Comparative Effectiveness Study of an Exercise Intervention Delivered Via Telerehabilitation and Conventional Mode of Delivery
Phase: NA
Conditions: Multiple Sclerosis
Sponsor: Shepherd Center, Atlanta GA

 
 
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Protocol Title: Comparative Effectiveness of an Exercise Intervention Delivered 
via Telerehabilitation and Conventional Mode of Delivery 
 
 
PI: Dr. Deborah Backus, Ph.D. 
 
 
Version: 6/17/2022 
 
 
Sponsor: Patient Centered Outcomes Research Institute (PCORI) 
 
 
NCT Number: NCT03468868 
  
 
 

 
 
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Table of Contents 
 
 
Background and Significance 
 
5 
Specific Aims 
 
6 
Research Methods 
6 
     Design 
6 
     Participants 
6 
     Study Procedures 
8 
 
Intervention 
 
 
15 
Adverse Event Management 
20 
 
Data Analysis 
 
22 
Data Management 
23 
 
Study Site Coordination 
 
25 
 
 
Appendices 
27 
 
 
 
 

 
 
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Abbreviations 
GEMS-T:   
Guidelines for Exercise in MS - Telerehabilitation  
GEMS-S:  
Guidelines for Exercise in MS - Supervised 
UAB:    
University of Alabama at Birmingham 
iCMS:   
iConquer MS 
EDSS:   
Expanded Disability Scale Score  
PDDS:  
Patient Determined Disability Steps 
EPHS:  
Exercise Preparticipation Health Screening 
T25FWT:   
Timed 25-Foot Walk Test 
6MWT:   
Six Minute Walk Test 
MSWS-12:   12-item, Multiple Sclerosis Walking Scale 
GLTEQ:   
Godin Leisure-Time Exercise Questionnaire 
MSIS-29:   
29-item, Multiple Sclerosis Impact Scale 
MFIS-21 
Modified Fatigue Impact scale-21 
Neuro-QOL 
Neuro Quality of Life 
SAHL-E 
Short Assessment of Health Literacy - English 
HR:    
Heart Rate 
SCT:    
Social Cognitive Theory 
HIPAA:   
The Health Insurance Portability and Accountability Act 
MAR:   
Missing at Random 
HTE:    
Heterogeneity of Treatment Effect 
DMT:   
Disease Modifying Therapy 
RRMS:   
Relapsing-remitting Multiple Sclerosis 
PMS:   
Progressive Multiple Sclerosis 
CI:   
 
Confidence Interval 
DSMB:  
Data Safety Monitoring Board 
MGH:  
Massachusetts General Hospital 
UGA:  
University of Georgia 
UNC:  
University of North Carolina 
 
Responsible parties: 
PI: Deborah Backus, PT, PhD, Shepherd Center 
Co-PI: Professor Robert Motl, PhD, University of Alabama at Birmingham 
Co-Investigators: Kevin McCully, PhD, University of Georgia; Francois Bethoux, MD, 
Cleveland Clinic, OH; Jeffrey Hebert, PT, PhD, University of Colorado; Alex Ng, PhD, 
Marquette University, WI; Dr. Prudence Plummer, University of North Carolina, Chapel Hill & 
Massachusetts General Hospital, Boston; Joann Dickson-Smith, BS.  
Project manager: Casey Kandilakis, PT, DPT, CCRP, Shepherd Center 

 
 
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Abstract 
This protocol outlines the methodology and procedures for implementing and evaluating 
Comparative Effectiveness of an Exercise Intervention Delivered via Telerehabilitation and 
Conventional Mode of Delivery. Funded by PCORI, this four-year, multi-site study aims to 
assess the comparative impact of a 16-week telerehabilitation exercise program and a facility-
based exercise program on MS outcomes. The research study design is a two-stage randomized 
choice design aimed at non-inferiority.  
Four hundred participants who have ambulatory difficulties will be recruited across eight sites. 
First level randomization will assign participants to one of two groups – choice or no choice. The 
participants in choice will be able to choose in which program they wish to participate 
(telerehabilitation or facility-based). Individuals in the no choice group, will be randomized to 
either the telerehabilitation or facility-based program. The research protocol and associated tools 
will be reviewed and approved by the Shepherd Center Research Review Committee before any 
research takes place. The study will comply with best practices in human subjects’ research 
including following HIPAA guidelines and using strict informed consent procedures. Clinical 
reported outcome measures and patient reported outcome measures will be administered at 
baseline, immediately post-intervention (at 16-weeks), and at 12 months post-intervention. 
Patient reported outcomes will also be administered at 2-months after the start of the intervention 
and at 6 months post exercise.  
Dr. Deborah Backus is the principal investigator (PI) and Prof. Robert Motl is the co-Principal 
Investigator supported by collaborating Co-Investigators at six other research sites and the 
iConquerMS outcomes data collaborative. Shepherd Center is the primary and coordinating site 
for all study activities under Dr. Backus, who is supported by Louise Palmer, Project Manager. 
University of Alabama at Birmingham (UAB) under the leadership of Prof. Motl will oversee 
delivery of the training programs, and under the direction of Dr. Gary Cutter will provide 
research design, statistical analysis and randomization expertise.   
This study will yield important data regarding the comparative impact of exercise programs on 
MS outcomes and provide information to people with MS, health providers, payers, exercise 
partners, and policy makers about how people with MS who have ambulatory difficulties can 
safely and effectively exercise.  
 
 

 
 
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BACKGROUND AND SIGNIFICANCE 
Multiple Sclerosis (MS) is a chronic, often progressive disease of the central nervous system 
affecting over 400,000 people in the United States and over 2.5 million people worldwide. One 
of the most common problems reported by people with MS is impaired mobility.1 Most people 
living with MS will eventually require assistance with mobility due to disease progression.2,3,4  
Decreased mobility leads to less physical activity.5,6,7 Physical inactivity in turn leads to and 
perpetuates deconditioning, which in turn will lead to further mobility impairment.8,9  At some 
critical point, mobility will be limited to such an extent that there is irreversible disability 
resulting in secondary health conditions that will be difficult, if not impossible, to treat.10,11,12 
This progression of disability can result in apathy and depression,11 further contributing to 
decreased social, recreational, and vocational participation and ultimately a poor quality of 
life.13-18 The decrease in participation and work productivity together with an increase in 
secondary health conditions and medical needs have a significant economic impact in both the 
United States19 and Europe.20   
 
Although evidence suggests that exercise can improve mobility and perhaps decrease the 
rate and extent of disability (i.e. impaired function) in people with MS, most studies related 
to exercise have failed to screen for people with walking problems using objective 
assessment.21-38 Evidence does show, however, that traditional, facility-based exercise training, 
particularly in a setting where other people with MS are exercising or under the supervision of 
exercise personnel, may help people with MS consistently participate in exercise or to exercise at 
a higher, more intense level. Despite this evidence, lack of access to these programs may make it 
difficult to engage in a GEMS-S program.39-43 Telerehabilitation (telerehab) has great potential to 
overcome challenges associated with facility-based programs. Telerehab can include 
videoconferencing, remote monitoring of signs and activity, and dissemination of specialized and 
individualized information via electronic mechanisms. Both facility-based and telerehab exercise 
training have yielded positive results in people with MS,21-38 but have not been compared head-
to-head. The current study will fill this gap in the evidence base and compare the outcomes of 
delivering the same exercise interventions in a facility (facility-based exercise training or GEMS-
S) or in the home/community using a telerehab approach (telerehab delivered exercise training or 
GEMS-T). The interventions are designed to be identical in content, with the only difference 
being the mode of training delivery.  
 
This study will yield important data to inform people with MS who have objective walking 
impairment, as well as healthcare providers, exercise trainers, payers, and policy makers, about 
exercise options for people with MS. Our main hypothesis is that there will be no difference in 
outcomes when the evidence-based individualized exercise program is delivered in a facility 
(GEMS-S) or via telerehab (GEMS-T) (i.e., walking and other outcomes will improve similarly 
between conditions). Our null hypothesis is that GEMS-T is inferior to GEMS-S. A secondary 
hypothesis is that patients who perform their preferred choice of program (GEMS-T(Choice) or 
GEMS-S(Choice)) will have better outcomes in self-efficacy, adherence, and adoption of 
exercise than no choice conditions. 
 
 
 
 

 
 
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SPECIFIC AIMS 
Our specific aims (SAs) are as follows:  
SA1: Compare the extent of change pre-test to post-test in walking and mobility outcomes, 
social and vocational participation, and quality of life between the identical evidence-
based individualized exercise program delivered via GEMS-S or GEMS-T in adults with 
MS who have slowed walking (greater than 6 seconds on the T25FWT);  
SA2: Evaluate and compare the effectiveness between participants randomized to their 
preferred delivery mode (GEMS-T(Choice) or GEMS-S(Choice)) and those who are not 
randomized to their preferred delivery mode (GEMS-T or GEMS-S);  
SA3: Evaluate changes in self-efficacy, and adoption of exercise between these groups 
(GEMS-T, GEMS-S, GEMS-T(Choice), GEMS-S(Choice)).  
 
RESEARCH METHODS 
 
Design  
 
This is a multi-site, 2-staged randomized, choice design study aimed at noninferiority, to 
compare the effectiveness of delivering an individualized exercise program in a facility (facility-
based exercise training or GEMS-S) versus via telerehabilitation (telerehab-based exercise 
training or GEMS-T) in people with MS. Noninferiority assumes both interventions (GEMS-S 
and GEMS-T) produce no statistically different outcomes.  
 
Shepherd Center is the Clinical Coordinating site, led by Dr. Deborah Backus, and UAB is the 
Training Site, led by Dr. Rob Motl. UAB will also house the Statistical Center, led by Dr. Gary 
Cutter. The Data Management Center led by Dr. Robert McBurney will be maintained by 
iConquerMS of the Accelerated Cure Project. 
 
This protocol will first outline site specific procedures and tools, and then will provide details 
regarding the coordination of the multiple study sites by the investigators at the Shepherd Center.  
 
Participants  
 
We will enroll 400 participants across the following eight centers: The Shepherd Center, Atlanta, 
GA; the University of Georgia, Athens; the Cleveland Clinic Mellen Center for MS Treatment 
and Research, Ohio; the University of North Carolina, Chapel Hill; Massachusetts General 
Hospital, Boston (MGH); the University of Colorado; the University of Alabama, Birmingham 
(UAB) in collaboration with The Tanner Center and Foundation for Neurological Diseases 
(Tanner Center); and Marquette University, Wisconsin. The criteria for eligibility will be 
identical at all sites. Participants will qualify for the study if they meet the following criteria: 
 
Inclusion criteria: 
1. Physician-confirmed diagnosis of MS 
2. Expanded Disability Status Scale (EDSS) score of 4.0 through 6.5  
3. Age between 18 and 65 years  
4. Able to travel to a GEMS-S site for testing and training   
5. Accessible, technological platform for GEMS-T (i.e. computer or DVD player and TV, 

 
 
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and telephone)  
6. A score of between 25 and 75 on the MSWS-12 
7. Timed 25-foot walk test (T25FWT) time of between 6 seconds and 3 minutes 
8. Medically stable or approval from physician to participate in exercise studies 
9. A score of between 3 and 6 (inclusive) on the Patient Determined Disability Steps 
 
Exclusion criteria: 
1. Documented MS relapse in the past 30 days 
2. Have had falls in the past three months that the study investigator determines makes 
participation unsafe 
3. Unable to walk 25 feet 
4. Already exercises at recommended levels as determined by a score of 25 or higher on the 
Godin Leisure-Time Exercise questionnaire 
5. Has other neurological (e.g., stroke) or musculoskeletal conditions or other co-
morbidities 
6. Has cognitive difficulties as determined by a Mini Mental Status Exam score <19 
7. Is not proficient in English 
8. Is physically unable to complete the second T25FWT trial 
9. Any other concern that the investigators deem would jeopardize the safety of the 
potential participant. 
 
We will randomize 200 participants to the Choice group and 200 to the No Choice group. Those 
in the Choice group will choose which exercise program to undertake – GEMS-T or GEMS-S. In 
the No Choice group, we will randomize 100 participants to GEMS-S and 100 to GEMS-T (see 
Figure 1). Four sites (Shepherd Center with help from UGA, Marquette University, Cleveland 
Clinic, and University of Colorado) will each recruit 80 participants. UNC and MGH will 
together recruit a total of 40 participants. UAB will recruit at least 40 participants with help from 
the Tanner Center, a Birmingham-based multidisciplinary center providing neurology, nursing, 
infusion, clinical research, neurodiagnostic testing, occupational therapy, physical therapy, 
speech/language pathology, licensed professional counseling, group wellness classes, and 
individual personal training in one central location. 
 
Figure 1: Randomization Scheme for Each Participant 
 

 
 
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Recruitment methods  
The same recruitment strategies will be utilized at all sites. Participants will be recruited via 
existing research databases and clinical databases at each site, or by direct contact on site (by 
providers and other clinical or research staff), or by word-of-mouth using a flyer describing the 
research study and participation requirements. We will supplement this recruitment strategy as 
needed by advertising through local National MS Society chapters, iConquerMS, and other 
partners. We will also develop recruitment advertisements to be shared via social media, such as 
Facebook and Twitter (see sample post in the Appendix). 
 
UAB will collaborate with the Tanner Center for recruitment purposes only. The Tanner Center 
has a history of assisting UAB with participant recruitment efforts, including for PCORI trials. A 
research coordinator at the Tanner Center will conduct a chart review of their patients to identify 
potentially eligible STEP for MS participants. The research coordinator will only review charts 
for those patients who have consented to be contacted about research studies, which is noted on 
their intake forms. The Tanner Center will also use the recruitment strategies outlined above.  
 
After identifying potential participants, the Tanner Center research coordinator will contact the 
patient to describe the study and ask basic prescreening questions, such as: do you currently 
exercise? Can you travel to UAB at Lakeshore to exercise twice a week (in case they are 
randomized or desire the facility training, GEMS-S)? These prescreening questions will be 
logged in a securely stored spreadsheet and only used for the purposes of determining potential 
eligibility for the STEP trial. If a potentially eligible participant expresses interest in being 
screened, the Tanner Center research coordinator will send the potential participant a URL link 
to an online consent form hosted on REDCap. The consent form will ask the potential participant 
to authorize the Tanner Center to release their contact information and basic medical 
information, such as a diagnosis of MS and EDSS score, if available, to UAB. Upon receipt of 
consent, the Tanner Center research coordinator will send this PHI via REDCap to the research 
coordinator at UAB. REDCap is a HIPAA-compliant, secure document transfer tool. The 
research coordinator at UAB will then conduct follow up and screening with the potential 
participant. 
 
Study Procedures  
Screening and Enrollment 
The procedures outlined here will be utilized at each site. We anticipate screening approximately 
800 individuals to reach our sample size goal of 400. Each site’s research coordinator will be 
responsible for all recruitment and enrollment of participants.  
 
An overview of procedures for each participant is provided in Figure 2. Screening will occur in 
three phases to determine eligibility.  
 
Screen 1 assesses basic criteria such as age, ability to travel to the site, relapse status, other 
comorbidities (see Table 1 for full set of criteria). Screen 1 will also ask some questions 
regarding falls in the last three months and any other concerns to determine safety to participate 
in the exercise program. Given that the exercise program can be modified for people at risk of 
falling, a history of falls in the past three months will be collected but will not automatically 
exclude a participant. The research coordinator will gather as much information as possible about 

 
 
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any falls and determine with the site investigator if the potential participant is eligible to 
participate. 
If the individual meets the basic criteria, the research coordinator will read a consent script (see 
telephone consent script in the appendix) requesting permission to perform and record the 
responses to three additional surveys (Screen 2). The telephone consent script will describe the 
purpose of the assessments and how the data will be used and securely stored. The research 
coordinator will document whether verbal consent is provided, or not. If an individual declines to 
provide verbal telephone consent, the screening ends. If the individual provides verbal telephone 
consent, the research coordinator will proceed to Screen 2.  
 
Screen 2 implements the MS Walking Scale-12 (MSWS-12), the Patient Determined Disability 
Steps (PDDS), and the Godin Leisure-Time assessments.  
If the individual passes Screens 1 and 2 and still wishes to be considered for enrollment in the 
study, the research coordinator will complete the Exercise Preparticipation Health Screening 
questionnaire (EPHS) to determine if the participant requires medical consent to participate. 
Once the individual obtains medical clearance, they will notify the research coordinator who will 
schedule them for Visit 1 for final screening assessments and enrollment. The research 
coordinator will send any potential participant who meets these initial criteria the informed 
consent form for their review prior to Visit 1. All screening will be conducted by the research 
coordinator or designee. Screening measures and instruments are outlined in Tables 1 and 2. 
Screens 1 and 2 will be conducted either by phone or in person by the research coordinator or 
designee. 
 
Screens 1 and 2 are necessary to ensure that we are asking only the individuals who meet the 
basic inclusion criteria to come to the center for further testing. For instance, if they are already 
performing adequate levels of exercise per week, they would be unlikely to experience 
substantial gains through our program and would thus be inappropriate for this study. Likewise, 
if an individual is unable to ambulate at all, they will be unable to perform the evidence-based 
exercise program for this study. Therefore, this three-stage screening approach will decrease the 
screening burden on individuals by screening out those who are obviously unqualified for the 
study. This approach will also ensure efficient use of resources, such as the award funds and 
personnel time to perform the assessments.  

 
 
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Figure 2: Study procedures for each participant 
Visit 1 will be conducted at the study site. At the beginning of this visit, the research coordinator 
will review the informed consent process with the individual, providing additional detail and 
answering questions as necessary. If the individual agrees to continue with the process and 
provides informed consent (see Appendix for informed consent form), the individual will 
complete additional clinician administered screening assessments and questionnaires. 
Specifically, a blinded, NeuroStatus certified evaluator will perform the Expanded Disability 
Status Scale (EDSS) assessment. A trained blinded evaluator will conduct the Timed 25 Foot 
Walk Test (T25FWT) and the Six-Minute Walk Test (6MWT) per the respective data collection 
protocols. If the participant is physically unable to perform the second T25FWT trial, they will 
not complete the 6MWT, but will complete the EDSS. If the participant has an EDSS score 
between 4.0 and 6.5 and can complete the T25FWT in 6 to 180 seconds, they will undergo a 
Mini-Mental Status Exam (MMSE) to determine if they have the cognitive abilities to safely 
participate in the intervention for this study. If they score at least a 19 or greater, they will be 
considered eligible for the study. If not, they will not be enrolled in the study.  
Enrollment  
After a participant is determined eligible to participate, the research coordinator will input the 
results from the 6MWT and implement a final instrument - Short Assessment on Health Literacy 
(SAHL-E). The research coordinator will subsequently enroll the participant in the study by 
creating a participant account in the Portal. The participant will then complete a demographics 
and medical history survey and additional baseline patient reported outcome (PRO) measures, 
including the Modified Fatigue Impact scale-21 (MFIS-21), the MSWS-12, the Neuro Quality of 
Life (Neuro-QOL) scale, and a social cognitive theory (SCT) battery of measures (see Tables 1 
and 2). Individuals will have the option of completing measures remotely at home, if necessary.  

 
 
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Table 1: Study measures 
Tool 
Description 
Screen 1 
Screen 2 
Visit 1 
Enrollment 
8 weeks 
16 weeks 
6 months 
12 months 
Basic eligibility criteria – 
screen 1 instrument 
Self-report question to assess basic eligibility: Age 18-65; confirmed 
MS diagnosis; relapse in past 30 days; ability to travel to facility; 
technical requirements for telerehab; other neurological/ 
musculoskeletal conditions & co-morbidities; English proficiency; 
exercise habits; self-reported ability to walk 25ft; basic cognitive 
screen questions; how did you hear about the study? 
X 
 
 
 
 
 
 
 
Fall assessment – 
included in screen 1 
instrument 
Self-report questions to assess whether a history of falls in the last 3 
months prevents safe participation: Have you experienced more than 
one fall in the last three months? Have you experienced an injurious 
fall in the past three months that required medical attention?  
X 
 
 
 
 
 
 
 
Patient Determined 
Disability Steps 
Participant chooses one of 9 categories that describes their MS 
disability level.  
 
X 
 
 
 
X 
 
X 
MS Walking Scale-12 
A 12-item self-report survey; measures the impact of MS on walking 
ability and daily activities over the past 2 weeks.  
 
X 
 
X 
X 
X 
X 
X 
Godin Leisure-Time 
Exercise Questionnaire  
4 questions; 7-day recall of leisure-time physical activity to determine 
if individual is already exercising at adequate levels.    
 
X 
 
 
X 
X 
X 
X 
Exercise Preparticipation 
Health Screening  
Questionnaire about physical health to determine if medical consent 
to participate is required.   
X 
 
Expanded Disability 
Status Scale 
A 30-minute multiple item disease-specific instrument that 
characterizes disability level and determines disability progression in 
people with MS. 
 
 
 
X 
 
 
X 
 
X 
Timed 25 Foot Walk Test 
Measure of walking speed; participant will perform twice. Only one 
trial must be in the eligibility range for inclusion (6 to 180 seconds). 
The time of both trials will be averaged for the outcome measure. 
Participants will be ineligible if physically unable to complete trial 2. If 
the assistive device/orthosis changes from pre- to post training, 
participants will be tested with the previous device. 
 
 
 
X 
 
 
X 
 
X 
6-Minute Walk Test 
Measures the distance an individual can walk over a total of six 
minutes on a hard, flat surface. The goal is for the individual to walk as 
far as possible in six minutes. The individual can self-pace and rest as 
needed as they traverse back and forth along a marked walkway. If 
the assistive device/orthosis changes from pre- to post training, 
participants can choose device type, or no device at all.  
 
 
X 
 
 
X 
 
X 
Mini-Mental Status Exam 
11-item test of cognitive impairment.  
 
 
X 
 
 
 
 
 
Demographic 
survey/medication 
Age; gender; type and history of MS; race/ethnicity; insurance status; 
living arrangements. 
 
 
 
X 
X 
X 
X 
X 
Short Assessment of 
Health Literacy-English 
(SAHL-E) 
SAHL-E contains 18 items to assess an English-speaking adult’s ability 
to read and understand common medical terms and estimate an 
adult’s health literacy level. 
 
 
 
X 
 
 
 
 
Neuro-QOL 
A validated outcome measure of quality of life sponsored by the 
National Institute of Health recommended by the American Academy 
of Neurology.  
 
 
 
X 
X 
X 
X 
X 
Modified Fatigue Impact 
Scale-21 
A 21-item self-report of the severity of fatigue and its effect on the 
participant’s activities and lifestyle over the past 4 weeks.  
 
 
 
X 
X 
X 
X 
X 
Multiple Sclerosis Impact 
Scale-29  
A 29-item self-report of participant’s views on the impact of MS on 
day-to-day life during the past two weeks. 
 
 
 
X 
X 
X 
X 
X 
Social Cognitive Battery 
See Table 2. 
 
 
 
X 
X 
X 
X 
X 
Participant Feedback 
Survey 
27-item survey obtaining participants’ feedback with the exercise 
program to assist with program modification and post-study 
dissemination. 
 
 
 
 
 
X 
 
 

 
 
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Adherence log is maintained weekly by participant to evaluate fidelity of the intervention across 
groups, as well as measure adherence with the protocol. 
Reason for group choice: If randomized to the choice group, the research coordinator will 
complete the Choice form, which asks questions to determine if the COVID pandemic influenced 
their decision-making process. If not administered at randomization, the Choice form will be 
completed at 16 weeks.  
Table 2. Social Cognitive Theory Battery 
Tool 
Description 
Exercise Self Efficacy Scale78  
10-item Likert scale measuring an individual’s self-efficacy to undertake 
exercise related tasks and overcome barriers related to exercising. 
Exercise Goal Setting Scale79 
10-item Likert scale assessing the extent an individual sets exercise goals.  
Multidimensional Outcome 
Expectancies for Exercise Scale80 
19-item Likert scale measuring an individual’s beliefs or expectations 
about the benefits of regular exercise or physical activity. 
Exercise Barriers 
8 questions to measure an individual’s beliefs about the barriers related 
to exercising.  
Social Provisions Scale82 
6-item scale measuring the degree to which respondent's social 
relationships provide various dimensions of social support in relation to 
physical activity. 
Physical Activity Self-Regulatory 
Scale84 
12-item scale measuring an individual’s self-regulation in relation to 
exercise. 
Barriers for Self-Efficacy  
13-item scale measuring individual’s self-efficacy to participate in 
exercise when encountering barriers.  
 
Once all baseline outcome measures are obtained, participants will be randomized and notified 
soon after by the site research coordinator of their group assignment. Randomization completes 
enrollment. 
 
COVID-19 Screening and Enrollment Procedures 
While trial sites are closed due to the COVID-19 pandemic, no screen 1s, screen 2s, Visit 1s, or 
associated enrollment activities will take place. Participants currently in the screening and 
enrollment process, will pause where they are. The recruitment coordinator from the enrolling 
site will contact those participants and let them know the study is on pause due to the pandemic 
and that they will be contacted again when enrollment resumes.  
• If enrollment resumes past the 60-day screening eligibility window (60 days from screen 
2 to visit 1; 60 days from visit 1 to starting exercise), the participant will be rescreened as 
determined appropriate by the site investigators.   
 
Prescreening activities, such as chart review and preliminary phone calls with interested 
participants will continue. Interested people will be informed the study is on hold and they will 
be contacted when enrollment resumes.  
 
Transfer of participant to coach 
Once a participant is randomized to their intervention group (GEMS-T or GEMS-S), the research 
coordinator will provide the respective coach the contact information for the participant. They 
will also provide the following information:  

 
 
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• If the site PI or RC deems the participant is a fall risk 
• The participant’s EDSS score 
• Whether the participant uses an assistive device 
 
To convey this information to the GEMS-T for the GEMS-T participants, the research 
coordinators will send an encrypted email to a secure, HIPAA-compliant email address at UAB 
with this information. This information is to inform the coach of functional status of the 
participant so that they can modify exercises to prevent falls.  
Follow-Up Assessment Procedures 
Timing of subsequent outcome assessments are summarized in Table 1. CROs and PROs will be 
administered again immediately post-intervention (at 16-weeks), and at 12 months post-
intervention. PROs will also be assessed at 8-weeks after the start of the intervention and at 6 
months post-intervention. Participants will complete their PROs at Visit 1, and 16-weeks, and 12 
months post-intervention in a private onsite room with the support of the research staff as 
needed, with the option of completing the SCT battery at home via the study portal. The research 
staff will not influence the survey responses but provide technical support to enhance 
completeness and quality of data. Participants will complete the 8-week and 6-month PROs via 
the secure online study portal (described below). 
COVID-19 Follow-up Assessment Procedures 
All enrolled participants will continue with their assessments on schedule. However, the type of 
assessments administered will differ from Table 1 while there are restrictions on accessing trial 
site facilities due to the pandemic. Specifically, no clinically reported outcomes (T25FWT, 
EDSS, 6MWT) will be administered. Research coordinators will verbally consent participants in 
waves 1 through 9 who are due for assessments via telephone prior to administering the PDDS at 
16 weeks and 12 months. Once COVID-19 restrictions are lifted, participants will be reconsented 
at their next on-site assessment visit to take the PDDS. Participants from wave 10 onwards will 
sign the amended ICF that includes the PDDS as a follow up assessment measure at enrollment. 
 
Data Collection Procedures 
All study data will be collected and maintained in a database accessible through a secure, HIPAA 
compliant study portal, developed by iConquerMS. To maintain confidentiality, all data collected 
and input to the portal will be linked to individuals via an individual identifying number, as 
described below under “Study portal security” (p18-19) and in the informed consent form. The 
research coordinator will help each individual create a portal account at Visit 1. 
We will use several measures to ensure that all post-intervention assessments (summarized in 
Table 1) are completed on time: 1) the research coordinator will contact participants 2 weeks 
prior to when outcomes are required via the participant’s preferred mode of communication (eg., 
email, text to smartphone or phone call; 2) the research coordinator will also place a reminder 
communication as above 24-48 hours before the post-test appointment; 3) the portal will also 
send electronic reminders to research coordinators and participants when assessments need to be 
completed and when PROs are not fully completed; and 4) the coaches will also remind 
participants during their scheduled coaching sessions about upcoming data collection dates.  
 

 
 
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The PRO and CRO data collected at each site will be entered into the study portal. The study 
portal provides real-time data checking alerting both research personnel and the participant 
immediately if data are not entered, or if there is a logical inconsistency with the data entered. In 
addition to the automated data verification, dedicated staff at iConquerMS will monitor 
completeness and fidelity of data on an ongoing basis and provide feedback to each site weekly 
regarding missing data. Simultaneously, the Project Manager at the Clinical Coordinating Center 
(Shepherd Center) will be provided with a report regarding data completeness and fidelity. Thus, 
there are daily indicators of completeness and quality of data, as well as daily oversight and 
weekly opportunities to rectify problems with data collection, entry and flow. The Project 
Manager, along with the PI (Backus) will work with the research coordinator at each site not 
only to obtain missing data when possible, but also to devise an individualized plan at any site 
that is routinely missing data.  
 
6-Month Assessments: The 6-month assessments were implemented after waves 1 through 4 
were consented and enrolled. The procedures for contacting and consenting these participants is 
as follows: 
• Waves 1 and 2 will receive an email from the Portal at 6 months post intervention 
explaining the addition of the 6-month assessments and requesting participants click on a 
link to an online consent form and complete the assessments (see email and online 
consent form in Appendix) 
• Waves 3 and 4 will be re-consented at their 16-week visit with a new paper informed 
consent form (ICF) that includes a description of the 6-month assessment 
• Waves 6 onwards will sign a new ICF that includes a description of the 6-month 
assessment at their baseline visit 
• Depending on the consenting date for wave 5, they will either be consented with the new 
ICF at baseline, or will follow the procedure for wave 3 and 4.  
• At 6 months, waves 3 onwards will receive an email from the Portal alerting them that it 
is time for them to log on and complete the 6-month surveys. 
All participants with outstanding assessments will receive weekly email reminders to log on and 
complete the 6-month assessments, and a reminder two days before the deadline. Research 
Coordinators will receive similar emails alerting them to contact participants to remind them to 
complete the assessments.  
 
Management of Withdrawals or Dropped Participants 
 
Lost to Contact 
If a participant is lost to contact for 2 weeks, the research coordinator will try to contact them via 
all modes of communication, including personal phone, emergency contact, text, email, and 
postal service.  
If the participant is lost for an additional 2 weeks (a total of 4 weeks), then they will be 
considered lost and dropped from the study. 

 
 
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If a participant is randomized to a treatment group but makes no contact in the first week, they 
will be dropped from the study.  
If a participant withdraws or is dropped from the study, the research coordinator documents the 
date and reason in the Portal. This information will be summarized annually for the site-specific 
IRBs as well as for the Shepherd (Primary site) IRB, the Advisory Board, and the Data Safety 
Monitoring Board (DSMB), and will be reported in the Final Project report. We will not 
automatically replace withdrawals, but will develop a strategy based on the attrition rate after the 
first few waves have completed the study.  
 
Other Withdrawals 
To assist with the study intent to treat analyses, the study will attempt to collect data from 
withdrawals. Research Coordinators will offer participants who withdraw three options: 
1) Early Termination Visit: Participants will return to the facility to complete a full set of 
CRO and PRO assessments (including the feedback survey) and subsequently their 
withdrawal will be processed. Participants receive the $25 travel stipend for the visit. 
2) Continue with assessments only: Participants will cease the exercise program but 
continue with assessments on schedule and per protocol. 
3) Complete an immediate withdrawal: Participants withdraw immediately and fully from 
both the exercise program and assessments.  
 
Should a participant choose 1) or 2), they will sign a new consent form with information about 
participating in these withdrawal assessments (ICF Withdrawal – Early Termination Visit or ICF 
Withdrawal – Assessments Only).  
 
INTERVENTION 
There are two modes of delivering the evidence-based, individualized exercise program: Facility-
based exercise training (GEMS-S) and Telerehab-based exercise training (GEMS-T). GEMS-S 
will be delivered at each of the eight recruiting sites (n=200) and GEMS-T will be delivered via 
UAB within a participant’s home/community (n=200). Both GEMS-S and GEMS-T consist of an 
identical, individualized exercise program based on evidence-based exercise guidelines. 
Participants will undertake both aerobic and resistance training of moderate intensity twice per 
week for 16 weeks (4 months), based on these conditions: 
a. The prescription is individualized, based on each participant’s ability. All participants are 
provided a low-level prescription to try for one week. They are asked to monitor how 
they feel, and at the end of the first week, they are contacted by a coach (GEMS-S 
participants in person at the facility; GEMS-T participants via video-chat). The goal is for 
the participant to gradually progress toward meeting the exercise guidelines.  
b. The elements of the intervention were chosen to facilitate self-management of exercise, 
as well as to maintain the integrity of the intervention across delivery modes (GEMS-S 
and GEMS-T). All participants will receive a hip-worn pedometer to monitor steps. This 
information is to monitor fidelity of the exercise implementation only, and the participant 
will also record this information on their adherence log for each session. For aerobic 
training, the walking speed in the natural environment (GEMS-T) are adjusted to get the 
desired 100 steps/minute and target heart rate (HR) based on HR reserve and target zones 

 
 
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defined by the American College of Sports Medicine.44 The target stepping rate and HR 
correspond to moderate-intensity exercise in persons with MS. 
c. Resistance training consists of 1-2 sets, 10-15 repetitions of 10 exercises targeting lower 
body, upper body, and core muscle groups performed 2 days per week. Participants start 
with the amount of resistance at which they can perform 10-15 repetitions. GEMS-T 
participants will receive bands to use at home, and GEMS-S participants will be given 
bands to use and keep by each site.  
d. There are three separate levels of difficulty of the exercise intervention (orange, blue, 
white) that the participant chooses in discussion with their behavioral coach. This mutual 
decision is based on participants’ experience following the first two weeks of the 
program and coaches’ perception of how they did. The levels of difficulty vary in terms 
of progression toward meeting the exercise guidelines. This feature is critical for 
accommodating the various levels of ability we anticipate for our participants. Much like 
those who do not have a disability, each participant may start at a different level; the goal 
is for each participant to exercise at moderate intensity by week 10 of the intervention.  
e. Participants in both groups receive a detailed manual outlining safety information, 
description of equipment/materials, and all exercises. GEMS-S participants will have 
access to a coach in the facility who can provide guidance regarding exercise training. 
GEMS-T participants will receive a DVD and a printed exercise manual with actual 
demonstrations of all the resistance exercises, including modifications for differing levels 
of physical capability to maximize safety. Two people with MS and one member of the 
research team serve as the models for the exercises. 
f. Procedures to prevent falls include providing all participants with a fall risk prevention 
information packet during enrollment and or during the first coaching session. Coaches 
will also implement the following coaching instructions: 
a. If the participant is at risk for falls, they will perform the resistance exercises in 
sitting; 
b. If the participant uses an assistive device, they will be instructed to use one while 
doing the walking exercises; 
c. If the participant needs someone with them to be steady, or if there is a wall 
where they can walk, they should use these resources to be safe; 
d. The participant will be instructed to only walk as fast as they can do so safely, and 
to focus on increasing their number of steps first. 
g. Each participant will maintain an exercise logbook that will provide training specific data 
that will be used to evaluate fidelity of the intervention across groups, as well as to 
measure adherence with the protocol. Participants will record missed sessions and the 
reason for the miss, and if the session was made up during the corresponding week. 
Participants will also log steps information from their pedometers on the exercise 
logbook after each exercise session. For GEMS-S, the site coach will collect the exercise 
logbook on a weekly basis and enter the data into the Portal. For GEMS-T, participants 
will input their adherence data directly into the Portal each week.   
h. The exercise coach will check the exercise logbook for each participant and will 
document in the study portal: 
i. 
Missed sessions 
ii. 
Any reports of adverse events 

 
 
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GEMS-T coaches will review participant logs prior to their scheduled one-on-one 
sessions. If there is missing data, the coach will obtain the information during the 
coaching session, including any information about adverse events (AEs). The GEMS-
T Project Coordinator will review the exercise logs each Friday on non-coaching 
weeks for submission status and notification of AEs. For participants who have 
missing data, the GEMS-T Project Coordinator will attempt to contact them to remind 
them to complete the missing log entries and check to see if they are having any 
issues accessing the portal. 
If a GEMS-S participant misses an exercise session, the facility coach will 
attempt to contact the participant to find out why and if the participant has had an AE. 
For follow up calls regarding missed exercise logs or sessions, the GEMS-T and 
GEMS-S Coaches will log the call date, result (reached/message left), and any 
important details in their log. If the coach cannot reach the participant, they should 
leave a voicemail reminding the participant to complete the log. If the participant has 
not updated their weekly log by the following Friday, the coach will attempt to 
contact them again. 
i. 
At the end of the 16 weeks of exercise, GEMS-S coaches will make a copy of the 
exercise logbook and upload it to a site-specific, secure Microsoft OneDrive folder 
housed by UAB. Research coordinators will request that GEMS-T participants bring in 
their exercise logbooks to their 16-week visit, whereupon they will make a copy of the 
logbook and upload to OneDrive. GEMS-T participants who forget to bring their 
logbook to the visit, will be given a stamped, addressed envelope to mail it to the site. 
The logbook will subsequently be returned by mail to the participant. See Data Safety 
and Adequacy section below for details on Microsoft HIPAA compliance.  
j. 
In order to respond to adverse events in a timely manner, the Project Coordinator at 
UAB will check exercise logs weekly and follow the adverse event reporting procedures 
outlined below.  
k. 
The project manager will follow up with the coaches for all the above items and take any 
necessary appropriate action. 
 
COVID-19 Intervention Procedures 
While site training facilities are closed, we will implement the following procedures for GEMS-S 
participants in weeks 1 to 16 of exercise: 
• Wave 7: Wave 7 participants were in weeks 15 or 16 of the intervention at the time of the 
March 2020 COVID shutdown. Participants ceased on-site exercise and received their 
exercise materials and final instructions by mail. 
o Both coaches and research coordinators called participants to let them know that 
while the training in the facility had to stop, they remained active participants in 
the trial. This meant that research staff would contact them to complete follow up 
assessments at 16 weeks, 6 months, and 12 months as per the protocol and 
schedule.  
• Wave 8: Wave 8 participants were in weeks 5 or 6 at the time trial facilities were closed 
and were informed their exercise on-site and their one-on-one coaching sessions would 
cease. Subsequently, the Steering Committee decided to offer these participants the 
opportunity to continue their GEMS program with supervision at home “GEMS-S 

 
 
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remote.” GEMS-S remote exercise continued per the procedures described below and in 
the figure. 
• GEMS-S remote intervention procedures: In the case of site restrictions for on-site 
research activities, Research Coordinators will call the GEMS-S participants to describe 
the option to continue exercising at home (GEMS-S remote) with supervision by the 
facility coach provided via IRB-approved video conferencing or telephone. 
o Interested participants will provide verbal consent, which will be logged in the 
study portal.  
o Research staff will mail each participant their exercise kits and the coach will 
schedule twice weekly exercise sessions and the one-on-one coaching session if 
appropriate (dependent on the week of the exercise program).  
o The exercises will be performed per the GEMS-S protocol starting at a week 
agreed upon by the coach and participant. Only the resistance exercises (not 
walking) will take place by videoconferencing/phone call. The exercise sessions 
will not be recorded. 
o The schedule will continue as originally defined with the exercise ending at 16 
weeks. 
o Participants can opt to not participate in the GEMS-S remote option. Those who 
decline consent will be asked to continue in the trial by completing assessments 
on schedule. Those who decline will be withdrawn from the trial.  
 
GEMS-S remote Exercise Procedures 

 
 
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• GEMS-T participants will continue with their virtual coaching and exercise sessions on 
schedule. GEMS-T coaches will add advice to their coaching sessions relating to how to 
exercise while maintain safe COVID-19 social distancing measures. They will also log 
any interruptions in training related to COVID-19. 
• Any participants enrolled in wave 9 will not begin exercising until site COVID-19 
restrictions are lifted. Research coordinators will call wave 9 participants and let them 
know that they will contact them again when the study resumes exercising. Depending on 
when this is, participants may require further screening. 
 
Behavioral Training 
The physical exercise program is supplemented with a behavioral training intervention 
developed by Motl et al., based on Social Cognitive Theory (SCT) in people with MS.56 The 
behavioral component entails regular meetings with MS exercise specialists (i.e., behavioral 
coaches), informational newsletters, detailed training manuals, and log books for self-
monitoring. Personal interactions with coaches are conducted in person for GEMS-S participants 
and via one-on-one, semi-structured, online video-chat sessions for GEMS-T participants using 
web cameras and a HIPAA compliant teleconference system based on participant resources and 
preferences. If participants do not have access to the internet, the video-chats are replaced with 
phone calls. The in-person and online video-chat sessions will coincide with delivery of 
newsletters and supplement the content of the newsletters. The newsletters provide instructional 
material, websites for more information, testimonials of individuals who have experienced 
benefits of exercise, and tips for participants to try at home. GEMS-S participants will receive 
newsletters in person and GEMS-T participants will receive them electronically. 
 
The sessions with the coach are designed to provide participants with feedback and information 
on how to progress through the exercise program as well as social accountability. Coaches will 
be research staff at each site for GEMS-S and at UAB for GEMS-T. Participants will be assigned 
to one coach based on availability. Before beginning the study, coaches will receive training 
from Dr. Motl in behavior change for physical activity, and this will be comprised of information 
regarding SCT and its application for motivating ongoing behavior change through supportive 
accountability and discussions of newsletter content. We will maximize consistency among 
coaches by using standardized scripts for guiding each video-chat. The scripts will contain (a) 
questions to obtain feedback from participants on progress in the program, (b) confirmation of 
receipt and reading of the relevant newsletter (c) discussion points linked with the relevant 
newsletter, and (d) opportunities for participants to ask any questions. Coaches will meet weekly 
and discuss interactions with participants to facilitate cohesion on how coaches respond to 
participants’ needs, questions and experiences. 
 
Coach auditing 
Coaching sessions will be audited to ensure that coaches are delivering the intervention as 
intended. Once per week, on coaching weeks (when coaches discuss newsletters), a coach will 
randomly choose a coaching session to audio record. A different participant will be audited each 
time a coaching session occurs. Coaches may record sessions on whichever recording device 
they choose, as long as it is in compliance with site IRB regulations.  
 

 
 
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Prior to audio recording, the coach will obtain the participant’s permission by asking the 
participant to sign the HIPAA authorization and release agreement to be audio-recorded. 
 
UAB will review the audio and conduct the audit using a coaching audit checklist. Subsequently, 
UAB will then provide feedback to the coaches via email.  
 
See Data Safety and Adequacy section below for details on how the audio will be securely 
shared with UAB and audio recording security measures. 
 
ADVERSE EVENT MANAGEMENT 
We define adverse events as follows: 
• Adverse Event - Any untoward medical event occurring in a patient or subject enrolled in 
a clinical trial, regardless of whether the event has a causal relationship with the 
treatment under investigation.  
• Serious Adverse Event - Any adverse experience that results in any of the following 
outcomes: death, a life-threatening event, requires or prolongs inpatient hospitalization, 
results in persistent or significant disability/incapacity. Important medical events that 
may not result in death, be life-threatening or require hospitalization may be considered a 
serious adverse event when: a) they may jeopardize the patient or subject, b) may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition, or 
c) a reasonable possibility exists that the event may have been caused by the test article.  
 
Ongoing reporting of adverse events (AEs) and serious adverse events (SAEs) to the IRB and 
PCORI will follow the policies and procedures of the Shepherd Center, as outlined in policy 
AC.RES.01.06 “Unanticipated Problem, Death, and Adverse Event Reporting” and participating 
IRBs. Specifically: 
• The Study PI is responsible for accurate and timely reporting of adverse events in the 
source documentation. The PI is responsible for reporting SAEs and unanticipated 
problems (UPs) to the IRB within 10 days of their occurrence.  
• Site Co-Investigators are responsible for reporting SAEs and UPs to the study PI at 
Shepherd within 72 hours using the portal AE form. For SAEs and UPs only, the 
reporting site personnel should also send an email to the study PI, site PI, coach, research 
coordinator, and the study Project Manager to ensure all receive timely notification.  
• Either coaches or research coordinators can file the AE/SAE form on the portal and must 
communicate with each other to ensure the report is filed within the required timeline 
(see Table 3). If coaches start an AE form, they should simultaneously email the site 
research coordinator with a description of the event and the research coordinator will 
complete follow up and submit the form.  
• All study investigators are responsible for recording all new clinical experiences, 
exacerbations, and/or deterioration of any existing clinical condition occurring after a 
study subject has signed informed consent. Research staff will also provide follow-up 
information on all adverse events until resolution or an appropriate endpoint is reached.  
• Adverse Events will be documented and reported as follows: 
o Participant experiences an event, logs a description of the event in their 
participant diary/log and immediately contacts his/her coach or site research 

 
 
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coordinator, who follows the site-specific reporting steps (see Table 3 and Figure 
3).  
o The UAB Project Coordinator checks the exercise logs weekly for GEMS-T 
participants and identifies an AE, and follows the reporting steps in Table 3 and 
Figure 3. Or,  
o Participant experiences an event while with his/her coach, and the coach logs the 
event and follows the site-specific next steps (Table 3 and Figure 3). 
 
Table 3. Unanticipated Problem, Death, and Adverse Event Reporting (AC.RES.01.06) 
Internal Event 
Reporting Timeline 
Internal  
Death of any subject 
Report promptly within 72 hours of site’s knowledge of event using the 
portal AE form and send email to study PI, site PI, Project Manager (PM), 
and site research coordinator (RC). PM reports to Shepherd RRC within 10 
calendar days using Shepherd Research Review Committee (RRC) “UP, 
Death & SAE Report Form.”  
Internal  
Unanticipated Problem (UP) 
Report promptly within 72 hours of site’s knowledge of event using the 
portal AE form and send email to study PI, site PI, PM and RC. PM reports 
to Shepherd RRC within 10 calendar days using Shepherd RRC “UP, 
Death & SAE Report Form” on the study Portal. 
Internal  
Serious Adverse Event (SAE) (non-
UP) 
Report promptly within 72 hours of site’s knowledge of event using the 
portal and send email to study PI, site PI, PM and RC. PM reports to 
Shepherd RRC within 10 calendar days using Shepherd RRC “UP, Death 
& SAE Report Form.”  
Internal 
Adverse Event (AE) that is Not 
Serious 
Do not report to RRC. Record event using the AE reporting form on the 
study Portal within 10 days of initial report.  
 
Note:  An Adverse Event that is not serious by definition may be reported 
promptly, if in the opinion of the investigator, the event occurred with 
greater frequency, duration, or at a higher level of severity than expected. 
Internal 
Unanticipated Adverse Device 
effect (UADE) 
Report promptly within 10 calendar days of site’s knowledge of event 
using Shepherd RRC “UP, Death & SAE Report Form” on the study 
Portal. 
Internal 
Investigational New Drug Safety 
Reports, i.e. investigator initiated 
If the report meets the criteria for UP, report promptly within 10 calendar 
days of site’s knowledge of event using Shepherd RRC “UP, Death & SAE 
Report Form” on the study Portal 
 
If a physician instructs a participant to pause exercising, the site research coordinator must obtain 
medical clearance from the participant’s physician before resuming exercise. If the participant’s 
physician does not instruct a participant to stop exercising, the site PI determines whether or not 
medical clearance after an AE is required.  
 
Site research coordinators will inform the participant’s coaches when medical consent has been 
obtained and the participant is approved to resume exercising. 
 
Figure 3 below provides additional detail regarding how AEs are reported and addressed. 

 
 
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Figure 3: AE Reporting and Follow up Procedures 
 
DATA ANALYSIS 
Data analysis plan 
The primary hypothesis is a non-inferiority test of the changes in T25FWT between GEMS-T 
and GEMS-S. This will be tested using a linear model with site as the stratification factor and an 
intention to treat approach. The primary analysis will adjust for covariates age, gender and 
baseline EDSS or PDDS. Further addition of covariates may be examined in sensitivity analyses 
based on any differences seen on examination of baseline variables between groups. Secondary 
endpoints include change in 6MWT and EDSS/PDDS. In all endpoints, we are assessing 

 
 
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improvement over baseline values. We will examine the frequency of worsening as a safety 
comparison. We will also examine the primary endpoint of a 20% improvement in the T25FWT 
(yes or no) using logistic regression. Further, to characterize the changes over time, we will use 
linear mixed models to assess the slopes of change for GEMS-S versus GEMS-T groups. We 
will also examine the relationship between the dose of exercise measured by compliance and the 
change in the primary and secondary outcomes. These are exploratory outcomes to see if the 
compliance measures predict the benefits on the outcomes. This information is important for 
translation and information dissemination to people with MS. 
 
To evaluate and compare the effectiveness between participants randomized to their preferred 
delivery mode (GEMS-T [Choice] or GEMS-S [Choice]) with those who are not randomized to 
their preferred delivery mode, we will use the same analysis model but examine an interaction 
term for choice and treatment. We will assess if the effect of Choice is the same for both 
treatments. Logistic regression will be used to assess the interaction between choice and 
adherence and attendance or dropouts. We also will examine time to dropout and/or time until 
dropout or poor compliance (which will be defined prior to final analyses). We also are 
interested in examining the intensity or compliance of the intervention to the choice as well as 
impact on the primary endpoint as noted above. 
 
We will also utilize mediation analyses to understand if the changes induced by exercise are 
mediated via the changes in self-efficacy. Here we will use the approach by MacKinnon built on 
Judd and Kenny.45-51 The MSWS-12, MFIS-21 and Neuro-QOL will all be analyzed using 
regression models similar to the timed walk models above and will utilize the same contrasts for 
examining choice as well as treatment effects. 
 
DATA MANAGEMENT 
The Data Management Center (DMC) will be housed at the Accelerated Cure Project/iConquerMS 
led by project co-investigator, Robert McBurney, PhD. The DMC will collaborate and communicate 
with the Steering Committee and Advisory Board as outlined in Table 4.  
Table 4. Responsibilities/Tasks of Data Management Center (iConquerMS/McBurney) 
Review the proposed trial protocol and contribute to finalizing that document 
Develop electronic and paper case report forms for data collection 
Develop Standard Operating Procedures and a study Manual of Procedures 
Develop and maintain an electronic data management system that will include a web-based data entry system and 
project website for the study 
Create, distribute and oversee data entry processes for all sites 
Train and certify users from each site in the data entry 
Receive, collect, process, store provide quality control and assist in data analysis of data collected from the 
participating clinical sites and central reading centers 
Prepare and distribute periodic technical and statistical reports to the Steering Committee, participating sites, 
committees (including the DSMB) and the PCORI office, as appropriate 

 
 
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Data safety and adequacy 
Each participant will be assigned a study ID number when they create an account after passing 
eligibility criteria. This will be the only identifier in all databases and systems used in this study. 
Each site investigator will have access to their own master file linking participants with their 
randomized assignment, but this file will be stored on the Portal and kept separately from 
participants’ assessments.  
 
Research data will be entered online through the secure portal system and source documents, 
such as the CRO forms, will be kept in a secure fashion. All hard copy documents, such as 
consent forms, will be kept in a locked cabinet, and all soft copy documents, such as screening 
and adherence logs, will be password protected.  
 
To ensure the EDSS is performed uniformly across all sites, research coordinators will upload 
scanned, completed EDSS source documents to Shepherd Center’s Microsoft 365 cloud. In order 
to ensure HIPAA compliance, Shepherd Center has a Business Associates Agreement (BAA) 
with Microsoft as well as appropriate security controls in place to ensure the confidentiality, 
integrity, and availability of the source documents.. Each research site will have their own site-
specific folder to upload their EDSS forms to. EDSS forms should not contain any personally 
identifiable information, only the participant ID number and evaluator name.  
 
For coaching audits, the coach will upload the file to their site-specific folder housed by UAB’s 
Microsoft 365 cloud. UAB also have a BAA with Microsoft. Files will be labeled: [site 
name]_[wave #]_ session #_ date_participant ID. After uploading the file, the coach will delete 
the audio file from the recording device. Audio recordings will be stored on a password-
protected computer on a server central to UAB.  All audio data will be erased upon the 
completion of each wave of recruitment. 
 
Copies of exercise log books we be uploaded to a site-specific Microsoft 365 cloud folder 
housed by UAB, saved with the participant’s study ID. 
 
Staff from iConquerMS will monitor and track errors, completeness with routine reports and 
feedback to the sites. Data will be shared with the Statistical Center at UAB, who will provide 
analyses using SAS, SPSS, R and other programs, as necessary.  
 
Study portal security 
The Portal components are created in the web content management system 
Drupal (https://drupal.org/). The Portal has design aspects that are sensitive to those with vision 
issues due to symptoms of the disease (e.g. color, size of type, etc.,) as well as compliance with 
Section 508 of the 1998 amended Rehabilitation Act. The portal has been designed to be usable 
on tablets and higher resolution smart phones to make it possible for all users – those with access 
to PCs or without – to participate. The portal’s Survey Engine leverages the CURE 
framework, an enterprise data collection tool (eDCT) originally developed for the NIH-
NCI (https://github.com/NCIP/edct-formbuilder). 
Data collected through the Portal is stored in a commercial-grade, cloud-based, HIPAA 
compliant, secure data center. Data is backed up daily. Offsite backups may be held by a third 
party to guard against data loss.  

 
 
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Appropriate security measures have been put in place to minimize risks such as loss 
of confidentiality, identity theft, electronic fraud/security breaches, electronic monitoring, 
stalking or bullying, hacking, and phishing. Access to the data center is physically limited to 
authorized personnel. Password-protected access to the server will be granted to study staff and 
vendors with access permissions set based on their roles in the study. Data is encrypted at rest 
with keys available only to appropriate users. All data transmission (uploading and downloading) 
occurs over secure, encrypted channels.  
 
Individual accounts requiring unique usernames and passwords will be created for participants. 
Identifiers will be stored separately from other data types to protect the privacy of individual 
participants. Data will be de-identified when viewed by anyone but the participants themselves 
and authorized study staff. ACP will legally require anyone accessing participant-contributed 
data to agree not to attempt to learn the identity of any participant, or present or publish data in 
which an individual can be identified.  
 
STUDY SITE COORDINATION 
This is a multi-site trial, with Shepherd Center as the prime site and eight other collaborating 
sites: the University of Alabama, Birmingham; the Tanner Center, Birmingham; the University 
of Georgia, Athens; the Cleveland Clinic Mellen Center for MS Treatment and Research, Ohio; 
the University of North Carolina, Chapel Hill; Massachusetts General Hospital, Boston; the 
University of Colorado; and Marquette University, Wisconsin. 
 
Figure 4 presents the organizational structure for the study. Dr. Backus and Dr. Motl will provide 
oversight of all study activities.  
 
 
Figure 4: Organizational Structure 
 
 
 

 
 
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Training 
A Study Binder will be created that will specifically define all data collection and recording 
processes, and provided to each site. Training materials will be accessible electronically by all 
sites.  
Shepherd Center investigators will train all collaborating sites in all study procedures as defined 
in this protocol, and provide each site with the Study Binder that will provide detail of all study 
procedures and processes. All research staff collecting outcomes will be trained in these 
procedures prior to the commencement of the study. This will include training in all recruitment 
and enrollment procedures for which they will use IRB-approved recruitment tools that we 
develop. We will provide each site with the appropriate forms for data collection, and training 
regarding recording procedures, as well as use of the study portal and database.  
There will be an annual follow up at each site to ensure that processes and procedures are being 
followed with fidelity. If there is a change in the study personnel, the new personnel will be fully 
trained in the same processes and procedures. Data collection training will also be repeated 
annually. Data will be entered in the HIPAA-compliant, secure portal and maintained by 
iConquerMS with oversight by Ms. Palmer and Dr. Backus. Sites will be responsible for 
maintaining all aspects of the database entered from the clinic, and staff support from 
iConquerMS will be available to trouble shoot technical questions. Access to this data will be 
restricted to study personnel only. Individual site coordinators will each have a unique username 
and password to enter the participant information.  
The Project Manager will monitor enrollment numbers monthly to ensure that all sites are 
reaching milestones for recruitment. If one site is not reaching milestones, the co-PIs will 
reevaluate the recruitment strategy and determine if another site(s) can recruit/enroll more 
participants to cover the shortfall.  

 
 
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APPENDICES 
Consent Script for Verbal Consent 
Informed Consent Form 
Informed Consent Form for Withdrawal - Early Termination Visit 
Informed Consent Form for Withdrawal – Assessments Only 
Recruitment Flyer 
Social Media Recruitment Post 
Staff CVs 
CITI Certificates 
Project Milestones 
Fall prevention packet 
Medical consent form – follow up after Adverse Events 
Consent to audio record coaching sessions 
Email to wave 1 and 2 participant 
Email to wave 3 onwards participants 
Online consent for wave 1 and 2 participants 
NMSS Mood and Cognition Handout 
Tanner Center online consent 
Letter to wave 7 GEMS-S participants 
 
 

 
 
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