Comparative Effectiveness Trial Between a Clinic- and Home-Based Complementary and Alternative Medicine Telerehabilitation Intervention for Adults With Multiple Sclerosis (MS)
Phase: NA
Conditions: Multiple Sclerosis
Sponsor: University of Alabama at Birmingham

Comparative Effectiveness Trial Between a Clinic- and Home-Based 
Complementary and Alternative Medicine Telerehabilitation Intervention for 
Adults with Multiple Sclerosis (MS) 
NCT #: NCT03117881 
TEAMS Study Protocol and Statistical Analysis 
Plan Document Version Date: August 20th, 2022 

 
1 
METHODS 
Study Overview 
The TEAMS study was a cluster randomized, comparative effectiveness trial comparing 
the effectiveness of TeleCAM and DirectCAM delivered at 43 clinics across Alabama, Mississippi, 
and Tennessee.  There were 40 clinics initially randomized and 3 satellite sites including 
Cookeville, Ashland City and Mobile were added later. These 3 satellite sites were not 
randomized as they were close to and were associated with support groups at the existing 
randomized sites. The satellites sites were recruited to alleviate logistical challenges in 
throughput around baseline testing after enrollment.   
  Using the clinics as the units of randomization, our criteria while identifying clinic sites 
were to minimize the risk of contamination while having enough sites for a cluster 
randomization, ability to detect a small to moderate effect size, and ability to recruit efficiently.  
The randomization list was run by a study statistician who was not involved in any participant 
interaction and intervention delivery.  Given the nature of this study design, group assignments 
were not blinded to participants and study staff involved in the intervention delivery but were 
blinded to data analysts.   
Study Setting 
Main Study 
The clinical partners consisted of 5 occupational therapists and 83 physical therapists 
and assistants at 43 clinics in three States: 19 in Alabama, 16 in Mississippi and 8 in Tennessee. 
Of these 43 clinic sites, 5 of the sites were considered small towns or rural, 10 were considered 

 
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micropolitan, and 28 were considered urban metropolitan.  All clinics were considered 
outpatient rehabilitation clinics; however, 4 were located within hospitals, 38 were considered 
private practice and one site was a comprehensive MS center.  Figure 1 highlights the 
geographic location of clinical partners within each state (Alabama, Mississippi, and Tennessee).  
 
Figure 1. Geographic Location of the TEAMS Clinical Partners (clinics= 43) 
 
 
 
 

 
3 
 
Enhancement Study  
For the Enhancement study, participants received all testing through a teleassessment 
platform, followed by 20 synchronous telerehabilitation sessions in line with our original study 
design for the other two arms (TeleCAM, DirectCAM).  A total of 8 physical therapists were 
involved in the testing and rDirectCAM delivery of the Enhancement study.  
 
Participants 
The study population included people with MS in the states of Alabama, Mississippi, and 
Tennessee. Interested participants were enrolled if they self-reported a diagnosis of MS, with a 
PDDS score between 0 and 7.  The PDDS is an ordinal scale ranging from 0 (Normal) to 8 
(Bedridden).  It is a simple and practical tool for measuring self-reported disability status for 
people with MS56-58 and has a strong correlation (rs=0.8) with the Expanded Disability Status 
Scale (EDSS)56.  Additional inclusion criteria included ages of 18 to 70 years, able to use arms 
and legs for exercise, and physician clearance.  Exclusion criteria included: 1) significantly 
impaired acuity that prevented seeing a tablet screen to follow home exercise program; 2) 
cardiovascular disease event within the past six months, severe pulmonary disease, renal 
failure; 3) active pressure ulcer; 4) currently pregnant; 5) within 30 days of receiving an exercise 
or rehabilitation program; 6) Godin Leisure Time Exercise Questionnaire (GLTEQ) score ≥ 24. 
The GLTEQ contains two questions.  The first question asks participants to report weekly 
frequencies of activities they perform at different intensities. A total weekly leisure activity is a 
sum of activity scores calculated by multiplying the weekly frequencies of strenuous, moderate, 
and light activities by 9, 5, and 3, respectively. The second question asks participants the 

 
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frequency of weekly leisure-time activities performed that are long enough to work up a sweat.  
The scale has been validated and used in previous research with people with MS59,60. 
Adverse events (AEs) were monitored following types defined by the Behavior Change 
Consortium of the National Institutes of Health61, which included: falls, cardiovascular-related 
episodes, musculoskeletal-related events and health care use. The study was approved by the 
Institutional Review Board of the institution and was conducted in accordance with a clinical 
trial protocol registered at ClinicalTrials.gov.   
 
Interventions and Comparators or Controls 
 
The two study arms received the same CAM intervention, and the comparison was 
between the on-site delivery (DirectCAM) versus the asynchronous delivery (TeleCAM). The 
CAM intervention is a 12 week intervention (3 month) composed of 20 sessions that were 
structured into two segments: the first 8 weeks consisted of two 1-hour sessions per week that 
included 3 components: 20-minute yoga exercise routine62-69; 20-minute Pilates exercise 
routine70-74; and a 20-minute routine of dual tasking and functional exercises that involved 
multifaceted training such as multidirectional upper extremity reaching while carrying on a 
conversation, and ball bouncing while tracking the ball with head and eye movements75,76.  
From weeks 9 to 12, the intervention transitioned to one session per week that focused on 
yoga and Pilates.  The intervention was adapted and tailored toward the functional level of 
each participant, determined by the time it took for participants to complete the Timed 25-Foot 
Walk (T25FW) test.  There were 4 functional levels provided.  A participant who had a T25FW 
score of less than 6 seconds was assigned to TEAMS 1, a T25FW score of 6 to 7.99 seconds was 

 
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TEAMS 2, a T25FW score of more than 8 seconds was TEAMS 3, and if unable to complete the 
T25FW, TEAMS 4 was assigned. If the participant self-reported a diagnosis of osteoporosis and 
was able to complete the T25FW, they were assigned to TEAMS 3-OP. Those with a diagnosis of 
osteoporosis that were unable to complete the T25FW were assigned to TEAMS 4-OP.  TEAMS 1 
and TEAMS 2 completed the intervention exercises in prone, supine, long sitting, standing, and 
quadriped. TEAMS 3 and TEAMS 3-OP completed the exercises in a chair and with an assistive 
device for support in standing. TEAMS 4 and TEAMS 4-OP completed all the exercises in a chair. 
All TEAMS levels included ways to tailor the exercises to better align each participant’s 
functional level.  Figure 2 demonstrates examples of the exercises and adaptation of the CAM 
intervention.  
Figure 2. Examples of the CAM Intervention Exercise and Adaptation 
Program 
Component 
Sample Content 
Modification Examples 
Yoga 
Exercise 
(20 
minutes) 
Tree Pose Standing:  1) 
Begin in standing. Bring 
shift your weight to 
your left side and bend 
your right knee sliding 
your foot against your 
inner thigh to your 
farthest range 2) Bring your hands into prayer 
position with your thumbs resting on your chest. 3) 
Hold this pose for four breaths. 
Chair: 1) Begin sitting in a chair. Extend your left leg 
out straight and shift your weight to your left side. 
2) Bend your right knee and slide your foot against 
your inner thigh to your farthest range. 3) Bring 
your hands into prayer position with your thumbs 
resting on your chest. 4) Hold this pose for 2 
breaths 
Lower difficulty: Bring the right 
foot to the left ankle to rest on 
the toes without sliding up. 
 
Higher difficulty: Extend arms 
out above instead of in prayer 
position. 

 
6 
Pilates 
Exercise  
(20 
minutes) 
Spine Twist Long sitting: 1) Start with sitting on the 
floor with legs extended in front of you and arms 
open to your sides at shoulder height. 2) Exhale and 
rotate your torso to the right side (twist); make 
sure your head and arms follow 3) Inhale and 
return to starting position. 3) Exhale and rotate 
your torso to the left side (twist); make sure your 
head and arms follow  
Chair: 1) Sitting in a chair with both feet on the 
floor and arms open at your sides at shoulder 
height. 2) Exhale and rotate your torso to the right 
side (twist); make sure your head and eyes follow 
as well. 3) Inhale and 
return to starting 
position. 4) Exhale and 
rotate your torso to the 
left side (twist); make 
sure your head and eyes 
follow as well. 
Lower difficulty:  Cross arms 
across chest instead of 
extended at sides. 
 
Higher difficulty: 1) Utilize a 
TheraBand with arms extended 
for long sitting exercise 
challenge 2) Sit on the Pilates 
disc for chair exercise 
challenge.  
Dual 
Tasking 
Exercise  
(20 
minutes) 
Dual Tasking: Vision: 
Smooth pursuits and 
Vestibular Ocular Reflex 
exercises; Cognition: 
Process Speed exercises 
through alphabet object 
naming and simple 
mathematic tasks; Gross and fine motor 
coordination: Dysdiadochokinesia exercises  
Lower Difficulty: 1) Perform 
same tasks while sitting 
supported in chair. 
Higher difficulty: 1) Perform 
same tasks while sitting on 
physioball or Pilates Disc; 2) 
Perform same tasks while 
standing in partial tandem, 
tandem or on a Pilates Disc. 
 
Participants were given exercise equipment after baseline testing for the Main Study. Both 
arms received the same equipment based on their TEAMS level. The TeleCAM arm received a 
tablet and tablet stand in addition to the exercise equipment. The DirectCAM received the 
exercise equipment to use at home, and the clinic kept a set of equipment for use at onsite 
visits.   Table 2 provides an overview of the CAM intervention for the Main study.   
 

 
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Table 2. Exercise Equipment by TEAMS Level 
Equipment 
TEAMS Level 1  
TEAMS Level 2 
 
TEAMS Level 3 
 
TEAMS Level 4 
 
Racquet Ball 
√ 
√ 
√ 
√ 
Yoga Strap 
√ 
√ 
√ 
√ 
Theraband 
√ 
√ 
√ 
√ 
Pilates Disc 
√ 
√ 
√ 
√ 
Sliders 
√ 
√ 
√ 
√ 
Yoga Mat 
√ 
√ 
√ 
√ 
Yoga Block 
√ 
√ 
√ 
 
Physioball 
√ 
√ 
√ 
 
Half Roll 
√ 
√ 
 
 
Tablet 
(TeleCAM) 
√ 
√ 
√ 
√ 
Tablet Case 
(TeleCAM) 
√ 
√ 
√ 
√ 
Tablet Stand 
(TeleCAM) 
√ 
√ 
√ 
√ 
TEAMS: Tele-Exercise and Multiple Sclerosis, CAM: Complementary and Alternative Medicine, T25FW: Time 25 Foot Walk score.  
TEAMS level 1: T25FW <6 seconds, TEAMS level 2: T25FW 6-7.99 seconds, TEAMS level 3: T25FW >8 seconds, TEAMS level 4: 
unable to complete T25FW. 
For the Enhancement study, participants received an additional set of equipment (in addition to 
the exercise equipment) that was shipped to their home for completing the teleassessment 
protocol.  The teleassessment equipment provided to participants in the Enhancement study is 
outlined in Table 3. For safety considerations, rDirectCAM participants who had a PDDS score of 
5, 6, and 7 were not given any tests related to ambulation. Hence, two different sets of 
equipment were provided: one for participants with a PDDS score of 0-4 and another for 
participants with a PDDS score of 5-7.  
DirectCAM. DirectCAM participants were asked to work with a therapist at the assigned 
clinic to complete the 20 one-hour training sessions as described in Figure 2.  A 
therapists training manual and a DirectCAM session checklist were used to ensure 
intervention fidelity across therapists (see Appendices A and B).  At the end of the 12-

 
8 
week intervention, the DirectCAM participants received a set of instructions and 
handouts (see Appendix C) with photos demonstrating the exercises and were asked to 
continue the program in their home for up to one-year post-intervention initiation (i.e., 
9 months after the completion of the intervention delivered at the clinic).  
TeleCAM.  The TeleCAM participants received the same intervention content as 
DirectCAM. The only difference was that the TeleCAM participants received the 
intervention via exercise videos preloaded to a tablet that was given to them upon 
enrolling in the study. The exercise videos were filmed with a person with MS instructing 
and demonstrating the CAM program.  Each TeleCAM participant began with one onsite 
training session with a study therapist.  In the training session, participants were shown 
how to turn the tablet on and off to watch the videos, perform the basic exercises 
correctly, and use the yoga and Pilates equipment. Participants were asked to bring a 
family member or friend with them in case they needed assistance using the tablet.  The 
TeleCAM participants were contacted by an Interactive Voice Response (IVR) system-
initiated call at their preferred dates and times (aligned with the general intervention 
timeline) to promote adherence to the yoga/Pilates exercise and neurorehabilitation 
practice.  The IVR system is an automated communication system that includes 
computers, specialized phone hardware, and operating software to allow immediate 
computer-assisted interaction with participants by telephone.  It was developed during 
our research team’s past physical activity research and in the current study was adapted 
to address the specific concerns of individuals with MS (physical activity progress, pain, 
fatigue, and key motivational variables from the SCT).  The IVR calls were sent to only 

 
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TeleCAM participants weekly for the first six months, and then biweekly for months 6-12 
to monitor physical activity, pain, fatigue, and quality of life for SCT variables.  
rDirectCAM. The rDirectCAM was developed in response to the Covid-19 pandemic and 
was the Enhancement study intervention. Participants enrolled in rDirectCAM received 
the same intervention as DirectCAM. The only difference was that the rDirectCAM 
participants utilized a remote platform at home to work synchronously with a therapist. 
 
Study Outcomes 
For the Main Study, all data collection for both DirectCAM and TeleCAM participants 
was conducted using standardized protocols and was performed by a therapist or therapist 
assistant at each clinic site who was not involved in the intervention delivery. In addition, 
demographic (age, sex, and race) and clinical characteristics (health history, disease severity via 
PDDS, heart rate, and blood pressure)77 were assessed.  
Primary Outcomes. The primary outcomes of interest to our stakeholders included changes in 
fatigue, pain, quality of life, and physical activity. Fatigue was assessed using the Modified 
Fatigue Impact Scale, pain assessed using SF-36 pain subscale and quality of life via SF-36 
questionnaire’s physical component and mental component scores. Physical activity was 
measured using the GLTEQ. Note that the scales and questionnaires were self-reported by the 
participants. 
Modified Fatigue Impact Scale (MFIS).  The MFIS consists of 21 items that assess the 
effects of fatigue related to physical, cognitive, and psychosocial functioning.  It is a 

 
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modified version of the Fatigue Impact Scale.  The scale has been widely used in MS 
research78.  
SF-36. The SF-3679 is a widely used questionnaire that assesses aspects of health-related 
quality of life. It contains eight subscales including: energy/fatigue, physical functioning, 
bodily pain, general health perceptions, role limitations due to physical health problems, 
role limitations due to personal or emotional problems, social functioning, and 
emotional well-being. Scores range from 0 to 100, with lower scores indicating more 
disability. From these eight scales, 2 composite scores: physical component score (PCS) 
and mental component score (MCS) were calculated by multiplying each subscale with 
specific weights.80 These 2 scores are measuring QOL. 
Secondary Outcomes. The secondary outcomes were changes in functional scores for balance, 
endurance, gait, and strength. These tests were assessed by therapists at the clinic for both 
DirectCAM and TeleCAM participants. 
Berg Balance Scale (BBS). The BBS is administered by a single rater who scores an 
individual’s balance performance from a value of 0 (cannot perform) to 4 (normal 
performance) on a total of 14 tasks 81. Tasks incorporate several activities related to 
static balance such as sitting to standing, retrieving an object from the floor, standing 
with eyes closed, and standing on one foot. The test was administered with a ruler, two 
chairs (height: 45–47 cm; one with armrests and one without), a footstool, a 15-foot 
walkway, and a stopwatch. Previous research has reported a minimum detectable 
change of seven points in multiple sclerosis82. 

 
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Five Time Sit To Stand (FTSTS). The FTSTS was used to assess balance, it measures the 
amount of time it takes for an patient to transfer from a seated position to standing 
position and back to sitting five times. The FTSTS test has been shown to effectively assess 
lower extremity strength in individuals with MS 83. Furthermore, its reliability and validity 
have been established in various other neurological disorders such as stroke and 
Parkinson's disease84. 
Six Minute Walk Test (6MWT). The 6MWT was used to assess walking endurance, in 
which total distance traveled over 6-minute period was recorded in meters85,86.  The test 
was administered in a hallway with an unobstructed 50-foot path marked with two 
cones. Perception of fatigue was measured and recorded with the BORG Rating of 
Perceived Exertion (RPE) before and after the test.  The test has been reported to have 
excellent test-retest (ICC = 0.97) in the stroke population and people with MS85,87 and 
has known validity for use in measuring endurance in persons with MS85. 
Timed Up and Go (TUG). The TUG test was used to assess mobility and balance, which 
involves recording the time required to rise from a chair, walk to a 3-meter mark, turn 
around, walk back to the chair, and sit down88,89.  The test is a valid test of mobility, 
balance, and walking ability in people with MS90, with excellent test-retest reliability (ICC 
= 0.96)91.  
Grip Strength Hand Dynamometer. Hand grip strength was measured using a hand 
dynamometer with the dominant and non-dominant hands.  The mean of three trials for 
each hand was used as the actual score.  The text was conducted with the participant 
siting in a chair, shoulder adducted and neutrally rotated, elbow by their side and flexed 

 
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to a 90° angle, and forearm and wrist in neutral position.  Grip strength has previously 
shown a high interrater reliability and test-retest reliability in persons with MS92.  
Time 25 Foot Walk. T25FW is commonly administered within the MS functional 
composite (MSFC), and it has also been employed independently in clinical 
investigations93,94. It is a quantitative mobility and leg function performance test based 
on a timed 25-walk. The patient is guided to a designated starting point on a clearly 
outlined 25-foot walk and is advised to walk the distance as swiftly as they can while 
ensuring safety. Timing begins when the instruction to commence is given and 
concludes once the individual reaches the 25-foot mark. The process is repeated 
immediately with the individual walking back the same distance. Participants are 
permitted to utilize assistive devices during this activity. 
Mediators. Four mediators were assessed to address the tertiary aim. 
Social provision scale (SPS). The SPS was used to assess the degree to which a 
participant perceived his or her social relationships and various dimensions of social 
support95. The scale has been validated in people with MS96. 
Exercise Self-Efficacy (EXSE): The EXSE measures self-efficacy related to physical activity 
and consists of 6 items that assess an individual's belief in their capability to participate 
in moderate physical activity for at least 20 minutes, three times a week, within one-
month intervals. Participants rated each item on a scale from 0 (not confident at all) to 
100 (completely confident) and the scores were averaged to create a composite score 
ranging from 0 to 100. Higher scores indicate higher levels of confidence in regularly 
engaging in physical activity97.  

 
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Exercise Goal-Setting Questionnaire (EGSQ): The EGSQ comprises 10 items that assess 
goal-setting behaviors for exercise. Participants rated each item on a 5-point scale 
ranging from 1 (does not describe) to 5 (describes completely). The scores of the 
individual items were then added together to calculate an overall score, ranging from 10 
to 50. Higher scores on the EGSQ indicate a greater inclination towards setting goals for 
engaging in physical activity98. 
Multidimensional Outcome Expectations for Exercise Scale (MOEES). The MOEES was 
used to assess outcome expectations for exercise. The scale consists of 15 items 
representing three subdomains of outcome expectations: physical, social, and self-
evaluative. Within these subdomains, six items pertain to physical outcomes, four items 
to social outcomes, and five items to self-evaluative outcomes. Participants rated each 
of the 15 items on a 5-point scale, ranging from 1 (strongly disagree) to 5 (strongly 
agree). The scores for each subscale were then added together, resulting in three 
separate scores reflecting physical, social, or self-evaluative outcome expectations. 
Higher scores in each subscale indicate a stronger belief in the expected positive 
outcomes related to physical, social, or self-evaluative aspects of exercise99. 
Figure 3 shows mediation model with the effect of 4 Social Cognitive Theory (SCT) 
construct variables as mediating variables.  

 
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Figure 3. Illustration of the mediation analysis: 
 
X: the independent variable, c: the coefficient relating the independent variable and the dependent variable, c′: 
the coefficient relating the independent variable to the dependent variable adjusted for the mediator, b: the 
coefficient relating the mediator to the dependent variable adjusted for the independent variable, a: the 
coefficient relating the independent variable to the mediator. 
 
Table 3 provides an overview of the primary, secondary, and exploratory outcomes and the 
frequency and mode of data collection. To further tailor our intervention, the T25FW test was 
administered. In addition,  the Dynamic Gait Index (DGI) was administered at clinic sites that 
had uniform steps to assess the test and compare its utility with BBS100.  However, these were 
exploratory outcomes and were not part of our original proposal; Hence, they were not 
accounted for while developing power calculations for the study in terms of the number of 
multiple comparisons for the family wise error rate.  
Table 3. TEAMS Study Outcome Measures 
Variables 
Instrument 
Role, Frequency, Mode of Collection 
 Fatigue 
Modified Fatigue Impact 
Scale  
SF-36 PCS 
SF-36 MCS 
 
Primary Outcome 
 
Baseline, 3rd, 6th and 12th month 
 
Self-reported 
 
Pain  
Quality of life 
Physical activity 
Godin Leisure Time Exercice 
Questionnaire101 
Balance 
Berg Balance Scale102 
Secondary Outcome 

 
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Five Time Sit to Stand83 
 
Baseline, 3rd, 6th and 12th month 
 
At the clinic (for Main study) 
Gait 
Timed Up & Go (TUG)103-105 
Time 25 Foot Walk93,94 
Endurance 
6-minute Walk Test 
(6MWT)105-111 
Strength 
Hand-held 
Dynamometer/Grip 
Strength112-114 
Quality of life 
SF-36 Physical functioning, 
Pain, Energy/Fatigue, 
Emotional wellbeing, Role 
limitation due to physical 
health, Role limitation due 
to emotional health, Social 
functioning, General health 
Exploratory outcomes  
Baseline, 3rd, 6th and 12th month 
 
Self-reported 
 
Gait  
Dynamic Gait Index Scale 
Exploratory outcomes  
Baseline, 3rd, 6th and 12th month 
 
Objective outcomes 
Outcome expectations 
for exercise 
Multidimensional Outcome 
Expectations for Exercise 
Scale (MOEES)115 
Mediators 
 
  
Baseline, 3rd, 6th and 12th month 
 
Exercise self-efficacy 
Exercise Self-efficacy 
Scale116,117 
Social support for 
exercise 
Social Support and Exercise 
Survey118 
Exercise self-
regulation 
Exercise Goal-setting 
Scale119 
IVR: Interactive Voice Response. 
Enhancement Study 
Outcome measures for the Enhancement study were collected using teleassessment via the 
remote platform. To ensure strong fidelity across therapists, each therapist underwent 
extensive training on use of the technology, risk management for remote assessment and 
intervention, and teleassessment and intervention protocols.  The goal of the protocols was to 
mirror onsite clinic assessments and intervention. The measures utilized were based on the 

 
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participants’ PDDS score.  Participants with a PDDS score between 0-4  (indicative of minimal 
mobility disability) completed the following measures: Grip strength test, Five Times Sit to 
Stand test, TUG, and BBS.  Participants with a PDDS score between 5-7 completed all measures 
except the TUG and BBS due to safety concerns (potential risk of falling) of performing these 
tests at home.  The teleassessment equipment provided to participants in the Enhnacement 
study is outlined in Table 4. For safety considerations, rDirectCAM participants who had a PDDS 
score of 5, 6, and 7 were not given any tests related to ambulation. Hence, two different sets of 
equipment were provided: one for participants with a PDDS score of 0-4 and another for 
participants with a PDDS score of 5-7. More details of the teleassessment are presented in the 
Appendix D. 
Table 4. Teleassessment Equipment for the Enhancement Study 
PDDS Level 
Equipment 
PDDS 0-4 
Chromebook 
CAMRY Digital Hand Dynamometer Grip / 90 Kgs 
A&D Medical Wrist Blood Pressure Monitor 
SumVibe Soft Tape Measure 120 Inches 
American Challenge Soccer Mini Disc Cone 
Wall tape 
Paper indicating 5” line 
PDDS 5-7 
Chromebook 
CAMRY Digital Hand Dynamometer Grip / 90 Kgs 
A&D Medical Wrist Blood Pressure Monitor  
PDDS: Patient Determined Disease Steps.  
Potential covariates 
In addition to age, sex, education-level, height, and race, which were collected at 
baseline, information on all participants’ time-varying covariates were collected through a 
questionnaire at baseline and the three follow-up time points.  These covariates included: 
weight, type of MS, prescribed and non-prescribed medications, distance from the clinic 

 
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(address), caregiver support, assisted devices, PDDS. The type of MS, PDDS, age and geographic 
locations based on participants zip code (urban/non-urban) were our prespecified moderators 
for the study outcomes. 
Sample Size Calculations and Study Power 
 
For the Main study an a priori power analysis was conducted based on sample size 
estimation for longitudinal designs with attrition with at least 30 sites. Based on the 
conservative power and sample size calculations, the project was powered for a minimum of 
533 participants completing the study with an assumption of a 35% attrition rate; therefore, a 
total estimated sample size of 820 was needed to detect a between group effect. We 
assumed intent to treat analyses, 80% power, two-sided family-wise error rate of 0.05, intra-
class correlation of 0.05, and a correlation of 0.3 among repeated measures. We also 
assumed an attrition rate of 35% and a small minimally detectable effect size of 0.2.  We 
make a conservative assumption that the correlation between repeated measures would be 
0.3.  We have four primary and four secondary outcomes and hence the sample size was 
estimated after accounting for multiple testing and with a type 1 error rate of 0.00625 for 
each hypothesis test. 
 
For the Enhancement study, we assumed ANCOVA with a pre-post correlation of 0.7, 
80% power, one-sided test with statistical significance of 0.05, and attrition rate of 25%. 
Further, these sample size calculations assumed a non-inferiority margin of -4 units for MFIS, 
where fatigue is one our key primary outcome identified by the stakeholders in our project. A 
change of 4 or greater has been found clinically meaningful for quality of life. Based on these 
assumptions a sample size of 55 completers in rDirectCAM were needed and with an attrition 

 
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rate of 25%, we needed 74 participants in rDirectCAM.   
 
Time Frame for the Study 
For the Main study, TEAMS launched its participant recruitment in October 2017 and 
ended participant enrollment in 2019.  Figure 4 shows the timeline for a few of the major 
milestones completed during the study period.  Recruitment for the rDirectCAM group 
(Enhancement study) was not necessary as we had interested participants who already signed 
up the study via our website or through our clinic partners but were not able to enroll before 
the Main study needing to be ceased due to the pandemic. We established a protocol for 
conducting the teleassessments and tele-training and developed a structured set of procedures 
for equipment purchase and shipping/scheduling based on the Enhancement supplement 
received in May 2020.  We began participant screening for the Enhancement study on 
September 10, 2020, with 100% enrollment completed on March 22, 2021. The study was 
closed on November 1, 2021. 
Figure 4. Major Milestone Completion Timeline of the Main Study 

 
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Table 5 provides an overview of the timeline for the data collection, intervention, and regular 
check-ins of the Main and Enhancement studies.  
Table 5 Overview of the Data Collection, Intervention, and Check-ins Timeline for the Main 
and Enhancement Studies 
Main Study 
Main Study 
Enhancement 
Assessment time 
point 
DirectCAM 
TeleCAM 
rDirectCAM 
Month 0 
Baseline assessment (on-
site) 
Baseline assessment + 
Training (on-site) 
Baseline assessment (real-
time via video conference) 
Months 1 to 2 
Biweekly sessions (on-
site) 
Biweekly new videos (at-
home) + IVR calls weekly 
Biweekly sessions (real-
time via video conference) 
Month 3 
Weekly sessions (on-site) Weekly new videos (at-home) 
+ IVR calls weekly 
Weekly sessions (real-time 
via video conference) 
End of Month 3 
(post 
intervention: 12 
weeks) 
3 month assessment (on-
site) 
3 month assessment (on-site) 3 month assessment (real-
time via video conference) 
End of Month 6 
6 month assessment (on-
site) 
6 month assessment (on-site) 6 month assessment (real-
time via video conference) 
End of Month 12 
1 year assessment (on-
site) 
1 year assessment (on-site) 
NA 
Months 4 to 12 
Continue to exercise (at-
home) 
Continue to exercise (at-
home) + IVR calls 4-5 months 
weekly/ 6-12 months 
biweekly 
Continue to exercise (at-
home) 
 
Data Collection and Sources 
 
 
Study data were collected by the therapists at the clinic sites via paper and scanned into 
a secure cloud storage environment Box approved for UAB investigators. The data were then 
transferred and managed using REDCap (Research Electronic Data Capture). REDCap is a secure, 
web application designed to support data capture for research studies, providing user-friendly, 
web-based case report forms, real-time data entry validation (e.g., for data types and range 
checks), audit trails and a de-identified data export mechanism to common statistical packages 
(SAS version 9.4120, R version 4.3.2 ).  Network transmissions (data entry, survey submission, 

 
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web browsing, etc.) in REDCap are protected via Secure Sockets Layer (SSL) encryption.  All data 
was quality checked by different team personnel to detect and correct data entry errors.  
 
 
Missingness in the weekly feedback, monthly motivational, and clinic assessment data 
stored in the REDCap database was tracked periodically. Data were imported into the REDCap 
server on a weekly basis and queried for missingness. Reminder calls were sent to participants 
to reduce missed appointments and to remind participants to respond to IVR calls in TeleCAM.  
If more than 2 data points were missed, the study team called both therapists and participants 
to inquire why, and to reengage as many as possible and retrieve the missing data. Clinics were 
provided with checklists to ensure that all measures were collected at each assessment session 
in a consistent order according to study protocol. Checklists minimized data loss due to 
technical difficulties. Missed appointments were rescheduled immediately. Reasons for drop-
out (and whether drop-out was therapist or participant-initiated) were documented in detail in 
Box, REDCap and in the monthly CONSORT diagram. To minimize loss to follow-up, multiple 
types of contact information were collected. Protocols were developed by our stakeholders for 
contacting participants in an approachable nature throughout the study through both 
telephone and emails.  
 
Analytical and Statistical Approaches 
Main Study 
Our analysis was following ITT protocol as all participants assigned to the randomized clinics 
and completed baseline assessment were included in the analysis. 

 
21 
 
Our primary hypotheses were about comparing the change in the 11 outcomes (listed in 
Table 4) between baseline and 12th month follow-up across the two arms. We considered these 
11 hypothesis tests for the 11 outcome variables as part of a single family of hypotheses. We 
employed the Holm-Bonferroni method121 for controlling the overall family wise error rate and 
computed adjusted p-values. For each outcome we used a linear mixed effects model, with 
TeleCAM arm as the reference category, and accounting for the correlated nature of the data 
due to the nesting of participants within a clinic as random effects. Crude models included fixed 
effects included both Arms (TeleCAM, DirectCAM), Time (baseline [reference], 3 month, 6 
month, 12 month), an Arms X Time interaction, and accounted for randomization strata (clinic 
location being urban vs. non-urban). The interaction of Arms and Time variables was the 
primary effect of interest since it quantified the differences within Arm change in the outcome 
from baseline over time of the two Arms. For example, based on the fitted model that included 
the interaction between Arm and Time, the difference in change over time from baseline to 12 
months between DirectCAM and TeleCAM were estimated. Contrast statements were used to 
test the null hypotheses in conjunction with the fitted model coefficients and standardized 
differences in the average treatment effect reported. The estimates of the change in health and 
function outcomes for each arm and their 95% confidence interval were also reported. As a 
sensitivity analysis, similar models additionally adjusted for sex, race, and post-COVID data 
collection measure indicated were also ran. Note that, since post-COVID, data collection for 
patient reported outcomes was conducted remotely for remaining participants, the former was 
also included as a covariate in the adjusted model. Next, missingness in primary and secondary 
outcomes were addressed using multiple imputation technique (MCMC) via PROC MI in SAS, 

 
22 
assuming missing at random.  Additional sensitivity analyses were conducted using wild 
bootstrap to assess the robustness to model assumptions. 
The estimated changes between groups and within groups were then compared to minimally 
clinically important difference (MCID) published in literature for the studied outcomes among 
people with MS. For primary outcomes, the published MCID was for MFIS= 4122 and SF-36 pain 
score = 4.9123. For secondary outcomes, MCID for 6MWT= 21.56124, BBS= 3125, TUG= 10.6, 
FTSTS= 13126 and grip strength= 10.5127. For exploratory outcomes, MCID was published for SF-
36 physical functioning (MCID= 7.1123).  
 
Aim 2 was about evaluating pre-specified confirmatory HTE analyses by testing the role of 4 
prespecified moderators (age, geographic location/residence based on participants zip codes, 
type of MS and severity of MS) on each of the primary self-reported outcomes: MFIS, SF-36 
MCS, SF-36 PCS, SF-36 pain domain scale, and GLTEQ.  We had 4 families of hypothesis tests 
within this aim – one for every moderator with 2 levels (PDDS 0-3 [without assistive devices] 
and PDDS 4-7 [with assistive devices]).  Our model was like the one used in the primary aim 
except that we augmented the model with an additional two-way interaction term between 
moderator (e.g., education level) and Arm (moderator X Arm), and a 3-way interaction term 
between moderator x Arm x Time. When a 3-way interaction was observed, post-hoc tests 
were performed to determine the differential influence of the moderator to one treatment 
versus another, controlling for family-wise error utilizing the Holm-Bonferroni method. We 
expected no greater than 11 post-hoc tests per pre-specified moderator and used contrast 
statements to achieve this. Our missing data strategy was similar to that in the primary aim.  

 
23 
 
We examined the role of SCT construct variables (social support, outcome expectancies, 
self-efficacy, self-regulation) as mediating variables between the intervention and primary 
outcomes. As part of our tertiary aims, we had 4 families of hypotheses, one for each mediating 
variable listed in Table 4. Each family of hypotheses had 5 hypotheses tests, one for each 
primary outcome. We applied the product of coefficients test framework as our primary 
approach to compute the mediated effects for each of the primary outcomes as suggested by 
MacKinnon128,129. Additionally, we did mediation analysis for the 6 secondary and the 7 
exploratory outcomes. Note that these analyses were conducted using multiple imputed 
datasets created for aim 1 sensitivity analyses. 
Enhancement Study 
We used a quasi-experimental design to compare rDirectCAM with DirectCAM. Our 
hypothesis posits that the observed difference in outcome effects between rDirectCAM and 
DirectCAM is less than a predetermined non-inferiority margin (-Δ).  These margins were 
selected based on the MCID or minimal detectable change (MCD) of the studied outcomes 
among MS population published in literature (MFIS= 4122, BBS= 3125, TUG= 10.6130, FTSTS= 13126, 
Grip-strength= 10.5127, SF-36 Physical functioning= 7.1123 and SF-36 pain= 4.9123).  
Specifically, we hypothesized that the effect of rDirectCAM was not inferior to that of 
DirectCAM by a margin that was considered clinically acceptable, thereby affirming the non-
inferiority of rDirectCAM in comparison to DirectCAM. In other words, if the resulting p-
valuewas significant, this would mean that we rejected the null hypothesis which stated that 
the difference in the effect between two arms were more than the non-inferiority margin. 
Statistical significance level of 0.05 and at confidence interval 95%, same as superiority trials, 

 
24 
was applied to determine non-inferiority.131 To achieve a balance between the study arms, 
several analyses involved regression-based parametric adjustment measures that are sensitive 
to model misspecification. Propensity scores are another widely used measure to achieve 
balance or matching between the study arms. These scores model the probability of being 
assigned to the given treatment conditional on observed baseline covariates obtained via 
measures including matching, inverse probability treatment weighting (IPTW), and stratification 
and covariate adjustment. Matching-based measures such as nearest neighbor matching 
algorithm often led to study participants being excluded when a match was not available. This 
may have potentially biased the effect estimates. When this occurred, we utilized stabilized 
IPTW, a non-parametric balancing strategy, to achieve balance between the two study arms 
(rDirectCAM and DirectCAM). Using this weighted analysis, we modeled the causal parameter 
as the inverse of the conditional probability of receiving the treatment given the observed 
covariates, a technique that provides asymptotically unbiased estimates and uses data on all 
available study participants across the two arms. 
Our general analytic approach was to leverage the linear mixed modeling framework to 
account for repeated nature of data. Appropriate contrasts were applied using the fitted model.  
Sensitivity analyses were performed to assess distributional and other modeling assumptions. 
Missing data was imputed using multiple imputation where necessary. The non-inferiority (-Δ ) 
of the rDirectCAM was assessed by comparing the lower limit of confidence interval for each 
outcome to its corresponding margin so that if the lower bound was above this margin, then 
the rDirectCAM was deemed non-inferior 132. For the MFIS and TUG assessments, wherein an 
elevated score signified a deterioration in the outcome, we juxtaposed the upper limit of the 

 
25 
confidence interval against a predefined margin. Non-inferiority was deemed established when 
the upper bound was less than -Δ133. 
 
 

26 
Changes to the Original Study Protocol 
Research Plan Changes: 
1. January 12, 2018
a. Increased the number of Drayer Physical Therapy clinic sites from 24 to 25 due
to Drayer’s purchase of the Fulton, MS clinic.
2. May 16, 2019
a. Four Upstream Rehabilitation Inc. sites (Wiggins, Smyrna, Prattville and Saltillo)
were replaced with four sites due to contamination issues, site not opening, and
low recruitment opportunities. The replaced sites included two new sites
(Forest, MS and Bristol, TN) under Upstream Rehabilitation Inc. and two sites
(Phenix City, AL and Grenada, MS) under Encore Physical Therapy.
b. Five new sites were added, with two as study sites and three as satellite sites.
The two newly added study sites were Ruleville, MS under North Sunflower
Medical Center and Greenville, MS under River City Rehabilitation. These two
sites were added to serve the Delta area of Mississippi.  The three newly added
satellite sites were Ashland City, TN and Cookeville, TN under Upstream
Rehabilitation Inc. and Mobile, AL under Encore Physical Therapy. Satellite sites
were added to help with recruitment and testing needs.  Therefore, the number
of participating clinic sites increased to 43, with three of the sites serving as
satellite sites.
3. March 24, 2020

27 
a. Our stakeholder panel and the research team determined that meeting physical
activity guidelines should be added to the inclusion/exclusion criteria to ensure
that the intervention being delivered was the catalyst for change and not
another exercise routine. Therefore, the Godin Leisure Time Exercise
Questionnaire (GLTEQ) was added to the exclusion criteria and a GLTEQ score ≥
24 was used as an indicator of individuals meeting physical activity guidelines
during the screening process. This addition was approved by our IRB on July 25,
2017.
b. The EDSS (1-7) was changed to PDDS (0-7) as an inclusion criterion. The rationale
for this change was discussed with our stakeholder panel and research team
upon realization that very few people with MS knew their EDSS score.  This
change was approved by our IRB on July 25, 2017.
c.
To honor our commitment to participants enrolled in the study and provide
them with the intervention and follow-up assessments remotely during Covid-
19, we requested approval for the following modifications:
i. Contacted all therapists and participants to suspend onsite visits and
requested their participation in completing the intervention (rDirectCAM)
and/or performing all testing remotely (teleassessment).
ii. The following steps were followed for offering rDirectCAM to
participants:
•
For those enrolled in DirectCAM who had started the Intervention
(n-=25):

28 
o
Sent participants a tablet with access to a Zoom link for
rDirectCAM.
o
Trained therapists to deliver rDirectCAM remotely through
the Zoom platform.
•
For participants who did not have internet access, we offered a
phone call option in which the therapist went through the
exercises with the participants via phone, utilized the provided
DirectCAM booklet (e.g., “Ok. Now turn to page 3 and let’s do the
Warrior pose.”)
4. August 20, 2022
a. The Covid-19 Enhancement study was added into the research plan.
Research Analysis Changes: 
The seven SF-36 subscales were studied as exploratory outcomes. This was done 
because they captured all aspects of QOL, and we were interested to explore what was the 
effect of intervention on each domain.