Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients
Phase: NA
Conditions: Ankle Inversion Sprain, Chronic Instability of Joint
Sponsor: University of North Carolina, Chapel Hill

 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 1 of 157 
 
 
 
 
 
 
 
Neuromuscular Mechanisms of Manual Therapies  
in Chronic Ankle Instability Patients 
 
 
NCCIH: 1 R21 AT009704-01 
 
ClinicalTrials.gov:  NCT03418051 
 
 
 
 
 
Version 1:  October 11, 2017 

NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 2 of 157 
Table of Contents 
 
MOOP:  Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients 7 
SECTION A: Schedule of Visits & Evaluations ...................................................................................... 8 
SECTION B: Study Flow .......................................................................................................................... 10 
SECTION C: Study Organization ........................................................................................................... 12 
C.1 Roster ................................................................................................................................................. 13 
C.2 Coordination of Study ........................................................................................................................ 14 
C.3 Pharmacy Activities ........................................................................................................................... 15 
C.4 Steering Committees ......................................................................................................................... 15 
C.5 Executive Committee ......................................................................................................................... 15 
SECTION D: Training Plan ...................................................................................................................... 16 
D.1. Training Process ............................................................................................................................... 17 
D.2. Informed Consent Process ............................................................................................................... 17 
D.3.  Communication ............................................................................................................................... 17 
D.4. Communication Records .................................................................................................................. 18 
SECTION E: Communication Plan ......................................................................................................... 19 
SECTION F: Recruitment Screening & Eligibility Criteria ................................................................... 21 
F.1 Recruitment Plan ............................................................................................................................... 22 
F.2 Screening ............................................................................................................................................ 22 
F.3 Screening Log ..................................................................................................................................... 22 
F.4 Eligibility Criteria ................................................................................................................................ 22 
SECTION G: Informed Consent & HIPAA ............................................................................................ 24 
G.1 Informed Consent Process ................................................................................................................ 25 
G.2 Informed Consent Document ............................................................................................................ 25 
G.3 HIPAA Authorization.......................................................................................................................... 25 
SECTION H: Randomization ................................................................................................................... 26 
SECTION I: Blinding / Unblinding ........................................................................................................... 28 
SECTION J: Study Intervention .............................................................................................................. 30 
SECTION K: Participant Evaluations & Follow-Up .............................................................................. 32 
K.1 Timeline and visit schedule................................................................................................................ 33 
K.2 Scope .................................................................................................................................................. 33 

NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 3 of 157 
K.2.a Pre-Study (Participant Eligibility) ................................................................................................ 33 
K.2.b Visit 1: ......................................................................................................................................... 33 
K.2.c Visit 2-14:  Treatments ................................................................................................................ 38 
K.2.d Visit 15 ........................................................................................................................................ 38 
K.3 Retention Initiatives........................................................................................................................... 38 
SECTION L: Participant Retention ......................................................................................................... 41 
SECTION M: Data & Safety .................................................................................................................... 43 
M.1 Concomitant medications ................................................................................................................ 44 
M.2 Data & Safety Monitoring Plan ......................................................................................................... 44 
M.2.a Purpose of Study ....................................................................................................................... 44 
M.2.b Adherence Statement ............................................................................................................... 44 
M.2.c Protocol Amendments ............................................................................................................... 44 
M.2.d Confidentiality ........................................................................................................................... 44 
M.2.e Expected Risks ........................................................................................................................... 44 
M.2.f Adverse Event/ Unanticipated Problems ................................................................................... 45 
M.2.g Definitions ................................................................................................................................. 45 
M.2.h Time Period and Frequency for Event Assessment and Follow-Up .......................................... 46 
M.2.i Characteristics of an Adverse Event ........................................................................................... 46 
M.2.j Reporting Procedures ................................................................................................................. 47 
M.2.k Halting Rules .............................................................................................................................. 48 
M.3 Quality Control and Quality Assurance ............................................................................................ 48 
M.3.a Data Management ..................................................................................................................... 48 
M.3.b Data Entry  Procedures, Flow, and Checks ................................................................................ 48 
M.3.c Quality Control Procedures ....................................................................................................... 49 
M.3.d Training Plan .............................................................................................................................. 49 
M.4 Subject Accrual and Compliance ...................................................................................................... 50 
M.4.a  Measurement and Reporting of Subject Accrual ..................................................................... 50 
M.4.b Measurement and Reporting of Participant Adherence to Treatment Protocol ..................... 50 
M.5 Justification of Sample Size .............................................................................................................. 51 
M.6 Stopping Rules .................................................................................................................................. 51 
M.7 Designation of a Monitoring Committee ......................................................................................... 51 
M.8 Safety Review Plan ........................................................................................................................... 51 

NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 4 of 157 
M.8.a Study Report Outline for the Independent Monitors(s) (Interim or Annual Reports) .............. 52 
M.8.b Submission of On-Site Monitoring/Audit and Inspection Reports ........................................... 52 
M.8.c Table A ....................................................................................................................................... 52 
M.9 Data Handling and Record Keeping .................................................................................................. 52 
M.9.a General Instructions for Completing Forms .............................................................................. 53 
M.9.b Data Management Responsibilities .......................................................................................... 54 
M.9.c Database Protection .................................................................................................................. 54 
M.9.d Source Document Protection .................................................................................................... 54 
M.10 Schedule and Content of Reports .................................................................................................. 54 
M.11 Informed Consent ........................................................................................................................... 54 
M.12 Reporting Changes in Study Status ................................................................................................ 55 
SECTION P: Documentation ................................................................................................................... 56 
P.1 Source Documentation ...................................................................................................................... 57 
P.2 Study Forms ....................................................................................................................................... 57 
P.3 General Instructions for Completing Forms ...................................................................................... 58 
SECTION Q: Data Flow ........................................................................................................................... 60 
SECTION R: Retention of Study Documentation ................................................................................ 62 
SECTION S: Administrative Forms ........................................................................................................ 64 
SECTION T: IRB Policies ........................................................................................................................ 66 
APPENDICES............................................................................................................................................ 68 
Appendix 1: 
Study Protocol ................................................................................................................. 69 
1 Background ........................................................................................................................................... 69 
2 Aims & Hypotheses ............................................................................................................................... 70 
3 Study Design ......................................................................................................................................... 71 
4 Primary & Secondary Endpoints ........................................................................................................... 71 
5 Type & Number of Sites ........................................................................................................................ 71 
6 Patient Population & Numbers ............................................................................................................. 71 
7 Inclusion & Exclusion Criteria ............................................................................................................... 72 
8 Randomization Plan .............................................................................................................................. 73 
9 Screening Process, Baseline Evaluation, Study Treatment, & Final Evaluation ................................... 73 
9.a Screening Process .......................................................................................................................... 73 
9.b Baseline & Post-Test Evaluations................................................................................................... 74 

NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 5 of 157 
9.c Study Treatments ........................................................................................................................... 77 
10 Definition of Evaluable Patients ......................................................................................................... 78 
11 Blinding / Unblinding Issues................................................................................................................ 78 
12 Statistical Plan ..................................................................................................................................... 78 
13 Data Management .............................................................................................................................. 79 
14 Safety Issues ........................................................................................................................................ 81 
15 Confidentiality..................................................................................................................................... 82 
16 IRB Approval Procedures .................................................................................................................... 82 
17 Informed Consent Procedures ............................................................................................................ 82 
18 Plans for and Responsibilities of the Independent Monitoring Committee ...................................... 82 
18.a  Independence of the IMC ........................................................................................................... 83 
18.b  Executive Secretary ..................................................................................................................... 83 
18.c  Safety Monitoring Plan................................................................................................................ 83 
18.d  Safety Reports ............................................................................................................................. 83 
18.e  Roles and Responsibilities of the IMC ......................................................................................... 83 
Appendix 2: Balance Questionnaire ....................................................................................................... 86 
Appendix 3: Ankle Instability Instrument ............................................................................................... 87 
Appendix 4: Foot & Ankle Ability Measure ............................................................................................ 88 
Appendix 5: Treatment Expectations Questions .................................................................................. 91 
Appendix 6: Informed Consent Documents .......................................................................................... 92 
Appendix 7: Documenting the Consent Process Form ....................................................................... 97 
Appendix 8: Protocol Deviation Form & Log ......................................................................................... 98 
Appendix 9: AE & Serious AE Reporting ............................................................................................ 100 
Appendix 10:  Adverse Event Form ..................................................................................................... 104 
Appendix 11:  Unanticipated Problem (UP) ........................................................................................ 105 
Appendix 12: Serious Adverse Event Form ........................................................................................ 107 
Appendix 13: Participant Eligibility Checklist ...................................................................................... 109 
Appendix 14: Screening Log ................................................................................................................. 111 
Appendix 15: Master Subject List ......................................................................................................... 112 
Appendix 16: Training Log ..................................................................................................................... 113 
Appendix 17: Data Collection Sheet .................................................................................................... 114 
Appendix 18: IRB Protocol .................................................................................................................... 117 

NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 6 of 157 
Appendix 19: IRB Approval Forms ....................................................................................................... 138 
Appendix 20: Participant Payment Log ............................................................................................... 140 
Appendix 21: Participant Self-Monitoring Guidelines ........................................................................ 141 
Appendix 22: Study Completion Form ................................................................................................. 142 
Appendix 22: IMC Report Template ..................................................................................................... 143 
 
 

 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 7 of 157 
 
 
MOOP:  Neuromuscular Mechanisms of Manual 
Therapies in Chronic Ankle Instability Patients  

SECTION A: Schedule of Visits & Evaluations 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 8 of 157 
 
 
 
 
 
 
 
 
 
 
 
 
SECTION A: Schedule of Visits & Evaluations 
 
 
 
 

SECTION A: Schedule of Visits & Evaluations 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 9 of 157 
***Further detail regarding each test session and individual test can be seen in the Study Protocol (Appendix 1).*** 
Study Visits / 
 Study Days 
Balance 
Questionnaire 
(Appendix 2) 
PRO Testing 
AII (Appendix 3) 
FAAM (Appendix 
4) 
FAAM-S 
(Appendix 4) 
Treatment 
Expectations 
(Appendix 5) 
Informed 
Consent 
(Appendix 
6) 
Neuromuscular 
Mechanism Testing 
Joint Position 
Sense 
Light-touch 
Thresholds 
H-Reflex 
Corticomotor 
mapping 
Corticomotor 
excitability 
Cortical 
Activation 
% Modulation  
Biomechanical 
Testing 
Gait Analysis 
Jump Landing 
Balance 
Testing 
Range of 
Motion 
Testing 
Treatment 
Delivery 
Adverse 
Event 
Monitoring 
Visit 1 
Eligibility 
Screening 
X 
X 
 
 
 
 
 
Visit 2 
Baseline 
Testing 
 
 
X 
X 
X 
X 
X 
Visits 3-7- 
 
 
 
 
 
X 
X 
Visit 8 
Post-Test 1 
 
 
 
X 
X 
 
X 
Visit 9 
4-week follow 
up 
 
 
 
X 
X 
 
X 
 
 

SECTION B: Study Flow 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 10 of 157 
 
 
 
 
 
 
 
 
 
 
 
 
 
SECTION B: Study Flow 
 
 
 
 

SECTION B: Study Flow 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 11 of 157 

SECTION C: Study Organization 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 12 of 157 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SECTION C: Study Organization 
 
 
 
 

SECTION C: Study Organization 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 13 of 157 
C.1 Roster 
 
Primary Investigator 
Erik A. Wikstrom, PhD, ATC 
Department of Exercise & Sports Science 
University of North Carolina at Chapel Hill 
311 Woollen Gymnasium 
Chapel Hill, NC 27599 
(P) 919-962-2260 
(F) 919-962-6325 
wikstrom@unc.edu 
 
 
Co-Investigators 
Brian Pietrosimone, PhD, ATC 
Troy Blackburn, PhD, ATC 
Jason Franz, PhD 
Feng-Chen Lin, PhD 
 
Graduate Research Assistants 
To Be Determined 
 
 

SECTION C: Study Organization 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 14 of 157 
For the following situations, please contact the listed individual(s): 
Protocol Questions:  
 
Erik Wikstrom 
 
To report an Adverse Event at UNC: 
 
Erik Wikstrom 
 
To report a Protocol Deviation at the UNC:  
Erik Wikstrom 
 
All protocol deviations and adverse events will be reported to the PI and Internal Quality 
Assurance Coordinator, then to the respective IRBs and finally to the sponsor.  See 
Appendices 8 and 9 for the protocol deviation log and adverse event reporting 
procedures.  Appendix 10-12 represent the adverse event reporting forms. 
 
C.2 Coordination of Study 
As this investigation has a research team, the official coordinator is Dr. Wikstrom.  If 
unable to contact Dr. Wikstrom, the Internal Quality Assurance Coordinator should be 
contacted.  The following activities will be discussed and agreed upon from monthly in 
person meetings. 
 
▪ Development and maintenance of the MOOP 
▪ Randomization scheme and procedures 
▪ Development and implementation of schedules and data tracking 
▪ Development of procedures for data entry, error identification, and error correction 
▪ Adverse event monitoring and reporting  
▪ Communication, scheduling of meetings, responding to and documenting ad hoc 
communications 
▪ Quality control procedures 
▪ Creating reports – enrollment, adverse events, participant status (e.g., withdrawals)  
▪ Maintaining the study binder (regulatory and clinical documents) 
▪ Preparing study materials 
▪ Assuring the study is conducted according to the protocol and MOOP 
▪ Participating in a Steering Committee and other committees 
▪ Identifying, recruiting, screening and enrolling participants 
▪ Protecting participants' rights 
▪ Obtaining informed consent from each participant 
▪ Collecting study data and following participants through study completion 

SECTION C: Study Organization 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 15 of 157 
▪ Compliance and accountability of administration of study intervention 
▪ Retaining specific records, (e.g., questionnaires) 
▪ Preparing and sending required reports, assuring IRB review and approval 
C.3 Pharmacy Activities 
N/A 
C.4 Steering Committees 
As this is a single site investigation, the steering committee will consist of the PI and Co-
Investigators (Pietrosimone, Blackburn, Franz, Lin) as well as other key members of the 
research team (e.g. Graduate Research Assistants.  The steering committee will be 
responsible for: 
▪ General design and conduct of the study 
▪ Preparation of the essential study documents, including the protocol, protocol 
amendments, MOOP, and data collection forms 
▪ Review of data collection practices and procedures 
▪ Changes in study procedures as appropriate 
▪ Review of study progress in achieving goals 
▪ Review and implementation of recommendations from the Safety Officer.  
▪ Review and response to other general advice and/or recommendations (e.g., from 
the NIAMS Program Officer) 
C.5 Executive Committee 
The executive committee of this investigation will be the same as the steering 
committee.
 
 

SECTION D: Training Plan 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 16 of 157 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SECTION D: Training Plan 
 
 
 
 

SECTION D: Training Plan 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 17 of 157 
D.1. Training Process 
All staff will be trained through the Collaborative Institutional Training Initiative for 
Biomedical Research involving human subjects.  In addition, all staff will be trained by 
the PI or a senior member of the research team based on expertise in the following prior 
to engaging in any research activities associated with this project: 
1. Determining subject eligibility 
a. Proper instructions for each questionnaire (Appendices 2-4) 
b. Using the eligibility checklist (Appendix 13) 
c. Enrolling a participant who is eligible (Appendix 7) 
2. Securing informed consent (Appendix 6 and &) 
3. All data collection procedures (Appendix 1) 
4. Randomization process and sequence for each participant (Appendix 1) 
5. Data storage and analysis. (Appendix 1) 
6. Reporting adverse events and protocol violations (Appendices 8 & 10-12) 
7. Using the MOOP 
The training of each staff member will be documented using the training checklist 
included as Appendix 16 and signed by both the staff member and the PI/QA 
coordinator.   
D.2. Informed Consent Process 
All staff will be trained in the consent process to ensure that each member understands 
that participants are initially screened with the questionnaires mentioned in Appendices 
2-4.  If a potential participant is considered to be eligible, the staff member will read 
through the consent form with the participant and answer any questions.  If the 
participant would like to enroll in the study, he/she will be asked to sign and date the 
consent form on the signature page.  A copy of the signed consent form will be given to 
each participant enrolled in the study.  The original consent form will be stored in the 
participant’s folder which will be stored in the Sports Medicine Research Lab.  Records 
of obtaining consent will be maintain as observed in Appendix 6. 
D.3.  Communication 
While the primary study personnel are familiar with the data collection and intervention 
procedures monthly meetings will be used to discuss issues that arise with both data 
collection and treatment delivery.  Additionally, PI will meet annually with study 
personnel involved at their respective sites to ensure proper and timely dissemination of 
the following information: 
1. Adverse Events,  
2. Protocol violations 
3. Compliance issues 
4. Protocol amendments 

SECTION D: Training Plan 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 18 of 157 
D.4. Communication Records 
In order to ensure consistency in communication across the sites, minutes of each 
meeting will be recorded and distributed to all study personnel within 72 hours of the 
phone conversation.  Similarly, all study personnel involved with this project will be 
required to maintain current training through the Collaborative Institutional Training 
Initiative and remain up to date on the study protocol and amendments (Appendix 1), 
AEs and SAEs (Appendix 9-12, or Section M of the MOOP), and the documentation 
plan.
 
 

SECTION E: Communication Plan 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 19 of 157 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SECTION E: Communication Plan 
 
 
 
 

SECTION E: Communication Plan 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 20 of 157 
 
Monthly conversations and/or meetings among the key personnel have been a regular 
occurrence.  This communication pattern will be maintained throughout the duration of 
the study in the form of a monthly in person meeting.  A log will be kept of meeting 
minutes.  These will be shared between the research team within 72 hours of the 
meeting.
 
 

SECTION F: Recruitment, Screening, & Eligibility Criteria 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 21 of 157 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SECTION F: Recruitment Screening & Eligibility Criteria 
 
 
 
 

SECTION F: Recruitment, Screening, & Eligibility Criteria 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 22 of 157 
F.1 Recruitment Plan 
The primary recruitment method at each institution will be word of mouth.  This 
recruiting technique will occur primarily in classroom settings where the PI or research 
assistants will describe the study and ask those individuals who are interested to 
complete the screening questions listed above (Appendix 1, section 9.a and section F.2 
of the MOOP).  The secondary recruitment methods at each institution will be posters 
and research advertisements (email) that have been approved by their respective IRBs.   
F.2 Screening 
Interested individuals will be asked to complete 4 questionnaires (per section A of the 
MOOP and 9.1 in Appendix 1), the balance questionniare, Ankle Instability Instrument 
(AII); a Foot and Ankle Ability Measure (FAAM); and a FAAM Sport (Appendix 2-4).  
Based on their responses, eligibility will be determined. 
F.3 Screening Log 
Because of the use of a partial waiver of consent, as approved each institution’s IRB, a 
minimal screening log (Appendix 14) will be maintained.  This is because the partial 
waivers allow the research team to quickly assess eligibility before consent is obtained 
and therefore it would be unethical to collect certain information about the individual in 
question such as age, ethnicity and race.  This information will be collected on those 
enrolled in the study (Appendix 13).  See format below: 
 
Example Screening Log Table 
Number Date 
Eligible for 
Study 
Date Enrollment 
Confirmed 
Ineligible 
for Study 
Reason 
1 
9-1-17 
X 
9-8-17 
 
 
2 
9-3-17 
 
 
X 
FAAM score was 
above 90% 
3 
9-15-17 
X 
9-18-17 
 
 
F.4 Eligibility Criteria 
Inclusion Criteria (per Appendix 13):  Males and females between the ages of 18 and 45 
with self-reported CAI; defined as self-reported episodes of recurrent ankle sprains 
and/or the feeling of instability or “giving way” after an initial ankle sprain. Inclusion 
criteria will consist of a history of at least two episodes of “giving way” within the past 6 
months; answering 5 or more questions of “Yes” on the Ankle Instability Instrument (AII) 
(Appendix 2); a score of <90% on the self-reported Foot and Ankle Ability Measure 
(FAAM); a score of <80% on the FAAM Sport (Appendix 3 & 4). 
 
Exclusion Criteria (per Appendix 13):  Exclusion criteria will consist of failing to meet the 
inclusion criteria as well as reporting an acute ankle sprain within the past 6 weeks; a 
previous history of ankle surgeries; lower extremity surgeries associated with internal 

SECTION F: Recruitment, Screening, & Eligibility Criteria 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 23 of 157 
derangements, reconstructions, or repairs; lower extremity injuries within the past 6 
months (other than ankle sprains); and balance deficits, neuropathies or other disorders 
or conditions known to affect balance.   
 
Each investigator who evaluates the eligibility of a potential participant will complete an 
eligibility checklist (Appendix 13) to determine whether the participant fits the inclusion 
criteria for the study.  The investigator is required to check the appropriate boxes, 
identify and mark the relevant gender and racial/ethnic information (once eligibility is 
determined), and sign and date the checklist.  The PI will then sign the form as well.
 
 
 
 

SECTION G: Informed Consent & HIPAA 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 24 of 157 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SECTION G: Informed Consent & HIPAA 
 
 
 
 

SECTION G: Informed Consent & HIPAA 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 25 of 157 
G.1 Informed Consent Process 
After eligibility is determined, based on the approved IRB protocol (see Appendix 18 
and informed consent document (Appendix 6) [see Appendix 19 for approval letters] 
participants will be scheduled to come in and meet with the PI or research assistant to 
review the informed consent document (see Appendix 6) and begin the first test 
session.  All questions will be answered before any data collection begins and the 
participants will be given as much time as they desire to read the informed consent 
document and ask questions of the PI or research assistant.  When satisfied, both the 
participant and PI or research assistant will sign the form and a copy of the signed 
document will be given to the participant upon request.  Included in the informed 
consent material is language indicating that the participants are volunteers and that 
there is no penalty for not participating.  Records of obtaining consent will be maintained 
per Appendix 7. 
 
If a participant is determined to be ineligible for the investigation (per Appendix 1, 
section 9.a and section F.2 of the MOOP) then the data collected (to determine 
eligibility) will be immediately destroyed.  Specifically, the Balance questionnaire, AII, 
FAAM, and FAAM-S data sheets will be shredded to protect participant rights.  No other 
data will be collected prior to the potential participant reading and signing the informed 
consent document. 
G.2 Informed Consent Document 
See Appendix 6 for the approved Informed Consent documents. 
G.3 HIPAA Authorization 
HIPAA authorization is not applicable for this investigation since protected health 
information will not be collected at any time.
 
 
 

SECTION H: Randomization 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 26 of 157 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SECTION H: Randomization 
 
 
 
 

SECTION H: Randomization 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 27 of 157 
Participants will be randomized to one of the three groups (Massage, Joint 
Mobilizations, or Control) in a 1:1:1 ratio using sealed envelopes generated by the 
biostatistician.  More specifically, we will be using a block randomization technique at 
each institution so that preliminary data analysis, data monitoring, and safety 
evaluations will be based on similar, if not identical, numbers in each group.  Each block 
of envelopes will be made and sealed before study enrollment begins and 
randomization will occur after the baseline evaluation (see section 9.b of Appendix 1).  
The biostatistician will generate the master randomization list and distribute the 
envelopes.  Each participant will select a sealed envelope containing their group 
assignment.  This assignment will be noted by the research team and recorded.  
 
 
 

SECTION I: Blinding / Unblinding 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 28 of 157 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SECTION I: Blinding / Unblinding 
 
 
 
 

SECTION I: Blinding / Unblinding 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 29 of 157 
As per section 11 of Appendix 1 blinding will be used in the current investigation.  Due 
to the nature of the intervention, participants will not be blinded but the assessors of the 
outcome measures will be blinded to group assignment.  
 
 

SECTION J: Study Intervention 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 30 of 157 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SECTION J: Study Intervention 
 
 
 
 

SECTION J: Study Intervention 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 31 of 157 
The treatments as outlined in section 9.c of Appendix 1 will include: 
Sensory-Targeted Rehabilitation Strategies.  This intervention will consist of 6, 5-minute 
treatments the following over a 2-week period: 
Ankle Joint Mobilization:  The joint mobilization treatment will consist of 2 sets of Grade 
III anterior-to-posterior ankle joint mobilizations and one minute between sets. This 
mobilization will be operationally defined as large-amplitude, 1-s rhythmic oscillation 
from the joint’s mid-range to end range with translation taken to tissue resistance. The 
objective of this therapy technique is to glide the ankle into the area which restricts 
range of motion and gently stretch the restricted area. To begin this treatment, a mild 
traction to the ankle joint to lightly distract the bones of the ankle joint. Then two sets of 
joint mobilizations, each for two minutes, will be applied. Each repetition will consist of 
gently gliding the ankle joint in the backward direction until an area of restriction is 
reached. We will mobilize the joint into the restriction and then glide the ankle back to 
the starting position. This grade of joint mobilization was selected because it attempts to 
increase the capsular endpoint and the oscillation spans the length of the joint providing 
the greatest stimulation of joint receptors. This manual therapy technique is commonly 
used in athletic training practice and presents minimal risk to participants.  
 
Plantar Foot Massage:  The plantar foot massage treatment will consist of 2 sets of 2 
minutes of plantar foot massage.  This massage will be operationally defined as two 
minutes of light petrissage (similar to kneading bread) and effleurage (gentle stroking 
motions) to the plantar surface of the foot from the ball of the foot to the heel. The 
objective of this therapy technique is to provide stimulation to the plantar cutaneous 
receptors of the foot. To begin this treatment, we will place our hands on the 
participant’s foot with his thumbs on the plantar surface and his fingers of both hands on 
the dorsal surface of the foot.  We will then apply two sets of massage, each for two 
minutes. Each set will consist of gently massaging the plantar surface of the foot to the 
comfort of the participant. This manual therapy technique is commonly used and 
presents minimal risk to participants. 
 
 
 

SECTION K: Participant Evaluations & Follow-Up 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 32 of 157 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SECTION K: Participant Evaluations & Follow-Up 
 
 
 
 

SECTION K: Participant Evaluations & Follow-Up 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 33 of 157 
K.1 Timeline and visit schedule 
See section A (schedule of visits and evaluations) and section B (study flow) of the 
MOOP. 
K.2 Scope 
Step by step procedures of each visit are outlined below and illustrated in Figure 1, a 
replication of section A. 
K.2.a Pre-Study (Participant Eligibility) 
Interested participants will be asked to fill out on-line questionnaires regarding their age, 
history of ankle injury (AII), ankle function (FAAM, FAAM-S), and any balance issues to 
determine eligibility for participation in the study (Appendix 2-4).  To be eligible, 
individuals must meet the following criteria as outlined in section 7 of Appendix 1 and 
section F.4 of the MOOP.  In addition, participants will complete three 1-item 
questionnaires related to their expectations of treatment efficacy (Appendix 5).  These 
responses will be used to match participants based on their expectations of the 
treatments to be provided. 
 
Males and females between the ages of 18 and 45 with self-reported CAI; defined as 
self-reported episodes of recurrent ankle sprains and/or the feeling of instability or 
“giving way” after an initial ankle sprain. Inclusion criteria will consist of a history of at 
least two episodes of “giving way” within the past 6 months; answering 5 or more 
questions of “Yes” on the Ankle Instability Instrument (AII); a score of < 90% on the self-
reported Foot and Ankle Ability Measure (FAAM); a score of < 80% on the FAAM Sport. 
Exclusion criteria will consist of reporting an acute ankle sprain within the past 6 weeks; 
a previous history of ankle surgeries; lower extremity surgeries associated with internal 
derangements, reconstructions, or repairs; lower extremity injuries within the past 6 
months (other than ankle sprains); and balance deficits, neuropathies or other disorders 
or conditions known to affect balance.   
 
**If a participant is determined to be ineligible for the investigation, then the data 
collected (to determine eligibility) will be immediately destroyed.  Specifically, the AII, 
balance questionnaire, FAAM, and FAAM-S, data sheets must be shredded 
immediately.  No other data can be collected prior to the participant reading and signing 
the informed consent document.   
K.2.b Visit 1:  
Informed Consent Process 
Once eligible, participants will be schedule to report to the research laboratory of the PI 
at their respective institution.  Once there, eligible participants will first read and sign the 
informed consent document as outlined in section H.  Information will then be collected 
regarding height, leg length, foot measurements, and weight (see Appendix 17) as well 
as physical activity and overall function (see Appendix 3 & 4).  Height, leg length, and 

SECTION K: Participant Evaluations & Follow-Up 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 34 of 157 
foot size will be measured with a tape measure. Weight will be measured with a scale. 
Participants will be asked to wear shorts for all testing procedures.  
 
 
1st Evaluation (Baseline) 
The following neuromuscular mechanisms and secondary measures will be completed 
at baseline: 
 
Peripheral Neuromuscular Mechanisms: 
Ankle joint position sense will be used to assess changes in a participant’s ability to 
detect the position of the foot/ankle complex relative to the body.  The theoretical 
premise of this mechanism is that CAI participants have an impaired ability to detect 
ankle joint position due to altered input from damaged mechanoreceptors.7  Postural 
control improvements following manual therapies may be the result of improved input 
from mechanoreceptors.  Ankle joint position sense will be assessed at the mid-range of 
plantar flexion and inversion as these positions have the greatest sensitivity to CAI 
associated impairments.  Participants will be seated with their foot in neutral (0 degrees 
of plantar flexion) before an active repositioning technique is used to quantify the 
absolute and constant error for each movement.  
Plantar light-touch thresholds will assess changes in somatosensation on the plantar 
foot.  These thresholds are increased in CAI patients and thought to be the result of 
repetitive trauma to the mechanoreceptors.  The effects of manual therapies may be the 
result of improved plantar mechanoreceptor sensitivity in CAI patients.  To assess this 
neuromuscular mechanism, we will use a protocol that requires participants to lie prone 
while thresholds are assessed at the head of the 1st and base of the 5th 
metatarsal.  Thresholds will be determined using Semmes-Weinstein monofilaments 
and a highly reliable 4-2-1 stepping algorithm.100 
Spinal Level Neuromuscular Mechanisms: 
The Hoffman reflex (H-Reflex) is the electrical analog of the monosynaptic stretch reflex 
and thought to provide insights into the neuromuscular mechanism mediating postural 
control.  H-Reflex modulation is reduced in CAI patients and correlated to self-reported 
functional limitations.  Thus, improvements in spinal reflexive excitability (increased H-
Reflex values) may represent an underlying neuromuscular mechanism responsible for 
improved postural control following ankle joint mobilization and plantar massage.  We 
will assess spinal reflexive excitability in the soleus and fibularis longus using our 
established methodology.  While lying supine, a stimulating electrode will be positioned 
over the sciatic nerve in the popliteal space.  Peak-to-peak Hoffmann reflexes (H-reflex) 
will be measured and the stimulus intensity increased until a maximal H-reflex is 
observed.  Three H-reflexes for each muscle will be recorded and normalized to the 

SECTION K: Participant Evaluations & Follow-Up 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 35 of 157 
maximal M-response, representing the ratio of the motor neuron pool reflexively 
activated to the amount of the motor neuron pool available (H:M ratio).  Higher H-reflex 
values and H:M ratios indicate greater excitability.  
Supraspinal Level Mechanisms: 
The corticospinal motor system plays a critical role in controlling movement by 
optimizing muscle activation.  Abnormal facilitation or inhibition from the corticospinal 
pathway is associated with impairments of the ankle joint musculature and hypothesized 
to contribute to the postural instability associated with CAI.  As such, cortical excitability 
may represent a plausible neuromuscular mechanism underlying improvements 
following ankle joint mobilization and plantar massage.  Corticomotor measures of the 
soleus and fibularis longus will be assessed using Transcranial Magnetic Stimulation 
(TMS) methodology previously used by the research team.  A Magstim 200 (Magstim 
Company, Wales, UK) will be used to produce a magnetic stimulus (max 2.0 Tesla) over 
the motor cortex contralateral to the test limb.  Testing will be performed over the area 
generating the greatest motor evoked potential (MEP) while participants perform mild 
isometric contractions (20%) on an isokinetic dynamometer. Active motor threshold 
(AMT) will be determined as the lowest stimulator intensity required to elicit an MEP 
peak-to-peak amplitude ≥100µV in at least 4 of 8 trials.  A higher AMT indicates 
decreased excitability, as a greater stimulus intensity is required to elicit an MEP.  Eight 
stimuli will be delivered at 120%, 130%, and 140% of AMT, and peak-to-peak MEP 
amplitudes will be recorded for each trial.  The cortical silent period (CSP) will be 
measured as the distance from the end of the MEP to a return of the mean EMG signal 
plus two times the standard deviation of the baseline (pre-stimulus) EMG signal.  A 
longer CSP indicates a greater corticospinal inhibition. 
Corticomotor output mapping provides further insight into the function of the motor 
cortex by identifying the size of an area within the motor cortex associated with a select 
muscle.  Improved postural control following manual therapies may be the result of a 
reorganization of the corticomotor output in CAI patients (i.e. an increased map area 
and/or volume of a given muscle).  Corticomotor mapping of the soleus and fibularis 
longus muscle will be assessed using TMS methods consistent the literature and our 
own protocols.  After AMT is quantified, a 6x6 cm grid (3cm lateral-medial and 3cm 
anterior-posterior) will outline the hotspot for each muscle and a stimulator intensity of 
100% AMT will be used.  Three consecutive stimuli will be delivered at each grid 
location in a random order in order to produce reliable and reproducible maps.  Average 
peak-to-peak MEP amplitudes for each grid site will be normalized to M-max.  Cortical 
representation of the soleus and fibularis longus will be calculated using map area and 
map volume.  Map area is the number of stimulus positions whose stimulation evoked 
an average MEP ≥MEP threshold and an increase would suggest an expansion of the 
cortical representation of a selected muscle.  Map volume will be calculated as the sum 
of the mean normalized MEPs recorded with an increase suggesting greater cortical 
excitability. 

SECTION K: Participant Evaluations & Follow-Up 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 36 of 157 
Alterations in cortical activation could represent an underlying cause of postural control 
improvements following manual therapies as postural control improves following the 
application of manual therapies and balance is controlled, at least in part, cortically.  To 
assess changes in cortical activity, participants will complete single limb balance 
assessments with eyes open and closed while cortical activation is simultaneously 
assessed using electroencephalography (EEG).  A V-Amp 16 active channel EEG 
system (BrainVision LLC, Morrisville, NC) will be used to acquire the EEG data from 
three channels (Fz, Cz and POz) based on a 10-20 system.  The impedance of each 
electrode will be kept below 40 kW.  Bandpass filters of 0.1 Hz and 65 Hz at 3 dB 
attenuation will be used to remove environmental artifacts.  Post-processing will include 
identifying and decontaminating artifacts as previously described.  The primary 
mechanisms of interest are the power spectral densities (PSD) of the alpha (8-12 Hz), 
beta (13-19Hz), and sigma (30-40Hz) bandwidths which will be computed for each 
condition to create a relative PSD.  Changes in the relative PSD will be compared 
among the interventions and control group.  
Sensory Organization Strategies [Primary Mechanism of Interest] represents a plausible 
neuromuscular mechanism as evidence indicates that in lieu of reliable somatosensory 
information, CAI patients increase reliance on visual information.  Further, an increased 
reliance on visual information is hypothesized to explain the repeated ankle sprains and 
episodes of giving way associated with CAI.  Changes in sensory organization 
strategies may represent the underlying neuromuscular mechanism of ankle joint 
mobilizations and plantar massage and these manual therapies improve postural control 
and reduce giving way episodes in CAI patients.  Changes in our primary mechanism of 
interest will be calculated using the % Modulation measure used previously by our 
group.  This measure estimates the weight given to visual information during eyes open 
stance based on the magnitude of postural instability that occurs when vision is 
removed.  Raw ground reaction force data will be collected at 200Hz using an 
Accusway Plus Balance force platform (AMTI, Watertown, MA).  Raw data will be 
filtered appropriately before the % Modulation for center of pressure velocity is 
calculated from eyes open and eyes closed stance data. Additional postural control 
measures such as time-to-Boundary (TTB) will also be calculated.0 
Secondary Measures 
Both walking gait and jump landing biomechanics will be assessed.  Three-dimensional 
kinematics (sampled at 100Hz) and kinetics (sampled at 1000Hz) will be obtained 
during both tasks using a 10-camera Vicon motion capture system.  During gait trials, 
participants will walk at a self-selected speed over multiple embedded force 
plates.  Speed will be enforced with timing gates centered over the force plates during 
the five test trials.  Jump landing biomechanics will be assessed with a drop vertical 
jump protocol that requires participants to jump from a 30cm platform placed at a 
distance of 50% of the participants' height away from the edge of the force platform, 
with an immediate rebound jump for maximum height.  Five test trials will be 
completed.  Both discrete variables and profile plots of the kinematic and kinetic data 
will be calculated for the ankle, knee, and hip in the sagittal, frontal, and transverse 

SECTION K: Participant Evaluations & Follow-Up 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 37 of 157 
planes.   All secondary measure methodology is consistent with those previously used 
by our research team.   
 
Tertiary Measures 
All participants will also be asked to stand barefoot on one leg with eyes closed and 
hands on hips on the floor for 20 seconds to quantify their balance.  Each participant will 
perform up to 5 trials on each leg.  During each trial, the investigator will count the 
amount of balance errors the participant commits.  Errors include any of the following: 
(1) lifting the hands off the iliac crests; (2) opening the eyes; (3) stepping, stumbling, or 
falling; (4) moving the hip into more than 30 degrees of flexion or abduction; (5) lifting 
the forefoot or heel; or (6) remaining out of the test position for longer than 5 seconds.  
The Weight Bearing Lunge Measure (WBLT) is a method of measuring dorsiflexion 
range of motion and is completed barefoot by placing the participant’s great toe in line 
with their heel on top of a tape measure on the floor. While keeping the heel firmly on 
the ground, participants are asked to bend their supporting knee to touch the wall in 
front of them. This is completed through a slow and controlled lunging action. Using the 
tape measure on the floor, the maximum distance each participant can place their foot 
away from the wall while keeping both the heel flat on the floor and knee touching the 
wall will be recorded. This test will be repeated 6 times during each laboratory session.  
All tertiary measure methodology is consistent with those previously used by our 
research team.   
 
Randomization 
As per section 8 of Appendix 1 and H of the MOOP, participants will be randomized to 
one of the three conditions in a 1:1:1 ratio using sealed envelopes after being stratified 
based on treatment expectations (Appendix 5).  More specifically, we will be using a 
block randomization technique so that preliminary data analysis, data monitoring, and 
safety evaluations will be based on similar, if not identical, numbers in each group.  
Each block of envelopes will be made and sealed before study enrollment begins by the 
biostatistician and randomization will occur after the baseline evaluation (see section 
9.b of Appendix 1 or K.1.a of the MOOP).  Each participant will select a sealed envelope 
containing their group assignment.  This assignment will be noted by the respective PI 
and recorded.   
First Treatment Session 
Participants in the manual therapy groups (massage and joint mobilization) will undergo 
their first treatment session immediately after randomization.  Participants in the control 
group will be given instructions on when to return in 2-weeks.  All participants should 
maintain normal activities over the 2-week period. 
 

SECTION K: Participant Evaluations & Follow-Up 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 38 of 157 
K.2.c Visit 2-14:  Treatments 
Participants in the manual therapies group will then receive treatments over the next 2 
weeks (see section K.2.b.2 of the MOOP).  Each treatment day should be separated by 
at least 24 hours over the course of 2 weeks.  Preferably, 3 treatments will be spread 
across each week of the 2 week intervention.  Visit 7 will be the final treatment. 
K.2.d Visit 15 
Post Test 1 
Following the last treatment (within approximately 72 hours) each participant will be 
reassessed on the measures described above. 
4-week Follow up 
Each participant will be reassessed on the measures described above.   
K.3 Retention Initiatives 
Participants will be actively followed through all visits in the study.  In order to follow 
participants across the study duration, all participants will be contacted at the end of 
each week of participation.  The investigators will set a treatment schedule that 
accommodates that schedule of each participant and send email reminders to each 
participant within 48 hours of the next treatment or assessment session. 
 
If a study participant is discontinued from the study (for any reason), he/she will still be 
followed to the end of their respective study period in order to monitor or adverse 
events.   

SECTION K: Participant Evaluations & Follow-Up 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 39 of 157 
Figure 1 
Copy of Section B: Schedule of Visits & Evaluations 
Study 
Visits / 
 Study 
Days 
Balance 
Questionnaire 
(Appendix 2) 
PRO Testing 
AII (Appendix 
3) 
FAAM 
(Appendix 4) 
FAAM-S 
(Appendix 4) 
Treatment 
Expectations 
(Appendix 5) 
Informed 
Consent 
(Appendix 
6) 
Neuromuscular 
Mechanism 
Testing 
Joint 
Position 
Sense 
Light-touch 
Thresholds 
H-Reflex 
Corticomotor 
mapping 
Corticomotor 
excitability 
Cortical 
Activation 
% 
Modulation  
Biomechanical 
Testing 
Gait Analysis 
Jump 
Landing 
Balance 
Testing 
Range of 
Motion 
Testing 
Treatment 
Delivery 
Adverse 
Event 
Monitoring 
Visit 1 
Eligibility 
Screening 
X 
X 
 
 
 
 
 
Visit 2 
Baseline 
Testing 
 
 
X 
X 
X 
X 
X 
Visits 3-7- 
 
 
 
 
 
X 
X 
Visit 8 
 
 
 
X 
X 
 
X 

SECTION K: Participant Evaluations & Follow-Up 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 40 of 157 
Post-Test 1 
Visit 9 
4-week 
follow up 
 
 
 
X 
X 
 
X 

SECTION L: Participant Retention 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 41 of 157 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SECTION L: Participant Retention 
 
 
 
 

SECTION L: Participant Retention 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 42 of 157 
In order to maximize retention for this protocol, the investigator will ensure the ongoing process of 
participant retention from the beginning of the protocol with participant recruitment all the way to 
the 3-month follow-up by : 
▪ Compensating the participants monetarily ($250) for their participation.  Compensation will be 
tracked with a payment log (see Appendix 20). 
o $100 at Post Test 1 
o $150 at the 1-month follow-up 
▪ Emphasizing the importance of congeniality, respectfulness and friendliness in interactions with 
participants  
▪ Giving patients and their families the opportunity to address questions and concerns pertaining to 
chronic ankle instability. 
▪ Enhancing participant’s understanding of the study’s mission and the protocol  
▪ Stressing the idea that participants have an active role in the research and are part of the 
research team 
▪ Verbally surveying participants on a regular basis, understanding their expectations, and gaining 
insight into their experiences and satisfaction 
▪ Identifying potential problems and key retention factors and developing intervention strategies 
regarding retention 
▪ Assessing each patient’s drop out potential and intervening as needed to keep patients interested 
in continuing to participate. 
▪ Emailing participants reminders prior to each assessment and treatment session to ensure that 
they know what time and what place to meet. 
 
 

SECTION P: Documentation 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 43 of 157 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SECTION M: Data & Safety  
 
 
 
 

SECTION P: Documentation 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 44 of 157 
M.1 Concomitant medications 
There is no concomitant medication restrictions associated with this protocol. 
 
M.2 Data & Safety Monitoring Plan 
M.2.a Purpose of Study 
The purpose of this study is to elucidate the neuromuscular mechanisms underlying the significant 
positive effects observed following 2-weeks of independent ankle joint mobilization and plantar 
massage interventions in chronic ankle instability patients. 
M.2.b Adherence Statement 
The Data Safety Monitoring Plan (DSMP) outlined below for 1 R21 AT009704-01 will adhere to the 
protocol approved by the University of North Carolina at Chapel Hill IRB. 
M.2.c Protocol Amendments 
All protocol amendments, other than minor administrative changes as defined by the NCCIH 
Guidance on Changes in Clinical Studies in Active Awards will be submitted in a prospective manner 
to NCCIH except when necessary to protect the safety, rights, or welfare of subjects. Prior to 
submission to NCCIH the proposed changes will be reviewed and approved by the Independent 
Monitor(s).  IRB-approval will not be sought until after NCCIH approval of the protocol amendment 
has been obtained. 
M.2.d Confidentiality 
Protection of Subject Privacy 
Subject confidentiality will be strictly held in trust by the investigators, study staff, and the sponsor(s) 
and their agents.  This confidentiality will extend to cover testing of biological samples and genetic 
tests, should such data be collected in future protocol amendments, in addition to any study 
information relating to subjects. 
The study protocol, documentation, data, and all other information generated will be held in strict 
confidence.  No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor. 
The study Independent Monitoring Committee (IMC) 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 subjects.  The 
study site will permit access to such records. 
Confidentiality During Adverse Event (AE) Reporting  
AE reports and annual summaries will not include subject or group-identifiable material. Each report 
will only include the identification code. 
 
M.2.e Expected Risks  
Expected risks to the subject are as follows: 

SECTION P: Documentation 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 45 of 157 
• Rare (<1%) of mild skin irritation due to taping the kinematic markers sensors to the skin. This 
risk will be minimized by a member of the research team removing the tape with care. 
• Rare (<1%) of seizure.  Overall estimate is that seizure risk is < 1:1000 (0.1%) and this risk is 
associated with Repetitive TMS, which will not be conducted in this investigation.   
• Infrequent (5%) of head and neck aches, hearing shifts, and fainting during and/or immediately 
after TMS.  The research team will disclose this information to the participant prior to 
enrollment and remind them prior to testing.  This is attributed to local stimulation of muscles 
and nerves near the stimulating coil, a tapping of the scalp by the coil during discharge, and 
wearing a tight-fitting swim cap. Other stimulation-related effects include teeth aches, facial 
twitches, odd taste in mouth, and discomfort from blinking and twitches of scalp muscles.  All 
symptoms resolve after cessation of the TMS protocol. TMS may induce fainting or feelings of 
lightheadedness or dizziness.  If symptoms of dizziness, lightheadedness, or feeling faint 
occur, the TMS protocol will be stopped. The subject will be allowed to lay down or put their 
head down to prevent fainting. If subjects faint, they must not be allowed to leave the 
laboratory until fully recovered. TMS produces a loud clicking sound when a current is passed 
through the stimulation coil. This loud click can result in temporary ringing in the ear and 
subclinical auditory threshold shifts. To prevent transient hearing threshold shifts due to TMS, 
subjects and investigators will be wear earplugs during TMS.  
• Infrequent (10%) of itching/scratching of the scalp during EEG testing.  Care will be taken 
during the application of the EEG cap, electrodes to measure brain wave activity, and the 
insertion of the gel. 
These risks are considered to be minimal and are addressed in the protocol and consent form.” 
 
Because the manual therapies can cause mild discomfort (<1%), all participants will be 
monitored at each treatment session during the study.  The manual therapies are designed to 
be pain free and are commonly applied in clinical scenarios but because of the rare risk of 
discomfort, participants will be monitored for expected and unexpected AEs related to the 
manual therapies. 
 
M.2.f Adverse Event/ Unanticipated Problems 
M.2.g Definitions  
Adverse Event (AE) 
An adverse event (AE) is any untoward medical occurrence in a subject during participation in the 
clinical study or with use of the experimental agent being studied. An adverse finding can include a 
sign, symptom, abnormal assessment (laboratory test value, vital signs, electrocardiogram finding, 
etc.), or any combination of these regardless of relationship to participation in the study. 
Unanticipated Problems (UP) 
The Office for Human Research Protections (OHRP) considers 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; 

SECTION P: Documentation 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 46 of 157 
• 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. 
 
Serious Adverse Event (SAE) 
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. 
M.2.h 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 study visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit.  
Events will be followed for outcome information until resolution or stabilization. 
 
M.2.i Characteristics of an Adverse Event 
Relationship to Study Intervention 
To assess relationship of an event to study intervention, the following guidelines are 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) 

SECTION P: Documentation 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 47 of 157 
a. There is no temporal relationship between the intervention and event onset. 
b. An alternate etiology has been established. 
Expectedness of SAEs 
The Study PI and Independent Monitoring Committee will be responsible for determining whether an 
SAE is expected or unexpected.  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.   
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 ADL 
3. Severe: significant symptoms requiring invasive intervention; subject seeks medical attention, 
needs major assistance with ADL 
M.2.j Reporting Procedures 
Unanticipated Problem Reporting  
Incidents or events that meet the OHRP criteria for unanticipated problems require the creation and 
completion of an unanticipated problem report form.  OHRP 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: 
• Research protocol 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, 
Independent Safety Monitor(s), and NCCIH within 7 days of the investigator becoming aware 
of the event.  
• Any other unanticipated problem will be reported to the IRB, Independent Safety Monitor(s), 
and NCCIH within 14 days of the investigator becoming aware of the problem.  
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. 

SECTION P: Documentation 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 48 of 157 
Reporting of Pregnancy 
Women that are known (via self-report) to be pregnant will be excluded.  If a woman becomes 
pregnant while enrolled, she will not be removed from the study and treatment will be discontinued.  
Safety follow-ups will be continued for the projected treatment time period.  Reporting of participants 
who become pregnant and are withdrawn from the study will be included in the regular IMC reports as 
participant drop outs. 
M.2.k Halting Rules 
Safety findings including, but not limited to, higher than anticipated SAEs, a higher number of a 
particular SAE than anticipated, and/or increased frequency of AEs.    
M.3 Quality Control and Quality Assurance 
M.3.a Data Management 
Data will be collected both in hard copy & electronically.  All computers in the associated research 
laboratories are password protected.  In order to protect the integrity of the original electronic data 
files, copies will be made of electronic data files to be used for data manipulation at a later date.  Any 
data file that is amended, cleaned, or updated will be given a new name with the corresponding name 
of the original file followed by _modified and dated with the month_, day_, and 2-digit year it was 
modified (i.e. 01_trial_1_modified_4_1_17). 
Additionally, data collected in hard copy will be de-identified and transferred to our electronic 
database as soon as possible.  Additionally, hard copy files that have yet to be transferred and 
originals will be stored in a locked cabinet within the laboratory (i.e. double lock protection).  The 
transfer of data between the PIs for the purpose of monitoring and analysis will only use de-identified 
data.  Further details can be seen in the Confidentiality section below. 
 
M.3.b Data Entry  Procedures, Flow, and Checks 
1. The programs and data entry sequence that will be used to record the data entered into an 
electronic database system are as follows: 
i. Members of the research team will be using Microsoft Excel to electronically record the 
data from the hard copy forms collected from the participants. 
ii. Upon completion of data entry in Excel, the data will then be transferred to an electronic 
database on Microsoft Sharepoint that is identical to the Excel spreadsheet.  The 
Sharepoint account will be maintained at the University of North Carolina at Chapel Hill 
and only the research team will have access to the site using a unique user name and 
password. 
2. All hard copy data will be entered in to the Excel and Sharepoint electronic databases by 
members of the research team.  The data will be entered in/transferred to the electronic 
databases within 5 business days of data capture. 
3. Process for data checks.   
i. Based on data entry plan, this will be a single data entry check.  In order to ensure 
consistency of data entry, the research team will discuss and inspect data entry in the 
Sharepoint database in the teams regular meetings.   
ii. Any issues associated with data entry will be discussed during these meetings and may 
be resolved with a double data entry audit.   

SECTION P: Documentation 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 49 of 157 
iii. In order to ensure consistency of changes, the PIs will also modify the database files 
and denote the change in the title of the file (e.g. NMC 
STARS_database_revised_11_1_18). 
4. Audit and tracking system for evaluating data flow and data entry. 
i. The team will discuss the flow of the database and any data entry issues that they may 
have in their meetings.   
ii. In the event that the investigators run into an item that does not produce the desired 
results (e.g. a question that could be worded more clearly for participants on a form), 
the PIs will discuss it, come up with a strategy to address it, implement the strategy, and 
ensure that only the most revised version of the item in question is used.   
5. Description of data transmission from the databases to the statistical analysis package IBM 
SPSS Statistics (SPSS). 
i. All data from the Sharepoint databases will be formatted to transfer directly into SPSS 
via copy and paste. 
ii. All electronic trials will be analyzed using MatLab.  The analyzed output in MatLab has 
been designed to be directly pasted into an Excel database. 
1. During MatLab analysis, all results will be immediately pasted into the Excel 
database. 
iii. The team will discuss and review the SPSS database in their meetings to ensure 
consistency of data. 
 
M.3.c Quality Control Procedures 
The team will hold regular meetings to discuss any issues with the study.  If problems arise, they will 
be addressed in a timely manner as outlined above.  The team will conduct a self-assessment every 
six months of their performance of collecting, maintaining, reporting, and storing relevant study 
materials and information.  Every month, the PI will audit study materials to ensure consistency in 
documenting and signing consent forms as well as use the quality control checklist to perform a data 
entry audit. 
 
The MOOP will be reviewed every six months to ensure that the procedures outlined reflect the most 
current state of study collection and data entry.  If there is a change to the protocol that requires an 
amendment to the MOOP, this change will be made by Dr. Wikstrom and distributed to all study 
personnel, the IMC, and NCCIH. 
 
M.3.d Training Plan 
All staff will be trained through the Collaborative Institutional Training Initiative for Biomedical 
Research involving human subjects.  In addition, all staff will be trained by the PI in the following prior 
to engaging in any research activities associated with this project: 
8. Determining subject eligibility 
a. Proper instructions for each questionnaire  
b. Using the eligibility checklist 
c. Enrolling a participant who is eligible 
9. Securing informed consent 
10. All data collection procedures 
11. Randomization process and sequence for each participant 
12. Data storage and analysis 

SECTION P: Documentation 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 50 of 157 
13. Reporting adverse events and protocol violations 
14. Using the MOOP 
The training of each staff member will be documented using the training checklist included in the 
MOOP and signed by both the staff member and the PI.   
 
All staff will be trained in the consent process to ensure that each member understands that 
participants are initially screened with the approved questionnaires.  If a potential participant is 
considered to be eligible, the staff member will read through the consent form with the participant and 
answer any questions.  If the participant would like to enroll in the study, he/she will be asked to sign 
and date the consent form on the signature page.  A copy of the signed consent form will be given to 
each participant enrolled in the study.  The original consent form will be stored in the participant’s 
folder which will be stored in a locked filing cabinet in the PI’s office.   
 
Regular monthly meetings of the research team will be used to discuss issues that arise with both 
data collection and treatment delivery.  Additionally, the PI will meet with study personnel involved 
with this project to ensure proper and timely dissemination of the following information: 
5. Adverse Events 
6. Protocol violations 
7. Compliance issues 
8. Protocol amendments 
 
In order to ensure consistency in communication, minutes of meeting will be recorded and distributed 
to all study personnel within 72 hours of the meeting.  Similarly, all study personnel involved with this 
project will be required to maintain current training through the Collaborative Institutional Training 
Initiative and remain up to date on the study protocol and amendments, AEs and SAEs, and the 
documentation plan. 
 
Quality control and quality assurance checks will be conducted monthly by the PI/Internal QA 
Reviewer. 
 
M.4 Subject Accrual and Compliance 
M.4.a  Measurement and Reporting of Subject Accrual 
Review of the rate of subject accrual and compliance with inclusion/exclusion criteria will occur monthly during the 
recruitment phase to ensure that a sufficient number of participants are being enrolled, in keeping with proposed 
recruitment projections, and that they meet eligibility criteria and fulfill the targeted ethnic diversity goals outlined in 
the grant proposal (Targeted/Planned Enrollment Table). 
 
M.4.b Measurement and Reporting of Participant Adherence to Treatment Protocol  
Data on adherence to the treatment protocol will be collected for each participant by research staff 
and reviewed monthly by the PI/Internal QA Reviewer.  Adherence of participants will be evaluated by 
review of the scheduled vs attended treatment sessions. Available data on the use of manual 
therapies suggests an overall compliance rate of 100%.  If adherence falls below the suggested rate, 
which might inhibit the ability of the study to test its primary hypotheses, the Internal QA Reviewer will 
suggest a conference call for study investigators to discuss methods for improving adherence. 
 

SECTION P: Documentation 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 51 of 157 
M.5 Justification of Sample Size  
Changes in sensory organization strategies has been chosen as the primary mechanism of interest 
and will be assessed by calculating the % Modulation of the resultant center of pressure velocity 
between eyes open and eyes closed stance.   
To achieve Aim 1, 18 participants per group are needed to ensure significant changes in the primary 
mechanism of interest following both interventions relative to the control group.  Between group (i.e. 
massage vs. control [d=0.53] & mobilization vs. control [d=0.69]) pre to post effect sizes from our 
preliminary data (See Preliminary Studies) were used to calculated the needed sample size.  Using 
GPower (3.1), a repeated measures, between factors ANOVA model for three groups and two time 
points was used.  Parameters included a purposefully conservative intra-measure correlation=0.90, 
α=0.05, and 1-β=0.90.  To achieve Aim 2, 16 participants per group are needed to identify significant 
correlations.  This value was calculated based on previously established correlations between 
neuromuscular mechanisms and biomechanical measures of postural control.  Parameters for this 
analysis included a correlation of r=0.5 (range from literature: 0.50 to 0.58), an α=0.05, and 1-β=0.90.  
Thus, we will recruit 20 participants per group and plan for a 10% dropout rate, which would leave 18 
subjects per group.  Our previous work42 had a 98.75% (79/80) retention rate using the same 
intervention protocol and all participants completed 100% of the treatment sessions.   
M.6 Stopping Rules  
This study will be stopped prior to its completion if: (1) the intervention is associated with adverse 
effects that call into question the safety of the intervention; (2) difficulty in study recruitment or 
retention will significantly impact the ability to evaluate the study endpoints; (3) any new information 
becomes available during the trial that necessitates stopping the trial; or (4) other situations occur that 
might warrant stopping the trial.”  
M.7 Designation of a Monitoring Committee   
The Independent  Monitoring Committee for this study is comprised of Drs. Ty Hopkins, Cathleen 
Crowell, and Dr. Cynthia Coffman.  Drs. Hopkins, Crowell, and Coffman are not associated with this 
research project and work independently of the PI, Dr. Erik Wikstrom. They are not part of the key 
personnel involved in this grant and are not affiliated with the University of North Carolina at Chapel 
Hill. No member of the Committee has collaborated or co-published with the PI within the past three 
years. They are qualified to review the patient safety data generated by this study because of their 
unique expertise. Dr. Coffman is a PhD biostatistician.  The CVs of all members of the IMC are 
attached. 
M.8 Safety Review Plan  
Study progress and safety will be reviewed monthly (and more frequently if needed).  Progress 
reports, including patient recruitment, retention/attrition, and AEs will be provided to the IMC semi-
annually.  An Annual Report will be compiled and will include a list and summary of AEs.  In addition, 
the Annual Report will address (1) whether AE rates are consistent with pre-study assumptions; (2) 
reason for dropouts from the study; (3) whether all participants met entry criteria; (4) whether 
continuation of the study is justified on the basis that additional data are needed to accomplish the 
stated aims of the study; and (5) conditions whereby the study might be terminated prematurely.  The 
Annual Report will be sent to the IMC and will be forwarded to the IRB and NCCIH.  The IRB and 
other applicable recipients will review progress of this study on an annual basis 

SECTION P: Documentation 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 52 of 157 
M.8.a Study Report Outline for the Independent Monitors(s) (Interim or Annual Reports)  
The study team will generate Study Reports for the IMC and will provide information on the following 
study parameters:  including patient recruitment, retention/attrition, and AEs.  Study Report tables will 
be generated only from aggregate (not by group assignment) baseline and aggregate safety data for 
the study population. 
M.8.b Submission of On-Site Monitoring/Audit and Inspection Reports 
The IRB, IMC, and NCCIH Program Officials will receive copies of all study monitoring/audit or 
inspection reports within 14 day of PI receipt.  For example, the NCCIH (Westat) monitoring report will 
be submitted to the IRB and IMC (NCCIH does not require copies of Westat monitoring reports).  Any 
FDA inspection report will be submitted to the IRB, IMC, and NCCIH Program Officials.  
M.8.c Table A 
M.9 Data Handling and Record Keeping 
The investigators are responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported.  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 type 
Frequency of review 
Reviewer 
Subject accrual (including 
compliance with protocol 
enrollment criteria) 
Monthly 
PI, Internal QA Reviewer 
Semi-annually 
Independent Monitor(s) 
Status of all enrolled subjects, 
as of date of reporting  
Monthly 
PI, Internal QA Reviewer 
Semi-annually 
Independent Monitor(s) 
Data entry quality control 
checks on 5% of charts 
Monthly 
QA Reviewer 
 
 
 
Adherence data regarding 
study visits and intervention 
Monthly 
PI, Internal QA Reviewer 
Semi-annually 
Independent Monitor(s) 
AEs and rates (including out-
of-range lab values) 
Monthly 
PI, Internal QA Reviewer 
Semi-annually 
 
Independent Monitor(s) 
Annually 
NCCIH, FDA (If Applicable) 
SAEs (unexpected and related) 
Per occurrence 
PI, Independent Monitor (s) 
NIH/NCCIH, FDA (if 
applicable) 
SAEs (expected or unrelated) 
Per Occurrence 
PI, Internal QA Reviewer 
Annually 
Independent Monitor (s), 
NIH/NCCIH 
Unanticipated Problems 
Monthly 
PI, Internal QA Reviewer 
Per Policy 
IRB, FDA (if applicable) 

SECTION P: Documentation 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 53 of 157 
M.9.a General Instructions for Completing Forms 
When completing study forms, PRINT IN CAPITAL LETTERS using black ink. Note, participants must 
not be identified by name on any study document submitted with the forms (e.g., ECG tracing, lab 
reports).  Replace the participant name with the participant initials and identification (ID). number.  
 
▪ 
Header:  Complete the header information on EVERY page, including pages for which no study 
data are recorded.  
 
▪ 
Participant ID:  The participant ID must be recorded on EVERY page, including pages for which 
no study data are recorded. 
 
▪ 
Time:  Use a 24 hour clock (e.g., 14:00 to indicate 2:00 p.m.) unless otherwise specified. 
 
▪ 
Dates: All dates must be verifiable by source documents. Historical dates are sometimes not 
known (e.g., date of first symptom); therefore, conventions for missing days and/or months 
should be described (e.g., UNK or 99).    
 
▪ 
Abbreviations:  Use of abbreviations not specifically noted in the instructions for completing the 
forms can be problematic and should be held to a minimum. 
 
▪ 
Extraneous Writing: Comments written extraneously on forms cannot be captured in the 
database; thus, write only in the spaces indicated.   
 
▪ 
Correcting errors:  If an error has been made on the study forms, place a single line through 
the erroneous entry and record the date and your initials. Indicate the correct response. 
o Example of correcting an error:  Make sure to strike through the error with a single line and 
make the correction immediately following the error.  Then initial and date. 
 
• Participant complained of pain on Wednesday Tuesday, September 8th. 
 
▪ 
Skipping items: Do not skip any items. Some items may carry "Unknown" or "Not Applicable" 
response choices which should be checked when necessary.  
 
▪ 
Incomplete data: Data may not be available to complete the form for various reasons.  Circle 
the item for which data is not available and indicate the reason near the appropriate field: 
o If an evaluation was not done, write ND and provide a reason. 
o If the information is not available, but the evaluation was done, write NAV.   
 
Note:  Only in rare circumstances, as in the case of lost documentation, should NAV be 
recorded on the form.  Every effort should be made to obtain the information requested. 
o If an evaluation is not applicable, write NA. 
 
Incomplete or Illegible forms: Incomplete forms that do not have adequate explanation (as 
described above) compromise the integrity of the entire study. Errors, such as incomplete or 
illegible forms, are problems that require time and energy to resolve.   
 
▪ 
If an entire page of the forms cannot be completed (e.g., no parts have any responses), and it is 
unlikely that it will be completed, draw a diagonal line through the form and write NOT DONE, 
NOT AVAILABLE or NOT APPLICABLE, as appropriate 
 

SECTION P: Documentation 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 54 of 157 
▪ 
The header information must be completed even though no data are recorded on the form.  If a 
form can only be partially completed at the time of monitoring, but will be completed when the 
information becomes available, follow the direction of the clinical monitor 
 
▪ 
Do not leave forms incomplete or unused without explanation 
M.9.b Data Management Responsibilities 
Data collection and accurate documentation are the responsibility of the study staff under the 
supervision of the PI.  All source documents and laboratory reports must be reviewed by the study 
team and data entry staff, who will ensure that they are accurate and complete.  Unanticipated 
problems and adverse events must be reviewed by the investigator or designee.   
 
M.9.c Database Protection  
This study will use a Sharepoint database.  The database will be secured with password protection.  
The research team will only enter coded information.  Electronic communication with the research 
team will involve only unidentifiable information. The Sharepoint folder allows for an electronic audit 
trail and modified database files will be labeled as indicated above. 
 
M.9.d Source Document Protection 
All participants will be coded upon entry into the investigation.  The master sheet (listing names with 
code numbers) will be stored on a password protected computer in the primary investigator's personal 
office.  Data will be collected both in hard copy & electronically.  Hard copy coded data sheets will be 
kept in a locked filing cabinet until they are transferred to electronic format.  Upon transfer, they will 
remain in a locked filing cabinent inside the research laboratory associated with the project (double 
lock protection).  As data sheets are transfer to electronic files for data analysis (within 5 days), the 
electronic records associated with the investigation will also be coded and de-identified, and kept on 
the password protected computer in a separate folder/location from the master sheet.  Electronic data 
will be collected on computers in the research laboratories which are accessed via unique passwords 
for each member of the research team.  As soon as feasible, the PIs will transfer the, already de-
identified, electronic data to the study databse (Sharepoint folder/file).  The Sharepoint folder is also 
password protected and passwords are unique to each member of the research team.  Hard and 
electronic copies of the MOOP and associated source forms will be maintained in the research 
laboratory and the PI’s office.    
M.10 Schedule and Content of Reports 
Reports will be generated per the schedule outlined in Table A.  In addition, preliminary data analysis 
will occur on a semi-annual basis. 
M.11 Informed Consent 
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 subjects and their families, if applicable.  A consent 
form describing in detail the study procedures and risks will be given to the subject.  Consent forms 
will be IRB-approved, and the subject 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 
subject and answer any questions that may arise.  The subject will sign the informed consent 

SECTION P: Documentation 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 55 of 157 
document prior to any study-related assessments or procedures.  Subjects will be given the 
opportunity to discuss the study with their surrogates or think about it 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 subjects for their records.  The rights and welfare of the 
subjects will be protected by emphasizing to them that the quality of their clinical care and/or 
academic status 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. 
To complete the informed consent process at the end of study participation, study staff will inform the 
subject when his/her participation has come to an end and will document the discussion in the study 
record. 
M.12 Reporting Changes in Study Status 
During the funding of this study, any action by the IRB, the IMC, or one of the study investigators 
that results in a temporary or permanent suspension of the study will be reported to the NCCIH 
Program Official within 3 business days of notification.  
 
 

SECTION P: Documentation 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 56 of 157 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SECTION P: Documentation 
 
 
 
 

SECTION P: Documentation 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 57 of 157 
P.1 Source Documentation 
The following have been identified as source documentation: 
▪ 
Electronic Source documents (recorded data) 
o Gait Trials 
o Jump Landing Trials 
o EEG Trials 
o TMS Trials 
o H-Reflex Trials 
o Balance Trials 
▪ 
Case Report Forms (data collection sheet) 
o Single Limb Balance 
o Dorsiflexion range of motion 
o Joint Position Sense 
o Light-Touch Thresholds 
▪ 
Signed consent forms 
▪ 
Questionnaires completed by the participant 
o Balance History Questionnaire 
o FAAM 
o FAAM-S 
o AII 
o Treatment Expectations 
P.2 Study Forms 
Data must be collected consistently across participants and sites so that any variability is limited to 
participants’ characteristics and responses to the intervention. Study forms, also called CRFs, provide 
the vehicle for consistent data collection. Below is the list of study forms: 
 
• Study forms and their collection schedule  
o Treatment Expectations 
▪ Collected at the eligibility session. 
▪ See appendix #5 for complete description. 
o Foot and Ankle Ability Measure 
▪ Collected at the eligibility session. 
▪ See appendix #4 for complete description. 
o Ankle Instability Instrument 
▪ Collected at the eligibility session. 

SECTION P: Documentation 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 58 of 157 
▪ See appendix #3 for complete description. 
o Balance questionnaire 
▪ Collected at the eligibility session 
▪ See appendix #2 for complete description. 
o Adverse Event Reporting Form 
o Master list of participant names and ID numbers 
• Maintenance of forms 
o All forms will be maintained by Dr. Wikstrom who will serve as the contact person for 
answering any questions about the forms to other study personnel.  If there are any 
amendments to the forms, these will be approved by the IMC and IRB prior to 
implementing them into the study.  All amendments will be noted in the minutes of the 
research team meetings. 
P.3 General Instructions for Completing Forms 
When completing study forms, PRINT IN CAPITAL LETTERS using black ink. Note, participants must 
not be identified by name on any study document submitted with the forms (e.g., ECG tracing, lab 
reports).  Replace the participant name with the participant initials and identification (ID). number.  
 
▪ 
Header:  Complete the header information on EVERY page, including pages for which no study 
data are recorded.  
 
▪ 
Participant ID:  The participant ID must be recorded on EVERY page, including pages for which 
no study data are recorded. 
 
▪ 
Time:  Use a 24 hour clock (e.g., 14:00 to indicate 2:00 p.m.) unless otherwise specified. 
 
▪ 
Dates: All dates must be verifiable by source documents. Historical dates are sometimes not 
known (e.g., date of first symptom); therefore, conventions for missing days and/or months 
should be described (e.g., UNK or 99).    
 
▪ 
Abbreviations:  Use of abbreviations not specifically noted in the instructions for completing the 
forms can be problematic and should be held to a minimum. 
 
▪ 
Extraneous Writing: Comments written extraneously on forms cannot be captured in the 
database; thus, write only in the spaces indicated.   
 
▪ 
Correcting errors:  If an error has been made on the study forms, place a single line through 
the erroneous entry and record the date and your initials. Indicate the correct response. 
o Example of correcting an error:  Make sure to strike through the error with a single line and 
make the correction immediately following the error.  Then initial and date. 

SECTION P: Documentation 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 59 of 157 
 
▪ 
Participant complained of pain on Wednesday Tuesday, September 8th. 
 
▪ 
Skipping items: Do not skip any items. Some items may carry "Unknown" or "Not Applicable" 
response choices which should be checked when necessary.  
 
▪ 
Incomplete data: Data may not be available to complete the form for various reasons.  Circle 
the item for which data is not available and indicate the reason near the appropriate field: 
o If an evaluation was not done, write ND and provide a reason. 
o If the information is not available, but the evaluation was done, write NAV.   
 
Note:  Only in rare circumstances, as in the case of lost documentation, should NAV be 
recorded on the form.  Every effort should be made to obtain the information requested. 
o If an evaluation is not applicable, write NA. 
 
Incomplete or Illegible forms: Incomplete forms that do not have adequate explanation (as 
described above) compromise the integrity of the entire study. Errors, such as incomplete or 
illegible forms, are problems that require time and energy to resolve.   
 
▪ 
If an entire page of the forms cannot be completed (e.g., no parts have any responses), and it is 
unlikely that it will be completed, draw a diagonal line through the form and write NOT DONE, 
NOT AVAILABLE or NOT APPLICABLE, as appropriate 
 
▪ 
The header information must be completed even though no data are recorded on the form.  If a 
form can only be partially completed at the time of monitoring, but will be completed when the 
information becomes available, follow the direction of the clinical monitor 
 
▪ 
Do not leave forms incomplete or unused without explanation
 
 

SECTION Q: Data Flow 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 60 of 157 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SECTION Q: Data Flow 
 
 
 
 

SECTION Q: Data Flow 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 61 of 157 
All participants will be coded upon entry into the investigation.  The master sheet (listing names with 
code numbers) will be stored locally at each site in the site primary investigator's personal office 
within a locked filing cabinet.  Data will be collected both in hard copy & electronically.  Hard copy 
coded data sheets will be kept in a locked filing cabinet until they are transferred to electronic format.  
As data sheets are transfer to electronic files for data analysis (done as soon as possible), the 
electronic records associated with the investigation will also be coded and de-identified, and kept 
within a Sharepoint folder and files.  Electronic data will be collected on computers in the research 
laboratories associated with this study which are password protected (unique passwords for each 
study team member) until the data is uploaded to Sharepoint.  
 
 

SECTION R: Retention of Study Documentation 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 62 of 157 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SECTION R: Retention of Study Documentation 
 
 
 
 

SECTION R: Retention of Study Documentation 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 63 of 157 
All documents and data collected from participants in this study must be retained for three years in 
accordance to IRB protocol.
 
 

SECTION S: Administrative Forms 
 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 64 of 157 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SECTION S: Administrative Forms 
 
 
 
 

SECTION S: Administrative Forms 
 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 65 of 157 
The MOOP should contain a complete set of administrative forms. Administrative forms assist study 
documentation and may include the following, as relevant: 
▪ 
Informed Consent Documentation Form – Appendix 7 
▪ 
Protocol Deviation Log – Appendix 8 
▪ 
AE Reporting Form – Appendix 10 
▪ 
Unanticipated Problem Reporting Form – Appendix 11 
▪ 
Serious AE Reporting Form – Appendix 12 
▪ 
Eligibility Log – Appendix 13 
▪ 
Screening Log - Appendix 14 
▪ 
Master List –Appendix 15 
▪ 
Training Log – Appendix 16 
▪ 
Data Collection Form – Appendix 17 
▪ 
Payment Log – Appendix 20 
▪ 
Study Completion Form – Appendix 22 
▪ 
IMC Reporting Template – Appendix 23 
 
 
 

 
 
SECTION T: IRB Policies 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 66 of 157 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SECTION T: IRB Policies 
 
 
 
 

 
 
SECTION T: IRB Policies 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 67 of 157 
 
See https://research.unc.edu/files/2017/05/SOP-June-2-2017-bookmarked-and-TOC-links.pdf for IRB 
SOPs. 
 
 

 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 68 of 157 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDICES 
 
 

APPENDEX 1: Study Protocol 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 69 of 157 
Appendix 1: Study Protocol 
1 Background 
Musculoskeletal injury associated with 
physical activity is a leading reason for 
physical activity cessation.  Physical 
inactivity is clearly linked to a decreased 
quality of life and significant long-term 
negative sequelae.  CAI is associated with 
reduced physical activity levels and lower 
quality of life.  Thus, proper treatment of 
CAI is crucial to preventing sedentary 
behavior and disease.   
Lateral Ankle Sprains & their Sequelae 
Represent a Significant Healthcare 
Burden.  An estimated 932,000 lateral 
ankle sprains were seen in United States 
(US) emergency departments in 2010.  
Just the acute care of these lateral ankle 
sprains resulted in over $1 billion in 
healthcare charges.  The total financial 
impact of initial treatment and time-loss is 
estimated at $12,000/lateral ankle sprain.  
Coupled with our data, this equates to 
potentially spending >$11 billion annually 
on lateral ankle sprains.  However, lateral 
ankle sprains are not a one-time injury as 
40-75% of those who sustain a lateral 
ankle sprain will develop CAI and up to 78% of those with CAI develop post-traumatic 
ankle osteoarthritis.  The financial burden of treating CAI has remains unknown but CAI 
surgical procedures rose by >17% from 2007-2011.   
Neuromuscular Impairments Perpetuate a Continuum of Disability.  Peripherally, 
diminished proprioception and increased cutaneous receptor thresholds in CAI patients 
are thought to alter gait biomechanics and the increased reliance on visual information 
while balancing (i.e. altered sensory organization strategy).  These alterations may 
subsequently increase recurrent injury risk.  Spinal level dysfunction, as measured by 
diminished H-reflex/M-Response ratios and slower reflex reactions have been noted, as 
have reduced cortical excitability and reduced corticomotor map sizes of the fibularis 
longus.  These supraspinal alterations suggest a functional reorganization of motor 
networks and a systemic effect on the neuromuscular control system.  These 

APPENDEX 1: Study Protocol 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 70 of 157 
neuromuscular impairments manifest clinically as an inability to generate appropriate 
motor responses that perpetuates the continuum of disability (left).  Until, the 
neuromuscular mechanisms responsible for the significant positive effects of manual 
therapies are elucidated, clinicians will not be able to strategically leverage manual 
therapies as a treatment to break the CAI associated continuum of disability.   
Ankle Joint Mobilization & Plantar Massage are Prevalent but understudied CAM 
Treatments.  The use of complementary and alternative medicine (CAM) linearly 
increased between 2002 and 2012, particularly in younger (18-44) Americans.65  Ankle 
joint mobilization and plantar massage are manipulative and body based therapies that 
are among the most commonly used by American adults.  In 2007 alone, American 
adults made over 354 million visits to CAM practitioners for an out-of-pocket expense of 
$11.9 billion and roughly 75% of the reported visits and out-of-pocket expenses were 
associated with manipulative and body based therapies.  CAM visits for musculoskeletal 
joint pain are common, especially among females who are at an increased risk of 
sustaining a lateral ankle sprain.   
 
2 Aims & Hypotheses 
The objective of this study is to elucidate the neuromuscular mechanisms underlying the 
significant positive effects observed following 2-weeks of independent ankle joint 
mobilization and plantar massage interventions in CAI patients.  The following specific 
aims will be used to achieve our objective: 
Aim 1:  Determine changes in peripheral, spinal, and supraspinal neuromuscular 
mechanisms after 2-week manual therapy interventions (ankle joint mobilization, 
plantar massage) relative to a non-treatment control group in CAI patients.  
Neuromuscular mechanisms will be quantified before and immediately after a 2-week 
intervention.  Mechanisms will include a comprehensive group of peripheral (ankle joint 
position sense, plantar light-touch discrimination thresholds), spinal (H-reflex of the 
soleus and fibularis longus), and supraspinal measures (cortical activity during stance 
using electroencephalography [EEG], corticomotor excitability and mapping of the 
soleus and fibularis longus via transcranial magnetic stimulation [TMS], and sensory 
organization strategies during stance).  Our primary mechanism of interest is sensory 
organization strategies.  Sixty CAI patients will be randomized into three equal groups 
(ankle joint mobilization, plantar massage, control) to complete 6 treatment sessions 
over 2-weeks.   
Hypothesis 1.  Both interventions, relative to the control group, will result in significant 
sensory organization strategy changes, representing a reduction in the CAI patient’s 
reliance on visual information during stance.   
Hypothesis 2.  Each intervention will result in unique combinations of peripheral, spinal, 
and supraspinal mechanistic pathways relative to the control group.   

APPENDEX 1: Study Protocol 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 71 of 157 
Aim 2:  Determine the associations among peripheral, spinal, and supraspinal 
neuromuscular mechanisms, secondary biomechanical measures, and sensory 
organization strategies in CAI patients.  These associations will be quantified to 
elucidate the unique combination of peripheral, spinal, and supraspinal mechanistic 
pathways thought to contribute to a reducing in the reliance of visual information during 
stance.  Secondary measures which will include jump landing and gait biomechanics 
will be assessed before and immediately after the 2-week interventions.  We will use an 
analytical approach (see statistical analysis) to determine simple associations at 
baseline, post-test, and among change scores in neuromuscular mechanisms and 
secondary measures.   
Hypothesis 1.  Each intervention will result in unique combinations of changes in 
peripheral, spinal, and supraspinal mechanistic pathways will be strongly associated 
with changes sensory organization strategies. 
Hypothesis 2.  Each intervention will result in secondary measure changes associating 
with changes in sensory organization strategies as well as peripheral, spinal, and 
supraspinal mechanistic pathways. 
 
3 Study Design 
We plan to use a single-blind randomized study design to quantify changes in the 
hypothesized neuromuscular mechanisms following ankle joint mobilization and plantar 
massage.  Assessors will be blinded to group assignment. 
 
4 Primary & Secondary Endpoints 
This study will have 1 primary endpoint at the conclusion of the 2-week intervention.  
This study will have 1 secondary endpoint 1-month after the conclusion of the 2-week 
intervention.  All outcomes will be assessed at both endpoints.   
 
5 Type & Number of Sites 
A total of 1 site will be used during this study: the University of North Carolina at Chapel 
Hill.   
 
6 Patient Population & Numbers 
Only those with CAI, as defined by the International Ankle Consortium (IAC) will be 
enrolled.  Specific inclusion criteria will be identical to our previous work and consist of a 
history of at least two episodes of “giving way” within the past 6 months; scoring ≥ 5 on 
the Ankle Instability Instrument (AII), scoring <90% on the Foot and Ankle Ability 
Measure (FAAM), and scoring <80% on the FAAM Sport (FAAM-S).  Exclusion criteria 

APPENDEX 1: Study Protocol 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 72 of 157 
will consist of acute ankle sprains <6 weeks, previous ankle surgeries, lower extremity 
surgeries associated with internal derangements, and conditions affecting 
neuromuscular control. 
Changes in sensory organization strategies has been chosen as the primary 
mechanism of interest and will be assessed by calculating the % Modulation of the 
resultant center of pressure velocity between eyes open and eyes closed stance.33   
To achieve Aim 1, 18 participants per group are needed to ensure significant changes in 
the primary mechanism of interest following both interventions relative to the control 
group.  Between group (i.e. massage vs. control [d=0.53] & mobilization vs. control 
[d=0.69]) pre to post effect sizes from our preliminary data (See Preliminary Studies) 
were used to calculated the needed sample size.  Using GPower (3.1), a repeated 
measures, between factors ANOVA model for three groups and two time points was 
used.  Parameters included a purposefully conservative intra-measure correlation=0.90, 
α=0.05, and 1-β=0.90.  To achieve Aim 2, 16 participants per group are needed to 
identify significant correlations.  This value was calculated based on previously 
established correlations between neuromuscular mechanisms and biomechanical 
measures of postural control.16, 95  Parameters for this analysis included a correlation of 
r=0.5 (range from literature: 0.50 to 0.58), an α=0.05, and 1-β=0.90.  Thus, we will 
recruit 20 participants per group and plan for a 10% dropout rate, which would leave 18 
subjects per group.  Our previous work42 had a 98.75% (79/80) retention rate using the 
same intervention protocol and all participants completed 100% of the treatment 
sessions.   
 
7 Inclusion & Exclusion Criteria 
Inclusion criteria will consist of the following: 
• Male or female 18-45 years of age 
• History of ankle sprain with at least two episodes of “giving way” within the past 
six months 
• Score of ≥ 5 on the Ankle Instability Instrument (AII) 
• Score of ≤ 90% on the FAAM-ADL 
• Score of ≤ 80% on the FAAM-S. 
 
Exclusion criteria will consist of the following: 
• Younger than 18 or older than 45 years 
• No history of ankle sprain or episodes of “giving way” in the past six months 
• Score of ≤ 5 on the Ankle Instability Instrument (AII) 

APPENDEX 1: Study Protocol 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 73 of 157 
• Score of ≥ 90% on the FAAM-ADL 
• Score of ≥ 80% on the FAAM-S. 
• An acute ankle sprain within the past 6 weeks. 
• Previous history of lower extremity surgery with internal derangements, 
reconstructions, or repair 
• Lower extremity injury within the past 6 months (other than ankle sprains) 
• Presence of balance deficits or conditions known to affect balance as noted on 
the Balance Questionnaire including diabetes and/or vertigo. 
 
8 Randomization Plan 
Participants will be randomized to one of groups in a 1:1:1 ratio after stratification based 
on treatment expectation responses.  This process will happen using sealed envelopes 
prepared by the study biostatistician.  More specifically, we will be using a block 
randomization technique at each institution so that preliminary data analysis, data 
monitoring, and safety evaluations will be based on similar, if not identical, numbers in 
each group.  Each block of envelopes will be made and sealed before study enrollment 
begins and randomization will occur after the baseline evaluation (see section 9.b 
below).  The biostatistician will be responsible for generating the master randomization 
list and each participant will select a sealed envelope containing their group 
assignment.  This assignment will be noted by the PI and recorded.  Assessors will be 
blinded to group assignment. 
9 Screening Process, Baseline Evaluation, Study Treatment, & Final Evaluation 
9.a Screening Process 
The screening process will be performed at a specific eligibility screening session.  At 
this session, potential participants will complete the Balance Questionnaire (Appendix 
2), AII (Appendix 3), FAAM (Appendix 4), FAAM-Sport (Appendix 4), and Treatment 
Expectation (Appendix 5) questionnaires.  If eligible, participants will be scheduled for 
baseline testing which will be the first of 3 testing sessions.  The first will take place on 
the day of baseline evaluation.  The second will take place at the end of the 2-week 
intervention.  The third will take place 1-month after the final treatment session.   
 

APPENDEX 1: Study Protocol 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 74 of 157 
9.b Baseline & Post-Test Evaluations 
The baseline evaluation will include gathering general 
information regarding age, height, leg length, foot 
measurements, weight.  Participants will then receive 
instruction on the testing procedures and will perform 
several warm-up trials on all assessments to become 
familiarized with the testing procedures.  Next, 
participants will have their ankle range of motion, postural 
control, and lower extremity biomechanics tested.  Finally, 
participants will complete the possible neuromuscular 
mechanism measures.  All outcomes will be performed at 
all test sessions.  More detailed descriptions are provided 
below:  
 
Peripheral Neuromuscular Mechanisms: 
Ankle joint position sense will be used to assess changes 
in a participant’s ability to detect the position of the 
foot/ankle complex relative to the body.  The theoretical 
premise of this mechanism is that CAI participants have 
an impaired ability to detect ankle joint position due to altered input from damaged 
mechanoreceptors.7  Postural control improvements following manual therapies may be 
the result of improved input from mechanoreceptors.  Ankle joint position sense will be 
assessed at the mid-range of plantar flexion and inversion as these positions have the 
greatest sensitivity to CAI associated impairments.  Participants will be seated with their 
foot in neutral (0 degrees of plantar flexion) before an active repositioning technique is 
used to quantify the absolute and constant error for each movement.  
Plantar light-touch thresholds will assess changes in somatosensation on the plantar 
foot.  These thresholds are increased in CAI patients and thought to be the result of 
repetitive trauma to the mechanoreceptors.  The effects of manual therapies may be the 
result of improved plantar mechanoreceptor sensitivity in CAI patients.  To assess this 
neuromuscular mechanism, we will use a protocol that requires participants to lie prone 
while thresholds are assessed at the head of the 1st and base of the 5th 
metatarsal.  Thresholds will be determined using Semmes-Weinstein monofilaments 
and a highly reliable 4-2-1 stepping algorithm.100 
Spinal Level Neuromuscular Mechanisms: 
The Hoffman reflex (H-Reflex) is the electrical analog of the monosynaptic stretch reflex 
and thought to provide insights into the neuromuscular mechanism mediating postural 
control.  H-Reflex modulation is reduced in CAI patients and correlated to self-reported 
functional limitations.  Thus, improvements in spinal reflexive excitability (increased H-
Reflex values) may represent an underlying neuromuscular mechanism responsible for 
improved postural control following ankle joint mobilization and plantar massage.  We 

APPENDEX 1: Study Protocol 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 75 of 157 
will assess spinal reflexive excitability in the soleus and fibularis longus using our 
established methodology.  While lying supine, a stimulating electrode will be positioned 
over the sciatic nerve in the popliteal space.  Peak-to-peak Hoffmann reflexes (H-reflex) 
will be measured and the stimulus intensity increased until a maximal H-reflex is 
observed.  Three H-reflexes for each muscle will be recorded and normalized to the 
maximal M-response, representing the ratio of the motor neuron pool reflexively 
activated to the amount of the motor neuron pool available (H:M ratio).  Higher H-reflex 
values and H:M ratios indicate greater excitability.  
Supraspinal Level Mechanisms: 
The corticospinal motor system plays a critical role in controlling movement by 
optimizing muscle activation.  Abnormal facilitation or inhibition from the corticospinal 
pathway is associated with impairments of the ankle joint musculature and hypothesized 
to contribute to the postural instability associated with CAI.  As such, cortical excitability 
may represent a plausible neuromuscular mechanism underlying improvements 
following ankle joint mobilization and plantar massage.  Corticomotor measures of the 
soleus and fibularis longus will be assessed using Transcranial Magnetic Stimulation 
(TMS) methodology previously used by the research team.  A Magstim 200 (Magstim 
Company, Wales, UK) will be used to produce a magnetic stimulus (max 2.0 Tesla) over 
the motor cortex contralateral to the test limb.  Testing will be performed over the area 
generating the greatest motor evoked potential (MEP) while participants perform mild 
isometric contractions (20%) on an isokinetic dynamometer. Active motor threshold 
(AMT) will be determined as the lowest stimulator intensity required to elicit an MEP 
peak-to-peak amplitude ≥100µV in at least 4 of 8 trials.  A higher AMT indicates 
decreased excitability, as a greater stimulus intensity is required to elicit an MEP.  Eight 
stimuli will be delivered at 120%, 130%, and 140% of AMT, and peak-to-peak MEP 
amplitudes will be recorded for each trial.  The cortical silent period (CSP) will be 
measured as the distance from the end of the MEP to a return of the mean EMG signal 
plus two times the standard deviation of the baseline (pre-stimulus) EMG signal.  A 
longer CSP indicates a greater corticospinal inhibition. 
Corticomotor output mapping provides further insight into the function of the motor 
cortex by identifying the size of an area within the motor cortex associated with a select 
muscle.  Improved postural control following manual therapies may be the result of a 
reorganization of the corticomotor output in CAI patients (i.e. an increased map area 
and/or volume of a given muscle).  Corticomotor mapping of the soleus and fibularis 
longus muscle will be assessed using TMS methods consistent the literature and our 
own protocols.  After AMT is quantified, a 6x6 cm grid (3cm lateral-medial and 3cm 
anterior-posterior) will outline the hotspot for each muscle and a stimulator intensity of 
100% AMT will be used.  Three consecutive stimuli will be delivered at each grid 
location in a random order in order to produce reliable and reproducible maps.  Average 
peak-to-peak MEP amplitudes for each grid site will be normalized to M-max.  Cortical 
representation of the soleus and fibularis longus will be calculated using map area and 
map volume.  Map area is the number of stimulus positions whose stimulation evoked 
an average MEP ≥MEP threshold and an increase would suggest an expansion of the 

APPENDEX 1: Study Protocol 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 76 of 157 
cortical representation of a selected muscle.  Map volume will be calculated as the sum 
of the mean normalized MEPs recorded with an increase suggesting greater cortical 
excitability. 
Alterations in cortical activation could represent an underlying cause of postural control 
improvements following manual therapies as postural control improves following the 
application of manual therapies and balance is controlled, at least in part, cortically.  To 
assess changes in cortical activity, participants will complete single limb balance 
assessments with eyes open and closed while cortical activation is simultaneously 
assessed using electroencephalography (EEG).  A V-Amp 16 active channel EEG 
system (BrainVision LLC, Morrisville, NC) will be used to acquire the EEG data from 
three channels (Fz, Cz and POz) based on a 10-20 system.  The impedance of each 
electrode will be kept below 40 kW.  Bandpass filters of 0.1 Hz and 65 Hz at 3 dB 
attenuation will be used to remove environmental artifacts.  Post-processing will include 
identifying and decontaminating artifacts as previously described.  The primary 
mechanisms of interest are the power spectral densities (PSD) of the alpha (8-12 Hz), 
beta (13-19Hz), and sigma (30-40Hz) bandwidths which will be computed for each 
condition to create a relative PSD.  Changes in the relative PSD will be compared 
among the interventions and control group.  
Sensory Organization Strategies [Primary Mechanism of Interest] represents a plausible 
neuromuscular mechanism as evidence indicates that in lieu of reliable somatosensory 
information, CAI patients increase reliance on visual information.  Further, an increased 
reliance on visual information is hypothesized to explain the repeated ankle sprains and 
episodes of giving way associated with CAI.  Changes in sensory organization 
strategies may represent the underlying neuromuscular mechanism of ankle joint 
mobilizations and plantar massage and these manual therapies improve postural control 
and reduce giving way episodes in CAI patients.  Changes in our primary mechanism of 
interest will be calculated using the % Modulation measure used previously by our 
group.  This measure estimates the weight given to visual information during eyes open 
stance based on the magnitude of postural instability that occurs when vision is 
removed.  Raw ground reaction force data will be collected at 200Hz using an 
Accusway Plus Balance force platform (AMTI, Watertown, MA).  Raw data will be 
filtered appropriately before the % Modulation for center of pressure velocity is 
calculated from eyes open and eyes closed stance data. Additional postural control 
measures such as time-to-Boundary (TTB) will also be calculated.0 
Secondary Measures 
Both walking gait and jump landing biomechanics will be assessed.  Three-dimensional 
kinematics (sampled at 100Hz) and kinetics (sampled at 1000Hz) will be obtained 
during both tasks using a 10-camera Vicon motion capture system.  During gait trials, 
participants will walk at a self-selected speed over multiple embedded force 
plates.  Speed will be enforced with timing gates centered over the force plates during 
the five test trials.  Jump landing biomechanics will be assessed with a drop vertical 
jump protocol that requires participants to jump from a 30cm platform placed at a 

APPENDEX 1: Study Protocol 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 77 of 157 
distance of 50% of the participants' height away from the edge of the force platform, 
with an immediate rebound jump for maximum height.  Five test trials will be 
completed.  Both discrete variables and profile plots of the kinematic and kinetic data 
will be calculated for the ankle, knee, and hip in the sagittal, frontal, and transverse 
planes.   All secondary measure methodology is consistent with those previously used 
by our research team.   
 
Tertiary Measures 
All participants will also be asked to stand barefoot on one leg with eyes closed and 
hands on hips on the floor for 20 seconds to quantify their balance.  Each participant will 
perform up to 5 trials on each leg.  During each trial, the investigator will count the 
amount of balance errors the participant commits.  Errors include any of the following: 
(1) lifting the hands off the iliac crests; (2) opening the eyes; (3) stepping, stumbling, or 
falling; (4) moving the hip into more than 30 degrees of flexion or abduction; (5) lifting 
the forefoot or heel; or (6) remaining out of the test position for longer than 5 seconds.  
The Weight Bearing Lunge Measure (WBLT) is a method of measuring dorsiflexion 
range of motion and is completed barefoot by placing the participant’s great toe in line 
with their heel on top of a tape measure on the floor. While keeping the heel firmly on 
the ground, participants are asked to bend their supporting knee to touch the wall in 
front of them. This is completed through a slow and controlled lunging action. Using the 
tape measure on the floor, the maximum distance each participant can place their foot 
away from the wall while keeping both the heel flat on the floor and knee touching the 
wall will be recorded. This test will be repeated 6 times during each laboratory session.  
All tertiary measure methodology is consistent with those previously used by our 
research team.   
 
9.c Study Treatments 
Sensory-Targeted Rehabilitation Strategies.  This intervention will consist of 6, 5-minute 
treatments the following over a 2-week period: 
Ankle Joint Mobilization:  The joint mobilization treatment will consist of 2 sets of Grade 
III anterior-to-posterior ankle joint mobilizations and one minute between sets. This 
mobilization will be operationally defined as large-amplitude, 1-s rhythmic oscillation 
from the joint’s mid-range to end range with translation taken to tissue resistance. The 
objective of this therapy technique is to glide the ankle into the area which restricts 
range of motion and gently stretch the restricted area. To begin this treatment, a mild 
traction to the ankle joint to lightly distract the bones of the ankle joint. Then two sets of 
joint mobilizations, each for two minutes, will be applied. Each repetition will consist of 
gently gliding the ankle joint in the backward direction until an area of restriction is 
reached. We will mobilize the joint into the restriction and then glide the ankle back to 
the starting position. This grade of joint mobilization was selected because it attempts to 
increase the capsular endpoint and the oscillation spans the length of the joint providing 
the greatest stimulation of joint receptors. This manual therapy technique is commonly 
used in athletic training practice and presents minimal risk to participants.  

APPENDEX 1: Study Protocol 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 78 of 157 
 
Plantar Foot Massage:  The plantar foot massage treatment will consist of 2 sets of 2 
minutes of plantar foot massage.  This massage will be operationally defined as two 
minutes of light petrissage (similar to kneading bread) and effleurage (gentle stroking 
motions) to the plantar surface of the foot from the ball of the foot to the heel. The 
objective of this therapy technique is to provide stimulation to the plantar cutaneous 
receptors of the foot. To begin this treatment, we will place our hands on the 
participant’s foot with his thumbs on the plantar surface and his fingers of both hands on 
the dorsal surface of the foot.  We will then apply two sets of massage, each for two 
minutes. Each set will consist of gently massaging the plantar surface of the foot to the 
comfort of the participant. This manual therapy technique is commonly used and 
presents minimal risk to participants. 
 
10 Definition of Evaluable Patients 
Evaluable patients will be operationally defined in the following ways: 
1)  Baseline Evaluation:  Any person eligible for the study. 
2) 2nd Test Session:  All enrolled participants in the intervention groups who completed 
all 6 sessions of the intervention and all participants in the control group who maintain 
normal daily activities during the intervention period.   
3) 3rd Test Session:  All enrolled participants who completed the 2nd test session. 
 
11 Blinding / Unblinding Issues 
Based on the study roster and planned data collection methods, blinding of the 
assessors will be used in the current investigation.   
 
12 Statistical Plan 
To achieve Aim 1 and quantify changes caused by the ankle joint mobilization and 
plantar massage interventions, neuromuscular mechanisms will be submitted to 
separate 2-way repeated measures (Group × Time) ANOVAs.  MANOVAs may be used 
based on inter-item correlation coefficients found during the preliminary analysis of the 
data.  Pairwise comparisons, when appropriate, will determine the location of significant 
interactions.  An alpha level of 0.05 will be used to assess changes in the primary 
mechanism of interest (% modulation).  An exploratory alpha level (0.10) will be used on 
all other peripheral, spinal, and supraspinal mechanisms and secondary measures to 
reduce the chance that possible changes would be overlooked in this initial R21 
investigation.  Hedge’s G effect sizes and confidence intervals based on the pre-to-post 
change scores42 will also be calculated and interpreted as follows: less than 0 as small, 
0.31–0.7 as moderate, and greater than 0.71 as large.  Finally, control group data will 
be used to calculate the minimal detectable change (MDC) scores for all mechanisms 

APPENDEX 1: Study Protocol 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 79 of 157 
and secondary measures.42, 98, 134  The MDC allows us to evaluate the interventions 
effects relative to the stability of the measures over time.  This 3-pronged approach 
affords us multiple criteria on which to base the interpretation of our results and power 
future clinical trials.   
To achieve Aim 2 and determine the associations among sensory organization 
strategies, neuromuscular mechanisms, and secondary measures following ankle joint 
mobilization and plantar massage interventions, we will calculate associations at 
baseline, at the post-test, and among change scores.  These associations will be 
calculated using Pearson Correlation Coefficients that will be interpreted as: ≤0.29 as 
negligible, 0.30-0.49 as low, 0.50-0.69 as moderate, 0.70-0.89 as high, and ≥0.9 as a 
very high correlation.135  The models will then be adjusted for identified covariates using 
a general linear model and an exploratory alpha level of 0.10.  We anticipate 
associations that will provide insights about how to specifically leverage the manual 
therapies mechanisms to target specific neuromuscular impairments and biomechanical 
deficits associated with CAI.   
All experimental conditions are detailed to ensure reproducibility and the proposed 
analytic plan ensures unbiased treatment and interpretation of the data.  We are 
committed to full transparency in reporting the results and to making the data available 
upon request for unbiased review. 
To explore how individual response variability influences plausible neuromuscular 
mechanisms, we will use a Bayesian statistical approach.71, 94144, 145  More specifically, 
we will determine how patient characteristics (e.g. age, height) and baseline measures 
influence the probability of having a meaningful change in % Modulation and other 
neuromuscular mechanisms.  Predicting treatment response with only demographic and 
baseline data would suggest that the neuromuscular mechanism(s) of ankle joint 
mobilization and plantar massage may be modulated by the patient’s sensorimotor 
constraints.   
13 Data Management 
Data will be collected both in hard copy & electronically.  All computers in the research 
laboratories are password protected.  As soon as feasible, the PIs will transfer the, 
already de-identified, electronic data to Sharepoint.  In order to protect the integrity of 
the original data files, copies will be made to be used for data manipulation.  Any data 
file that is amended, cleaned, or updated will be given a new name with the 
corresponding name of the original file followed by _modified and dated with the 
month_, day_, and 2-digit year it was modified (i.e. IC01_trial_1_modified_10_11_18). 
Additionally, data collected in hard copy will be de-identified and transferred to 
electronic data on Sharepoint as soon as possible.  All offices are locked and the 
personal computers in the PI’s respective offices are password protected.  Additionally, 
hard copy files that have yet to be transferred will be stored in a locked cabinet.  The 

APPENDEX 1: Study Protocol 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 80 of 157 
Sharepoint data will only consist of de-identified data.  Further details can be seen in the 
Confidentiality section below. 
 
Data Entry, Procedures, Flow, and Checks 
1. The programs and data entry sequence that will be used to record the data 
entered into an electronic database system are as follows: 
i. The research team will electronically record the data from the hard copy 
forms collected from the participants. 
ii. Upon completion of data entry, the data will then be transferred to 
Sharepoint.  The website account will be maintained at the University of 
North Carolina Chapel Hill and only the PIs will have access to the site 
using a unique user name and password. 
2. All hard copy data will be transferred to electronic files and a secure electronic 
database (Sharepoint) by members of the research team.  The data will be 
entered in/transferred to the electronic databases within 5 business days of data 
capture. 
3. Process for data checks.   
i. Based on data entry plan, this will be a single data entry check.  In order 
to ensure consistency of data entry, the research team will discuss and 
inspect data entry in the web-based electronic database in their monthly 
meetings.   
ii. Any issues associated with data entry will be resolved during these 
meetings.   
iii. In order to ensure consistency of changes, the research team will also 
modify the files and denote the change in the title of the spreadsheet (e.g. 
UNC_STARS_database_revised_11_1_18). 
4. Audit and tracking system for evaluating data flow and data entry. 
i. The research team will discuss the flow of the database and any data 
entry issues that they may have in their meetings.   
ii. In the event that the investigators run into an item that does not produce 
the desired results (e.g. a question that could be worded more clearly for 
participants on a form), the PIs will discuss it, come up with a strategy to 
address it, implement the strategy, and ensure that only the most revised 
version of the item in question is used.   
5. Description of data transmission from the databases to the statistical analysis 
package IBM SPSS Statistics (SPSS). 
i. All data from the secure web-based electronic database (Sharepoint) will 
be formatted to transfer directly into SPSS via copy and paste. 

APPENDEX 1: Study Protocol 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 81 of 157 
ii. Electronic trials, when appropriate, will be analyzed using MatLab.  The 
analyzed output in MatLab has been designed to be directly pasted into an 
Sharepoint database. 
1. During MatLab analyses, all results will be immediately pasted into 
the Sharepoint database. 
iii. The research team will discuss and review the SPSS database in their 
monthly phone meetings to ensure consistency of data. 
 
14 Safety Issues 
Expected risks to the subject are as follows: 
• Rare (<1%) of mild skin irritation due to taping the kinematic markers sensors to 
the skin. This risk will be minimized by a member of the research team removing 
the tape with care. 
• Rare (<1%) of seizure.  Overall estimate is that seizure risk is < 1:1000 (0.1%) 
and this risk is associated with Repetitive TMS, which will not be conducted in 
this investigation.   
• Infrequent (5%) of head and neck aches, hearing shifts, and fainting during 
and/or immediately after TMS.  The research team will disclose this information 
to the participant prior to enrollment and remind them prior to testing.  This is 
attributed to local stimulation of muscles and nerves near the stimulating coil, a 
tapping of the scalp by the coil during discharge, and wearing a tight-fitting swim 
cap. Other stimulation-related effects include teeth aches, facial twitches, odd 
taste in mouth, and discomfort from blinking and twitches of scalp muscles.  All 
symptoms resolve after cessation of the TMS protocol. TMS may induce fainting 
or feelings of lightheadedness or dizziness.  If symptoms of dizziness, 
lightheadedness, or feeling faint occur, the TMS protocol will be stopped. The 
subject will be allowed to lay down or put their head down to prevent fainting. If 
subjects faint, they must not be allowed to leave the laboratory until fully 
recovered. TMS produces a loud clicking sound when a current is passed 
through the stimulation coil. This loud click can result in temporary ringing in the 
ear and subclinical auditory threshold shifts. To prevent transient hearing 
threshold shifts due to TMS, subjects and investigators will be wear earplugs 
during TMS.  
• Infrequent (10%) of itching/scratching of the scalp during EEG testing.  Care will 
be taken during the application of the EEG cap, electrodes to measure brain 
wave activity, and the insertion of the gel. 
These risks are considered to be minimal and are addressed in the protocol and 
consent form.” 
 
Because the manual therapies can cause mild discomfort (<1%), all participants 
will be monitored at each treatment session during the study.  The manual 
therapies are designed to be pain free and are commonly applied in clinical 

APPENDEX 1: Study Protocol 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 82 of 157 
scenarios but because of the rare risk of discomfort, participants will be 
monitored for expected and unexpected AEs related to the manual therapies. 
 
For the protocol, all AEs will be reported promptly based on the requirements of the 
IRB.  Dr. Wikstrom will follow the procedures for reporting AEs.  Dr. Wikstrom will report 
the AE to the UNC IRB as well as the IMC and NCCIH within the required reporting 
periods.   
 
15 Confidentiality 
All participants will be coded upon entry into the investigation.  The master sheet (listing 
names with code numbers) will be stored on a password protected computer in the 
primary investigator's personal office for each site.  Coded data sheets will be kept in a 
locked filing cabinet in the office of the primary investigator.  As data sheets are transfer 
to electronic files for data analysis, the electronic records associated with the 
investigation will also be coded and de-identified, and kept on the password protected 
computed in a separate folder/location.  All documents and data collected from 
participants in this study must be retained for three years in accordance to IRB protocol.   
 
16 IRB Approval Procedures 
IRB approval (Appendix 19) will be maintained.  The PI will prepare the respective 
documentation to document consent (Appendix 6 and 18) in consultation with NCCIH.   
 
17 Informed Consent Procedures 
Participants interested in the study will contact the primary investigator to learn more 
about the study and set up an initial meeting.  During that meeting, potential participants 
will be given eligibility questionnaires to complete (based on partial waiver of consent as 
approved by the IRB).  If eligible, participants will be schedule to come in and meet with 
the PI to review the informed consent document and begin the first test session.  Any 
questions will be answered before any data collection begins.    
If a participant is determined to be ineligible for the investigation then the data collected 
(to determine eligibility) will be immediately destroyed.  Specifically, the AII, FAAM, 
FAAM-S and treatment expectation data sheets will be shreeded.  No other data will be 
collected prior to determining eligibility and the potential participant reading and signing 
the informed consent document. 
 
18 Plans for and Responsibilities of the Independent Monitoring Committee 
An Independent Monitoring Committee (IMC) will be appointed prior to the initiation of 
the study in consultation with the NCCIH. 
 

APPENDEX 1: Study Protocol 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 83 of 157 
18.a  Independence of the IMC 
To remain objective, the IMC must maintain independence from the study.  Accordingly, 
the IMC will not be directly or indirectly involved in the conduct of the study and does 
not have scientific, proprietary, financial or other interests that may affect independent 
decision-making.  
Annually the IMC will report to the NCCIH Program Officer that no conflict of interest 
exists between them, the PIs or any study personnel. Such a statement may also be 
required prior to each review.  
 
18.b  Executive Secretary 
Dr. Wikstrom will serve as the executive secretary to facilitate the distribution of reports.  
All communication between the study staff and the IMC will be facilitated by Dr. 
Wikstrom with NCCIH copied on the correspondence. 
 
18.c  Safety Monitoring Plan 
This protocol will be continuously monitored in real-time by the principal investigator for 
adverse events (AEs). Participants will be discharged from the initial treatment session 
with specific self-monitoring guidelines (See appendix #21) and instructed to call 
immediately for any concerning signs or symptoms throughout the rest of the treatment 
period.  
The full data and safety monitoring plan can be seen in Part M of the MOOP. 
 
18.d  Safety Reports 
At predetermined intervals, Dr. Wikstrom will prepare adverse event reports to be 
reviewed by the IMC.  The adverse events are reported in aggregate by treatment 
groups, as requested.  Serious adverse events are generally reported as they occur.  
The tables for reporting to the IMC are attached to this document.  See Appendix 23. 
 
18.e  Roles and Responsibilities of the IMC 
The IMC provides independent safety monitoring in a timely fashion to assure patient 
safety and study quality.  
At the beginning of the trial, the IMC will review the manual of operating procedures, 
containing the study protocol, study forms, and safety monitoring plan, for scope and 
comprehensiveness. The monitoring plan should delineate data preparation functions, 
the review process, and the role of the IMC. The monitoring plan also specifies the 
contents and format of the reports, their frequency, and triggers for ad hoc reviews. 
Stopping rules, if appropriate, should outline the conditions under which a study may be 
stopped prematurely. The IMC may suggest modifications to the protocol, the 
monitoring plan and the reports that will routinely be prepared by the PI.   

APPENDEX 1: Study Protocol 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 84 of 157 
The primary focus of the IMC’s activity is participant safety.  The IMC reviews adverse 
event reports prepared by the PI.   
Serious adverse events are generally reviewed as they occur. The IMC will notify the 
NCCIH if a pattern of events occurs and will suggest prevention measures (e.g., 
modifying the protocol to require frequent measurement of laboratory values predictive 
of the event). 
For unexpected and/or related serious adverse events, the IMC will contact the NCCIH 
Program representative. In addition, the IMC may request individual participant records, 
including objective data, subjective questionnaires, and other study related data, to 
evaluate these events against the known safety profile of the study treatment and the 
disease.  
The IMC may recommend actions including modifying or terminating the study.   
In addition to safety monitoring, the IMC may review enrollment data, demographic 
information, retention status, and other reports prepared by Dr. Wikstrom that describe 
study performance and progress. The IMC will provide a report to NCCIH that describes 
study safety, progress and performance and provides recommendations regarding safe 
continuation or early termination of the trial. 
The monitoring plan may require the IMC to evaluate the general performance of the 
study, including periodic assessment of participant recruitment, accrual and retention, 
protocol adherence, and data quality and timeliness. The IMC may also review any 
interim analyses to ensure that once the objectives of the study are met, outcome 
differences are detected or stopping rule thresholds are reached, the study will 
conclude.  
Confidentiality must be maintained throughout all phases of the trial, including 
monitoring, preparation of interim results, review, and response to monitoring 
recommendations.  Thus, the IMC should not receive participant identifiers, will maintain 
study confidentiality and will not share data. 
After review and evaluation of the specified periodic reports prepared by the PI, the IMC 
prepares a summary cover letter, according to pre-specified criteria, for submission to 
the NCCIH. The letter provides comments on the report, discusses any concerns or 
suggestions for change, and recommends to NCCIH continuation or cessation of the 
trial. 
 
 
 
 

APPENDEX 1: Study Protocol 
NMofMTinCAI Manual of Operating Procedures 
Version 1 
 
Page 85 of 157 
IMC Review Instructions 
 
1. The IMC Report will be distributed to the designated IMC by the PI. 
2. The IMC will review the report and use the below checklist to review 
performance, safety and efficacy of the study, and/or provide any additional 
comments pertaining to his/her review.  In addition, the IMC should specify their 
recommendation to continue or stop the study no later than 2-weeks after the 
report has been delivered. 
3. The IMC will return the checklist to the NCCIH for distribution to the PI.   
4. Dr. Wikstrom will distribute the IMC’s comments to the NCCIH (Appendix 23). 
 
 
 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
Appendix 2: Balance Questionnaire 
 
Participant Number________________________________  Date_____________________ 
 
Balance History Questionnaire (Version 1, Dec 2017) 
 
1. Have you injured your foot, ankle, knee or hip of either leg in the past six months?   
______ YES  
 
 
______ NO 
 
2. Have you ever had surgery on either leg? 
______ YES  
 
 
______ NO 
 
3. Have you had an injury or illness that affects your ability to balance in the past six months? 
______ YES  
 
 
______ NO 
 
4. Do you presently have a head cold or sinus problems that affect your ability to balance? 
______ YES  
 
 
______ NO 
 
5. Do you have any history of Vertigo or balance problems? 
______ YES  
 
 
______ NO 
 
6. Do you have any vision problems that affect your ability to balance? 
______ YES  
 
 
______ NO 
 
7. Do you have any nerve problems in your legs or any decrease or increase of sensation in your 
legs or feet? 
______ YES  
 
 
______ NO 
 
8. Do you have any history of circulation problems in your legs? 
______ YES  
 
 
______ NO 
 
9. Do you have Diabetes? 
______ YES  
 
 
______ NO
 
 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
Appendix 3: Ankle Instability Instrument 
Participant Number: ______________________  Date: ______________________ 
Ankle Instability Instrument  (Version 1, Dec 2017) 
Instructions 
This form will be used to categorize your ankle instability. Please fill out the form completely. If you have 
any questions, please ask the administrator of the survey. Please mark the ○ completely.  Thank you for 
your participation. 
1. Have you ever sprained an ankle? 
Right 
○Yes 
○ No 
 
Left 
○ Yes 
○ No 
2. Have you ever seen a doctor for an ankle sprain? 
Right 
○ Yes 
○ No 
 
Left 
○ Yes 
○ No 
3. Did you ever use a device (such as crutches) because you could not bear weight due 
to an ankle sprain? 
Right 
○ Yes 
○ No 
 
Left 
○ Yes 
○ No 
If yes, 
3a. In the most serious case, how long did you need the device? 
Right:  ○ 1-3 days   ○ 4-7 days   ○ 1-2 weeks   ○ 2-3 weeks   ○ >3weeks 
Left:    ○ 1-3 days   ○ 4-7 days   ○ 1-2 weeks   ○ 2-3 weeks   ○ >3weeks 
4.  Have you ever experienced a sensation of your ankle “giving way”? 
Right 
○ Yes 
○ No 
If yes, 
Left 
○ Yes 
○ No 
4a. When was the last time your ankle “gave way”? 
Right: ○ <1 month   ○ 1-6 months ago   ○ 6-12 months ago   ○ 1-2 years ago   ○ >2 yrs  
Left:   ○ <1 month   ○ 1-6 months ago   ○ 6-12 months ago   ○ 1-2 years ago   ○ >2 yrs  
5.  Does your ankle ever feel unstable while walking on a flat surface? 
Right 
○ Yes 
○ No 
 
Left 
○ Yes 
○ No 
6.  Does your ankle ever feel unstable while walking on uneven ground? 
Right 
○ Yes 
○ No 
 
Left 
○ Yes 
○ No 
7.  Does your ankle ever feel unstable during recreational or sport activity? 
Right 
○ Yes 
○ No 
○ N/A 
 
Left 
○ Yes 
○ No 
○ N/A 
8.  Does your ankle ever feel unstable going up stairs? 
Right 
○ Yes 
○ No 
 
Left 
○ Yes 
○ No 
9.  Does your ankle ever feel unstable going down stairs? 
Right 
○ Yes 
○ No 
 
Left 
○ Yes 
○ No 
 
 
 
 
 
 
 
 
 
 
Right  
Left 
How many times have you sprained your ankle in the past?      
  
 
_____  
_____ 
How long has it been since your last significant ankle sprain (in months)?  
 _____  
_____ 
How many times in the past 3 months has your ankle felt like it “gives way”? 
 _____  
_____ 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
 
Appendix 4: Foot & Ankle Ability Measure 
Participant Number: ________________________   
 
Date:________________ 
 
Foot and Ankle Ability Measure (FAAM) (Version 1, Dec 2017) 
Please answer every question with one response that most closely describes to your condition within the 
past week.  If the activity in question is limited by something other than your foot or ankle mark not 
applicable (N/A). 
 
Side 
No 
difficulty 
Slight 
Difficulty 
Moderate 
Difficulty 
Extreme 
Difficulty 
Unable 
to do 
N/A 
Standing 
Right 
□ 
□ 
□ 
□ 
□ 
□ 
 
Left 
□ 
□ 
□ 
□ 
□ 
□ 
Walking on Even 
Ground 
Right 
□ 
□ 
□ 
□ 
□ 
□ 
 
Left 
□ 
□ 
□ 
□ 
□ 
□ 
Walking on even 
ground w/o shoes 
Right 
□ 
□ 
□ 
□ 
□ 
□ 
 
Left 
□ 
□ 
□ 
□ 
□ 
□ 
Walking up hills 
Right 
□ 
□ 
□ 
□ 
□ 
□ 
 
Left 
□ 
□ 
□ 
□ 
□ 
□ 
Walking down hills 
Right 
□ 
□ 
□ 
□ 
□ 
□ 
 
Left 
□ 
□ 
□ 
□ 
□ 
□ 
Going up stairs 
Right 
□ 
□ 
□ 
□ 
□ 
□ 
 
Left 
□ 
□ 
□ 
□ 
□ 
□ 
Going down stairs 
Right 
□ 
□ 
□ 
□ 
□ 
□ 
 
Left 
□ 
□ 
□ 
□ 
□ 
□ 
Walking on uneven 
ground 
Right 
□ 
□ 
□ 
□ 
□ 
□ 
 
Left 
□ 
□ 
□ 
□ 
□ 
□ 
Stepping up and 
down curbs 
Right 
□ 
□ 
□ 
□ 
□ 
□ 
 
Left 
□ 
□ 
□ 
□ 
□ 
□ 
Squatting 
Right 
□ 
□ 
□ 
□ 
□ 
□ 
 
Left 
□ 
□ 
□ 
□ 
□ 
□ 
Coming up on toes 
Right 
□ 
□ 
□ 
□ 
□ 
□ 
 
Left 
□ 
□ 
□ 
□ 
□ 
□ 
Walking initially 
Right 
□ 
□ 
□ 
□ 
□ 
□ 
 
Left 
□ 
□ 
□ 
□ 
□ 
□ 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
Walking <5 mins 
Right 
□ 
□ 
□ 
□ 
□ 
□ 
 
Left 
□ 
□ 
□ 
□ 
□ 
□ 
Walking about 10 
minutes 
Right 
□ 
□ 
□ 
□ 
□ 
□ 
Left 
□ 
□ 
□ 
□ 
□ 
□ 
Walking 15 minutes 
or greater 
Right 
□ 
□ 
□ 
□ 
□ 
□ 
 
Left 
□ 
□ 
□ 
□ 
□ 
□ 
 
Because of your foot and ankle how much difficulty do you have with:  
Standing 
Side 
No 
difficulty 
Slight 
Difficulty 
Moderate 
Difficulty 
Extreme 
Difficulty 
Unable 
to do 
N/A 
Home responsibilities 
Right 
□ 
□ 
□ 
□ 
□ 
□ 
 
Left 
□ 
□ 
□ 
□ 
□ 
□ 
Activities of daily living 
Right 
□ 
□ 
□ 
□ 
□ 
□ 
 
Left 
□ 
□ 
□ 
□ 
□ 
□ 
Personal Care 
Right 
□ 
□ 
□ 
□ 
□ 
□ 
 
Left 
□ 
□ 
□ 
□ 
□ 
□ 
Light to moderate work 
Right 
□ 
□ 
□ 
□ 
□ 
□ 
 
Left 
□ 
□ 
□ 
□ 
□ 
□ 
Heavy work 
(push/pulling,  
climbing, carrying) 
Right 
□ 
□ 
□ 
□ 
□ 
□ 
Left 
□ 
□ 
□ 
□ 
□ 
□ 
Recreational activities 
Right 
□ 
□ 
□ 
□ 
□ 
□ 
 
Left 
□ 
□ 
□ 
□ 
□ 
□ 
 
How would you rate your current level of function during your usual activities of daily living from 0 to 100 
with 100 being your level of function prior to your foot or ankle problem and 0 being the inability to 
perform any of your usual daily activities? 
Right:  
.0 % 
Left:  
  
.0 % 
Total FAAM ADL Score:  Right: _________ 
Left: _________  (Investigators Only) 
 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
FAAM Sports Scale (Version 1, Dec 2017) 
 
Because of your foot and ankle how much difficulty do you have with: 
 
 
Side 
No 
difficulty 
Slight 
Difficulty 
Moderate 
Difficulty 
Extreme 
Difficulty 
Unable 
to do 
N/A 
Running 
Right 
□ 
□ 
□ 
□ 
□ 
□ 
 
Left 
□ 
□ 
□ 
□ 
□ 
□ 
Jumping 
Right 
□ 
□ 
□ 
□ 
□ 
□ 
 
Left 
□ 
□ 
□ 
□ 
□ 
□ 
Landing 
Right 
□ 
□ 
□ 
□ 
□ 
□ 
 
Left 
□ 
□ 
□ 
□ 
□ 
□ 
Starting and stopping 
quickly 
Right 
□ 
□ 
□ 
□ 
□ 
□ 
 
Left 
□ 
□ 
□ 
□ 
□ 
□ 
Cutting/lateral 
movements 
Right 
□ 
□ 
□ 
□ 
□ 
□ 
 
Left 
□ 
□ 
□ 
□ 
□ 
□ 
Low impact activities 
Right 
□ 
□ 
□ 
□ 
□ 
□ 
 
Left 
□ 
□ 
□ 
□ 
□ 
□ 
Ability to perform 
activity with your 
normal technique 
Right 
□ 
□ 
□ 
□ 
□ 
□ 
Left 
□ 
□ 
□ 
□ 
□ 
□ 
Ability to participate in 
your desired sport as 
long as you would like 
Right 
□ 
□ 
□ 
□ 
□ 
□ 
Left 
□ 
□ 
□ 
□ 
□ 
□ 
How would you rate your current level of function during your sports related activities from 0 to 100 with 
100 being your level of function prior to your foot or ankle problem and 0 being the inability to perform any 
of your usual daily activities? 
Right:  
.0 % 
Left:  
  
.0 % 
 
Overall, how would you rate your current level of function? 
Right:  
􀀀 Normal 􀀀Nearly normal 􀀀 Abnormal 􀀀 Severely abnormal 
Left: 
 
􀀀 Normal 􀀀Nearly normal 􀀀 Abnormal 􀀀 Severely abnormal 
 
Total FAAM Sport Score:  Right: _________ 
Left: _________   
(Investigators Only) 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
Appendix 5: Treatment Expectations Questions 
 
 
Manual therapies will improve my CAI related impairments? 
 
1 
 
2 
 
3 
 
4 
 
5 
No Confidence 
 
 
Neutral 
 
 
 
Very Confident 
 
 
 
 
Ankle joint mobilizations will improve my CAI related impairments? 
 
1 
 
2 
 
3 
 
4 
 
5 
No Confidence 
 
 
Neutral 
 
 
 
Very Confident 
 
 
 
 
Plantar massage will improve my CAI related impairments? 
 
1 
 
2 
 
3 
 
4 
 
5 
No Confidence 
 
 
Neutral 
 
 
 
Very Confident 
 
 
 
 
 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
 
Appendix 6: Informed Consent Documents 
 
University of North Carolina at Chapel Hill 
Consent to Participate in a Research Study 
Adult Participants  
 
Consent Form Version Date: 10-4-2017 
IRB Study # 17-2655 
Title of Study: Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients 
Principal Investigator: Erik Wikstrom 
Principal Investigator Department: Exercise and Sport Science 
Principal Investigator Phone number: (919) 962-2260 
Principal Investigator Email Address: ewikstro@email.unc.edu 
Funding Source and/or Sponsor: National Institutes of Health: National Center for Complimentary and 
Integrative Health  
_________________________________________________________________ 
 
What are some general things you should know about research studies? 
You are being asked to take part in a research study.  To join the study is voluntary. 
You may choose not to participate, or you may withdraw your consent to be in the study, for any reason, without 
penalty. 
 
Research studies are designed to obtain new knowledge. This new information may help people in the 
future.   You may not receive any direct benefit from being in the research study. There also may be risks to 
being in research studies. Deciding not to be in the study or leaving the study before it is done will not affect 
your relationship with the researcher, your health care provider, or the University of North Carolina-Chapel Hill. If 
you are a patient with an illness, you do not have to be in the research study in order to receive health care. 
 
 
Details about this study are discussed below.  It is important that you understand this information so that you 
can make an informed choice about being in this research study.  
 
You will be given a copy of this consent form.  You should ask the researchers named above, or staff members 
who may assist them, any questions you have about this study at any time. 
 
What is the purpose of this study? 
Lateral ankle sprains are the most common injury experienced by those who are physically active and recurrent 
disability, defined as chronic ankle instability, associated with these injuries is extremely common.  In this study, 
we aim to determine the neuromuscular mechanisms responsible for the benefits that chronic ankle instability 
patients experience after receiving ankle joint mobilization and plantar massage manual therapy treatments.  By 
understanding the mechanisms responsible for the observed improvements, we hope to optimize treatment 
protocols for chronic ankle instability patients and subsequently reduce the long-term negative consequences 
and slow the development of the early onset post-traumatic osteoarthritis associated with the condition. 
The purpose of this research study is to determine what neuromuscular changes occur following a 2-week 
treatment of ankle joint mobilization and plantar massage in people with chronic ankle instability (CAI).  
 
You are being asked to be in the study because you have chronic ankle instability, based on the answers you 
provided to the eligibility questionnaire. 
 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
Are there any reasons you should not be in this study? 
You should not be in this study if you do not have chronic ankle instability.  You should also not be in this study 
if you have known vestibular and vision problems, acute lower extremities and head injuries (<6 weeks), chronic 
musculoskeletal conditions known to affect balance (e.g., ACL deficiency) and a history of ankle surgeries to fix 
internal derangements.  You should also not be in this study if you have metal implants anywhere in the head 
(except in the mouth), pacemakers, implantable medical pumps, ventriculo-peritoneal shunts, intracardiac lines, 
a history of seizures, have had a stroke, or had a serious head trauma.   
 
How many people will take part in this study? 
There will be approximately 60 people in this research study. 
 
 
How long will your part in this study last? 
In addition to our previous interactions, you will be asked to complete three testing sessions that will last 
approximately 3.0 hours each.  Between the first and second test session, you will attend 5 treatment sessions 
that are 5-minutes each.   
 
What will happen if you take part in the study? 
 
The following test will be completed once before and twice after the intervention.   
■  Ankle joint position sense.  You will sit at the edge of a table and be asked to move your ankle to two different 
positions.  Each position will be shown to you before you will be asked to return to that position with your eyes 
closed.  You will return to each position 3 times. 
■  Plantar light-touch threshold.  You will sit at the edge of the table with your eyes closed.  We will apply a 
device, much like fishing line, to determine how sensitive specific points on the bottom of your foot are.  We will 
repeatedly ask you if you can feel the device we have applied to your foot.  We will continue to do this until we 
determine the sensitivity of both points on your foot.   
■  Hoffman reflex (H-Reflex).  You will lie on a table and the research team will place electrodes over several 
muscles on your lower leg and on the back of your knee.  To apply these electrodes, we will need to clean 
specific areas of your leg and we may have to shave a small portion of leg hair in each area, if applicable.  We 
will then apply an electrical stimulus to the back of your knee to cause a small muscle contraction in your 
muscles.  Some people find this to be slightly uncomfortable.  We will continue to apply these stimuli until we 
can determine can maximize the muscle contraction.  This usually takes about 7-10 stimuli. 
■  Transcranial Magnetic Stimulation (TMS).  You will be seated in a chair and have your foot resting on a 
platform.  This test, is similar to the H-Reflex test except that we deliver the electrical stimulus to a specific 
portion of your brain that tells the muscles to contract.  We will first map your brain to determine the area that 
causes the strongest reaction while you perform a small muscle contraction.  We will then deliver several more 
electrical stimuli (8-10) to determine the lowest level of stimuli that can still elicit a strong muscle contraction.  
Each stimuli will produce a loud click/pop and thus we will ask you to wear ear plugs.  For this test, we will also 
place several electrodes on your muscles and will have to clean and potentially shave those areas.  Some 
people get mild head and neck aches during this testing procedure but those go away shortly after the 
procedure is over.  If you have a history of fainting, please tell the research team as we will want to monitor you 
more closing during testing as there is a slight risk of faintly during TMS, especially if you have a history of 
fainting. 
■  Cortical Activity.  You will be asked to complete single limb balance assessments with eyes open and closed 
while wearing an EEG cap which measures your brain waves.  Each trial will last no more than 20 seconds and 
you will complete 3 trials with eyes open and 3 trials with eyes closed.  While preparing for this test, we will 
place a cap on your head and then place a gel in each of the cap’s electrodes.  Placing the gel may result in 
some light scratching of the scalp and may be itchy during and for a short time after the testing.   

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
■  Biomechanics.  You will be asked to complete a walking and jump landing task.  For both, we will put a series 
of small spheres on various landmarks on your body (e.g. hip, knee, shoulder, etc).  During walking trials, you 
will walk at a comfortable speed over a 15 foot space in the lab at least 5 times. For the jump landing you will 
jump down from a 12 inch box that is 50% of your height away from the target landing area.  As soon as you 
land, you will immediately jump as high as you can.  At least five trials will be completed.  You will be able to see 
demonstrations and practice each task.   
■  Balance & Range of Motion.  . To examine ankle range of motion, you will be barefoot, face a wall, and place 
the leg being tested slightly in front of the opposite ankle. You will then lunge forward until your knee touches 
the wall while your heel remains in contact with the ground. You will gradually be moved back from the wall until 
your knee is no longer able to make contact with the wall or your heel is no longer making contact with the 
ground. This test will be repeated 6 times, 3 times per leg. During this test you will have a small device strapped 
to your lower leg to measure range of motion.  To examine your balance, you will complete three balance trials 
per leg.  For this test, you will stand on a single leg for 20 seconds with your eyes closed and your hands on 
your hips.  While balancing, you should stand quietly and make any necessary adjustments (if balance is lost) 
and return to the initial testing position as quickly as possible. 
 
 
After completion of baseline testing, you will be placed into one of three groups: ankle mobilization, plantar 
massage, control.  Assignment is random, so no one will know what your group assignment will be ahead of 
time.  All interventions are to a single limb and require 6, 5-minute treatments over the next 2-weeks.  The first 
treatment session will be today, after completing the baseline testing.  If you are assigned to the mobilization 
group will receive 2, 2-minute bouts during each session with a one minute break.  We will grasp your ankle and 
lower leg.  Then we will move your ankle back and forth (front to back) while holding your lower leg still.  If you 
are assigned to the massage group, you will receive 2, 2-minute bouts with a 1-minute break between sets 
during each session.  The massage will be to the entire bottom of your foot.  If you are assigned to the control 
group, you will receive no treatment during the entire 2-week intervention period.  Please continue regular 
physical activity habits and daily routines over the course of 2-week intervention.  At the end of the two weeks, 
we will schedule another test session were we will repeat the baseline testing.  Finally, one month after the final 
treatment session, we will schedule the final test session and again repeat the same tests. 
The research would also like to keep your contact information, without links to your study ID, in case you are 
eligible for future investigations.  You do not need to let us keep your contact information to participate in this 
study.   
Can we keep your contact information (Circle one)? 
YES 
NO 
*If you later change your mind and wish to withdraw your contact information, please contact Dr. Erik 
Wikstrom at ewikstro@email.unc.edu and your contact information will be removed from the database.* 
 
What are the possible benefits from being in this study? 
Research is designed to benefit society by gaining new knowledge. The benefits to you from being in this study 
may be an improvement in range of motion at the ankle, better balance, and better function because of 
decreased ankle instability symptoms if you are assigned to the mobilization or massage groups.  These 
benefits may last at least a month after the intervention. 
  
 
What are the possible risks or discomforts involved from being in this study? 
The risks associated with participation in this research study are minimal and highly unlikely.  While the potential 
exists for you to be mildly sore after the treatments, this is highly unlikely because you are a young individual. 
You may experience some itching and scratching at the scalp while we assess cortical activity (EEG testing).  
You may also experience some irritation on your skin where we place the sphered to do the biomechanics 
testing but this would be rare.  Seizure is a very rare (0.01%) during the TMS testing.  This risk is associated 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
with a test protocol that we will not be undertaking in this investigation but please let the research team know if 
you have a history of seizures, or serious head trauma.  There is also a chance that you will have a mild 
head/neck ache, may become faint, or having a mild temporary hearing shift during the TMS testing.  Please let 
the research team know if you have a history of fainting.  To prevent hearing shifts, we will ask that you wear 
earplugs.  The head and neck aches fade quickly after the testing session is done.   
There may be uncommon or previously unknown risks. You should report any problems to the researcher. 
 
If you choose not to be in the study, what other treatment options do you have? 
None. This study is not part of medical care.  Therefore, if you do not wish to be in this study, you will not 
receive the treatments.       
 
What if we learn about new findings or information during the study?  
You will be given any new information gained during the course of the study that might affect your willingness to 
continue your participation.  
 
How will information about you be protected? 
Participants will not be identified in any report or publication about this study. Although every effort will be made 
to keep research records private, there may be times when federal or state law requires the disclosure of such 
records, including personal information.  This is very unlikely, but if disclosure is ever required, UNC-Chapel Hill 
will take steps allowable by law to protect the privacy of personal information.  In some cases, your information 
in this research study could be reviewed by representatives of the University, research sponsors, or government 
agencies (for example, the FDA) for purposes such as quality control or safety. 
 
What will happen if you are injured by this research? 
All research involves a chance that something bad might happen to you.  This may include the risk of personal 
injury. In spite of all safety measures, you might develop a reaction or injury from being in this study. If such 
problems occur, the researchers will help you get medical care, but any costs for the medical care will be billed 
to you and/or your insurance company. The University of North Carolina at Chapel Hill has not set aside funds 
to pay you for any such reactions or injuries, or for the related medical care. You do not give up any of your legal 
rights by signing this form. 
 
 
What if you want to stop before your part in the study is complete? 
You can withdraw from this study at any time, without penalty.  The investigators also have the right to stop your 
participation at any time. This could be because you have had an unexpected reaction, or have failed to follow 
instructions, or because the entire study has been stopped.   
 
Will you receive anything for being in this study? 
You will be compensated a total of $250 for participating in this study.  At the conclusion of the first post test 
(after treatment), you will receive $100.  At the conclusion of the second post-test, you will receive $150.  
Withdrawal from the study prior to these time points will result in the forfeiture of the scheduled compensation. 
 
Will it cost you anything to be in this study? 
It will not cost you anything to be in this study.  
 
What if you are a UNC student? 
You may choose not to be in the study or to stop being in the study before it is over at any time.  This will not 
affect your class standing or grades at UNC-Chapel Hill.  You will not be offered or receive any special 
consideration if you take part in this research. 
 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
What if you are a UNC employee? 
Taking part in this research is not a part of your University duties, and refusing will not affect your job.  You will 
not be offered or receive any special job-related consideration if you take part in this research. 
 
Who is sponsoring this study? 
This research is funded by the National Institutes of Health. This means that the research team is being paid by 
the sponsor for doing the study.  The researchers do not, however, have a direct financial interest with the 
sponsor or in the final results of the study. 
 
What if you have questions about this study? 
You have the right to ask, and have answered, any questions you may have about this research. If you have 
questions about the study (including payments), complaints, concerns, or if a research-related injury occurs, you 
should contact the researchers listed on the first page of this form. 
 
A description of this clinical trial will be available on www.clinicaltrials.gov, as required by U.S. Law. This website 
will not include information that can identify you. At most, the website will include a summary of the results. You 
can search this website at any time. 
 
What if you have questions about your rights as a research participant? 
All research on human volunteers is reviewed by a committee that works to protect your rights and welfare.  If 
you have questions or concerns about your rights as a research subject, or if you would like to obtain 
information or offer input, you may contact the Institutional Review Board at 919-966-3113 or by email to 
IRB_subjects@unc.edu. 
  
Participant’s Agreement: 
 
I have read the information provided above.  I have asked all the questions I have at this time.  I voluntarily 
agree to participate in this research study. 
  
 
______________________________________________________ 
Signature of Research Participant 
 
____________________ 
Date 
 
______________________________________________________ 
Printed Name of Research Participant 
  
 
______________________________________________________ 
Signature of Research Team Member Obtaining Consent 
 
____________________ 
Date 
 
______________________________________________________ 
Printed Name of Research Team Member Obtaining Consent 
  
 
 
 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
Appendix 7: Documenting the Consent Process Form 
Protocol Number and Title: 
 
PI/Site Name: 
 
Participant/Subject Name: 
 
Date: 
 
Consent Forms (CFs) reviewed: 
 Main Study CF, Version/Date: 
 
 Other CF, Specify: 
 Version/Date: 
 
 Other CF, Specify: 
 Version/Date: 
 
Language of CF(s) reviewed: 
 
 English 
 Spanish 
 Other, Specify: 
 
Study Staff Member(s) Conducting CF discussion: 
 
Was time allowed to ask/answer questions?  
 Yes 
 No 
If not, please explain: 
 
Was a copy of the signed CF(s) provided to the study subject? 
 Yes 
 No 
If not, please explain: 
 
Was/were the CF(s) signed prior to initiation of study procedures? 
 Yes 
 No 
If not, please explain: 
 
Was/were a copy of the signed CF(s) provided to the subject? 
 Yes 
 No 
If not, please explain: 
 
Additional Notes: 
 
 
___________________________________ 
________________________ 
Signature of person obtaining consent 
Date 
 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
 
Appendix 8: Protocol Deviation Form & Log 
Protocol ID/Number: 
   
Site 
Name/Number:    
Protocol Title 
(Abbreviated): 
   
Principal Investigator: 
   
Page number 
[1]: 
   
Ref 
No. 
Subjec
t 
ID 
Date of 
Deviatio
n 
Date 
Identifie
d 
Deviation Description 
Dev. 
Type 
[2] 
Result
ed in 
AE? 
Did 
Subject 
Continue 
in Study? 
Meets IRB 
Reporting 
Req. 
(Yes/No) 
IRB 
Reporting 
Date 
1 
   
   
   
   
   
   
   
   
   
2 
   
   
   
   
   
   
   
   
   
3 
   
   
   
   
   
   
   
   
   
4 
   
   
   
   
   
   
   
   
   
5 
   
   
   
   
   
   
   
   
   
6 
   
   
   
   
   
   
   
   
   
7 
   
   
   
   
   
   
   
   
   
Investigator Signature:  
 
Date:  

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
Form Instructions:  
[1] Each page should be separately numbered to allow cross-referencing (e.g., deviation 
#2 on p. 7) 
[2] Deviation Type: (A-J) See codes below—enter the appropriate deviation code from 
the list.  
Protocol Deviation Codes: 
A – Consent Procedures 
B – Inclusion/Exclusion Criteria 
C – Concomitant Medication/Therapy 
D – Laboratory Assessments/Procedures 
E – Study Procedures 
F – Serious Adverse Event Reporting/Unanticipated Adverse Device Effect 
G – Randomization Procedures/Study Drug Dosing 
H – Visit Schedule/Interval 
I – Efficacy Ratings 
J – Other 
 
 

Unanticipated Problem (UP) Version 1.0 
100 of 157 
31May2013 
 
Appendix 9: AE & Serious AE Reporting  
The UNC-Chapel Hill policy is based on this guidance. “Adverse events” that are not 
UPIRSOs are not required to be reported to the IRB. Therefore, it is important to delineate 
the definitions that inform reporting requirements. (See Appendix U, Decision Algorithm for 
Unanticipated Problems)  
 
Required Reporting of UPIRSOs  
Reporting is required of all UPIRSOs, including those which may occur after the participant 
has completed or is withdrawn from the study, or following study closure. Reporting is 
completed via IRBIS, UNC’s online IRB information system. 
 
Timing of Reports  
Events that meet the criteria for an UPIRSO and are also serious adverse events should be 
reported to the IRB within one (1) day of the investigator becoming aware of the event.  
Any other events that meet the criteria for a UPIRSO should be reported to the IRB within 
one (1) week of the investigator becoming aware of the problem.  
If the report cannot be completed in its entirety within the required time period, a preliminary 
report should be submitted. The report should be amended once the event is resolved 
and/or more information becomes available. 
 
Definitions: 
“Unanticipated problems involving risks to subjects or others” (UPIRSO) refers to any 
incident, experience, or outcome that:  
• is 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;  
• is related or possibly related to a subject’s participation 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.  
 
Events that satisfy all three criteria are reportable to the UNC-Chapel Hill IRB. See SOP 19.4 
for additional information.  
 
“Related to the research” refers to an incident, experience or outcome that is likely to have 
resulted from participation in the research study.  
 
“Possibly related to the research” refers to the reasonable possibility that the adverse event, 
incident, experience or outcome may have been associated with the procedures involved in 
the research (modified from the definition of associated with use of the drug in FDA 
regulations at 21 CFR 312.32(a)).  
 
An “adverse event” or “adverse experience” (AE) is any untoward or unfavorable medical 
occurrence in a human subject, including any abnormal sign (for example, abnormal physical 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
[Date] 
101 of 157 
Version# 
exam or laboratory finding), symptom, or disease, temporally associated with the subject’s 
participation in the research, whether or not considered related to the subject’s participation 
in the research. Adverse events encompass both physical and psychological harms and 
occur most frequently in the context of biomedical research, although they can occur in the 
context of social and behavioral research.  
 
Adverse events that meet all three criteria set forth in 19.1.1 (above) and are therefore an 
UPIRSO are reportable to the IRB. If investigators are unsure whether an AE is an 
UPIRSO, the event should be reported. The IRB will review the report and make a final 
determination as to whether the event constitutes an UPIRSO. 
 
“Serious Adverse Event” (SAE) is any adverse event temporally associated with the subject’s 
participation in research (whether or not considered related to the subject’s participation in 
the research) that meets any of the following criteria:  
• results in death;  
• is life-threatening (places the subject at immediate risk of death from the event as it 
occurred);  
• requires inpatient hospitalization or prolongation of existing hospitalization;  
• results in a persistent or significant disability/incapacity;  
• results in a congenital anomaly/birth defect; or  
• any other adverse event that, based upon appropriate medical judgment, may 
jeopardize the subject’s health and may require medical or surgical intervention to 
prevent one of the other outcomes listed in this definition (examples of such events 
include allergic bronchospasm requiring intensive treatment in the emergency room or 
at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse).  
 
Serious adverse events that meet all three criteria set forth in 19.1.1 (above) and are 
therefore an UPIRSO are reportable to the IRB. If the investigator is unsure whether an SAE 
is an UPIRSO, the event should be reported. The IRB will review the report and make a final 
determination as to whether the event constitutes an UPIRSO.  
 
“Unexpected Adverse Event” as defined by the FDA, is any adverse event, the specificity or 
severity of which is not consistent with the current Investigator Brochure; or, if an 
investigator brochure is not required or available, the specificity or severity of which is not 
consistent with the risk information described in the general investigational plan or 
elsewhere in the current application, as amended. 
 
Serious Adverse Event (SAE):  A serious adverse event will be considered any undesirable 
sign, symptom, or medical condition with one or more of the following outcomes: 
• 
is fatal, is life-threatening, 
• 
requires or prolongs inpatient hospitalization, 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
[Date] 
102 of 157 
Version# 
• 
results in persistent or significant disability/incapacity, 
• 
constitutes a congenital anomaly or birth defect, 
• 
is medically significant and which the investigator regards as serious based on 
appropriate medical judgment. 
• 
any serious psychological and emotional distress resulting in study participation 
(suggesting need for professional counseling or intervention).  
Unexpected Event:  Any adverse experience, event, incident, interaction or outcome that is 
not identified in nature, severity or frequency in the study documentation (protocol, consent, 
Investigator Brochure, package insert etc) is considered an unexpected adverse event.  Any 
event that is previously not known or anticipated to result from an underlying disease, 
disorder, or condition of the human subject or the study population may also be considered 
an unexpected  event. For Cancer Center Studies the DSMP tables A, B, or C have 
additional defining information regarding “unexpected” that is based on AE grade. 
 
Expected Event:  Any adverse experience, event, incident, interaction or outcome that is 
identified in nature, severity or frequency in the study documentation (protocol, consent, 
Investigator Brochure, package insert etc) is considered an expected adverse event.   Any 
event that is previously known or anticipated to result from the underlying disease, disorder, 
or condition of the human subject or the study population may also be considered an 
expected  event. For Cancer Center Studies the DSMP tables A, B, or C have additional 
defining information regarding “unexpected” that is based on AE grade.  
 
Unrelated Event:  Any adverse experience, event, incident, interaction or outcome for which a 
causal relationship with the study article, study intervention or study participation is not 
suspected. 
 
Related/Possibly Related Event:  Any adverse experience, event, incident, interaction or 
outcome for which a causal relationship with the study is suspected. 
IRB Reporting Criteria For Serious Adverse Events: 
Internal events:  The IRB-HSR requires that all Internal, Serious, Unexpected adverse events 
be reported to the IRB-HSR using the IRB Online program within 7 days of the time the study 
team  
receives knowledge of the event. 
External events:  External, Serious, Unexpected Adverse Events must be reported to the 
IRB-HSR using the IRB Online program ONLY if the event results in a change to the risk 
section of the consent and/or modification to the protocol.   
External, Serious, Unexpected Adverse Events that DO NOT result in change to the risk 
section of the consent and/or modification to  the protocol do not need to be submitted to the 
IRB unless the sponsor requires submission.   
Reporting Timeline:  Internal, unexpected SAEs and External SAEs resulting in modification 
to the protocol/consent must be submitted to the IRB-HSR within 1 days from the time the 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
[Date] 
103 of 157 
Version# 
study team received knowledge of the event.  This includes the electronic submission and the 
hard copy of the signed AE reporting form.   
If the internal SAE resulted in harm or death to the subject that was definitely caused by 
study participation the SAE should be reported to IRB-HSR, appropriate Dean and Office of 
Risk Management within 24-hours.   
The IRB-HSR will make a Late Reporting notation to all internal, serious, unexpected adverse 
event reported greater than 7 days from the time the study team received knowledge of the 
event.  

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
[Date] 
104 of 157 
Version# 
Appendix 10:  Adverse Event Form 
STUDY NAME 
Site 
Name:___________________________ 
Pt_ID:_________________________ 
This form is cumulative and captures 
adverse events of a single participant 
throughout the study.  
 
Severity 
Study 
Intervention 
Relationship 
Action Taken 
Regarding Study 
Intervention 
Outcome of AE 
Expected 
Serious 
Adverse 
Event 
(SAE) 
1 = Mild 
2 = Moderate 
3 = Severe 
4 = Life-
Threatening 
0 = Not 
related 
1 = Unlikely 
related 
2 = 
Possibly 
related 
3 = 
Probably 
related 
4 = 
Definitely 
related 
0 = None 
1 = Dose 
modification 
2 = Medical 
Intervention 
3 = 
Hospitalization 
4 = Intervention 
discontinued 
5 = Other 
1 = Resolved 
2 = Recovered with 
minor sequelae 
3 = Recovered with 
major sequelae 
4 = 
Ongoing/Continuing 
treatment 
5 = Condition 
worsening 
6 = Death 
7 = Unknown 
1 = Yes 
2 = No 
1 = Yes 
2 = No 
 
(if yes, 
complete 
SAE 
form) 
At end of study only: Check this box if participant had no adverse events 
 
None 
Adverse Event 
Start 
Date 
Stop 
Date 
Sever
ity 
Relation
ship 
Action 
Taken 
Outco
me of 
AE 
Expected
? 
SAE? 
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
 
 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
[Date] 
105 of 157 
Version# 
Appendix 11:  Unanticipated Problem (UP) 
Protocol Name and Number: 
Site Name: 
Subject ID Number or List of 
Affected Subjects: 
___________________________
_ 
___________________________
_ 
___________________________
_ 
 
1. Date UP Identified:  _   _ /  _   _   _ /  _   _   _   _  (dd/mmm/yyyy) 
2. Identify UP: 
 
3. The Unanticipated Problem was unexpected in terms of nature, severity, or frequency: 
 Yes 
 No 
4. The Unanticipated Problem is possibly related to participation in the research: 
 Yes 
 No 
5. The Unanticipated Problem suggests that the research places subjects or others at a 
greater risk of harm than was previously known or recognized:  
 Yes 
 No 
If the answers to questions 3–5 are ALL “YES,” report event as an Unanticipated 
Problem to NCCIH and the institutional review board  (if applicable). 
6. Briefly describe the UP. Attach additional pages or supplementary information as necessary. Include date of 
incident and date of discovery. Describe harm or potential harm that occurred to subject(s), whether the 
incident is resolved, and whether the subject(s) remains in the study: 
 
 
 
7. What action was taken with the study as a result of the Unanticipated Problem? (Check all that apply.) 
 No action 
 Revise protocol to eliminate apparent 
immediate hazards to subjects 
 Modification of inclusion or exclusion 
criteria to mitigate newly identified risks 
 Implementation of additional procedures for 
monitoring subjects 
 Suspension of enrollment of new subjects 
 Notify currently enrolled subjects 
 Suspension of research procedures in 
currently enrolled subjects 
 Modification of consent documents to 
include a description of newly recognized 
risks (site and/or study wide) 
 Provision of additional information about 
newly recognized risks to previously 
enrolled subjects 
 Other: __________________________ 

Serious Adverse Event (SAE)  
Report Form Version 3.0 
106 of 157 
13Jan2014 
8. Is the Unanticipated Problem a serious adverse event? 
 Yes 
 No 
If the Unanticipated Problem is a serious adverse event, submit this form and 
complete the Serious Adverse Event form. 
Statement of Principal Investigator: I have personally reviewed this report and agree with the above assessment. 
____________________________________________________ 
__ __/ __ __ __/ __ __ __ __ 
 
Signature of Principal Investigator 
Date 
____________________________________________________ 
__ __/ __ __ __/ __ __ __ __ 
 
Name of Person Completing the Form  
Date 
 
 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
Appendix 12: Serious Adverse Event Form 
 
STUDY NAME 
Protocol Number: 
 
Site Name: 
 
Pt ID: 
 
Date Participant Reported: 
            /                   /                        . 
 d d 
m m m 
y y y y 
 
1. SAE onset date: 
___ ___ / ___ ___ ___ / ___ ___ ___ ___ 
 
d d 
m m m 
y y y 
y 
2. SAE stop date:  
___ ___ / ___ ___ ___ / ___ ___ ___ ___ 
 
d d 
m m m 
y y y 
y 
3. Location of SAE: 
 
4. Was this an unexpected adverse event? 
 Yes 
 No 
5. Brief description of participants with no personal identifiers: 
Sex:   F 
 M 
Age:  
 
Diagnosis for study participation: 
 
 
 
6. Brief description of the nature of the SAE (attach description if more space is needed):  
 
 
 
 
7. Category of the SAE: 
 Date of death___/_____/_______ 
 
 
(dd/mmm/yyyy) 
 Life threatening 
 Hospitalization – initial or prolonged 
 Disability/incapacity 
 Congenital anomaly/birth defect 
 Required intervention to prevent 
permanent impairment 
 Other: 
 

 
8. Intervention type: 
 Medication or nutritional supplement (specify): 
 
 Device (specify): 
 
 Surgery (specify): 
 
 Behavioral/lifestyle (specify): 
 
9. Relationship of event to intervention: 
 Unrelated (clearly not related to the intervention) 
 Possible (may be related to intervention) 
 Definite (clearly related to intervention) 
10. Was study intervention discontinued due to event? 
 Yes 
 No 
11. What medications or other steps were taken to treat the SAE? 
 
 
12. List any relevant tests, laboratory data, and history, including preexisting medical 
conditions: 
 
 
13. Type of report: 
 Initial 
 Follow-up 
 Final 
Signature of principal investigator:  ______________________ Date:  _____________ 
 
 
 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
Appendix 13: Participant Eligibility Checklist 
 
Participant Name ______________________  
Date: _______________ 
Please check the box for all inclusion criteria satisfied. 
Inclusion Criteria Satisfied: 
 Male or female 18-45 years of age 
 History of ankle sprain with at least two episodes of “giving way” within the past 
six months 
 Score of ≥ 5 on the Ankle Instability Instrument (AII) 
 Score of ≤ 90% on the FAAM-ADL 
 Score of ≤ 80% on the FAAM-S. 
Notes about inclusion criteria: 
Exclusion Criteria Triggered: 
 Younger than 18 or older than 45 years 
 No history of ankle sprain or episodes of “giving way” in the past six months 
 Score of ≤ 5 on the Ankle Instability Instrument (AII) 
 Score of ≥ 90% on the FAAM-ADL 
 Score of ≥ 80% on the FAAM-S. 
 An acute ankle sprain within the past 6 weeks. 
 Previous history of lower extremity surgery with internal derangements, 
reconstructions, or repair 
 Lower extremity injury within the past 6 months (other than ankle sprains) 
 Presence of balance deficits or conditions known to affect balance as noted on 
the Balance Questionnaire including diabetes and/or vertigo. 
Notes about exclusion criteria: 
If all inclusion criteria are satisfied (all boxes checked) and none of the exclusion criteria 
are triggered, then the participant can be enrolled in the study.  If not all inclusion boxes 
are checked or one or more of the exclusion boxes are checked, participation in this 
study is no longer allowed. 
 
Screener Name:   ____________________________________ 
Screener Signature:  _____________________________   Date: ____________ 
PI Signature:  
 _____________________________  
Date: ____________ 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
 
 
Gender and Racial/Ethnic Categories of participant if eligible for inclusion into the 
study: 
 
Please circle the gender and racial/ethnic categories of the potential participant: 
 
Gender: 
 
Male  
 
Female 
 
Ethnicity: 
 
Hispanic/Latino 
 
Not Hispanic/Latino 
 
 
Race:  
 
  
Asian  
Black/African American 
 
White  
 
 
 
 
American Indian/Alaska Native 
Native Hawaiian or Other Pacific 
Islander 
 
 
 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
Appendix 14: Screening Log  
 
Screening Log Table 
Number Date 
Race 
Ethnicity Eligible 
for 
Study 
Date 
Enrollment 
Confirmed 
Ineligible 
for 
Study 
Reason 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
Appendix 15: Master Subject List 
 
Master Enrolled Subject List 
Number 
Name 
Concomitant Medications (if any) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
 
Appendix 16: Training Log 
Training Log 
IRB #: _________ _____________________________________________ 
Protocol #:  _____ 
Protocol Title:  Neuromuscular Mechanisms of Manual Therapies 
Sponsor:  NCCIH 
PI Name:______ __________________________________  
 
Trainee Name:__ ______________________  
Date training completed:      
 
Role:  
 Co-Investigator 
 
 
Data Management 
 
 
Participant Recruiter 
 
 
 
 
  Protocol Training including informed consent, study enrollment log, 
inclusion/exclusion, CRF and data collection sheet. 
  CRF/eCRF Training (if applicable) 
  Evaluation Procedures 
  AE’s/SAE’s 
  IP Overview 
  Data/Query Management (if applicable) 
  IVRS (if applicable) 
  Regulatory 
  Other  __________________________________________________________ 
 
Trainee Signature:_____________________________  Date Signed:____________ 
 
Trainer Name:________________________________________________________ 
 
Trainer Signature:______________________________  Date Signed:____________ 
 
PI Signature:______________________________________  Date:______________ 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
Appendix 17: Data Collection Sheet 
 
Participant Number: ________ Date: ____________ Time: __________ 
 
Age:____(years)  Height: ________(cm) Weight:________(kg) Gender: ________ 
 
Treatment Group:   CONTROL   
MASSAGE  
MOBILIZATIONS 
 
Treatment/Test Limb:   
 
Right  
 
Left 
 
SL BESS ERRORS 
Trial 1 
Trial 2 
Trial 3 
 
 
 
 
All errors are counted and include: 
1. Lifting the hands off the iliac crest 
2. opening the eyes 
3. stepping, stumbling, or falling 
4. moving the non-stance hip into more than 30° of abduction 
5. lifting the forefoot or heel 
6. Remaining out of the test position for more than 5 seconds. 
 
WBLT in cm (to the nearest 0.5cm) 
Practice 1 
Practice 2 
Practice 3 
Trial 1 
Trial 2 
Trial 3 
 
 
 
 
 
 
 
GAIT BIOMECHANICS (check if completed 
Trial 1 
Trial 2 
Trial 3 
Trial 4 
Trial 5 
 
 
 
 
 
 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
JUMP LANDING BIOMECHANICS (check if completed 
 
Trial 1 
Trial 2 
Trial 3 
Trial 4 
Trial 5 
Right 
 
 
 
 
 
 
LIGHT TOUCH THRESHOLD 
 
Trial 1 
Trial 2 
Trial 3 
1st Metatarsal 
 
 
 
5th Metatarsal 
 
 
 
 
JOIINT POSITION SENSE 
 
Trial 1 
Trial 2 
Trial 3 
Plantar Flexion 
 
 
 
Inversion 
 
 
 
 
TTB 
Foot Length:  _________(cm) Width:  
________(cm) 
 
Force Plate Coordinates 
Single Leg 
Coordinate (cm)  
(+X, -X) 
Coordinate  (cm) 
(+Y, -Y) 
Single Left 
 
 
Single Right 
 
 
 
TTB FAILED TRIALS (mark failed trials, zero for no fails) 
SINGLE LEG LEFT:   
EO:               TRIAL I  
_______ 
TRIAL II 
_____ TRIAL III 
_______ 
EC:               TRIAL I  
_______ 
TRIAL II 
_____ TRIAL III 
_______ 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
 
H-REFLEX 
 
Trial 1 
Trial 2 
Trial 3 
PL 
 
 
 
Soleus 
 
 
 
 
CORTICOMOTOR MAPPING / EXCITABILITY 
 
Trial 1 
Trial 2 
Trial 3 
MAPPING 
 
 
 
EXCITABILITY 
 
 
 
 
 
 
 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
Appendix 18: IRB Protocol 
 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
 
 
 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
 
 
 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
 
 
 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
Appendix 19: IRB Approval Forms 
 
 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
Appendix 20: Participant Payment Log 
 
Payment Log Table 
Number 
Payment 1 Date & Subject 
Initials 
Payment 2 Date & Subject Initials 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
Appendix 21: Participant Self-Monitoring Guidelines 
 
If, after receiving your treatment, you experience any of the following symptoms that 
may or may not affect your normal daily activity listed below, please contact your 
research coordinator immediately.    
1. Muscle soreness  
2. Pain 
3. Spasm 
4. Swelling 
5. Fever or redness of your ankle 
6. Altered sensation of your foot or ankle 
7. Increased feelings of instability 
8. Anything else that feels abnormal with your foot and/or ankle 
 
The University of North Carolina Research Coordinator is Erik Wikstrom.  He can be 
reached at 919-962-2260 or by email at wikstrom@unc.edu    
 
 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
Appendix 22: Study Completion Form 
 
Pt_ID:  
 
 
 
 
1. Date of final study visit: 
            /                   /                        . 
 
d 
d 
m 
m m 
y 
y 
y 
y 
2. Date of last-known study intervention: 
            /                   /                        . 
 
d 
d 
m 
m m 
y 
y 
y 
y 
3. Primary reason for terminating participation in the study: 
 Completed study 
 Participant was determined after enrollment to be ineligible (provide comments): 
 
 
 Participant withdrew consent 
 In the principal investigator’s opinion, it was not in the participant’s best interest to 
continue (provide comments):  
 
 Adverse event (If checked, complete the AE form.) 
 Death 
 Lost to followup 
 Other (specify):  
 
 Unknown 
Comments: 
 
 
 
 
PI Signature:  _____________________________________ 
Date:  ______________________ 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
Appendix 22: IMC Report Template 
 
Tool Summary Sheet 
Tool: 
Independent Monitoring Committee (IMC) Report Template 
Purpose: 
MS Word template to be used as a starting point for preparing a IMC report  
Audience/User: 
Statisticians and Principal Investigators responsible for preparation of IMC 
reports 
Details: 
This template includes a proposed structure for a IMC report as well as draft 
language and other guidance  
Best Practice 
Recommendations: 
• 
Review this template several months prior to the date of the 
first IMC meeting, and customize to the specific needs and 
requirements of the study. 
• 
In the template, the instructions and explanatory text are 
indicated by {blue italics} Instructional text will also be enclosed 
in braces to signify this text for screen-readers used by the 
visually impaired.   
• 
Text enclosed with <> is a placeholder for a specific detail 
(e.g., <protocol title>); replace as appropriate. 
• 
Delete template-specific instructional text as well as this Tool 
Summary Sheet during the report development process. 
• 
Leave the template version information in the lower left hand 
corner of the document. 
• 
It is easiest and cleanest to use the styles that are embedded 
in the document, rather than to create your own.  (In MS Word 
2007: From the Home menu, select the bottom right arrow key 
to bring up the styles box, select “Options”, under “Select 
Styles to Show” select “in current document”.) 
• 
Ensure that all placeholder and example text is replaced with 
the study specific information. 
 
Tool Revision History: 
Version 
Number 
Version Date 
Summary of Revisions Made: 
1.0 
13Apr2016 
First approved version 

Neuromuscular Mechanisms of Manual Therapies in Chronic Ankle Instability Patients  
Wikstrom (PI) 
 
Protocol Number:  1 R21 AT009704-01 
 
INDEPENDENT MONITORING COMMITTEE REPORT 
PROTOCOL TITLE: <Insert title of the protocol> 
PROTOCOL NUMBER: <Insert protocol number> 
PROTOCOL VERSION: <Insert version number and date of current 
protocol> 
PRINCIPAL INVESTIGATOR: <Name of PI 
PI’s Title 
Institution 
Address> 
MEETING DATE: <Insert date of the scheduled meeting> 
DATE REPORT ISSUED: <Insert date that the report is being issued> 
DATA CUTOFF DATE: <Insert the date of the data snapshot for the 
analyses in this report> 
DATE OF LAST DATA REVIEW: <Insert date of last IMC meeting>  
 
PREPARED BY: <Name of person who prepared the report 
Person’s Title 
Place of employment 
Address> 
 

<Abbreviated Study Title> 
IMC Report Meeting Date:<Insert Meeting Date Here> 
 
Table of Contents 
{This table uses the Table of Contents function in Microsoft Word that will automatically 
update headings and page numbers used in the body of the report. In the body of the 
report, add, delete, or modify headings as needed in order to best reflect your study.} 
Executive Summary 
146 
Protocol Synopsis 
148 
1.0 
Report Overview 
149 
2.0 
Response to Most Recent IMC Recommendations/Requests 
149 
3.0 
Enrollment Status 
149 
4.0 
Subject Status 150 
5.0 
Demographics (and Baseline Characteristics if Appropriate) 
150 
6.0 
Safety Summary 
151 
6.1 Stopping Rules 151 
6.2 Deaths 151 
6.3 Unanticipated Problems151 
6.4 Adverse Events 151 
6.5 Serious Adverse Events 153 
6.6 Laboratory Findings 
153 
6.7 Other Clinical Tests 
153 
7.0 
Protocol Deviations 
153 
8.0 
Quality Management 
153 
9.0 
Outcomes Data 154 
Appendix A: Additional Summary Tables 155 
Appendix B: Additional Figures 156 
Appendix C: Additional Data Listings 
157 
 

 
 
Executive Summary 
{Add, delete, or modify summary topics as needed.} 
Report Overview 
{Example text:}  
This report reviews enrollment and safety data available in 
the study database as of April 19, 2015. Summary tables are 
provided in the body of the report. Additional tables and 
figures referenced in the report are provided in the 
Appendices.  
Study Site Status 
{Example text:}  
Two of the 3 study sites have been activated. The third will 
be activated this month. 
Enrollment Status 
{Example text:}  
• 
100 subjects have been screened for this study. 
• 
20 subjects have been enrolled. 
Subject Status 
{Example text:}  
• 
5 subjects are awaiting dosing. 
• 
5 subjects have completed Month 1 follow-up. 
• 
5 subjects have completed Month 2 follow-up. 
• 
5 subjects have completed the protocol. 
• 
No treated subjects have been discontinued (withdrawn) from the 
study. 
Stopping Rules  
<or Halting Rules or 
Suspension 
Guidelines> 
{Use terminology that 
matches the protocol 
throughout this report} 
{Example text:}  
No stopping rules have been met since the previous IMC 
review. 
Or  
There are no new “Alerts” since the previous IMC review. 

 
 
Safety Summary 
{Example text:}  
• 
100 adverse events have occurred in 7 subjects. 
• 
50 adverse events were reported in the previous IMC report. 
• 
There have been no additional serious adverse events since the 
last IMC meeting. 
• 
Of the 50 adverse events, all were considered either mild or 
moderate. 
Protocol Deviations 
{Example text:}  
• 
50 protocol deviations associated with 5 subjects have been 
reported. 
• 
None of the deviations has impacted subject safety. 
• 
5 deviations have impacted scientific integrity  
Quality Management  
{Example text:} 
Quality management reviews are performed quarterly and 
were last completed on July 8, 2015 and October 7, 2015.   

 
 
Protocol Synopsis 
{Add, delete, or modify protocol headings as required.  Enter appropriate information in 
second column; some clarification guidance has been provided.} 
Protocol Title 
<Insert protocol title> 
Principal Investigator 
<Insert name of Principal Investigator> 
Study Sites 
<List name of each study site> 
Study Activation Date 
<Insert activation date of first site> 
Planned Accrual 
<Insert planned number of participants to be enrolled> 
Planned Accrual Period 
<Insert time (months, years, etc.)> 
Planned Duration 
<Insert time from first participant-first visit to last 
participant-last visit (months, years, etc.)> 
Study Design 
<Briefly describe study design> 
Study Objectives 
<Briefly describe study objectives> 
Treatment Description 
<Briefly describe study treatment(s)> 
Inclusion Criteria 
<List inclusion criteria> 
Exclusion Criteria 
<List exclusion criteria> 
Study Outcomes 
<Briefly describe study outcomes> 
Study Stopping Rules  
<or Halting Rules or 
Suspension 
Guidelines> 
{Use terminology that 
matches the protocol 
throughout this report.  
Replace headings as 
appropriate.} 
<Clarify stopping rules or suspension guidelines> 

 
 
{Add, delete, or modify headings as needed in order to best reflect your study. Place 
summary tables, listings, and figures within the body of the report; however, if the 
tables, listings, or figures are long, place them in the Appendices. For small numbers of 
subjects, listings may be more appropriate than summary tables.} 
Report Overview  
{Example text:}  
The purpose of this report is to review cumulative enrollment and safety data for the 
subjects enrolled in the Excellent study. This report reflects data from  the study 
database as of April 19, 2015. Within the body of the report are summary tables of 
enrollment, demographic characteristics, and adverse events. Additional tables, listings, 
and figures referenced in this report are provided in Appendices A-C. There have been 
five IMC meetings for this study, and the last review was on April 10, 2014. At that time, 
the IMC concluded that the available safety data supported the continuation of the trial. 
Readers of this report are asked to maintain the confidentiality of the information 
provided in this report. 
Response to Most Recent IMC Recommendations/Requests 
{Identify IMC recommendations/requests from the last meeting and clarify how those 
requests have been handled in the report and/or elsewhere.  If this is the first IMC 
meeting for this protocol or no previous recommendations/requests were made, indicate 
as such in this section.  Doing so will provide a future reminder to the author who is 
likely to use the previous report as a starting point for the subsequent report.} 
 
Enrollment Status 
{Describe enrollment and provide a summary table (see example below). Provide 
enrollment statistics by site if the study involves multiple sites. If the study is enrolling, 
provide the subject accrual target and estimated time to completion of enrollment. A 
figure showing expected/planned versus actual enrollment is helpful (see example on 
next page). 
Sample Table:} 
Table #. Subject Enrollment Status for All Subjects 
Type 
Site A Site B 
Total 
Pre-Screened 
100 
100 
200 
Consented and Screened 
50 
50 
100 
Eligible 
35 
40 
75 
 
 
 
{Sample Figure:} 

 
 
Figure #. Expected versus Actual Accrual 
 
Subject Status 
{Describe where patients are in the study in relation to major milestones, such as the 
number of subjects who have completed the baseline visit, the dosing visit, year 1 
follow-up, and the final study visit. A summary table providing the study milestones and 
the number of subjects who have completed those milestones is recommended. 
Also, provide the number of subjects who were terminated and the reason for their 
termination, such as voluntary withdrawal, death, lost to follow-up, adverse event, or 
completed the protocol. A summary table of subject disposition is also recommended. 
For some protocols, it is important to distinguish between subjects who withdrew early 
from the study and those who discontinued treatment but may or may not still be 
followed.} 
Demographics (and Baseline Characteristics if Appropriate) 
{Describe the demographic characteristics (age, race, and ethnicity) and key baseline 
characteristics of enrolled subjects (if appropriate). Provide a summary table (see 
example on the next page) or a listing of the data. Listings are preferable over summary 
tables if only a few subjects have been enrolled.  However, avoid listing any information 
that could potentially lead to the identification of a participant. 
Sample Listing:} 
Listing #. Listing of Demographic Information for All Consented Subjects 
Subject ID 
Age (yrs) 
Gender 
Race 
Ethnicity 
001 
60 
Female 
Black 
Not Hispanic or Latino 

 
 
Subject ID 
Age (yrs) 
Gender 
Race 
Ethnicity 
002 
65 
Female 
Black 
Not Hispanic or Latino 
003 
64 
Male 
White 
Hispanic or Latino 
004 
72 
Male 
White 
Not Hispanic or Latino 
005 
45 
Male 
Alaskan Native 
Not Hispanic or Latino 
006 
70 
Male 
White 
Not Hispanic or Latino 
Safety Summary 
Stopping Rules 
{List and describe any stopping rules that have been triggered since the previous IMC 
report and over the course of the study.} 
Deaths 
{List and describe any deaths that have occurred since the previous IMC report and 
over the course of the study.} 
Unanticipated Problems 
{Summarize or list unanticipated problems. The Office for Human Research Protections 
(OHRP) considers unanticipated problems, in general, to include any incident, 
experience, or outcome that meets all of the following criteria: 
1. 
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; 
2. 
Related or possibly related to participation in the research (in this guidance document, 
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 
3. 
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. 
OHRP notes that an incident, experience, or outcome that meets the three criteria 
above generally will warrant consideration of substantive changes in the research 
protocol or informed consent process/document or other corrective actions in order to 
protect the safety, welfare, or rights of subjects or others.} 
Adverse Events 
{Summarize or list the adverse events (AEs) that have occurred since the previous IMC 
report and over the course of the trial. Provide information on severity and relatedness 
to treatment and study procedures (see an example of a summary table below). Please 

 
 
ensure that categories summarized match those in the protocol.  For instance 
related/unrelated vs. the 5 category delineation. 
In addition, a summary table or listing of subjects experiencing adverse events by 
treatment group, system organ class, and preferred term should be considered. 
Extensive listings may be placed in the Appendix. 
Sample Table:} 
Table #. Summary of All Adverse Events for Consented Subjects 
Topics 
Site A 
Site B 
Total 
N=12 
Number of AEs reported 
38 
30 
68 
Number of Subjects with AEs [1] 
4 
3 
7 
Number of SAEs reported 
1 
0 
1 
Number of Subjects with SAEs [1] 
1 
0 
1 
Number of AEs by Severity* 
Site A 
Site B 
0 
Mild 
31 (81.1%) 
24 (80.0%) 
55 (80.9%) 
Moderate 
7 (18.9%) 
3 (10.0%) 
10 (14.7%) 
Severe 
0 (0.0%) 
3 (10.0%) 
3 (4.4%) 
Subjects with AEs by Severity [2]** 
 
 
 
Mild 
4 (100.0%) 
3 (100.0%) 
7 (58.3%) 
Moderate 
3 (100.0%) 
2 (66.7%) 
5 (41.7%) 
Severe 
0 (0.0%) 
1 (33.3%) 
1 (8.3%) 
 
 
 
 
Number of AEs by Relatedness to Treatment* 
Site A 
Site B 
Total N=12 
Unrelated 
25 (64.9%) 
23 (76.7%) 
48 (70.6%) 
Unlikely 
9 (24.3%) 
4 (13.3%) 
13 (19.1%) 
Possible 
4 (10.8%) 
3 (10.0%) 
7 (10.3%) 
Probable 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Definite 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Subjects with AEs by Relatedness to Treatment [2]** 
Site A 
Site B 
Total N=12 
Unrelated 
4 (100.0%) 
3 (100.0%) 
7 (58.3%) 
Unlikely 
3 (100.0%) 
2 (66.7%) 
5 (41.7%) 
Possible 
2 (66.7%) 
2 (66.7%) 
4 (33.3%) 
Probable 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Definite 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Number of AEs by Relatedness to Study Procedures 
Site A 
Site B 
Total N=12 

 
 
Topics 
Site A 
Site B 
Total 
N=12 
Unrelated 
26 (67.6%) 
21 (70.0%) 
47 (69.1%) 
Unlikely 
5 (13.5%) 
4 (13.3%) 
9 (13.2%) 
Possible 
4 (10.8%) 
4 (13.3%) 
8 (11.8%) 
Probable 
1 (2.7%) 
1 (3.3%) 
2 (2.9%) 
Definite 
2 (5.4%) 
0 (0.0%) 
2 (2.9%) 
Subjects with AEs by Relatedness to Study Procedures [2]** 
Site A 
Site B 
Total N=12 
Unrelated 
4 (100.0%) 
3 (100.0%) 
7 (58.3%) 
Unlikely 
2 (66.7%) 
2 (66.7%) 
4 (33.3%) 
Possible 
3 (100.0%) 
3 (100.0%) 
6 (50.0%) 
Probable 
1 (33.3%) 
1 (33.3%) 
2 (16.7%) 
Definite 
2 (66.7%) 
0 (0.0%) 
2 (16.7%) 
[1] Subjects who experience one or more AEs or SAEs are counted only once. 
[2] Subjects are counted only once within a particular severity grade or relatedness category. 
* Percentages are based on number of AEs reported for each treatment group. 
** Percentages are based on N for each treatment group. 
Serious Adverse Events 
{Summarize or list all serious adverse events (SAEs) that have occurred since the 
previous IMC report and over the course of the trial. Provide information on expedited 
reports, and include MedWatch forms in the Appendix if applicable.} 
Laboratory Findings 
{Summarize results from any clinical laboratory tests that are being monitored for 
subject safety. Laboratory results may be presented as summary tables, listings by 
subject, or plots. Depending on the study, identify by subject any significant changes 
from baseline, results that are clinically significant, or results that are considered 
adverse events.} 
Other Clinical Tests 
{You may list types of tests, such as imaging or physical examinations, as separate 
headings. 
Summarize any other clinical tests that are being monitored for subject safety. 
Depending on the study, identify by subject any significant changes from baseline, 
results that are clinically significant, or results that are considered adverse events.} 
Protocol Deviations 
{Summarize or list protocol deviations that have occurred since the previous IMC report 
and over the course of the study.} 
Quality Management  

 
 
{Provide details regarding quality management activities completed since the last IMC review, 
including frequency.  Summarize or list findings and identify measures or corrective actions 
taken to address the findings or issues.}  
Outcomes Data 
{As a general rule, interim results should not be performed or presented unless interim 
analyses are described in the protocol or the IMC has requested an interim analysis to 
assess a safety concern or study futility. The decision whether or not to present interim 
or final results in this report, or to present results in an open or closed session, should 
be discussed with the IMC and the study sponsor.} 

 
 
Appendix A: Additional Summary Tables 
{It is likely that these Appendices will originate as separate electronic files created by 
SAS or some other statistical software.  If you are creating an electronic version of the 
full report, use Adobe pdf (or equivalent) to combine the files with this document in a 
“published” Adobe report.  It is very useful to include a Table of Contents or, at a 
minimum, a list of items contained within each Appendix (e.g., a list of table numbers 
and names).   
Page numbering of the contents of the Appendices are at the discretion of the document 
owner.  Each Appendix file can 1) begin at page 1 or 2) can be numbered contiguously 
with this document.  The second option is advantageous but more difficult to achieve.   
A subset of these items  may also have been inserted into the report.  It is acceptable to 
also include those items in the corresponding appendix.  All other displays that are not 
inserted into the body of the report should be included herein.  It is good practice to 
ensure that all post-text displays are referenced somewhere in the body of the report. 
Include post-text Summary Tables here.}  

 
 
Appendix B: Additional Figures 
{Include post-text Figures here.} 
 
 

 
 
Appendix C: Additional Data Listings 
{Include post-text Data Listings here.}