.17 on the 0 to 10 
pain scale.74   
• Active and Passive Range of Motion of the Knee 

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The range of active and passive extension and flexion of both knees will be measured 
with a goniometer with the individual lying supine on the examination table.  Range of 
motion of the knee should be visually estimated prior to using a goniometer to measure 
the motion.  Range of motion will be measured to the to the nearest 1° with a large (11.5 
inch arms) clear plastic goniometer marked in 1° increments.  Range of motion of the 
non-involved knee will be measured first followed by measurement of the involved knee.  
The side to side difference in passive knee extension and flexion will be calculated and 
will be used to determine the IKDC Knee Ligament Rating System classification of 
range of motion.75.    Intra- and inter-tester reliability coefficients are .98 and .86 for 
passive knee extension and .99 and .90 for knee flexion respectively. 76 
• Diagnostic Tests 
Standard of care diagnostic tests including radiographs, stress radiographs, MRI, CT-
scan, ultrasound, vascular testing and/or EMG/nerve conduction velocity will be 
recorded on the Baseline Clinical Examination form. The date and indication for each 
diagnostic test will be recorded. 
• Knee Ligament Examination 
A manual knee ligament examination will be performed determine the knee ligament 
injury pattern.  The ligament laxity tests that will be performed include the Lachman test, 
total anterior-posterior (A-P) translation at 25° and 70° of knee flexion, varus and valgus 
stress tests at 20° of knee flexion, external rotation at 30° and 90° of knee flexion and 
pivot shift tests.  The ligament laxity test will be graded according to the IKDC Knee 
Ligament Rating System guidelines.75  All ligament laxity tests will be graded based on 
the side to side difference between the MKLI-injured and contralateral normal knee. 
• Neurovascular Status 
Assessment of neurovascular status will include assessment of pulses, sensation to 
pain and distal motor function.  The dorsal pedal and posterior tibialis pulses will be 
recorded as symmetrical, diminished or absent in comparison to the non-involved leg.  

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Sensation to pain (pin prick) distal to the knee will be recorded as normal, diminished or 
absent.  Distal motor function of the tibialis posterior, tibialis anterior, peroneus longus 
and extensor halluces longus will be recorded as strong/symmetrical to the contralateral 
leg, diminished or absent. 
• Plan Pre-Operative Management 
A standard of care pre-operative plan will be developed by the surgeon-investigator with 
recommendations to participants. Pre-operative recommendations will be at the 
surgeon-investigator’s discretion and can include aspiration of the knee, protected 
weightbearing, bracing, ROM restrictions, prescription of a home exercise program, 
application of an external fixator for less than 10 days or referral of the participant for 
physical therapy.  Each recommendation will be recorded by the research team. 
 
Baseline Visit 
After the screening procedures and final determination of eligibility, participants will be 
asked to complete patient-reported outcomes measures including the Multi-Ligament 
Quality of Life Questionnaire, International Knee Documentation Committee (IKDC) 
Subjective Knee Form, PROMIS Physical Function scale and PROMIS Global 10.  The 
participant will also complete other patient-reported measures that are expected to be 
associated with the study outcome including the Patient Acceptable Symptom State 
(PASS), Global Rating of Change, Tampa Scale for Kinesiophobia, and the Brief 
Resilience Scale. The site coordinator will review the participant’s medical record to 
complete the Concomitant Medications form in the electronic database (REDCap).  
Each of these patient-reported outcomes and other measures are described in Section 
8.1.8. 
 
 

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Study Interventions 
8.1.4.1 Early vs. Delayed Surgery for MLKI 
For the clinical trial that is performed for Specific Aim 1, we have operationally defined 
early definitive surgery to be surgery within 6 weeks of injury to repair and/or reconstruct 
the torn structures.  Delayed surgery to has been operationally defined as repair and/or 
reconstruction of the torn structures 12 and 16 weeks after injury.  Although early 
surgery is defined as within 6 weeks, every effort will be made to perform surgery as 
soon as possible, if randomized to early surgery.  Staged surgery will not be considered 
an option for surgical treatment of MLKIs in this study.  
In all cases, surgery will be performed in accordance with the principles of anatomic 
repair/reconstruction of injured structures in a manner that will allow for early range of 
motion.  Surgical reconstruction with allograft or autograft will be planned for mid-
substance tears of the ACL and/or posterior cruciate ligament (PCL), as previous 
studies have demonstrated suboptimal outcomes with primary repair.77,78  
Repair/reconstruction will also be planned for  injury to the medial collateral ligament 
(MCL) and the posterolateral corner (PLC) structures (fibular collateral ligament, 
popliteus tendon, and popliteofibular ligament).  Injuries to the biceps femoris tendon or 
iliotibial band will be addressed as necessary.  Medial and lateral meniscus tears will be 
repaired or debrided at the time of surgery.  Neuropraxic nerve injuries will not 
necessitate early intervention; however, if a neurotmesis injury is discovered on MRI, 
then early intervention for primary repair, grafting or benign neglect may be warranted.   
All surgical findings and procedures will be documented on electronic surgical case 
report forms.  As the Qualified Clinical Investigator for Surgery, Dr. Musahl will be 
available to answer any questions from surgeons regarding a subject’s participation in 
the study. 
Definitive surgical treatment of soft tissue injuries will follow a standardized algorithm 
comprising primary repair and/or graft reconstruction.  Surgery will be performed in 
accordance with the principles of anatomic repair and/or reconstruction of injured 
structures in a manner that will allow for early range of motion.  Graft choice for 

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reconstruction of injured tissues will be at the discretion of the operating surgeon and 
will not be standardized; however, graft choice will be recorded on the surgical case 
report form.     
8.1.4.2 Early vs. Delayed Post-Operative Rehabilitation 
Two post-op rehabilitation protocols have been created, differing only in the time to 
begin WB and ROM exercises. After surgery, all individuals will be placed in a hinged 
brace that is locked in extension.   
Individuals randomized to early rehabilitation will begin WBAT with the brace locked in 
full extension and unrestricted ROM within 1 week after surgery. Individuals in this 
group will be allowed to unlock the brace for ROM exercises but will keep the brace 
locked at all other times until the criteria to unlock the brace are met. Weightbearing will 
be gradually progressed to full WB no earlier than 3 weeks after surgery pending 
achievement of the criteria for doing so.  
Participants allocated to delayed rehabilitation will be non-WB and with no knee motion 
for four weeks after which time they will progress to WBAT and perform unrestricted 
ROM exercises.  
Immediately after surgery both groups will begin isometric quadriceps exercises with the 
knee in full extension (quad sets, straight leg raises) and high intensity neuromuscular 
electrical stimulation (NMES) for the quadriceps will be utilized. Use of the post-
operative brace will be discontinued no earlier than 6 weeks after surgery pending 
achievement of the criteria to do so.  
In the Motor Control and Functional Optimization phases of rehabilitation, progression to 
increasingly demanding activities will be time- and criterion-based to ensure that the 
individual is advanced safely, reducing the risk for further injury. 
 

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Post-Operative Clinical Visits 
Follow-up standard of care clinical visits will be performed at the discretion of the 
surgeon-investigator, which typically occur 1 week and 1, 3, 6 and 9 to 12 months from 
surgery.   
The findings from the clinical examination performed by the surgeon-investigator will be 
documented on a Clinical Follow-up Visit Form and will serve to provide additional 
secondary outcomes related to post-operative recovery.  The information that will be 
collected on the Clinical Follow-Up Visit form includes pain, pain medication usage, joint 
effusion, wound and neurovascular status, ROM, WB status, use of a post-operative 
rehabilitation brace, adherence to the allocated post-operative rehabilitation program, 
imaging and/or laboratory tests ordered and completed, complications, additional 
surgeries, changes in medications and recommendations for return to military duty, 
work and sports status.  Knee laxity will also be assessed during clinical follow-ups at 
the discretion of the surgeon-investigator. 
• Pain, Active and Passive ROM, and Neurovascular Status  
Pain, active and passive ROM, and neurovascular status will be assessed during the 
clinical follow-up visits in the same manner as describe for the baseline clinical visit (see 
Section 8.1.2.3).  
• Pain Medication Usage 
At each clinical follow-up visit we will record current pain medication usage.  We will 
specify the name of the medication, dose, frequency of use and indication.  
• Joint Effusion 
We will utilize the modified stroke test to assess and quantify effusion of the knee joint.  
To perform this test, the subject will lie in the supine position with the knee relaxed in full 
extension.  Starting at the medial joint line, the examiner will stoke upwards two to three 
times towards the suprapatellar pouch to move the joint effusion from the tibiofemoral 
joint into the suprapatellar pouch.  The examiner will then stroke downward on the distal 
lateral thigh from just superior to the suprapatellar pouch towards the lateral joint line 

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and observe for a fluid wave on the medial side of the knee. Inter-tester reliability for the 
stroke test was found to have 73% agreement with a Kappa value of 0.75.79 
• Wound Status 
At each clinical follow-up visit the status of the wound will be recorded as healed, 
healing, draining, open, erythema or presence of a superficial wound infection. 
• Adherence to Prescribed Rehabilitation 
Assessment of Participant’s Adherence to Allocated Rehabilitation Program 
At each clinical follow-up visit, the surgeon’s perspective on participant’s adherence with 
allocated post-operative rehabilitation program will be recorded as fully adherent, 
partially adherent or not adherent for both ROM and weight bearing status.  
• Use of Assistive Devices 
The use of assistive devices for ambulation will be recorded as yes or no. 
• Use of Post-Operative Brace 
Use of a post-operative brace will be recorded as yes or no.  If the brace is being used, 
the type of brace will be recorded. If a hinged brace is being used, the range of motion 
limits of the brace will be recorded.  If the brace is no longer being used, the date that 
brace use was discontinued will be recorded. 
• Additional Diagnostic Tests 
At each follow-up visit we will record any additional diagnostic tests that have been 
performed including radiographs, stress radiographs, MRI, CT-scan, ultrasound, 
vascular testing and/or EMG/nerve conduction velocity.  The date and indication for any 
additional diagnostic test will be recorded. 
• Knee Ligament Examination 
A manual knee ligament examination will be performed at the clinical follow-up visits at 
the discretion of the surgeon. The ligament laxity tests will be assessed during the 
clinical follow-up visits in the same manner as describe for the baseline clinical visit (see 
Section 8.1.2.3). 

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• Military Duty 
The surgeon’s recommendations regarding current military duty will be recorded as no 
duty, limited or modified duty or full duty. 
• Work/School Status 
The surgeon’s recommendations on work/school status will be recorded as no work, 
limited or modified work or full work. 
• Sports Activity 
The surgeon’s recommendation on sports activity status will be recorded as no sports, 
limited or modified return to sports or return to sports without restrictions. 
 
During the clinical follow-up visits, in addition to the Clinical Visit Form, the research 
team will also collect data on Complications, Additional Surgeries – clinical form, and 
Concomitant Medications. 
 
 
Research Follow-Up Visits 
The primary outcome will be time return to full pre-injury military duty, work and sports.  
We will also assess patient-reported physical function as measured with the Multiple 
Ligament Quality of Life (MLQoL) Questionnaire 6, 12 and 24 months after 
randomization.  To more precisely measure the time to return to military duty, work and 
sports, we will administer a brief Return to Activity Monitoring Survey monthly starting 6 
months after randomization and continuing through the 24-month follow-up.  Secondary 
outcome measures will include additional knee-specific and general patient-reported 
measures of physical function and health-related quality of life. We will also collect 
measures of kinesiophobia, resiliency and functional comorbidities because these 
constructs may impact return to military duty, work and sports.  Below we provide the 
details for each of the outcome evaluations to be made. 

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The PROs collected during the research follow-up assessments will be administered 
and monitored remotely by the DCC. 
 
 
Assessment of Outcomes 
8.1.7.1 Primary Outcome 
• Return to Pre-Injury Military Duty, Work and Sport 
Because of the expected heterogeneity of pre-injury activity level of individuals that 
sustain a MLKI, similar to our work related to return to pre-injury sports activity and 
participation for individuals following anterior cruciate ligament (ACL) reconstruction, we 
will combine return to pre-injury military duty, work and sports into an overall Return to 
Activity and Participation variable.  Individuals will be classified as having returned to 
activity if and when they have returned to their pre-injury level of military duty, work and 
sports.  Successful return to activity will be assessed using the patient-reported 
measures of military duty, work and sports described above and will be determined 
based on comparison of the individual’s pre-injury level of military duty, work and sports.     
Individuals in the military will achieve a “Full Return to Activity and Participation” 
designation if and when they indicate they have returned to full pre-injury level of 
military duty, work and sports without any restrictions based on their: 
• Reported ability to pass an Annual Physical Fitness Test at a level similar to pre-
injury status and are as deployable and mission capable as they were prior to injury 
(per the ISS); 
• Achievement of the same or higher Military Occupational Specialty Physical Demand 
Classification 
• Achievement of the same or better score on the Cincinnati Occupational Rating 
Scale and;  
• Achievement of the same or better score on the Marx Activity Rating Scale and 
participation in the same type and frequency of sports as prior to injury. 

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Individuals who are not in the military will achieve a “Full Return to Activity and 
Participation” designation if and when they have returned to full pre-injury work and 
sports without any restrictions based on their:  
• Achievement of the same or better score on the Cincinnati Occupational Rating 
Scale and;  
• Achievement of the same or better score on the Marx Activity Rating Scale and 
participation in the same type and frequency of sports as prior to injury. 
Any individual who does not meet all these criteria will be designated as having “Not 
Returned to Full Activity and Participation”.  Participants reporting that they have 
returned to military duty, work and sports in a limited or modified role will be considered 
as having “Not Returned to Full Activity and Participation”. 
Longitudinal Collection of Return to Military Duty, Work and Sports Activity and 
Participation Outcomes – To more precisely measure time to return to military duty, 
work and sports, we will administer a brief Return to Activity Monitoring Survey on a 
monthly basis, starting 6 months after randomization continuing through the 24-month 
follow-up.  To promote compliance with data collection and ease the burden of 
completion that is placed on study participants, the Return to Activity Monitoring Survey 
is a responsive branching survey.  At each follow-up time point, participants will be 
presented with three simple questions about returning to military duty, work and sports.  
They will be asked to indicate if they have not returned, returned in a limited fashion, or 
returned without any restrictions.  Participants indicating that they have returned in a 
limited role or without restrictions will be asked to complete the three-question scale 
from the Injury Surveillance System and Cincinnati Occupational Rating and Marx 
Activity Rating scales, as appropriate (see Figure 5).  This responsive branching design 
seeks to limit the questions asked in the monthly, recurring survey while still providing 
sufficient detail to make a true determination of the participant’s return to military duty, 
work and sports status. 

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Figure 5. Determination of Return to Pre-Injury Activities 
To administer the monthly Return to Activity Monitoring Survey we will utilize 
customized survey software (Twilio) administered through REDCap. Individuals will be 
contacted based on their preferred method (e-mail or text message) 1 week prior to the 
target date (based on the date they were randomized). An automated reminder (e-mail 
and text message) will be sent on the exact target date of completion. If the individual 
has not responded after the initial contact, a research assistant from the University of 
Pittsburgh will make up to three phone calls to contact the individual to administer the 
questionnaires over the phone or remind them to complete the questionnaire online. 
Similar methods have been used to track activity after ACL reconstruction with excellent 
reliability80 and follow-up completeness (93% complete follow-up on 100 patients up to 2 
years after ACL reconstruction)81.  

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• Activity Limitation Scale of the Multi-Ligament Quality of Life (MLQoL) 
Questionnaire 
The MLQoL Questionnaire 60 is a condition-specific patient-reported outcome measure 
for individuals that have sustained a MKLI.  Qualitative research involving individuals 
with a MLKI has demonstrated that existing knee-specific or generic patient-reported 
outcome measures lack items that represent the full spectrum of symptoms and activity 
limitations associated with vascular and neurological injuries.  Additionally, existing 
knee-specific patient-reported outcome measures focus on sports activity and 
participation with few items related to participation in social roles and the profound 
emotional effect that MLKIs have on individuals.60  The MLQoL Questionnaire was 
developed with stakeholder input from patients with a MLKI and clinicians that treat 
those patients to address the limitations of existing knee-specific and generic patient-
reported outcome measures that do not represent the full spectrum of content that is 
pertinent to individuals with a MLKI.   
The MLQoL questionnaire consists of 52 items that are divided into 4 domains: physical 
impairment (19 items), emotional impairment (15 items), activity limitations (12 items) 
and social involvement (6 items).  Items representing impairments are phrased in terms 
of frequency and activity limitations and social involvement are worded in terms of 
degree of difficulty or extent of limitation.  The item responses are based on a five-point 
Likert scale.  Separate scores are calculated for each domain by summing the item 
response scores within each domain and dividing the sum by the total possible score for 
the domain then multiplying by 100 to provide a score that ranges from 0 to 100 with 
lower scores representing better outcomes (less impairment or limitations).   
Interviews with patients that have a MLKI reveal that the content of the items is relevant 
to individuals with a MLKI.  We selected the Activity Limitations scale of the MLQoL 
Questionnaire as a secondary primary outcome measure based on input from patients 
with a MLKI that indicated items contained in this scale were most important and 
relevant over the long-term.60    Psychometric testing of the Activity Limitations scale in 
individuals with MLKI found no floor and ceiling effects and acceptable levels of internal 

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consistency (Cronbach’s Alpha .94) and test re-test reliability (ICC .91).  Evidence for 
construct validity was demonstrated by acceptance of seven of eight a priori hypotheses 
for the Activity Limitations scale.60 
8.1.7.2 Secondary Outcomes – Patient-Reported Outcomes 
We will also collect several patient-reported measures of physical functions and health-
related quality. These patient-reported outcome measures will be collected at baseline, 
6, 12 and 24 months follow-up from time of randomization. The measures are described 
in detail below. 
• International Knee Documentation Committee (IKDC) Subjective Knee Form 
The International Knee Documentation Committee Subjective Knee Form (IKDC-SKF) is 
an 18-question measure of symptoms, function and sports activities for individuals with 
a variety of knee conditions, including MLIKs injuries.  Individuals complete the IKDC 
Subjective Knee Form from the perspective of “the past 4 weeks or since your injury”.  
Each item is scored using an ordinal scale, such that a score of 0 is given to responses 
that represent the highest level of symptoms or the lowest level of function or activity.  
The IKDC-SKF is scored by summing the scores for the 18 items and then transforming 
the score to a scale from 0 to 100 by dividing the sum of the scores by the maximum 
possible score, which is 87 if the individual responds to all 18 questions.  Higher IKDC-
SKF scores indicate the absence of symptoms and higher levels of function and sports 
activities. 
If there are missing item responses, the IKDC-SKF score can still be calculated if there 
are responses to at least 90% of the items (i.e. when responses have been provided for 
at least 16 of the questions).  In the presence of up to 2 missing item responses, the 
IKDC-SKF score is calculated as the (sum of the completed items)/(maximum possible 
sum of the completed items) times 100.    
The IKDC-SKF has undergone extensive psychometric testing61-63 and normative data 
in a representative sample of the US population has been determined.64  Test re-test 
reliability was high (ICC .94) with a standard error of measurement of 4.6.  The IKDC-

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SKF is related to concurrent measures of physical function (r=.47 to .66) but not 
emotional function (r=.16 to .26).  A change score of 11.5 was found to distinguish 
between those who were improved and those who were not over an average of 19 
months follow-up.62  Since its development, the IKDC-SKF has be found to include 
questions that are important to individuals with an ACL injury82.  Most recently, the 
threshold for the patient acceptable symptom state (PASS) for the IKDC-SKF for 
individuals that are 1 to 5 years after ACL reconstruction have been established.65   
• Physical Impairment, Emotional Impairment and Social Involvement Scales 
of the MLQoL Questionnaire 
We will also administer the other three scales as secondary outcomes to capture the full 
range of physical and emotional impairments and social impact that a MLKI has on 
people’s lives. 
The psychometric testing for the physical impairment, emotional impairment, and social 
involvement scales found no floor and ceiling effects and acceptable levels of internal 
consistency (Cronbach’s Alpha 0.94, 0.93 and 0.91, respectively) and test re-test 
reliability (ICC 0.89, 0.86 and 0.88, respectively).60 
• Patient Reported Outcome Measurement Information System (PROMIS) 
Physical Function Scale 
The Patient Reported Outcome Measurement Information System (PROMIS) Physical 
Function Scale was developed by the PROMIS Network, which was an NIH Roadmap 
Initiative, to assess physical function regardless of the health condition present.  In 
contrast to classical test theory, which focuses on the total scale score, IRT focuses on 
individual items and models the probability of a response to an item as a function of the 
properties of the item and the ability level of the individual responding to the item.   
The PROMIS PF item bank consists of 121 items and can be administered as a 
computer adaptive test (CAT) or through short forms.  The CAT version of the PROMIS 
Physical Function Scale utilizes a computer algorithm to adaptively select items that 
provide the most information about an individual.  Selection of each item is dependent 

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on an individual’s responses to prior items and items are administered until either a 
fixed number items are administered or until the individual’s physical function is 
estimated with a pre-specified level of precision.  The advantage of the CAT version of 
the PROMIS Physical Function Scale is that it allows for shorter, more efficient and 
potentially more precise measurement of an individual’s level of physical function.  The 
PROMIS Physical Function scores are presented as standardized T-scores that are 
normalized to the United States population.  A T-score of 50 is equal to the population 
average with a standard deviation of 10.  Thus, a score of 55 represents an individual 
with a physical function score that is one-half of a standard deviation above the 
population average.  We will utilize the CAT version of the PROMIS Physical Function 
Scale that is available free through the REDCap library. 
The PROMIS PF Scale has been shown to be well suited to assess patient-reported 
outcomes in those with a variety of orthopaedic disorders.  The PROMIS Physical 
Function CATs have been used for patients with foot and ankle disorders66, following 
ACL reconstruction67, osteoarthritis,68 and knee osteoarthritis69and have demonstrated 
adequate internal consistency,66 test re-test reliability,68 decreased ceiling and floor 
effects,66 and shorter completion times,66,67  As part of an NIAMS-funded study, we 
recently demonstrated the PROMIS Physical Function CAT had moderate test re-test 
reliability (ICCs 0.55 to 0.68) over a 1 and 3 month time period in a stable cohort of 
individuals two or more years after ACL reconstruction and large effect sizes (ES) from 
before to 12 (ES 1.85 ) and 24 months (ES 1.80 ) after ACL reconstruction (unpublished 
data). 
• PROMIS Global 10 
The PROMIS Global 10 is a 10-item patient-reported measure of physical and 
emotional health.70  It consists of a self-rated health item (global-1), single pure physical 
health (global-3) and mental health (global-4) items and an item representing overall 
quality of life (global-2), which is strongly related to mental health.  The other items 
provide global ratings of physical function (global-6), fatigue (global-8), pain (global-7), 
emotional distress (global-10) and social health (global-5 and global-9).  

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Scoring the PROMIS Global 10 requires recoding three items (global-7 [average pain], 
global-8 [average fatigue] and global-10 [frequency of emotional problems]).  The global 
physical health score is created by summing the responses to four items (global-3, 
global-6, recoded global-7 and recoded global-8).  The global emotional health score is 
created by summing the responses to 4 items (global-2, global-4, recoded global-5 and 
recoded global-10).  The raw scores are converted to T scores using a look-up table.  
The T-score distribution is standardized such that a score of 50 represents the mean of 
the US general population with a standard deviation around the mean of 10 points.  
Therefore, a person that has T-scores of 60 for the Global Physical Health and Global 
Mental Health scales has physical and mental health scores that are one standard 
deviation better than the US population average.      
Exploratory and confirmatory analyses indicated the global health items fit a two-factor 
model that included global physical and global mental health.  The scales had an 
internal consistency of 0.81 and 0.86 respectively and the global physical health scale 
was more strongly correlated (r=0.76) with the EQ-5D then was the global mental health 
scale (r=.59).  We are including the PROMIS Global 10 as a measure of global health 
because global health items are predictive of future health care utilization and mortality 
• Patient Acceptable Symptom State/Global Rating of Change 
The Patient Acceptable Symptom State (PASS) is a single question that measures an 
individual’s satisfaction with their health state. The PASS is assessed by asking the 
participant the question: “Taking into account all the activity you have during your daily 
life, your level of pain and also activity limitations and participation restrictions, do you 
consider the current state of your knee satisfactory?” with the responses of “yes” or 
“no”. The PASS question has shown to be have sufficient test re-test reliability in 
patients after ACL reconstruction, with a kappa coefficient of 0.78.65 
The Global Rating of Change is a fifteen-point global rating of change (GRC) and will be 
administered at 6, 12, and 24 months after randomization. The global rating of change 
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enrollment/post-injury. The GRC is used to identify individuals who made a substantial 
improvement due to the treatment that was received (REF). 
 
 
Other Patient-Reported Measures 
Measures of kinesiophobia, resiliency and comorbidities will be collected because these 
constructs may impact return to military duty, work and sports.  These measures will be 
collected only at the time of enrollment in the study.   
• Tampa Scale for Kinesiophobia 
Several studies have shown that fear of re-injury was the major and most common 
reason cited by individuals for not returning to sports or for returning to a lower level of 
sports participation after ACL reconstruction.83-87  For individuals that sustain a MLKI 
there is no evidence on how fear of re-injury affects return to military duty, work or 
sports, however given the magnitude of the injury we expect that return to activity and 
participation following a MLKI will be associated with fear of re-injury.  Therefore, to 
account for this potentially confounding variable we will utilize the shortened version of 
the Tampa Scale for Kinesiophobia (TSK) to assess fear of re-injury.  The TSK aims to 
quantify fear of re-injury due to movement and physical activity for patients with 
musculoskeletal pain. The shortened version of the TKS consists of 11 statements 
related to an individual’s perception of their experience of injury and physical activity.   
Each statement is provided with a four-point Likert scale that ranges from “strongly 
agree” to “strongly disagree”.  The TSK item scores are summed to create a score that 
ranges from 11 to 44, with a higher score indicating more fear. This scale has been 
found to have acceptable internal consistency (Cronbach’s alpha 0.77 to 0.81) and the 
validity of the TSK was acceptable in patients with acute and musculoskeletal pain. 88-91 
The presence of fear as measured by the TSK is related to physical function after ACL 
injury and reconstruction,92 but it also can change over time.93  Therefore we will 
administer the TSK at the time of enrollment in the study as well as at the 6, 12 and 24 
month follow-ups after randomization. 

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• Brief Resilience Scale 
Resilience is a measure of an individual’s ability to “bounce back” or recover from 
ongoing health-related stresses.94 The Brief Resilience Scale is a 6-item questionnaire, 
in which individuals indicate their level of agreement to each statement using a 5-point 
Likert scale that ranges from “strongly disagree” to “strongly agree”. The score is 
created by calculating the mean of the 6 items, after reverse coding the scores for items 
2, 4 and 6. The scores range from 1 to 5, where higher scores indicate positive 
resilience capabilities.  The Brief Resilience Scale was evaluated in four samples and it 
was found to be an unidimensional and reliable measure (Cronbach’s alpha ranging 
from .80 - .91).94  We hypothesize that individuals with higher resilience will have a 
quicker return to return to pre-injury level of military duty, work and sports and higher 
levels of patient-reported physical function. 
• Functional Comorbidity Index 
Health status is likely to contribute to overall outcomes after surgery for a MLKI, 
therefore we will assess for the presence of medical comorbidities using the 18-item 
Functional Comorbidity Index (FCI).  Using medical comorbidities is an important factor 
in creating risk-adjustment models for orthopedic trauma.95  The FCI is a self-
administered report of medical comorbidities that has been shown to be associated with 
physical function,96 whereas other comorbidity outcomes focus on mortality.  The FCI 
measures the full spectrum health related to musculoskeletal, cardiopulmonary, 
sensory, neuromuscular, endocrine and mental health. The FCI was found to 
demonstrate a stronger association with that SF-36 physical function subscale (R2 = 
0.29) than the Charleston (R2 = 0.18) and Kaplan-Feinstein (R2 = 0.07) indices.96  A 
simple count of the number of comorbidities performed similarly to a weighted count of 
the comorbidities and thus for simplicity, the simple count of the number of co-
morbidities is recommended.  When individuals were classified into high and low 
function based on the SF-36 physical function score, the FCI correctly classified 77% of 
the cases. 

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9 ASSESSMENT OF SAFETY 
 
Specification of Safety Parameters 
All surgeries and post-operative rehabilitation will be performed according to established 
standards of care for individuals undergoing treatment for a MLKI.  All clinical 
assessments performed in this study are considered to be part of standard clinical 
practice. At each clinical visit and through the electronic surveys, the research team will 
actively query participants on the occurrence of any potential health related event since 
last contact.   
 
Unanticipated Problems 
The Human Research Protection Office (HRPO) and the University of Pittsburgh IRB 
consider unanticipated problems involving risks to subjects or others to include, in 
general, any incident, experience, or outcome that meets all of the following criteria: 
• 
unexpected in terms of nature, severity, or frequency given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent document; and (b) the characteristics 
of the subject population being studied; 
• 
related or possibly related to participation in the research (“possibly related” 
means 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. 
Per this definition, only a subset of adverse events would be characterized as 
unanticipated problems involving risks to subjects or others. There are other types of 
incidents, experiences, and outcomes that are not considered adverse events, but are 
characterized as unanticipated problems (e.g., breach of confidentiality or other 
incidents involving social or economic harm). 

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Adverse Events 
An adverse event (AE) is any untoward medical occurrence during a subject’s 
participation in the research study. The occurrence of adverse events will be monitored 
for each subject on an ongoing basis throughout the study at all sites. All AEs, 
regardless of its relatedness to the study intervention, it will be recorded on the 
electronic AE form. Standard medical terminology from the Common Terminology 
Criteria for Adverse Events (CTCAE) 
(https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf) will be used when recording AEs. This standardization will 
allow sorting and grouping of like events, which will facilitate calculation of the incidence 
of AEs and reporting. In addition, this standardization will promote consistent 
documentation across all 23 sites.  
As dictated by the CTCAE, the data elements that will be recorded in the AE CRF are: 
- 
Event term; 
- 
Event severity: mild, moderate, severe/life-threatening/disabling or death; 
- 
Start and end date of event; 
- 
Relatedness to study procedures: unrelated, unlikely, possible, probable or 
definite; 
- 
Action taken with study procedure: none, study procedure interrupted, 
discontinued or modified; 
- 
Other action taken: none, treatment given (describe), discontinued from study or 
hospitalization; 
- 
Status of Event: not recovered/not resolved, recovered/resolved, resolved with 
sequelae, recovering/resolving, fatal, unknown or lost to follow-up;  
- 
Serious adverse event; 
 

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Serious Adverse Events 
A serious adverse event (SAE) is one that meets one or more of the following criteria: 
• 
Results in death 
• 
Is life-threatening (places the subject at immediate risk of death from the event 
as it occurred) 
• 
Results in inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in a persistent or significant disability or incapacity 
• 
Results in a congenital anomaly or birth defect   
• 
An important medical event that may not result in death, be life threatening, or 
require hospitalization may be considered an SAE when, based upon appropriate 
medical judgment, the event may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
If determined on the AE form that the event was a serious adverse event, additional 
questions will become available to collect information pertinent to the SAE including: 
- 
Unexpected serious adverse event; 
- 
Outcome of serious adverse event; 
- 
Action required because of the serious adverse event. 
 
 
Time Period and Frequency for Event Assessment and Follow-Up 
Unanticipated problems will be recorded in the data collection system throughout the 
study. 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 research team will actively query participants on the occurrence of any potential health 
related event since last contact. Events will be followed for outcome information until 
resolution or stabilization. 

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Characteristics of an Adverse Event 
 
Relationship to Study Intervention 
To assess relationship of an event to the study intervention, the following guidelines will 
be used: 
1. Related (Possible, Probable, Definite) 
a. The event is known to occur with the study intervention. 
b. There is a temporal relationship between the intervention and event onset. 
c. The event abates when the intervention is discontinued. 
d. The event reappears upon a re-challenge with the intervention. 
2. Not Related (Unlikely, Not Related) 
a. There is no temporal relationship between the intervention and event onset. 
b. An alternate etiology has been established. 
 
Expectedness of SAEs 
An adverse event will be considered unexpected if the nature, severity, or frequency of 
the event is not consistent with the risk information previously described for the 
intervention in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document. 
 
Severity of Event 
The following scale will be used to grade adverse events: 
1. Mild: no intervention required; no impact on activities of daily living (ADL); 
2. Moderate: minimal, local, or non-invasive intervention indicated; moderate impact 
on ADLs; 
3. Severe: significant symptoms requiring invasive intervention; subject seeks medical 
attention, needs major assistance with ADLs; 
4. Life-threatening: urgent intervention indicated; 

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5. Death related to AE. 
 
 
Internal and External Review and Adjudication of AE and SAE 
documentation 
Close monitoring of the AE and SAE CRFs documentation will take place throughout 
the implementation of the study. Two AE review committees have been created to 
provide a two-level review process for all filed AEs. The first-level review will be 
conducted by the University of Pittsburgh Internal Review Committee, which is 
comprised of three voting members and three non-voting members. The second-level 
review will be conducted by the External AE Adjudication Committee, which is 
comprised of three voting members. Refer to table 3 for the composition of these two 
committees.  
Table 3: Internal and Extern AE Review Committees composition 
1st Level Review – University of Pittsburgh Internal Review Committee 
Voting Members 
Dr. Irrgang (PI) 
Dr. Musahl (Co-PI & Qualified 
Clinical Investigator) 
Dr. Lynch (Co-I & Qualified Clinical 
Investigator for Rehabilitation) 
Non-Voting members 
Dr. Moore (Co-I & 
DCC Director), 
Dr. Gil (Co-I & Quality Control 
Coordinator), 
Beatriz Catelani (STaR Trial 
Project Coordinator) 
2nd Level Review – External Adjudication Committee 
Dr. Kurt Spindler, MD; 
Department of 
Orthopaedic Surgery, 
Cleveland Clinic 
Dr. Kelley Fitzgerald, PT, 
PhD, FAPTA; Professor at 
Department of Physical 
Therapy, University of 
Pittsburgh 
Susan Spillane, RN CCRP; 
Clinical Research Coordinator, 
Center for Clinical Trials & Data 
Coordination, University of 
Pittsburgh 
All AE and SAEs will be documented into the REDCap electronic database on an 
ongoing basis (Figure 6). For the first-level review, weekly reports will be generated and 
reviewed during the weekly Pittsburgh site research team meeting. At least two voting 
members of the University of Pittsburgh Internal Adverse Events Review Committee will 
need to be present for the review. This internal review of AEs and SAEs will determine 

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the event term, severity, relatedness, seriousness, and expectedness.  Changes to the 
AE and SAE designations will be made as needed.  
The second-level review will be conducted by the External Adjudication Committee. 
Every two months, a cumulative report of AEs and SAEs will be send to the External AE 
Adjudication Committee with recommendations. The Committee will meet by conference 
call to discuss the overall report and any AE or SAE of concern. Once approved as the 
final status, the Research Coordinator responsible for processing AEs and SAEs will 
record the final status of each AE and SAE in the REDCap STaR Trial database. Every 
6 months, the Data Coordinating Center (DCC) will review how often there are changes 
to AE/SAE terms, severity, relatedness, seriousness, and expectedness for each site. 
This will be reported to the PI and the Quality Control Co-Investigator. This two-level 
review process will help identify sites that are not documenting AEs appropriately, and 
will trigger additional training of the AE documentation.  
 
Figure 6 - AEs Internal and External Adjudication Flow Chart 
   

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Reporting Procedures 
The RC, to whom the AE or SAE information is disclosed, will document the event in the 
REDCap system.  Any event that poses risks to subjects or others will be submitted 
promptly to the US Army Medical Research and Material Command (USAMRMC), 
Office of Research Protections (ORP), Human Research Protection Office (HRPO).  
 
Unanticipated Problem Reporting to IRB and HRPO 
Incidents or events that meet the HRPO criteria for unanticipated problems require the 
creation and completion of an unanticipated problem report form.  The HRPO 
recommends that investigators include the following information when reporting an 
adverse event, or any other incident, experience, or outcome as an unanticipated 
problem to the IRB: 
• Appropriate identifying information for the research protocol, such as the title, 
investigator’s name, and the IRB project number; 
• A detailed description of the adverse event, incident, experience, or outcome;  
• An explanation of the basis for determining that the adverse event, incident, 
experience, or outcome represents an unanticipated problem;  
• A description of any changes to the protocol or other corrective actions that 
have been taken or are proposed in response to the unanticipated problem. 
To satisfy the requirement for prompt reporting, unanticipated problems will be reported 
using the following timeline: 
• Unanticipated problems that are serious adverse events will be reported to 
the IRB and to HRPO within 1 week of the investigator becoming aware of the 
event.  
• Any other unanticipated problem will be reported to the IRB and to the HRPO 
within 2 weeks of the investigator becoming aware of the problem.  

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• All unanticipated problems should be reported to appropriate institutional 
officials (as required by an institution’s written reporting procedures), the 
supporting agency head (or designee), and OHRP within one month of the 
IRB’s receipt of the report of the problem from the investigator. 
 
Adverse Event and Serious Adverse Event Reporting to IRB and HRPO 
Adverse events or SAEs that pose a risk to the study participant, or that are related to 
study procedures, will be reported as follows from the time the information is disclosed 
to research coordinator: 
- 
For AEs that pose a risk to the study participant or are related to the study 
procedures, the RC will enter information related to the AE into the REDCap 
system and will report the AE to the site’s IRB of record within timeframe 
specified by the IRB’s policies, but no later than 5 business days.  Additionally, 
the RC will report the AE directly to the site PI.   
- 
All SAEs will be reported within 24 hours of learning of event.  To do so the RC 
will enter the information into the REDCap system for SAEs.  REDCap will 
automatically contact the study PIs (Drs. Irrgang and Musahl), the site PI, and the 
Independent Research Monitor.  The site PI will notify the site IRB of record 
within 24 hours. Note that the study personnel may not know of SAEs that are 
not study related until the monthly follow-up. If such SAEs occur, they will be 
documented as above as soon as the study personnel are aware of the 
occurrence of the SAE. 
 
Criteria for Intervention Discontinuation 
Participants will be discontinued from the study intervention (early vs. late surgery and 
early vs. late rehabilitation) if a medical condition develops that, due to safety concerns, 
precludes the continuation of allocated intervention.  In such events, the subject will 
continue to be followed per the study protocol and follow-up data will be obtained.  The 
subject will remain in the group to which they were initially assigned to according to the 
intention-to-treat principle. 

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10 STUDY OVERSIGHT 
 
Composition of the Data and Safety Monitoring Board 
In addition to the PIs’ responsibility for oversight, study oversight will be under the 
direction of an independent Data and Safety Monitoring Board (DSMB) comprised of 
seven individuals. Dr. Steven Svoboda, MD was appointed the chair of the DSMB for 
the study, and he will be responsible for generating minutes from each meeting.  The 
committee includes three orthopaedic surgeons with expertise related to treatment of 
complex knee injuries, three physical therapists with expertise related to rehabilitation of 
the knee, and a biostatistician.  When selecting the members of the DSMB, we ensured 
that there was one orthopaedic surgeon and one physical therapist each to represent 
the interests of the US military and civilian practices in the US and Canada included on 
the DSMB.  Written documentation attesting to absence of conflict of interest has been 
obtained to ensure that the members of the DSMB are independent of the investigators 
and have no financial, scientific, or other conflict of interest with the STaR Trial.    
Members of the DSMB, including their credentials are listed below in Table 4. 
 
Table 4. DSMB Committee Members 
 
Address 
Contact: Phone 
US Military Members 
Steven Svoboda, 
MD – Chair 
MedStar Georgetown University 
Hospital 
1133 21st Street Northwest 
Washington, DC 20036 
Tel: (202) 416-2000 
Cell: (210) 882-6413 
Email: 
stevensvoboda@mac.com 
Richard Westrick,  
PT, DPT, DSc, 
OCS, SCS 
Associate Professor 
Department of Physical Therapy 
MGH Institute of Health 
Profession 
36 1st Avenue 
Boston, MA  02129 
Tel: (617) 724-4846 
Email: rwestrick@mghihp.edu 
 
 
US Civilian Members 
Annunziato 
Amendola, MD 
 
Department of Orthopaedic 
Surgery 
Duke University 
Tel: (919) 613-6711 
Fax: (919) 681-6357  
Email: ned.amendola@duke.edu 

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Duke Sports Science Institute 
3475 Erwin Road 
DUMC Box 3639 
Durham, NC 27705 
 
 
Steven Z. George, 
PT, PhD 
Professor  
Director of Musculoskeletal 
Research  
Duke Clinical Research Institute  
Vice Chair of Clinical Research  
Orthopaedic Surgery  
 
Duke University 
OFFICE: 8020 North Pavilion  
MAIL: PO Box 17969, Durham, 
NC 27715 
DEL: 2400 Pratt Street, Room 
0311 Terrace Level, Durham NC 
27705   
Tel: (919) 668-0825 
Email: steven.george@duke.edu 
 
Canadian Members 
Peter B,  
MacDonald, MD, 
FRCS 
University of Manitoba 
Pan Am Clinic 
75 Poseidon Bay 
Winnipeg, MB R3M 3E4 
Canada 
Tel: (204) 925-7480 
Fax: (204) 453-9032 
Email: 
pmacdonald@panamclinic.com 
 
Michael Hunt, BHK, 
MPT, MSc, PhD  
 
 
Associate Professor and Director, 
Motion Analysis and Biofeedback 
Lab 
Department of Physical Therapy 
University of British Columbia,  
212 Friedman Building 
2177 Wesbrook Mall, 
Vancouver, British Columbia, CA  
V6T 1Z3 
Tel: (604) 827-4721 
Fax: (604) 822-2870 
Email: michael.hunt@ubc.ca 
 
Biostatistician Member 
Stephen R. 
Wisniewski, PhD 
Vice Provost for Data and 
Information,  
Office of the Provost 
Co-director, Epidemiology Data 
Center, Epidemiology 
Tel: (412) 624-2246 
2nd Tel: (412) 624-5218 
Fax: (412) 624-3775 
Email: stevewis@pitt.edu 
 

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4420 Bayard Street, Suite 600 
Pittsburgh, PA 15260 
 
 
Roles and Function of the DSMB   
The University of Pittsburgh Clinical and Translational Science Institute (CTSI) will 
provide logistical management and support of the DSMB. The first meeting will take 
place before initiation of the trial to discuss the protocol, approve commencement of the 
trial, and to establish guidelines for monitoring of the study. Thereafter, the DSMB will 
meet every six months.  An emergency meeting of the DSMB may be called at any time 
by the Chairperson should questions of patient safety arise. 
The ongoing responsibilities of the DSMB are to: 
1. Evaluate the progress of the trial, including periodic assessments of data quality and 
timeliness, participant recruitment, accrual and retention, participant risk versus 
benefit, performance of trial sites, and other factors that can affect study outcome; 
2. Consider factors external to the study when relevant information becomes available, 
such as scientific or therapeutic developments that may have an impact on the 
safety of the participants or the ethics of the trial; 
3. Review clinical center performance, make recommendations and assist in the 
resolution of problems reported by the Principal Investigators; 
4. Protect the safety of the study participants; 
5. Report on the safety and progress of the trial; 
6. Make recommendations to the Principal Investigators, and if necessary, to the 
HRPO concerning continuation, termination or other modifications of the trial based 
on the observed beneficial or adverse effects of the treatment under study; 
7. Monitor confidentiality of the trial data;  
8. Assist the Principal Investigators by commenting on any problems with study 
conduct, enrollment, sample size and/or data collection.  

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The DSMB will review SAEs and AEs at least twice annually and will be alerted by the 
research team to any interim concerns. At least twice annually, the DSMB will review 
enrollment to assure that enrollment targets are being met. The DSMB Chair will write a 
report after each meeting, summarizing the study status and outlining any concerns. A 
copy of this report will be provided to the DoD Program Officer. 
Tables (Appendix C) for the open DSMB reports will include information on 
prescreening, screening, screen failures, randomized, demographics, study status, 
protocol deviations, AEs and SAEs. The open reports will be stratified by trial, but not by 
study arm. 
Closed reports, if requested by the DSMB, will be stratified by study arm. 
 
Independent Research Monitor 
The funding agency (DoD) requires research determined as greater than minimal risk, 
that the IRB approve, by name, an independent research monitor with expertise 
consonant with the nature of risk(s) identified within the research protocol. The IRB has 
approved a written summary of the monitors’ duties, authorities, and responsibilities. 
The independent research monitor will perform oversight functions and report their 
observations and findings to the research team, the IRB, and DSMB. 
The independent research   monitor functions include: 
- 
Oversight of study interventions and interactions, 
- 
Oversight of data collection, storage and analysis 
- 
Reviewing monitoring plans and UPIRTSO reports, 
- 
Consulting on individual cases as necessary and review and evaluate adverse 
event reports, 

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- 
Discussing the research protocol with the investigators, interview human 
subjects, and consult with others outside of the study about the research and will 
promptly report any discrepancies or problems to the IRB; 
- 
Having the authority to stop research protocol in progress, if necessary, remove 
individual subjects from a research protocol, and take whatever steps are 
necessary to protect the safety and well-being of human subjects until the IRB 
can make an assessment; 
- 
Shall have the responsibility to promptly report the observations and findings to 
the IRB or other designated official and the HRPO. 
Dr. John R. Fowler Jr., MD will serve as the independent research monitor for this 
study. Dr. Fowler is an Assistant Professor and Assistant Dean for Medical Student 
Research in the Department of Orthopaedic Surgery at the University of Pittsburgh.  Dr. 
Fowler is a board certified orthopaedic surgeon with a certification of advanced 
qualifications in hand surgery.  He has conducted extensive clinical research, including 
participation in several multicenter clinical trials.  He is also a member of the University 
of Pittsburgh Institutional Review Board for Humans Subjects Research.  Dr. Fowler’s 
credentials to serve as the research monitor, as well as the duties, authorities and 
responsibilities of the research monitor have been reviewed and approved by the IRB. 
 
 
Study Committees 
This study is governed by an Executive Steering Committee and seven subcommittees. 
All committees consist of investigators or individuals associated with the STaR Trial, 
with the exception of the AE Adjudication Committee, which is comprised of individuals 
external to the study.   
- 
Executive Steering Committee (ESC) 

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The role of the ESC is to provide oversight of the trial. The committee will define the 
vision and scientific goals of the STaR 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. During the study, the ESC will 
resolve any conflicts arise between investigators.  The ESC will review and issue final 
approval or recommend modification for all subcommittee decisions. The ESC will meet 
monthly via conference call. 
- 
Forms Committee 
The Forms Committee drafted a set of forms that will be used in the study. During the 
study, the committee will review and approve all modifications to any forms used for 
data collection. The committee will regularly review and maintain the current set of 
approved forms. Additionally, the committee will be responsible for keeping a log of all 
form changes throughout the duration of the study. 
- 
Publications and Ancillary Studies Committee (PASC) 
The PASC has established policies and procedures for assigning writing groups and 
approving the STaR Trial-associated ancillary studies, secondary analysis of existing 
data and abstracts, presentations, and publications prior to their submission for 
dissemination. The PASC will also establish guidelines for authorship for investigators 
following the guidelines specified by the International Committee of Medical Journal 
Editors for authors who have contributed to the scientific design and merit of the study. 
- 
Rehabilitation Committee 
The Rehabilitation Committee has established the rehabilitation guidelines and 
protocols for subjects enrolled in the study. 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 

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materials for the home exercise programs for the study participants to use. Throughout 
the study, 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 review and affirm the quality of the conduct of the 
study including implementation of the surgical timing and rehabilitation 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 study on an ongoing basis to review loss to follow-up and 
protocol deviations in aggregate, and by individual site. Additionally, the Quality Control 
Committee will be responsible for the oversight of the site monitoring visit. Further 
information on site monitoring visits is described in Section 11.1. 
- 
Recruitment Committee 
The Recruitment Committee will establish a plan and monitor recruitment throughout the 
duration of the study. The committee will create recruitment materials to be used at all 
sites. Additionally, should a site be recruiting fewer subjects than recommended, the 
committee will evaluate the site and make recommendations to improve recruitment at 
the site. 
- 
Adverse Events Adjudication Committee 
The Adverse Events Adjudication Committee consists of three qualified surgical and 
rehabilitation professionals to provide an independent external review of all AEs that 
occur during the study. The committee will assign each AE a level of severity and will 
determine the relationship with the study intervention. Further information on the AE 
Adjudication process and committee is described in Section 9.4. 
 

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Table 5. Members of the Study Committees 
Committee 
Committee Members 
Executive Steering Committee 
James Irrgang, PT, PhD, ATC 
Volker Musahl, MD 
Andrew Lynch, PT, PhD 
Charity Patterson, PhD 
Travis Burns, MD 
Christopher Harner, MD 
Bruce Levy, MD 
Brett Owens, MD 
Robert Schenck, MD 
Daniel Whelan, MD 
Forms Committee 
Christopher Harner, MD -  Chair 
Brett Owens, MD – Co-chair 
Lane Bailey, PhD, DPT, CSCS 
Jonathan Cooper, MD 
Andrew Lynch, PT, PhD 
Charity Patterson, PhD 
Ryan Khan, CCRP 
James Irrgang, PT, PhD, ATC – Ex Officio 
Volker Musahl, MD – Ex Officio 
Publications and Ancillary 
Studies Committee 
Robert Schenck, MD – Chair 
Matthew Matava, MD – Co-chair 
Kenneth Cameron, PhD, MPH, ATC 
Andrew Lynch, PT, PhD 
Charity Patterson, PhD 
Matthew Posner, MD 
Brett Owens, MD 
Michael Stuart, MD 
James Irrgang, PT, PhD, ATC – Ex Officio 
Volker Musahl, MD – Ex Officio 
Rehabilitation Committee 
Andrew Lynch, PT, PhD – Chair 
Michael Stuart, MD – Co-chair 
Lane Bailey, PhD, DPT, CSCS  
Cathy Coady, MD 
Jonathan Cooper, DO 
David Pezzullo, PT, MS, SCS, ATC 
Robert Schenck, MD 
Daniel Whelan, MD 
Johnny Owens, MPT 
Terrance Sgroi, DPT, SCS, MTC 
Terese Chmielewski, PT, PhD, SCS 

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James Irrgang, PT, PhD, ATC – Ex Officio 
Volker Musahl, MD – Ex Officio 
Quality Control Committee 
Alexandra Gil, PT, PhD – Chair 
Charity Patterson, PhD – Co-chair 
Christopher Harner, MD 
Joseph Hart, MD 
Jeffrey Macalena, MD 
Matthew Matava, MD 
Bradley Nelson, MD 
James Irrgang, PT, PhD, ATC – Ex Officio 
Volker Musahl, MD – Ex Officio 
Recruitment Committee 
Mark Pallis, MD 
Cale Jacobs, PhD, ATC  
Timothy Mauntel, PhD, ATC 
Alan Getgood, MD 
Brian Waterman, MD 
James Irrgang, PT, PhD, ATC – Ex Officio 
Volker Musahl, MD – Ex Officio 
Adverse Events Adjudication 
Committee 
Kurt Spindler, MD 
G. Kelley Fitzgerald, PT, PhD 
Susan Spillane, RN, CCRP 
 

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11 CLINICAL SITE MONITORING PLAN 
In addition to the PI’s responsibility for oversight, study oversight will be under the 
direction of the Clinical Study Oversight Committee (CSOC).  The PI and CSOC have 
developed the Clinical Monitoring Plan (CMP) that establishes guidelines for conducting 
monitoring visits and related tasks to monitor the STaR Trial. The Clinical Coordinating 
Center (CCC) at the University of Pittsburgh will be responsible for CMP under the 
leadership of Dr. Alexandra Gil, Co-Investigator and Quality Control Coordinator (QCC), 
Maria Beatriz Catelani, Project Coordinator, in collaboration with Drs. Irrgang (Principal 
Investigator), Musahl (Co-Principal Investigator and Qualified Clinical Investigator [QCI] 
for Surgery) and Lynch (Co-Investigator and QCI for Rehabilitation) as well as Dr. 
Charity Moore, (Co-Investigator and Director for the Data Coordinating Center [DCC]).  
Dr. Gil and Ms. Catelani will serve as the Clinical Trial Monitors.   
The intent of the CMP is to ensure the rights of human subjects are protected; the study 
is implemented in accordance with the protocol; compliance with the International 
Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines, national 
and local regulations, and institutional policies across all sites; and that the quality and 
integrity of study data and data collection methods are maintained. The focus areas for 
the CMP include: 1) site assessment review 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 annual on-site monitoring visits and continuous remote monitoring that 
includes review of electronic records and regular communication with Research 
Coordinators (e.g. biweekly phone calls). 
 
Clinical Monitoring Communication Plan 
Communications for each monitoring visit will include a letter confirming the site 
monitoring visit, agenda for the monitoring visit, on-site post-monitoring visit debriefing, 
and a follow-up letter and/or visit report and Action Item Tracker.  All documents will be 
sent via email to the study PI, QCIs for surgery and rehabilitation, Director of the DCC 
and site PI and Research Coordinator (RC).  

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Scheduling of Visits 
The Quality Control Coordinator or her designee will work with the site PI and RC to 
schedule the monitoring visits. The study PI, QCIs, DoD Program Officer and Director of 
the DCC will be apprised of monitoring visit schedule. Prior to the visit, the site PI and 
RC will receive a visit confirmation letter and agenda. The site PI and RC will be 
expected to secure workspace for the Clinical Trial Monitor and to be available during 
the visit to facilitate monitoring activities. 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 RC are also expected to be available for a summary 
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 monitoring visits for this study including a Site Initiation 
Visit, Interim Visits, For-Cause Visits and Study Close-Out Visit.  
 Site Initiation Visit  
The site initiation visit will take place prior to site activation once IRB and Human 
Research Protections Office (HRPO) approvals 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;  
• 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 taking place the Quality Control Coordinator, Dr. Gil and 
the STaR Trial Project Coordinator, Beatriz Catelani, will develop the agenda, and 
follow the communication plan to ensure that all relevant parties are informed of the 

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meeting date and time commitment well in advance. The agenda will contain a list of 
topics in order of the 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 
IRB, University of Pittsburgh IRB, and HRPO;  
• All necessary site staff have been identified; and  
• All staff have been completed training on utilization of REDCap database. 
The QCC will utilize the following list of activities as a starting point for the Initiation Visit 
Agenda: 
• Protocol Overview 
o Type of study 
o Study objectives 
o Key inclusion/exclusion criteria 
 Completion of Screening and Eligibility Scenarios 
o Study procedures 
o Enrollment goals 
o Recruitment Plans 
o Informed Consent Discussion  
o Study visit schedule/schedule of events 
• Safety: Definitions, Collection, and Reporting 
o Review of Adverse Events (AEs), Serious AEs (SAEs), and Unanticipated 
Problems (UPs)  
o Completion of Reportable Events Scenarios 
o Review of timeline related to Reportable Events 
o Queries resulting from the above 
• Site Specific Study Procedures 
o Review of site specific study implementation 

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o Review creation and retention of source documentation 
o Review procedures for data entry.  
o Review of action items for Reportable Events 
o Discuss site specific communication plan with participants, physical 
therapists, site PI, local IRB and Clinical Coordinating Center. 
• Clinical Monitoring 
o Contacts 
o QCC and site responsibilities 
o Frequency 
o Close out procedures 
• Site Essential Documents File Review 
o Structure of the Regulatory Binder as well as Essential Documents to 
include: IRB approval documents: protocol, patient handouts, 
advertisements, consent document 
o Document updates 
• Tour of Facilities 
• Summary/Review of Action Items 
 
A site can be activated only after all of the requirements of the Clinical Terms of Award 
list (see Table 6 below) have been met. 
Table 6 – Site Activation Requirements Check List 
Item 
Date 
1. IRB 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 (MOP), electronic systems.  
(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) 
 

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• Facilities deemed acceptable 
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 subjects 
have been enrolled and followed for three to four months. Subsequent Interim Visits will 
be conducted annually and in-person.  The objectives for the Interim Visits are to 
confirm: 
• The subjects’ rights are being protected;  
• The study is being conducted according to the protocol and applicable regulations, 
including GCP; 
• Accurate reporting of interventions, subject safety data and study endpoints.  
In addition, to ensure accuracy and completeness of the data, the Clinical Trial Monitor 
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, RC 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 
as an Action Items Tracker attached to the monitoring visit documentation.  At a 
mutually agreed upon time, or approximately two to four weeks after monitoring visit, 
whichever is earlier, the Quality Control Coordinator or designee and site research staff 
designee will meet via telephone conference to discuss resolved, in process, and 
pending action items. At this time the need for and frequency of subsequent meetings 
will be discussed.  The follow-up letter, final monitoring visit report and Action Items 
Tracker will be sent within three weeks of the conclusion of the site visit.  

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 For-Cause Visits 
For-Cause Visits will be conducted to address any unanticipated issues that arise which 
require training, remediation or other situations for which the site requires assistance.  
For-Cause Visits can be conducted remotely or on-site if mandated by the Quality 
Control Coordinator, PI, or Director of the DCC or requested by the site. 
 Close-Out Visit 
The Close-Out Visit will be conducted to ensure that all study data and other study 
documentation is complete and accurate and that all study records have been 
reconciled. Study closure activities may require several remote visits which 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, HRPO, Data and Safety 
Monitoring Board, or Executive Steering Committee. 
 
 
Research Records and Documents to be Monitored 
Table 7 below summarizes the research records and documents to be monitored 
including the number of records to be monitored and method of monitoring. 
 
Table 7 – Monitoring of Research Records and Documents  
 
Records and Documents to Be 
Monitored 
 
# Records 
Remotely 
On-site 
visit 
Site Human Subject Protection Training 
Records 
100% 
  
 
IRB and HRPO Initial Approval and Annual 
Renewal Letters 
100% 
  
 
Signed Informed Consent Forms 
100% 
 
  
Eligibility Criteria 
100% 
  
 
Surgical Source Documentation vs. CRFs 
100% 
 
  

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Clinical Follow-up Visits Source 
Documentation vs. CRFs 
10% 
 
  
CRFs or Data Queries 
10% 
 
  
Process to Contact PTs when CRFs Were 
Not Submitted 
10% 
  
 
Missed Visits and Missing Data 
100% 
Interim 
reports 
biannually 
 
Documentation and Reporting of AEs, 
SAEs, Protocol Deviations Documentation 
100% 
  
  
Withdrawals and Dropouts Documentation 
100% 
  
 
Site Regulatory Documents 
100% 
At close-out 
visits 
At initiation 
and interim 
visits 
 

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12 STATISTICAL CONSIDERATIONS 
 
Study Hypotheses 
The overall objective of this study us to investigate the effects of timing of surgery (early 
vs. delayed) and timing of post-op rehabilitation (early vs. delayed) for the treatment of 
military personnel and civilians that have sustained a MLKI.  To achieve this objective, 
we will conduct two parallel randomized controlled trials.  The aims and hypotheses for 
these trials are: 
Aim 1: Determine the effects of timing of surgery and post-operative rehabilitation 
on time to return to pre-injury level of military duty, work and sports and patient-
reported physical function.   
We hypothesize that early surgery, early rehabilitation and the combination of early 
surgery with early rehabilitation will lead to an earlier and more complete return to pre-
injury military duty, work and sports and better patient-reported physical function.   
Aim 2: Determine the effects of timing of post-operative rehabilitation on time to 
return pre-injury level of military duty, work and sports and patient-reported 
physical function.   
We hypothesize that early rehabilitation will lead to an earlier and more complete return 
to pre-injury military duty, work and sports activity and better patient-reported physical 
function. 
 
 
Sample Size Considerations 
Based on our preliminary retrospective study, we estimate that across 25 clinical sites 
there will be 1213 MLKIs over a 2-year recruitment period.  After the exclusions for 
participation in the trial that randomizes timing of surgery and rehabilitation (Aim 1), we 
estimate that there will be approximately 650 eligible individuals with a MLKI that 
present to orthopaedics in time to make it possible to perform surgery within 6 weeks if 
randomized to early surgery.  If approximately 60% of the eligible subjects agree to 
participate in the study, this would provide a total sample size of 392 (n= 98 per cell).  

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Assuming 10% lost to follow-up over two years, we expect to have 352 subjects (n=88 
per cell).   
We had no preliminary data on time to return to pre-injury military duty, work and sports, 
therefore we conservatively estimated power using the 24-month rate of return to full 
pre-injury activity and participation and a two-sample test of proportions. This sample 
size would provide 80%-92% power to detect a 15% absolute difference (𝑎𝑎=0.05) in the 
rate of return to full pre-injury military duty, work and sports for the main effects (n=176 
for each arm) for timing of surgery or timing of rehabilitation, assuming the delayed arm 
has a return rate of 30% to 70%.  Power was calculated for a two-sided z test with 
pooled variance using PASS 13.97  Additionally we would have 80% power to detect a 
17% to 21% difference between the early surgery/early rehabilitation group (n=88) 
compared to any of the other 3 groups with rates from 30%-70%.  With 176 subjects per 
main effect arm, we would have 82% power to detect a 15% difference in return to 
military duty, work and sports (hazard ratio=0.65, 35% improvement in the time to rate 
of return to duty, work and sports) using a log-rank test assuming two-year accrual, two-
year follow-up for each participant, 10% dropout in each arm, and 5% crossover in each 
arm. 
For the MLQoL Questionnaire Activity Limitations Scale, we would have 80% power to 
detect a 6.2 point difference at 24 months between early surgery and delayed surgery 
(or early rehabilitation and delayed rehabilitation) using a two-sided two-sample equal 
variance t-test (α=0.05, standard deviation=20.8) assuming a 10% attrition rate. This is 
equivalent to a small effect size of approximately 0.30. We would also have 80% power 
to detect a 10.2-point difference between the early surgery/early rehabilitation group 
and any of the other three groups using the same standard deviation and test (α=0.0167 
adjustment for multiple comparisons). 
After accounting for those included in the trial that randomizes surgery and rehabilitation 
and applying the exclusions described above we estimate that approximately 440 
individuals with a MLKI will be eligible for participation in the trial for Aim 2 that 
randomizes only timing of post-op rehabilitation.  If approximately 68% of the eligible 

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subjects agree to participate in the trial for Aim 2 that randomizes only timing of post-
operative rehabilitation, this would provide a total sample size of 298 (n= 149 per cell).  
This total of subjects would provide 79% to 84% power to detect an absolute difference 
of 15% between the groups (𝑎𝑎=0.05) assuming the delayed rehabilitation group has a 
return to military duty, work and sports rate of 65 to 70% and 10% attrition. Power was 
calculated for a two-sided z test with pooled variance using PASS 13.97  
 
 
Safety Review 
Adverse events and serious adverse events will be named and classified using the 
CTCAE. No formal rules have been established to halt enrollment for safety concerns. 
All tabulations and comparisons of rates of AEs and SAEs by treatment group will be 
shared with the DSMB at their regularly scheduled meetings. As required by 
www.clinicaltrials.gov and biomedical journals, all safety data will be reported by 
treatment group as part of the final dissemination of study results. 
 
 
Final Analysis Plan 
We will first compare the distribution of baseline characteristics and important 
prognostic factors (age, sex, pre-injury activity level, KD classification etc.) between the 
groups for each trial (surgery and rehabilitation, rehabilitation only).  Continuous 
variables with fairly symmetric distributions will be summarized using means and 
standard deviations. Those with skewed distributions will be described using medians 
and inter-quartile ranges.  Categorical data will be summarized using frequencies and 
percentages.  
Because of the expected heterogeneity of pre-injury activity level of individuals that 
sustain a MLKI, we will combine return to military duty, work and sports into an overall 
return to activity and Participation variable.  Individuals will be classified as having 
returned to activity if and when they have returned to their pre-injury level of military 
duty, work and sports activity.  See Section 3.2 for details. 

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 Statistical Analysis for Specific Aim 1 (Randomization to Early vs. 
Delayed Surgery and Post-Operative Rehabilitation)  
All analyses for the two by two factorial design trial will follow the principle of intention-
to-treat. The primary outcome of return to military duty, work and sports will be 
assessed at monthly intervals via text message, email, or phone call from 6 to 24 
months after randomization.  This frequency of measurement will allow us to conduct 
more precise time to event analysis compared to having discrete time points several 
months apart. For those participants not returning to full activity and participation, the 
date of censoring for each participant will be the end of the two-year follow-up or last 
contact prior to 3 consecutive months of non-response/no data for this outcome. We will 
begin the analyses by estimating and comparing the time to event curves using Kaplan-
Meier estimation and log-rank tests. We will begin the analyses by assessing the 
proportional hazards assumption for the four intervention groups using a plot of the log 
of the negative log of the estimated survival density vs. the log of time (for parallel lines) 
and by testing the group (4 levels) by time interaction in a Cox proportional hazards 
model (group*log(t)).  If non-significant, we will assess using the collapsed main effects 
for surgery (early vs delayed) and post-operative rehabilitation (early vs delayed). We 
will also assess and test for non-proportional hazards by site and injury pattern 
(randomization stratification factors).  If the proportional hazards assumption is not 
violated for the group effects, we will proceed using Cox proportional hazards model to 
test for intervention effects on time to return to military duty, work, and sports. Although 
we are not powered for detecting an interaction, we will test the interaction between 
timing of surgery and timing of rehabilitation using Cox proportional hazards model prior 
to looking at main effects. Assuming the interaction is not significant, we will compare 
the time to return to return to military duty, work and sports for both main effects, 
adjusting for site and KD injury pattern. We will present results using hazard ratios and 
95% confidence intervals. If the proportional hazards assumption is violated, we will 
extend the Cox model to incorporate the group*log(t) term such that the hazards may 
vary over time across groups. If the proportional hazards assumption is violated for site 
or injury pattern, we will allow for this variability through stratification since the 
parameter estimates and testing for these two variables are not of interest. 

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We will use linear mixed models to compare and test the mean patient-reported 
physical function as measured by the MLQoL Activity Limitation Scale across the 
groups accounting for repeated measurements within patient. The fixed effects of 
surgery (early vs. delayed), rehabilitation (early vs. delayed), time (baseline, 6, 12, 24 
months), the two-way interactions, and the three-way interaction will be placed in the 
model controlling for site and KD injury pattern. Assuming the 3-way interaction is not 
significant, we will proceed to test the two-way interactions for surgery*time and 
rehabilitation*time.  If the two-way interaction is significant, we will test the separate 
treatment effects at 24 months (primary time point of interest) using contrasts.  All 
treatment effects will be presented using adjusted mean differences and 95% 
confidence intervals. Using the linear mixed models is advantageous in the presence of 
data missing completely at random or missing at random as these models efficiently 
handle the observed data and correlations among the repeated measures to estimate 
treatment effects and standard errors.   
With respect to missing outcome data, we will compare those patients missing follow up 
visits at 6, 12, and 24 on demographic and baseline clinical characteristics to assess the 
missing data mechanism.  As a sensitivity analysis, if the proportion of patients lost to 
follow up exceeds 15% or any time point has more than 15% missingness, we will use 
pattern mixture models under non-ignorable missingness to test the impact on the 
inference of our trial results.  
To determine if early surgery and early rehabilitation is better that the other 
combinations, we will specifically compare the early surgery/early rehabilitation group to 
each of the 3 other intervention arms using contrasts in the full models for both the time 
to event outcome and patient-reported physical function.   
Secondary outcomes that are scales or continuous measurements will be analyzed 
similar to the methods used for physical function. Secondary outcome measures that 
are categorical will be analyzed using random effects logistic regression to control for 
repeated measures within person. The rates of complications and adverse events will 

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be compared using chi-square analysis (at the participant level) by type of complication, 
event term (>10% occurrence) and by organ system. 
 Statistical Analysis for Specific Aim 2 (Randomization to Only Early vs. 
Delayed Post-Operative Rehabilitation) 
Analysis for the early versus delayed rehabilitation trial (Aim 2) will follow the principle of 
intention-to-treat.  Baseline characteristics will be compared between the two groups to 
assess comparability. We will estimate the time to full return to activity and participation 
using Kaplan Meier curves and test between the two groups using log-rank testing. We 
will then test the curves adjusting for site and KD injury pattern using Cox proportional 
hazards model similar to the analysis for the surgery and rehabilitation trial. The 
approaches to assessing and testing the proportional hazards assumption will be the 
same. We will use linear mixed models to compare and test mean patient-reported 
physical function between the two groups over time accounting for the repeated 
measurements within patient. The fixed effects of early vs. delayed rehabilitation and 
time (baseline, 6, 12, and 24 months) and their two-way interaction will be tested 
adjusting for site and KD injury pattern.  The approaches to investigating and handling 
missing data will be similar to those proposed in Specific Aim 1. All other secondary 
outcomes that are scales or continuous measures and will be analyzed similarly.  
Secondary outcome measures that are categorical will be analyzed using random 
effects logistic regression to control for repeated measures within person. The rates of 
complications and adverse events will be compared using chi-square analysis (at the 
participant level) by type of complication, event term (>10% occurrence) and by organ 
system. 
 

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13 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 REDCap using the scheduling function.  
After randomization occurs, Standard of Care clinical visits and PROs will be completed 
remotely and managed through scheduled timepoints in REDCap 
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 ligaments, 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 REDCap. 
Status of the data collection will be discussed at weekly clinical research meetings by 
Principal Investigator (Dr. James Irrgang) and Director of DCC and Biostatistician (Dr. 
Charity Moore Patterson) and members of the research team at the DCC.  Each site 
study coordinator 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. Patterson will delegate management of the REDCap 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, Section 4.9 and regulatory and institutional requirements for 
the protection of confidentiality of subjects.  Study staff will permit authorized 
representatives of the DoD and regulatory agencies to examine (and when required by 

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applicable law, to copy) research records for the purposes of quality assurance reviews, 
audits, and evaluation of the study safety, progress and data validity.   
Table 8 lists the electronic forms that are collected in REDCap as well as the 
information that will be obtained from the medical records and from paper forms that will 
be utilized for the study (see Appendix B for study forms). 
 
Table 8. List of forms and source of data collection. 
REDCap 
Medical Records 
Paper Form 
• Additional Surgeries – 
Patient Reported 
• Additional Surgeries – 
Clinical  
• Articular Cartilage 
Findings and 
Procedures 
• Baseline Injury 
Surveillance 
Survey/Military Activity 
• Brief Resilience Scale 
• Cincinnati 
Occupational Rating 
Scale 
• Clinical Visit Form 
• Complications 
Reporting  
• Concomitant 
Medications 
• Contact Information 
• Demographic & 
Participant Information 
• Examination Under 
Anesthesia 
• Functional Comorbidity 
Index 
• Global Rating of 
Change/PASS 
• ·IKDC Subjective Knee 
Evaluation 
• Surgical findings and 
procedures  
• Radiographs/MRI 
findings 
• Clinical course of 
recovery  
• Surgical 
complications 
• Concomitant 
Medications 
 
• Initial Screening Form 
• Contact Information 
• Demographic & 
Participant Information 
• Consent Forms 
• PRO’s (as requested 
by participant)  

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• Initial Screening Form 
• Inclusion/Exclusion 
Form 
• Ligament Findings and 
Procedures 
• Marx Activity Rating 
Scale 
• Meniscus Findings and 
Procedures 
• Multi-Ligament Quality 
of Life Questionnaire 
• Patient Reported 
Rehabilitation 
• Peroneal Nerve 
Findings 
• Physical Therapy Case 
Report 
• Post-Operative Home 
Exercise Log 
• PROMIS Global 10 
• PROMIS Physical 
Function 
• Return to Activity 
Monitoring Survey 
• Return to Military 
Activity 
• Return to Sports 
Activity 
• Return to Work Activity 
• Tampa Scale for 
Kinesiophobia 
 

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14 QUALITY CONTROL AND QUALITY ASSURANCE 
Quality Management in clinical research is the overall process of establishing and 
ensuring the quality of processes, data, and documentation associated with the clinical 
research activities.  It encompasses both quality control (QC), and quality assurance 
(QA) activities. Quality control is comprised by a set of operational activities intended to 
ensure the quality requirements are being met. It continuously reviews data collection 
forms and other records for completeness and logic. Quality assurance is comprised of 
a set of activities intended to: 1) establish quality requirements and procedures; 2) 
ensure that those requirements are being met and procedures are being followed; and 
3) verify that quality is being maintained. This includes creating procedural documents 
to guide quality activities and the review of documentation to assess adherence to 
written procedures, policies, and regulations.  
 
Quality Management 
Quality Management includes the QC and QA processes aimed at prevention of errors, 
as well as processes aimed at detection and correction of errors.  Activities related to 
Quality Management (QM) prior to study initiation will primarily focus on the prevention 
of errors and will include: 
• Reviewing consent documents to make sure that all proper elements are 
included and that the documents complies with all relevant regulations, local IRB 
requirements, and Good Clinical Practice, as appropriate 
• Face-to-face kick-off Investigator’s meeting to review study protocol 
• Research Coordinators’ conference calls and/or webinars for training on study 
protocol (e.g., screening, eligibility, clinical and research CRFs, adverse events, 
etc.).  These conference calls will take place every 2 weeks until all sites are 
approved to initiate recruitment. 
• Monthly Investigators’ conference calls for training and discussion related to the 
logistics of implementation of the study at the site level.    
• Executive Steering Committee conference calls will take place monthly.  

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• Development of the Reportable Events Policies by Site Standard Operating 
Procedures.  
• Testing of the electronic data capture system (REDCap) functionality and data 
validation features (detailed description in Section 16). 
• Training of research staff on case report forms (CRFs) for data collection, eCRFs 
in REDCap for data entry and overall utilization of the REDCap system for data 
collection. 
• Site Initiation Visit which will have the goals of: 
o Orienting and training staff on the protocol and study related processes;  
o Confirming readiness for study implementation; and 
o Identifying additional requirements that must be satisfied prior to site 
activation and subject.  
See Section 11 for detail list of activities. 
Throughout the conduct of the study, processes to prevent errors, discuss any new or 
unforeseen issues and preserve expected level of training and knowledge of study 
protocol will be maintained by:  
• Weekly STaR Trial research meeting at the Pittsburgh site; 
• Monthly Research Coordinators conference calls; 
• Annual Interim Site Visits;  
• Monthly Investigators conference calls; 
• Monthly Executive Steering Committee calls.  
In addition, we will implement processes for detection of errors.  Periodic reporting of 
key data elements to ensure protection of subjects’ rights and data integrity will take 
place. See table 9 below: 
 

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Table 9. Reports of Records and Documents to be Periodically Monitored. 
Records and 
Documents To Be 
Monitored 
How? 
Frequency? 
Who? 
Site Human Subject 
Protection Training 
Records 
• When a request for REDCap 
user access is submitted, 
permission is only granted 
when all training certifications 
are verified by STaR Trial 
Project Coordinator   
 
Project 
Coordinator 
IRB and HRPO 
Initial Approval and 
Annual Renewal 
Letters 
• Electronic calendar system 
including dates of initial 
approval and due date for 
renewal will alert STaR 
Project Coordinator if a site is 
delinquent. 
 
Project 
Coordinator 
Signed Informed 
Consent Forms 
• Signed IC forms will be 
scanned and uploaded into 
the REDCap system by each 
site’s Research Coordinator. 
Monthly 
Project 
Coordinator 
Eligibility Criteria 
• REDCap SMART Eligibility 
Criteria form is auto-
populated from Baseline 
Clinical Examination Form 
that is completed by the 
surgeon- investigators’ 
At form 
submission 
 

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answers and only those 
meeting all eligibility criteria 
will be permitted to be 
randomized.  
Surgical Source 
Documentation vs. 
CRFs 
• Direct entry during surgery. 
Surgeon calls out data and 
research staff enters directly 
into REDCap. (REDCap is 
the source document) 
Annually 
during site 
monitoring 
visits 
 
Dr. Gil & STaR 
Project 
Coordinator 
• Surgical report 
written/dictated by surgeon 
and is included in the 
Electronic Health Record. 
(EHR). 
• Documented on paper form 
and entered by research staff. 
In this case, comparison of 
paper CRF and REDCap will 
take place during the site 
monitoring visits. 
Clinical Follow-up 
Visits Source 
Documentation vs. 
CRFs 
• Direct data entry during 
clinical visit. Surgeon and/or 
physician assistant will enter 
data directly into REDCap. 
(REDCap form is the source 
document) 
Annually 
during site 
monitoring 
visits 
Dr. Gil & STaR 
Project 
Coordinator 

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• Examination and progress 
reports written/dictated by 
surgeon and in included in 
EHR. 
• Documented on paper form 
and entered by RA. In this 
case, comparison of paper 
CRF and REDCap will take 
place. 
CRFs or Data 
Queries 
• Direct data entry of PROs by 
subject using a tablet 
computer. (REDCap form is 
the source document)  
Weekly 
DCC 
Process to Contact 
PTs when CRFs 
Were Not Submitted 
• Research Assistants will log 
all attempts of communication 
in the Physical Therapy Data 
Center Portal/ Follow-up 
Dash Board. 
Weekly 
Research 
Assistants 
under 
supervision of 
Dr. Lynch 
Missed Visits and 
Missing Data 
• Interim Reports 
Twice 
annually 
DCC and 
DSMB 
Documentation and 
Reporting of AEs, 
SAEs, Protocol 
Deviations 
Documentation 
• Interim Reports 
• Email Alerts  
Weekly 
 
Internal 
Review 
Every 2 
months 
 
External 
Adjudication 
Review 

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Twice 
annually 
DSMB 
Withdrawals and 
Dropouts 
Documentation 
• Interim Reports 
Every 6 
months 
DCC, QCC 
and DSMB 
Site Regulatory 
Documents 
• Verification at on-site 
Initiation and Interim Visits 
Annually 
 
• Verification remotely at 
Close-Out Visit 
Event driven 
 
Corrective action plans to ensure QC and QA will be developed and implemented as 
necessary. Ongoing follow-up reports will enable the Clinical Coordinating Center to 
determine effectiveness of any corrective actions that are taken. Problems identified 
during the monitoring process may trigger additional training of site research staff. 
Continuing or serious protocol deviations discovered during the quality review process 
will be documented and reported to the site Principal Investigator, site RC and 
University of Pittsburgh IRB (see Assessment of Safety Section 9). 
At the time of the site close-out visit, the following items will be verified to ensure that: 
• All subjects have completed the final study-related visits; 
• All final site-level Quality Management activities have been completed; 
• All site data for all subjects have been entered in database; 
• All queries from the DCC have been resolved/closed 
• The Final Interim Monitoring Visit has been conducted as per approved Clinical 
Monitoring Plan; 

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• All action items identified during previous monitoring visits have been addressed 
and resolved; 
• Notification is provided to the DoD to indicate that the site is approved for close-
out visit. 
For an orderly closure of study documents, at the time of study close-out we will ensure 
that:  
• Appropriate source documentation is present for all subjects; 
• All electronic CRFs have been completed and submitted to the DCC, as 
applicable; 
• All electronic queries issued to date have been appropriately resolved, reviewed, 
and closed, where applicable; 
• All CRF pages requiring signature have been electronically signed and dated by 
the investigator; 
• All AEs, UAPs and SAEs have been captured, followed, and resolved per 
protocol, and reported to the appropriate parties according to protocol reporting 
requirements; 
• All required follow-up documentation has been retrieved, communicated to 
appropriate parties, and is present in the study files; 
• Signed consent forms are on file for all subjects; 
• All required documents are present in the Trial Master File, including collection of 
all required documents from all Investigator Site Files, where appropriate;  
• Reporting of study closure to the IRB and receipt/filing of confirmation of study 
closure in the investigator site files; 
• If study was terminated early, confirmation of notification of study termination has 
been sent to all enrolled subjects as appropriate; 

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• All protocol deviations have been noted in source documentation and reported to 
the IRB as appropriate; 
• All study logs, such as pre-screening, screening and enrollment, delegation of 
responsibilities, telephone and training log are complete. 
The study close-out activities to ensure that data analysis, manuscripts and publications 
have been completed will include: 
• Verification of final data analysis; 
• Writing, review and approval of the primary manuscript(s) by the investigative 
team as specified in the Publications and Ancillary Studies policy;  
• Submission of the results to PubMed and ClinicalTrial.gov 
 
The quality management plan as described above has been developed to ensure 
ongoing review of data collection forms and other records for completeness and logic. In 
addition, it establishes processes to ensure quality requirements and procedures; and 
that those requirements are being met and procedures are being followed. 

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15 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 Review Board 
The protocol, informed consent form(s), recruitment materials, and all participant 
materials will be submitted to the University of Pittsburgh IRB for review and approval.  
Additionally, the protocol, informed consent forms, recruitment materials and all subject 
materials must be reviewed and approved for compliance with Department of Defense 
(DoD) human subjects’ protection requirements and approved by the Office of Research 
Protections (ORP) Human Research Protection Office (HRPO).   Approval from both the 
IRB and HRPO for the protocol and the consent forms must be obtained before any 
participants are enrolled.  Amendments to the protocol will require review and approval 
by the both the IRB and HRPO before the changes are implemented in the study. 
For this study, the University of Pittsburgh IRB will serve as the single IRB of record for 
all military and civilian sites in the US.  Canadian sites will need to obtain local ethical 
board approval for the conduct of this study.  The Pitt IRB will not act as IRB of Record 
for the Canadian sites.  
A reliance agreement will need to be established between the relying sites and the 
University of Pittsburgh IRB to allow the relying institution to cede IRB responsibilities 
and oversight to the University of Pittsburgh.  

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Informed Consent Process 
Informed consent is a process that is initiated prior to the individual agreeing to 
participate in the study and continues throughout study participation.  Extensive 
discussion of risks and possible benefits of study participation will be provided to 
participants and their families, if applicable.  A consent form describing in detail the 
study procedures and risks will be given to and reviewed with the participant.  Consent 
forms will be IRB- and HRPO-approved, and the participant is required to read and 
review the document or have the document read to him or her.  The investigator or 
designee will explain the research study to the participant and answer any questions 
that may arise.  The participant will sign the informed consent document prior to any 
study-related assessments or procedures.  Participants will be given the opportunity to 
discuss the study with their surrogates prior to agreeing to participate.  They may 
withdraw consent at any time throughout the course of the study.  A copy of the signed 
informed consent document will be given to participants for their records.  The rights 
and welfare of the subjects will be protected by emphasizing to them that the quality of 
their clinical care will not be adversely affected if they decline to participate in this study.  
The consent process will be documented in the clinical or research record.   
Potentially eligible subjects will be informed of the study by the attending surgeon or a 
member of the surgeon’s clinical team.  If the patient expresses an interest in 
participating in the study, the physician will ask permission for the patient to be 
approached by the research staff.  At that time, the patient will be introduced to the 
research coordinator responsible for study recruitment.  The surgeon-investigator and 
research coordinator will inform the patient of the research study including the activities, 
expectations, risks and benefits, and rights as a research subject as related to 
participation in the study.  All questions and concerns will be addressed before the 
participant signs the consent form.  Investigators and coordinators will be available to 
answer questions about study participation throughout the duration of the clinical trial. 
The informed consent discussion will occur after the clinical diagnosis of a multiple 
ligament knee injury, but prior to surgery and rehabilitation.  The informed consent 
discussion will occur within the clinical practice of the treating physician, in the 

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outpatient office or within the hospital setting.  Potential participants will be given time to 
review the study information and ask any questions about the study they may have.  
Potential subjects will be able to discuss participation in the study with family members 
and/or other health care providers.  Once the potential participant is fully informed of the 
study and is voluntarily willing to take part in the study, the subject and the surgeon-
investigator will sign informed consent form.  Before agreeing to participate in this 
research study, or at any time during study participation, participants will be provided 
the opportunity to discuss the study with another doctor who is not associated with this 
research study. 
For active duty military personnel, no individuals in the participant’s chain of command 
will be involved in the recruitment process.  Because the surgeon is also an investigator 
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, subjects 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 trial for Aim 1 or 2.  For potential participants that are between the 14 
and 17 years of age, the study will be explained to both the child and the child’s parent 
or legal guardian as required by state (or Canadian) law and institutional policy of each 
site.  If the child is willing to participate in the study, permission from the child’s parent 
or legal 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.  The participant's physician will also be available to answer any questions that 
the subject has regarding his/her participation in the research study.  If the individual 
agrees to participate in the study, the subject's surgeon will sign the informed consent 
form. 
All subjects will be capable of providing direct informed consent for study participation. 
Participants with altered mental capacity due to traumatic brain injury or those unable to 
comply with study procedures will not be eligible to participate in the study.  Individuals 
will not be approached to provide informed consent if they are under sedation, 

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anesthesia, or other medical treatment or substance that alters decision making 
abilities. 
 
 
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. 
The study research monitor or other 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 
subject level information that is submitted for review to the DSMB, HRPO, University of 
Pittsburgh Office of Research Conduct and Compliance, and the IRBs, will be linked 
only to the subject’s case number and not the personal identity of the subject. 

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16 DATA HANDLING AND RECORD KEEPING 
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. 
 
Data Management Responsibilities 
The purpose of the clinical data management plan (DMP) is to provide specific 
information regarding the study’s data management practices including staff 
responsibilities, data collection, data standards and acquisition, data quality assurance, 
and dissemination. The DMP will be coordinated by the Physical Therapy Data Center 
in the Department of Physical Therapy at the University of Pittsburgh under the 
leadership of Dr. Charity (Moore) Patterson, DCC Director, in collaboration with Dr. 
Alexandra Gil, Quality Control Coordinator and Drs. Irrgang (Principal Investigator), 
Musahl (Co-Principal Investigator and Qualified Collaborator [QC]) for Surgery and 
Lynch (Co-Investigator and QC for Rehabilitation). 
 
 
Data Capture Methods 
The Research Electronic Data Capture (REDCap) system, hosted at the University of 
Pittsburgh, will be used as the web-based data collection and management system for 
this study.98 REDCap is a secure, web-based application designed with the flexibility to 
support data capture for a variety of research projects.  It provides: 
• A mechanism for managing user-access to the data and the various system 
applications; 
• A mechanism for validated data uploads from external sources; 
• An intuitive user interface for validated data capture through the execution of real-
time validation rules, such as univariate data type and range checks; 

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• An audit trail for tracking transactions within the system, such as study system setup 
and modifications, data imports, data entry and edits, and data exports and 
• A mechanism for seamless data downloads to common data formats (SAS datasets 
will be the format of choice for this study).  
 
 
Identifiers 
Each study participant will be assigned a Study Identification Number (SID) 
determined by site, system generated enrollment number and patient initials. The 
patient names and contact information will be stored in a table in the REDCap project 
that is not in the same tables as the research data. Name and contact information will 
be available to the local site where the participant was enrolled and to the staff at the 
University of Pittsburgh where the centralized follow-up is conducted via surveys. Dates 
of birth, injury, clinical visits, and surgery will be entered into the system. Date of birth 
and date of injury are necessary to ensure eligibility based on calculated age at the time 
of screening. Dates of surgery and clinical visits are necessary to ensure and monitor 
protocol compliance. Subjects will not be identified by name in any publications of 
research results. 
 
 
Confidentiality 
All study subjects will be identified by the SID on all data collection instruments, 
documents, and files used in the statistical analysis and manuscript preparation.  Only 
limited team members will have access to personal information needed for tracking and 
informed consent.  No personal information concerning study participants will be 
released without their written consent.  Authorized representatives of the U.S. Army 
Medical Research and Materiel Command (USAMRMC), which is the funding agency 
for this study, may review or obtain identifiable information (including subject SIDs) for 
monitoring the accuracy and completeness of the research data, for performing required 
scientific analyses of the research data, and as part of their responsibility to protect 
human research volunteers.  

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The DCC will work with the CCC to determine who will have access to the electronic 
data capture system and the type of access (i.e. data entry, data review, or analysis). 
The system is protected by a unique login and password. Once a research staff 
member has gone through data entry training and testing, the Systems Analyst or 
designee will permit access to the production system. A user access log will be 
maintained by the CCC and the DCC. We acknowledge that representatives of 
USAMRMC are eligible to review study records. 
In unusual cases, the investigators may be required to release identifiable information 
related to subject participation in this research study in response to an order from a 
court of law. If the investigators learn that a subject or someone with whom the subject 
is involved with is in serious danger or potential harm, they will need to inform the 
appropriate agencies, in response to an order by a court of law. 
 
 
Data Capture, Verification and Disposition 
The Case Report Forms (CRFs) will serve as the basis for the structure of the REDCap 
database with the data entry screens being as visually similar to the CRFs as possible. 
Blank CRFs, Study Protocol, and the Manual of Procedures (MOP) will be available in 
the document sharing application in the REDCap system. The MOP will include the 
forms and detailed descriptions of how to enter each data element.  Personnel at the 
DCC will be available to answer phone or e-mail questions during regular business 
hours. These include the DCC Director, the Systems Analyst, and Data Manager.  
Each aspect of the REDCap system will be tested before actual study data is collected. 
Mock data will be entered onto CRFs by DCC personnel to be used in the User 
Acceptance Testing process.  The University of Pittsburgh site project coordinator will 
serve as the User for acceptance testing, entering the mock data on the CRFs into each 
field of each data collection instrument and documenting the success or failure of a) the 
user interface for data entry, b) the on-line univariate and range data validation checks, 
and c) custom functions. The Systems Analyst or designee will verify the audit trail after 
the mock data are entered. The mock data will also be exported to SAS datasets by the 

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DCC Systems Analyst or Data Manager and the accuracy of the export will be verified 
by the DCC statistician. 
Specific items to be included in the testing are described in below (Table 10). 
 
Table 10 – List of items to be tested during REDCap development 
Item 
Details of Testing 
1. Univariate 
and 
valid 
value 
checks 
Confirm that checks have been properly built and 
documented. 
2. Multivariate (two or more items 
on the same CRF) and 
cross-checks (two or more 
items on separate CRFs) 
Confirm each check does and does not trigger 
appropriately. 
3. Custom functions 
Confirm each custom function behaves as 
intended. 
4. Generation of subject numbers 
Confirm that new subject IDs are generated as 
expected. 
5. Data completion guidelines 
Confirm that the completion guidelines are 
properly associated with each form/field. 
6. Derived variable computation 
Confirm variables are derived as expected. 
7. Role assignment 
Review system.  Confirm using list of role 
functionality, have testers assigned to each role, 
and ensure that they are only able to do/see what 
they are entitled to per their assigned role. 
8. Data Extracts 
Confirm extracted data matches annotated CRF 
specifications. 
9. Data Imports into REDCap 
If applicable, create test data, import, and review 
imported data. 
10. System Reports 
Review system reports and ensure that they are 
functioning according to expectations.  Run 
reports on test data. 
 
The Case Report Forms (CRFs) will serve as the basis for the structure of the REDCap 
database, which will produce a data dictionary with labels for each data field captured 
and specific validation rules associated with each data field.  Data values that violate 
these rules are identified at the time of data import or entry and require correction at the 

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entry source before they can be accepted into the database.  The REDCap database 
structure will be designed and built by the Systems Analyst or designee and only these 
participants can modify the structure.  User rights and access to all system data and 
applications will be assigned and managed by the Systems Analyst. 
All screening, clinical, surgical, rehabilitation, and performance measures data will be 
single-entered from the CRFs or directly entered into the REDCap data-entry screens 
by the coordinator at each site. Patient reported outcomes will be obtained using 
surveys sent via SMS text messages or email directly to the participants or via direct 
entry when surveys are conducted by interview (telephone or in person). REDCap has 
the capability to send SMS text messages to survey subjects by using a third-party web 
service named Twilio. Using this service, a subject will be invited to complete the CRF 
by sending them an SMS message or by calling them on their phone. Using this service 
the data are collected in REDCap directly from the subject’s phone without the need to 
use the webpage.   
The CRFs are electronic forms completed by clinical site staff or study participants. 
Some forms will be completed during the participant’s study visits, while others will be 
completed or verified using data extracted from the medical record (e.g. surgery 
dictation).  The CRFs will be available in the REDCap file repository application and can 
also be obtained by emailing the Systems Analyst or Data Manager.   
In addition to data capture through CRFs that will be specifically developed for this 
STaR Trial, the Patient Reported Outcome Measurement Information System 
(PROMIS) Physical Function Scale will be administered as a computer adaptive test 
(CAT) directly through the REDCap Shared Library.98  All instruments kept in the 
REDCap Shared Library have been approved and reviewed for their importance to 
research, function and coding precision, and copyright related issues.   
The web-based data submission software is REDCap ver. 7.4.7 built upon MySQL 
5.5.  The website is secured by HTTPS, individual usernames, and strong passwords. 
The database tables default engines are MyISAM and InnoDB. Non-secure ports of all 
servers are located behind the DCC network firewall and accessible only under the 

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following conditions: 1) a workstation physically present in the building and physically 
connected to the network 2) granted system access to the database server 3) a user 
name and password for that database server 4) a second username and password for 
database software 5) granted access to a data project 6) granted access to data items. 
All non-essential ports of the database server and web servers are closed.  Only one 
secure (HTTPS) port on the website server is open outside of the firewall.  All servers 
are physically located in a secured room which is accessible only by a key card; 
currently, only two system administrators, one financial administrator, and required IT 
maintenance and support staff have access to this room.  In addition, the secured room 
is located in a secured suite which is also accessible only by key cards given to current 
University of Pittsburgh employees located in the suite.  The building is locked and 
accessible only by University of Pittsburgh employees located in the building after 
business hours and on weekends. A network system administrator regularly monitors 
for occurrences of attempted access to the network by unauthorized users. There is a 
security administrator for the VM server where the application resides and a database 
administrator who monitors and authorizes appropriate use of REDCap and the MySQL 
database server. On-site backup of study data is performed nightly; off-site backups are 
taken twice weekly and stored at a secure University of Pittsburgh location, in a locked 
office in a secure suite. 
All DCC statisticians use SAS version 9.4 for report and statistical analyses. SAS runs 
off individual computers. The SAS data files and programs used for monitoring, 
reporting, and analysis will be stored on the School of Health and Rehabilitation 
Sciences password protected server under this directory: 
  L:\\PT Data Center\Irrgang\STaR\. 
The real-time validation and regular quality monitoring by the DCC are intended to 
detect and correct errors as they occur. Therefore, minimal data cleaning should be 
needed near the closing of the study. Upon enrollment of the final participant, the DCC 
will begin the final cleaning process, assessing outstanding queries, missing items, 
missing forms, and range and value checks. In addition, all documentation concerning 
data validations, queries, resolutions, and participant locking will be reviewed for 

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completeness and consistency. The targeted date for locking participant data is 3 
months after the final participant is off protocol for each study at which time the 
statistical analysis will begin. The full database lock will occur upon the approval of the 
Executive Steering Committee (ESC). Errors identified in the database after database 
lock will be documented. The correction process and database unlock will begin only 
with the approval of the ESC. This process will require documentation for the request for 
data change with justification, formal approval of the data change, the date of the 
change, and the future database lock date for the revised data. 
 
 
Data Reporting 
 
Table 11.  List of Data Management Reports 
Report Name 
Description/Purpose 
Frequency 
Recipients/ 
Users 
Methods for 
Provision  
Query override 
report for 
REDCap 
Lists all queries where 
the data entry user 
overrode the query 
with no change, 
includes the 
explanation for the 
change/DM review for 
acceptability of 
overrides. 
Monthly 
Data 
Managers 
and other 
DM staff  
Automated 
SAS report 
stored on 
local 
network. 
Executive 
Steering 
Committee 
(ESC) and 
Coordinator/Qu
ality Control 
Committee 
reports 
Screening and 
enrollment, attrition, 
missing data for 
primary and 
secondary outcomes, 
protocol deviations, 
SAEs, and 
unanticipated events 
Monthly 
Executive 
Steering 
Committee 
members, 
DoD 
program 
officer, and 
DCC team 
SAS report 
stored on 
local 
network and 
delivered by 
email to the 
ESC 
members, 
CQCC 
members, 
and the DoD 

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program 
officer. 
Data and Safety 
Monitoring 
Board (DSMB) 
Screening and 
enrollment, attrition, 
missing data for 
primary and 
secondary outcomes, 
protocol deviations, 
SAEs, and 
unanticipated events 
Every 6 
months or 
Annually 
(depending 
on meeting 
timeline 
established 
by DSMB) 
Data and 
Safety 
Monitoring 
Board 
members, 
and Study PI 
SAS report 
stored on 
local 
network and 
delivered by 
email to the 
DSMB and 
Study PI. 
Adverse Events 
Adjudication 
Committee 
(AEAC) 
Adverse Events and 
SAEs 
Every 2 
months 
Adverse 
Events 
Adjudication 
Committee 
members 
SAS report 
stored on 
local 
network and 
delivered by 
email to the 
AEAC. 
Data queries 
Lists all queries on 
multivariate checks 
(within the same form) 
and cross-checks 
(across different 
forms). 
Bi-weekly 
then 
monthly 
after the 
first 5 
participant
s are 
enrolled.  
DCC Team 
and Site 
coordinators 
Automated 
REDCap 
and SAS 
reports 
stored in 
REDCap or 
on local 
network and 
uploaded 
into 
REDCap 
system. 
On-site 
monitoring 
List of all participants 
enrolled, date of 
consent, patient 
information, serious 
adverse events, and 
protocol deviations. 
As-
needed. 
On-site 
monitoring 
team 
Automated 
SAS reports 
stored on 
local 
network and 
delivered by 
secure 
email. 
 
 

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Study Records Retention 
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 SHRS 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 email using e-mail, ftp, or other mutually agreeable transmission method.  The 
public-use version of the database will be made 2 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. 
 
 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical study protocol, Good Clinical 
Practice, or Manual of Procedures requirements.  The noncompliance may be on the 
part of the subject, the investigator, or study staff. Protocol deviations will be captured 
on the Protocol Deviation Form and entered into the database. As a result of deviations, 
corrective actions are to be developed by the study staff and implemented promptly to 
remedy any problems. In addition, study staff will perform follow-up evaluations of 
actions taken, if necessary. 
These practices are consistent with investigator and sponsor obligations in ICH E6: 
• Compliance with Protocol, Sections 4.5.1, 4.5.2, 4.5.3, and 4.5.4. 
• Quality Assurance and Quality Control, Section 5.1.1 

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• Noncompliance, Sections 5.20.1 and 5.20.2. 
 

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17 PUBLICATION/DATA SHARING POLICY 
Publications and Ancillary Studies Committee (PASC) will consist of Robert Schenck 
(Chair), Matthew Matava (Co-Chair, site PI for Washington University), Kenneth 
Cameron (Co-I, Keller Army Hospital), Andrew Lynch, Charity Moore Patterson, 
Matthew Posner (site PI for Keller Army Hospital), Brett Owens, Michael Stuart (site Co-
I for Mayo Clinic), James Irrgang (Ex Officio), Volker Musahl (Ex Officio).  The PASC 
has policies and procedures for assigning working groups and approving STaR Trial-
associated ancillary studies, secondary analyses of existing data and abstracts, 
presentations, and publications prior to their submission for dissemination.  The PASC 
has guidelines for authorship for investigators following the guidelines specified by the 
International Committee of Medical Journal Editors 
(http://www.icmje.org/recommendations/browse/roles-and-responsibilities/defining-the-
role-of-authors-and-contributors.html) 99 for authors that have contributed to the 
scientific design and merit of the study. See the Manual of Operations for additional 
details related to publication of data from the STaR Trial. 
The International Committee of Medical Journal Editors (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 STaR trial will be registered with 
ClinicalTrials.gov prior to enrollment of the first participant. 

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18 LITERATURE REFERENCES 
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15. 
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29. 
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45. 
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APPENDICES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX A: STUDY TIMELINE 
Aim 1: Determine the effects of timing of surgery and post-operative rehabilitation on time to return to pre-injury level of military duty, 
work and sports and patient-reported physical function. 
Aim 2: Determine the effects of timing of rehabilitation on time to return to pre-injury level of military duty, work and sports and 
patient-reported physical function. 
Abbreviations: CCC = Clinical Coordinating Center; DCC = Data Coordinating Center; MS = Military Sites; USS = US Sites; 
CS = Canadian Sites 
Major Tasks 
Sites involved 
Year 1 
Year 2 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
Study Start-up 
CCC, DCC, 
MS, USS, CS 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject Recruitment 
CCC, DCC, 
MS, USS, CS 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Monitoring & 
Quality Control 
CCC, DCC 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Subject Follow-up 
CCC, MS, 
USS, CS 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Governance 
CCC, DCC, 
MS, USS, CS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Analyze & 
Disseminate Results 
CCC, DCC, 
MS, USS, CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Major Tasks 
cont.: 
Sites involved 
Year 3 
Year 4 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
37 
38 
39 
40 
41 
42 
43 
44 
45 
46 
47 
48 
Study Start-up 
CCC, DCC, 
MS, USS, CS 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Subject Recruitment 
CCC, DCC, 
MS, USS, CS 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Clinical Monitoring & 
Quality Control 
CCC, DCC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Subject Follow-up 
CCC, MS, 
USS, CS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Governance 
CCC, DCC, 
MS, USS, CS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Analyze & 
Disseminate Results 
CCC, DCC, 
MS, USS, CS 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
 
 
 
 
 
 
 
 

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APPENDIX B: SCHEDULE OF EVENTS 
Forms 
Screening/
Baseline 
Pre-Op/ 
Surgery 
Clinical Follow-Up 1 
Research Follow-Up Visits 
1 
wk 
1 m 
3 m 
6 m 
9-12 
m 
6 m 
12 m 
24 m 
Monthly 
6-24 mo 
Contact Information 
X 
 
 
 
 
 
 
 
 
 
 
Demographic and 
Participant 
Information 
X 
 
 
 
 
 
 
 
 
 
 
Baseline Clinical 
Exam 
X 
 
 
 
 
 
 
 
 
 
 
Baseline Injury 
Surveillance Survey 
(Military Only) 
X 
 
 
 
 
 
 
 
 
 
 
Functional 
Comorbidity Index 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
 
 
Cincinnati 
Occupational Rating 
Scale 
X 
 
 
 
 
 
 
X 
X 
X 
X 
Marx Activity Rating 
Scale 
X 
 
 
 
 
 
 
X 
X 
X 
X 
IKDC Subjective 
Knee Evaluation  
X2 
X3 
 
 
 
 
 
X 
X 
X 
 
Multi-Ligament 
Quality of Life 
(MLQoL) 
X2 
X3 
 
 
 
 
 
X 
X 
X 
 
PROMIS Physical 
Function 
X 
X3 
 
 
 
 
 
X 
X 
X 
 
PROMIS Global 10  
X 
 
 
 
 
 
 
X 
X 
X 
 
PASS/Global Rating 
of Change 
X 
X3 
 
 
 
 
 
X 
X 
X 
 
Tampa Scale for 
Kinesiophobia 
X 
 
 
 
 
 
 
X 
X 
X 
 
Brief Resilience 
Scale 
X 
 
 
 
 
 
 
X 
X 
X 
 
Concomitant 
Medications 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
Pre-Op Clinical Visit 
form 
 
X 
 
 
 
 
 
 
 
 
 
Examination Under 
Anesthesia 
 
X 
 
 
 
 
 
 
 
 
 
Meniscus Findings 
and Procedures 
 
X 
 
 
 
 
 
 
 
 
 

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Ligament Findings 
and Procedures 
 
X 
 
 
 
 
 
 
 
 
 
Articular Cartilage 
Findings and 
Procedures 
 
X 
 
 
 
 
 
 
 
 
 
Peroneal Nerve 
Findings 
 
X 
 
 
 
 
 
 
 
 
 
Complications 
Reporting 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Clinical Visit Form 
 
 
X 
X 
X 
X 
X 
 
 
 
 
Additional Surgeries 
– Clinical   
 
 
X 
X 
X 
X 
X 
 
 
 
 
Additional Surgeries 
– Patient Reported 
 
 
 
 
 
 
 
X 
X 
X 
 
Return to Activity 
Monitoring Survey 4 
 
 
 
 
 
 
 
X 
X 
X 
X 
Physical Therapy 
Case Report 
 
 
 
X 
X 
X 
 
 
 
 
 
Patient Reported 
Rehabilitation 
 
 
 
X 
X 
X 
 
 
 
 
 
1 week Home 
Exercise Post-Op 
Log 
 
 
X 
 
 
 
 
 
 
 
 
Post-Operative Home 
Exercise Log 
 
 
 
X 
 
 
 
 
 
 
 
Adverse Event/ 
Serious Adverse 
Event 
AS NEEDED 
Protocol Deviation 
AS NEEDED 
Change in Status 
AS NEEDED 
Unanticipated 
Problems 
AS NEEDED 
1 Clinical Follow-Up: additional clinical visits will also be recorded as Interim Visits, and data would include: Concomitant 
Medications, Complications Reporting, Clinical Visit Form, Additional Surgeries, and Rehabilitation information should be 
collected. 
2 IKDC-SKF and MLQoL will be completed at baseline by participants who are greater than 6 weeks from injury at the time 
of screening/baseline. Participants who are screened that are less than 6 weeks from injury will only complete the MLQoL 
Activity Limitations Subscale. 
3 Pre-op PROs only expected if pre-op date is greater than 28 days from baseline date. If the participant was less than 6 
weeks from injury at baseline but is greater than 6 weeks at pre-operative visit, they will get the full MLQoL and IKDC at 
the pre-operative visit even if the pre-operative visit is less than 28 days from baseline. 
4 Return to Activity contains questions from the following:  
Return to Activity Monitoring Survey 
Return to Work Activity 
Return to Sports Activity 
Return to Military Activity  
Cincinnati Occupational Rating Scale 
Marx Activity Rating Scale 
 

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APPENDIX C: STUDY FORMS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX D: DATA SAFETY AND MONITORING BOARD TABLES