Mobile Technology-Based Simultaneous Aerobic Exercise and Memory Training Intervention for Older Adults With Mild Cognitive Impairment
Phase: NA
Conditions: Amnestic Mild Cognitive Impairment
Sponsor: Jennifer Bramen

Title: MSIM: Mobile Simultaneous Aerobic Exercise and Memory Training Intervention 
for Amnestic Mild Cognitive Impairment (mSIM) 
 
ClinicalTrials.gov ID: NCT04185298 
 
Document Date: 10/26/2021 
 

Sponsor: National Institute of Health (NIH) 
Protocol #: mSIM (NIH 1R21AG061494-01) 
Version #/Date: Ver. 04/26-Oct-2021 
 
 
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Study Title: 
Mobile Technology-Based Simultaneous Aerobic Exercise and Memory Training Intervention 
for Older Adults with Mild Cognitive Impairment 
 
SPONSOR/ 
PRINCIPAL INVESTIGATOR:  Jennifer Bramen, Ph.D. (Pacific Brain Health Center) 
 
 
FUNDED BY:   
 
National Institute of Health 
 
STUDY LOCATION(S):   
PACIFIC BRAIN HEALTH CENTER 
                                            
PACIFIC NEUROSCIENCE INSTITUTE 
                                            
 
                                            
1301 20TH STREET 
                                            
SANTA MONICA, CA 90404 
                                            
P: (310) 582-7641  
 
                      
PROVIDENCE SAINT JOHN’S HEALTH CENTER 
                                                    2121 SANTA MONICA BLVD. 
                                                    SANTA MONICA, CALIFORNIA 90404 
       
1. BACKGROUND 
 
According to the World Health Organization, 50 million people worldwide have dementia with 
an annual incidence of 10 million new cases every year1. Individuals diagnosed with mild 
cognitive impairment (MCI), specifically those with primary amnestic/memory loss (aMCI), are 
one of the highest risk groups for conversion to dementia, with approximately 34% developing 
dementia within one year2. Prevention strategies for cognitive decline are critical during this 
risk period3. The lack of medical treatments able to stop or slow down the development of 
dementia has shifted the research field focus towards the urgent need to develop 
preventative, non-pharmacological approaches and psychosocial therapies for people at-risk 
for the disease. 
Both cognitive remediation and exercise training strategies have been developed for 
interventions in MCI patients and show small but not yet definitive improvements on 
cognition4,5. A large body of evidence suggests that regular physical exercise can improve 
cognition, specifically enhancing memory, attention, and executive functions in older adults6,7 
and is associated with a 35–38% reduction in the risk of cognitive decline and dementia8. 
However, a recent meta-analysis of exercise interventions in older adults concluded there is 
not yet enough evidence to support the definitive benefits of exercise alone on cognition9. 
Cognitive remediation interventions that target restoration of cognitive functioning through 
compensatory cognitive skills training in MCI patients show a clear advantage over the more 
generalized computer-based drill and practice neurocognitive training programs10. In contrast, 
studies that implement both targeted neurocognitive and exercise training interventions 

Sponsor: National Institute of Health (NIH) 
Protocol #: mSIM (NIH 1R21AG061494-01) 
Version #/Date: Ver. 04/26-Oct-2021 
 
 
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(rather than each alone) are showing greater promise on improving cognitive function in older 
adults11, 12 as well as having real-world functioning benefits in MCI and dementia1314. Study PI 
(McEwen) and Co-I (Merrill) recently published the first study that attempted to leverage the 
synergistic benefits of simultaneously performing compensatory memory skills training during 
aerobic exercise (stationary aerobic cycling; SIM training) in older adults with subjective 
memory impairments15. In our clinic-based, pilot RCT we validated the feasibility of the SIM 
training in older adults and found that it was more impactful on improving memory, attention 
and reasoning skills than in a group that performed the training separately.  
Unfortunately, older adults experience extensive barriers to engaging in the 
aforementioned preventative practices due to mobility constraints, lack of access, and low 
motivation to engage in activities that are not tailored to their needs. Delivering low-cost, 
effective, prevention-focused interventions to cognitively impaired older adults could reduce 
these barriers by increasing ability, motivation, and adherence. Prior technology-enabled 
interventions to increase physical activity levels have included providing older adults with 
fitness trackers16. One study conducted in older adults found that the provision of a Fitbit 
monitor alone to objectively track one’s own activity leads to increased physical activity levels 
beyond those of whom are concurrently receiving coaching prompts (via text message)17. T 
Consistent feedback through notifications, as well as integration wth social support and 
competition through “leaderboards” and “rewards,” encourage participants to exercise, which 
led to overall increases in physical activity. 16. Together, studies on this technology  suggest 
that goal setting is effective for increasing physical activity. A comprehensive review of activity 
trackers used in research studies “that having a fitness tracker could actually be an 
intervention in and of itself17” and concluded that the use of fitness trackers, show a great 
deal of promise for measuring and encouraging physical activity. Therefore, for this pilot RCT, 
we will provide our “control” arm with continuous activity monitoring and provide instructions 
and training on device and feature usage. We anticipate an increase in their physical activity 
levels even without the rigorous schedule and program that our “mSIM” group is receiving.We 
are primarily trying to compare our intervention with “standard of care,” which normally 
includes clinicians advising MCI patients to increase their physical activity habits. 
Animal studies provide important mechanistic insights into the benefits of exercise in 
improving cognition. Specifically, aerobic exercise increases the density of blood capillaries 
(angiogenesis) and birth of new neurons (neurogenesis)18,19. Skilled-based exercises increase 
neuronal sprouting and synaptogenesis, important for re-establishing brain circuits impaired in 
disease states and required for normal cognition20,21. However, no study has been conducted 
in aMCI patients that explores the effects of memory skills training during aerobic exercise on 
cognition and functioning.  
The underpinnings of exercise and cognitive training-induced memory improvements 
may lie in neurochemicals such as brain-derived neurotrophic factor (BDNF) and 
norepinephrine (NE).  BDNF is the most widely distributed neurotrophin in the brain, with the 
highest density found in the hippocampus. BDNF can modulate neurogenesis, neuronal 
plasticity, and survival22,23. Furthermore, increased central BDNF expression has been causally 
linked to the learning and memory enhancement that is seen in both cognitive training and 

Sponsor: National Institute of Health (NIH) 
Protocol #: mSIM (NIH 1R21AG061494-01) 
Version #/Date: Ver. 04/26-Oct-2021 
 
 
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physical exercise interventions with animals24–26. BDNF decreases with aging27 and increases 
with physical activity and associated memory improvements in older adults28 and those with 
MCI29. NE is released by the locus coeruleus (LC) during physical activity and may be 
facilitating these effects also. The LC is the main source of NE during physical activity. This 
activates the reticular system, thus increasing arousal levels, aiding to vigilance and attention 
during cognitive training30. LC neuronal loss is prominent in AD neuropathology and 
contributes to cognitive impairments31. Reduced concentrations of NE are believed to occur 
early in the course of the illness as seen in MCI patients32. Activation of the NE system during 
exercise may facilitate the long-term impact of memory training .   
 
Electroencephalography (EEG) is a non-invasive method of measuring the electrical 
activity of the brain. Quantitative EEG (QEEG) is a method for recording and analyzing EEG 
data efficiently in a clinical setting. The brain has many brain rhythms, each associated with 
different mental states. As more populations of neurons act in greater synchrony, the 
amplitudes of these rhythms increase. The Alpha rhythm is 8-12 Hz and was originally 
identified as a resting state/idling brain rhythm.  More advanced models show that Alpha is 
important for the inhibitory tone of the brain. Higher alpha power means more brain systems 
are being inhibited, whereas a low Alpha power means the brain is experiencing less 
inhibition, allowing for the engagement of more active states33. Alpha plays a critical role in 
the timing of neurological and cognitive processes34 including working memory, attention, and 
anticipation. These and more decline with age and neuropathology35. Peak Alpha frequency 
slows with age and is correlated with cognitive decline. In older adults with poorer cognition, 
there is a greater degree of slowing in the Alpha band36,37. 
GABA is the neurotransmitter in the brain primarily responsible for inhibition. Animal 
studies show potential mechanisms by which exercise may improve cognition by restoring 
inhibitory tone. Mice that carry the APOE4 gene are, like humans, at risk for Alzheimer’s. 
These mice have hyperexcitable brains when compared with normal mice37. They experience 
dysregulated and increased brain activity because they do not respond to their native 
GABAergic networks as well as normal mice. Another study, this time in aged rats, 
demonstrated that an aerobic fitness intervention was able to reduce the age-related 
hyperactivity in the rat brain and worked through improving the GABAergic system38. 
Increases in peak Alpha frequency may be a result of the mSIM intervention in humans and 
these findings could be mediated by the normalization of GABA-related signaling post 
intervention. 
 
    
2. OBJECTIVES OF THE STUDY 
One major study objective is to develop and conduct beta testing of a web-based application 
that will deliver a mobile-based simultaneous exercise and memory skills training program 
(mSIM) for aMCI patients. A second major objective of the study is to evaluate the efficacy of 
mSIM on memory performance and everyday functioning using two study arms: Group 1 or 
the activity monitoring control group (CON) and Group 2 or the activity monitoring plus 

Sponsor: National Institute of Health (NIH) 
Protocol #: mSIM (NIH 1R21AG061494-01) 
Version #/Date: Ver. 04/26-Oct-2021 
 
 
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immediate treatment with the mSIM intervention group (mSIM).  The CON will serve as the 
control group and be recommended to wear a Fitbit to track their physical activity habits, 
which has been shown to be an effective intervention to increase physical activity levels16,17, 
throughout the duration of the intervention. They will also report one week’s physical activity 
via phone calls with research staff at baseline, mid-intervention, and post-trial. Study 
objectives include measuring treatment related changes in quality of life and cognitive and 
functional abilities.  
A third major objective of this study is to test mSIM treatment response on 
concentration levels of peripheral biomarkers [BDNF and NE] and neural markers (eg. peak 
alpha frequency) measured with QEEG.  Study objectives include testing the relationship 
between increased peak alpha frequency, concentrations in BDNF and NE, and improvements 
in memory.  
An exploratory objective of this study is to test treatment response to the mSIM 
intervention using magnetic resonance imaging (MRI). We will analyze functional resting state 
fMRI, structural MRI, arterial spin labelling (ASL) and diffusion tensor imaging (DTI) data for 
this study. We hypothesize that patients in the mSIM intervention, compared to  the controls, 
will have increased default mode network (DMN) connectivity, increased frontal and temporal 
volumes, and increased temporal perfusion. We will seek to examine exploratory measures on 
structural connectivity using DTI. It is believed that the white matter deficits precede grey 
matter neuronal loss in preclinical AD since neuronal degradation begins in neuronal 
periphery, which consists of axons and dendrites. A meta-analysis of 41 DTI studies in MCI and 
AD39 revealed almost all white matter tracts are implicated in the disease state. Limbic fibers, 
which have direct connections to the medial temporal lobe, had reduced integrity. 
Additionally, the cingulum bundle, mainly within the medial temporal lobe,  the splenium of 
the corpus collosum, and the fornix were all reduced and were correlated with severity of 
reduced cognition as implicated on the MMSE and memory tests. The left cingulum bundle 
(within the hippocampus) showed decreased FA and increased MD, which were specifically 
associated with worse symptoms and ADAS-cog scores. Interventional exercise research in 
older adults has revealed that short-term exercise interventions have a positive benefit on 
white matter integrity in the corpus collosum.40 Therefore, we hypothesize that the mSIM 
intervention will increase white matter integrity especially in the cingulum bundle, corpus 
collosum, and the fornix.  
 
 
 
    
3. STUDY DESIGN 
 
Overview 
Participants with primarily amnestic MCI (aMCI) will be enrolled in the trial. MCI will be 
defined according to either the Peterson or Jak/Bondi criteria41,42 neuropsychological 
approach in which tests are organized by cognitive domain and criteria are set for defining 
impairment within any particular domain. Assessments of memory confirming diagnosis will 

Sponsor: National Institute of Health (NIH) 
Protocol #: mSIM (NIH 1R21AG061494-01) 
Version #/Date: Ver. 04/26-Oct-2021 
 
 
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have occurred within 6 months prior to consent or  will be conducted at screening to confirm 
eligibility. 
 
Subject Identification and Recruitment 
Study subjects will be recruited using a variety of techniques to identify participants that meet 
inclusion and exclusion criteria and who are able to participate in the trial. Recruitment 
techniques will include (1) identification of patients from a high-volume memory clinic (PBHC), 
(2) advertisement to participants in the Los Angeles area, and (3) establishment of a website 
landing page that permits interested individuals to contact the trial coordinator. A total of up 
to 30 aMCI participants (50-80 years old) will be enrolled in this prospective randomized study 
(15 for each arm). Because there are several inclusionary/exclusionary criteria that must be 
assessed after obtaining informed consent, up to 60 participants may consent to participate in 
this study.  
 
Procedures for Obtaining Informed Consent 
All subjects will receive and sign the Experimental Research Subject’s Bill of Rights prior to 
signing the informed consent form (ICF). Subjects will also complete an authorization of use 
and disclosure of protected health information (PHI), and a second authorization of medical 
record release for the subject’s treating physician, prior to enrolling in the study. A copy of all 
signed ICFs will be given to the subject, and the investigator will retain the originals.  
 
Screening and Enrollment 
Subjects interested in participating in the study will be screened based on the inclusion and 
exclusion criteria listed below.  
 
Inclusion Criteria 
• Subjects must be age 50 to 80 at time of informed consent. 
• Subjects must confirm an aMCI diagnosis either by providing records from a clinical 
assessment within 6 months of enrollment in this study or through a brief memory 
assessment by study staff at screening. 
• Subjects must be proficient in spoken and written English for consenting as well as for 
study participation since the intervention in this study is currently only available in 
English. 
• Subjects with medical conditions must be stable for these conditions. Stable control on 
medication is acceptable.  
• Subjects, with or without assistance, must be able to use a computer and web 
interface. If assistance is needed, it must be readily available to them.  
• Subjects are required to have internet with Wi-Fi at the location of their mSIM training. 
• Subject must have normal visual acuity (or corrected to normal) and normal color 
vision as indicated by self-report. 
• Subject must have adequate hearing acuity as indicated by self-report. 
• Subject must have adequate motor capacity to use a mobile phone/iPad/computer as 
indicated by self-report. 

Sponsor: National Institute of Health (NIH) 
Protocol #: mSIM (NIH 1R21AG061494-01) 
Version #/Date: Ver. 04/26-Oct-2021 
 
 
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• Subjects must be able to provide medical clearance to participate in an unsupervised, 
moderate intensity exercise program from a physician. 
 
Exclusion Criteria 
• Subjects must not have an existing diagnosis of a neurodegenerative disorder (e.g., 
Alzheimer’s Disease, Lewy Body Dementia, Frontal-Temporal Dementia). 
• Subjects must not have a prior diagnosis that might impact cognition and movement 
abilities including: significant cardiovascular disease, significant respiratory disease, 
illness or injury, substance abuse, schizophrenia, bipolar disorder, or other neurological 
diseases. 
• Subjects must not have a previous Mini Mental State Exam (MMSE) score below 19. 
• Subjects must not have a previous Clinical Dementia Rating (CDR) global score of ≥2. 
• Subjects must not have a Montreal Cognitive Assessment (MoCA)43 score of below 18 
previously or during their screening evaluation. 
• Subjects must not demonstrate a progression of aMCI to dementia at screening based 
on the best judgement of a study Clinical Neuropsychologist.  
• Subjects must not currently participate in a high level of physical activity prior to study 
start as assessed by the International Physical Activity Questionnaire (IPAQ) at 
screening. 
• Subjects must not endorse that they are unable to participate in moderate intensity 
aerobic activities, such as fast walking or passing/kicking a ball to a partner at 
screening. 
 
Participants may enroll in the RCT but not receive a brain MRI if they do not pass MRI 
screening. Participants will be excluded from MRI procedures (but not the RCT) if they have 
any of the following: 
 
• Brain Aneurysm Clip 
• Implanted neural stimulator 
• Implanted cardiac pacemaker or defibrillator 
• Cochlear implant 
• Ocular foreign body (e.g. metal shavings) 
• Other implanted medical devices (e.g. Swan Ganz catheter) 
• Insulin pump 
• Metal shrapnel or bullets in their bodies 
• They are pregnant (participants who are uncertain as to whether they are pregnant will 
be required to have a screening urine or blood pregnancy test) 
• They have had surgery of uncertain type where the presence of metal clips or wires 
cannot be excluded. 
• They have unstable angina or New York Heart Association functional class IV heart 
failure 
 

Sponsor: National Institute of Health (NIH) 
Protocol #: mSIM (NIH 1R21AG061494-01) 
Version #/Date: Ver. 04/26-Oct-2021 
 
 
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Participants with claustrophobia may participate in a truncated MRI protocol under sedation, 
if they elect to participate. 
 
Randomization 
A computerized randomized block design will be used for subjects who meet inclusion and 
exclusion criteria. Study staff will not see the assignments to arms provided by the computer 
in advance.  
 
Data Collection and Assessments 
We will monitor participants in the RCT for up to 26 weeks and perform evaluations to 
determine cognitive trajectory between the two arms. . Total participation will be 
approximately 6 months. We will specifically evaluate data consisting of biomarkers (BDNF, 
NE), QEEG metrics (for example, peak alpha frequency), brain MRI, lifestyle, physical activity, 
and objective and subjective neurocognition. We will use statistical and computational 
methods in an effort to explain the causal underpinning of any observed differences between 
the two arms. 
 
 
At pre-screening, the following will occur: 
• Phone screening 
• Medical records release to confirm eligibility and determine if they will require 
additional assessments at screening 
 
At Screening, the following will occur: 
• Informed consent 
• Intake questionnaires 
• MRI Safety Screening Questionnaire 
• May be required to participate in a brief memory assessment 
• PARQ+ and Medical Clearance to Exercise  
• Virtual neuropsychological, cognitive, and functional assessments. If clinical 
neuropsychologist determines that the participant has progressed to dementia or the 
participant scores below 18 on the MOCA, participant will not pass screening 
 
At Baseline, the following will occur: 
• Randomization into Group 1 or Group 2 
• Biomarker draw (blood) 
• Physical status assessment including: physical measurements and questions regarding 
current physical status   
• QEEG Assessment 
• Brain MRI (unless contraindicated based on MRI Safety Screening Questionnaire) 
• Participant receives Fitbit device and information on usage 
• On-going collection of lifestyle data from FitBit device 

Sponsor: National Institute of Health (NIH) 
Protocol #: mSIM (NIH 1R21AG061494-01) 
Version #/Date: Ver. 04/26-Oct-2021 
 
 
8 
• Phone call with study staff for patient to report one week’s cognitive activity  
• Group 2 (mSIM): Participant receives binder with homework to be completed during 
the course of the mSIM intervention 
• Group 2 (mSIM): Participant signs credit card authorization form for damages to study 
equipment. Form will be shredded at the end of study when participant returns all 
study equipment  
• Group 2 (mSIM): Stationary bike is adjusted for the participant, and they receive 
instruction on the proper use of the bike 
• Group 2 (mSIM): Participant receives instruction on the tablet and mobile application 
usage 
• Group 2 (mSIM): Participant may be required to see a cardiologist for medical 
management as part of their standard of care if additional ischemic or hypertensive 
risk factors are uncovered during the physical status assessment. If participant’s blood 
pressure continues to be above ACSM guidelines and the participant cardiologist will 
not clear them to participate in a moderately intense, unsupervised exercise program, 
the participant will be withdrawn from the study 44  
 
Study equipment set-up, the following will occur: 
• On-going collection of lifestyle data from FitBit device 
• Group 2 (mSIM): Delivery company will set up study equipment at participant’s home 
• Group 2 (mSIM): 2 (but up to 6*) weeks aerobic exercise ramp-up using the exercise 
equipment provided 
  
Study intervention period: 
• Group 2 (mSIM): Begin 24-session mSIM exercise and cognitive training intervention 
(24x/12 weeks at home) 
• Group 2 (mSIM): May be asked to take blood pressure before each exercise session if 
deemed necessary 
• Group 2 (mSIM): Weekly calls with a member from the research staff for 
troubleshooting and navigating the mSIM program, and for checking homework 
completion 
 
Mid-intervention testing: 
• Virtual neuropsychological, cognitive, and functional assessments 
• Phone call with study staff for patient to report one week’s  cognitive activity  
• Group 2 (mSIM): Participant satisfaction through a survey 
 
 
Study equipment break-down (Group 2: mSIM): 
• Delivery company will breakdown and remove equipment from participant’s home 
 
Post-trial testing, the following will occur: 

Sponsor: National Institute of Health (NIH) 
Protocol #: mSIM (NIH 1R21AG061494-01) 
Version #/Date: Ver. 04/26-Oct-2021 
 
 
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• Virtual neuropsychological, cognitive, and functional assessments. 
• Biomarker draw (blood) 
• Physical status assessment including: physical measurements and questions regarding  
current physical status   
• QEEG Assessment 
• On-going collection of lifestyle data from FitBit device 
• Phone call with study staff for patient to report one week’s cognitive activity  
• Brain MRI (unless contraindicated based on MRI Safety Screening Questionnaire) 
• Group 2 (mSIM): Participant satisfaction with mSIM program through a survey 
 
 
If participant wants to receive compensation for participation, participant must provide a W9 
to study staff before the end of study.                     
 
*The optimal exercise ramp-up duration is 2 weeks based on our prior exercise study in this 
population15,45. However, participants may require up to 6 weeks depending on their baseline 
physical activity levels and ability to tolerate the aerobic exercise ramp-up phase. If, after 6 
weeks of ramp-up, participants are unable to sustain 40-60%HRR during their exercise 
sessions, they may then be withdrawn from the trial by the principal investigator.  
 
See APPENDIX I  for a table view of the study timeline. Note all timepoints might be plus or 
minus one week. 
 
 
Mobile-Based Simultaneous Exercise and Memory Skills Training Program (mSIM): The mSIM 
intervention will be carried out in participants assigned to 
Group 2 (mSIM). Before the in-home training intervention 
can begin, a research staff member will set-up the 
participant’s equipment while they are on site at PBHC, 
troubleshoot, plan exercise training days and times, and 
inform them of the exercise ramp-up procedures. The 
equipment required for the mSIM home training sessions is 
compact and low-cost and will include: a folding, stationary 
exercise bike, Fitbit heart rate and activity monitor synced 
to the participant’s study account, and a tablet to access 
our mSIM web-based application (see Figure 1).  
 The mSIM participants (Group 2 (mSIM))  will begin by 
undergoing a minimum of 2 weeks,15,45,46 but up to 6 weeks 
if necessary, of aerobic exercise ramp-up. Participants will 
wear heart rate monitors (FitBit) to self-monitor and ensure that the exercise was completed 
within their prescribed aerobic target heart rate zone, which is 40-60% heart rate reserve 
(HRR)46,47. The target heart rate zone will be determined by the Karvonen formula47, which 
determines the individual participant’s HRR and training zone. The Karvonen Formula is:  
Figure 1. Home set-up of the mobile 
technology-based simultaneous exercise and 
memory skills training (mSIM) program.  

Sponsor: National Institute of Health (NIH) 
Protocol #: mSIM (NIH 1R21AG061494-01) 
Version #/Date: Ver. 04/26-Oct-2021 
 
 
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220 - age = maximum heart rate 
Maximum heart rate - resting heart rate = heart rate reserve 
(Heart rate reserve X training%) + resting heart rate 
 
 
The ramp-up for mSIM participants will start with 2 days per week for 2-6 weeks, 
where they will be asked to maintain an aerobic intensity of up to 40-60% HRR for 10-40 
minutes, depending on their baseline physical activity level45. After the ramp-up phase the 
mSIM (Group 2) participants will begin the 12-week intervention, comprised of 2 times/week, 
65-minute sessions. Each mSIM session will include up to 15 minutes of sedentary new 
memory skills introduction learning or review. They will then have a 5-minute warm-up on the 
bike (30% HRR), followed by 35 minutes of memory skills training and practice while aerobic 
cycling in their estimated 40-60% aerobic training zone. They will then have 5 min of interval 
training which is continuously monitored on the FitBit wrist-worn watch.The resistance level 
will be pre-set on their bike to meet their aerobic training zone. They will then finish with a 5-
minute cool-down that may include a 5-minute summary of skills learned in the session. 
Participants will be instructed in the importance of staying within their target heart rate zone 
and not exceeding their heart rate zone. A research staff member will be available during the 
first 2 weeks of mSIM training sessions via phone to help with any technical issues the 
participant has during the training session. Participants will be asked to open the FitBit App 
during their training session to sync their FitBit and indicate the start and stop time of their 
training session on a session log, so data can be monitored in real-time with the Fitibit data 
aggregator by research staff and to aggregate study compliance data. All FitBit data will use a 
de-identified study email address so that no personal identifying data will be linked with either 
FitBit or the FitBit data aggregator. Participant will be trained on how to ensure they are 
within their individualized 40-60% HRR and of the safety reasons for not going above 60%HRR.  
 
Subject ID Assignment 
Upon enrollment, each participant will be assigned a study ID that will be used to link all data. 
Only the PI/Sub-PI, and designated members of the research team will have access to a 
method to link each participant with their subject ID. This database will be password 
protected and reside within the institution’s HIPAA compliant system. 
 
Fees for Participation  
There are no costs associated with participating in this research. Routine medical care will be 
billed to the subject’s insurance.  
 
Compensation 
Group 1 (activity monitoring group) will receive access to the web-based program after they 
complete their post-trial testing. All participants will be compensated per completed 
assessment ($25.00 x ≤ 3 for neuropsychology testing, $25.00 x ≤ 2 for QEEG assessment, 
$25.00 x ≤ 2 for MRI assessment, $25.00 x ≤ 2 for blood draw) not done during clinic visits to 
cover time, travel, and inconvenience. The mSIM participants will be compensated $10 x ≤ 12 
weeks for completing study-related activities, which will be paid out at the end of their study 

Sponsor: National Institute of Health (NIH) 
Protocol #: mSIM (NIH 1R21AG061494-01) 
Version #/Date: Ver. 04/26-Oct-2021 
 
 
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participation if they have reached at least 80% compliance (19/24 sessions). This includes for 
the mSIM group: completing mSIM training sessions and homework. The activity monitoring 
group participants will be compensated the same total amount over the course of the study 
($10 x ≤ 12 weeks) for completing their study-related activities during the intervention, which 
will be paid out at the end of their study participation if they have reached at least 80% 
compliance (10/12 weeks). This includes daily wearing of the FitBit for an entire week and 
weekly syncing of the device, as well as completing cognitive activity monitoring. Parking 
validation will be provided for study-specific visits. If the participant is enrolled in the RCT and 
completes all study visits, intervention sessions, data collections, and completed their lab 
visits and QEEG not during clinic visits, the maximum amount they will receive is $345.  All 
participants will be able to keep their FitBit after they complete the intervention period. 
 
 
4. EVALUATIONS AND ASSESSMENTS  
 
Physical Status Assessment 
Each participant who is randomized into the RCT will undergo a physical status 
assessment.48 During the physical status assessment  participants will  have their blood 
pressure, weight, and waist and hip circumferences measured. This assessment will occur at 
baseline and post-trial for Group 1 and Group 2 participants. 
 
Biomarker Data 
Each participant who is randomized into the RCT will be assessed for biomarker data. All 
biomarker data will be collected as fasting AM samples. Participants will have fasted overnight 
and will not participated in exercise or consumed alcohol or coffee in the past 24 hours.   
 
Fasting blood will be collected for the BDNF and NE analysis at baseline and at post-
trial at by  nurses or licensed phlebotomists. A nurse or phlebotomist will draw up to 3 
tablespoons of blood from the participant’s forearm into one whole blood and one serum 
separator tube. By comparison, the amount of blood collected when people donate blood is 1 
pint, or roughly 500 mL. The SJCI lab will conduct sample analysis post-trial via Bionesis and 
Cat Combi ELISA assay kits using the protocol described in Cat Combi49. 
 
Cognitive and Functional Assessments 
Each participant who is randomized into the RCT will be assessed for cognitive and functional 
abilities using the following assessments: 
 
• NIH Toolbox50 is administered at screening, mid-intervention, and post-trial. 
• The Rey Auditory Verbal Learning Test (RAVLT) is a measure of memory functioning. 
Administered at screening, mid-intervention, and post-trial.  
• Wechsler Memory Scale–Fourth Edition (WMS-IV) Logical Memory I and II is a measure 
of memory functioning. Administered at screening, mid-intervention, and post-trial.  

Sponsor: National Institute of Health (NIH) 
Protocol #: mSIM (NIH 1R21AG061494-01) 
Version #/Date: Ver. 04/26-Oct-2021 
 
 
12 
• Wechsler Memory Scale–Fourth Edition (WMS-IV) Visual Reproduction I and II is a 
measure of memory functioning. Administered at screening, mid-intervention, and 
post-trial.  
• Oral Trails B is a measure of processing speed. Administered at screening, mid-
intervention, and post-trial.  
• Functional Activities Questionnaire (FAQ)51 is a measure of functional impairment. 
Administered at screening, mid-intervention, and post-trial. 
• 
Multifactorial Memory Questionnaire (MMQ)52 is a measure of memory functioning. 
Administered at screening, mid-intervention, and post-trial. 
• Montreal Cognitive Assessment (MoCA)43 is a measure of global memory. 
Administered at screening, mid-intervention, and post-trial. 
 
Medical Record Collection 
A participant’s medical record will be collected from their treating physician’s office at 
screening/baseline for medication types, dosage, and frequencies as well as other existing 
medical conditions and their treatment. The data will be entered into an electronic data 
capture system by research staff at PBHC. In the event that a particular participant’s data has 
extreme or outlier characteristics, their medical record will be reviewed to identify 
explanatory factors.  
 
Lifestyle Data 
Physical activity, heart rate, and sleep data will be collected automatically and on a nearly 
continuous basis by using a FitBit activity tracker, or similar commercially-available tracker, 
which will be provided to each participant in the study.  
Participants will be asked to log their cognitive activities for 7 days around the time of 
their baseline, mid-study, and post-trial time points.We will also collect the IPAQ standardized 
measure of physical activity at baseline and post-trial time points to obtain a metric of METs of 
physical activity. 
 
 
5. DATA AND SAMPLE STORAGE AND MONITORING 
 
 
Data Collection and Storage 
Biological samples may be stored for up to 50 years at a biostorage facility. A code number will 
be assigned to all samples. Participants’ names, medical record numbers, or other identifying 
information will not be stored with the samples. Participants’ names and contact information 
will be stored at SJCI and PBHC and not be shared with researchers outside of  SJCI and PBHC. 
Researchers, other than those providing direct medical care, will not have access to personally 
identifying information.  
  
All biological and questionnaire data described above, but not medical records, will be 
collected into a centralized secure database and protected by technological, physical, and 

Sponsor: National Institute of Health (NIH) 
Protocol #: mSIM (NIH 1R21AG061494-01) 
Version #/Date: Ver. 04/26-Oct-2021 
 
 
13 
administrative safeguards as provided by HIPAA and other applicable privacy laws. Only 
clinical staff, research staff, and authorized operations personnel will have access to this data.  
Data may also be de-identified, then stored in a separate secure database for potential future 
use. SJCI and PBHC will also store archived biological specimens for future research. All 
samples will be stored as coded samples with no personal identifiers. Codes will be stored 
separately, password protected, and only accessible to authorized personnel. All cognitive 
assessment data and medical information collected from subject medical records (e.g., 
medication and existing medical conditions) will be entered in an electronic data capture 
system. Research data and de-identified medical information may be stored for up to 50 years 
at SJCI and PBHC. 
 
Data Analysis and Data Monitoring 
The process of analyzing participant study data may continue indefinitely. We will analyze the 
incoming participant data using multiple regression analysis for statistical changes in clinical 
health markers over time. Only individuals who have completed all applicable HIPAA training 
will be provided access to PHI.  
 
Data Storage and Confidentiality 
All data will be kept private and shared with the participant as outlined above. Participants’ 
biological data is stored in one database with one set of security credentials and Personally 
Identifiable Information is stored on a different database with separate security credentials. 
All data will be stored in a password-protected secured server and only specifically identified 
study personnel will have access to the data. Discoveries derived from participant data that 
may be published and shared publicly will have all data de-identified. 
 
6. ANALYTICAL METHODS 
To determine feasibility of the protocol, we will analyze adherence and feasibility data from  
participants via a secure data-aggregation program from which will pull de-identified FitBit 
session data and also from the session dashboard profiles from the mSIM web-based 
application.  During the intervention, we will collect data related to program adherence in the 
mSIM web-based application. 
In order to determine whether the mSIM treatment protocol produces significant 
improvements in cognitive abilities, our primary analytic tool will be the linear regression 
model, which will be implemented as an ANCOVA in SPSS or similarly capable statistical 
software (e.g., R statistical software and SAS). Outcomes will be the post-trial assessment 
measurements, baseline measurements of the outcomes will be used as covariates, and 
treatment group (Group 2 (mSIM) or Group 1 (CON)) will be the key variable to assess the 
treatment effect.  
We will also perform an analysis of peripheral biomarker data to help us understand 
the biological underpinnings of any cognitive changes produced by the mSIM treatment 
protocol. Outcomes will be the post-trial biomarker measurements of BDNF or NE corrected 
concentration levels, baseline measurements of BDNF or NE corrected concentration levels 
will be used as covariates, and treatment group (Group 2 (mSIM) or Group 1 (CON)) will be the 

Sponsor: National Institute of Health (NIH) 
Protocol #: mSIM (NIH 1R21AG061494-01) 
Version #/Date: Ver. 04/26-Oct-2021 
 
 
14 
key variable to assess the treatment effect. We will also conduct an exploratory analysis 
where we will evaluate the extent to which changes in BDNF and NE separately relate to 
changes in memory performance (composite memory Z-score) through correlational analyses. 
To quantify the effects of the mSIM intervention on cognitive inhibitory tone, we will 
perform an analysis of the QEEG data. Our primary indicator is a metric called peak Alpha 
frequency.  Outcomes will be the post-trial peak alpha frequency, baseline measurements 
peak alpha frequency will be used as covariates, and treatment group (Group 2 (mSIM) or 
Group 1 (CON)) will be the key variable to assess the treatment effect. We will also conduct an 
exploratory analysis where we will evaluate the extent to which changes in peak alpha 
frequency separately relate to changes in memory performance (composite memory Z-score) 
or other biomarker data  through correlational analyses. Additional metrics from the QEEG will 
be explored. EEG will be provided in-kind by Evox and not the NIA-funded study. 
An exploratory objective of this study is to test the mSIM treatment response 
measured with brain MRI. We will analyze functional resting state fMRI, structural MRI, ASL, 
and DTI data for this study using standard neuroimaging tools to explore structural and 
functional brain changes related to the intervention. 
 
 
7. PROCEDURES FOR STUDY DOCUMENTATION 
 
Informed Consent 
If consent is conducted in person, a copy of all signed informed consent forms (ICFs) will be 
given to the subject, and the investigator will retain the originals. Section 3 provides further 
details regarding the specific requirements for informed consent. 
 
If informed consent is conducted remotely, the study team will provide a copy of the 
informed consent document by email or mail to give the participant ample time to read the 
document. The study team will go over the details of the consent and answer questions by 
phone or HIPAA-compliant telehealth platform (e.g., Zoom). If the participant elects to 
participate, the participant and study team will provide electronic signatures using DocuSign. 
Digital copies of the signed ICF will be given to the subject and retained by the investigator. 
 
Investigator Study File 
Documentation concerning the study including, but not limited to, study protocol and any 
amendments, the IRB documents, study logs, monitoring activities and correspondences, and 
case report forms (CRFs) will be kept on-site in a secure location. 
 
Monitoring and Quality Assurance 
Quality assurance procedures will include training of all study personnel, monitoring of data 
and reviews to verify that all elements of Good Clinical Practice (GCP) guidelines and FDA 
regulations are met. Monitoring will be conducted to assure that data are accurate and in 
agreement with source documentation; verify that consent for study has been properly 
obtained and documented; confirm that participants enrolled in the study meet inclusion and 

Sponsor: National Institute of Health (NIH) 
Protocol #: mSIM (NIH 1R21AG061494-01) 
Version #/Date: Ver. 04/26-Oct-2021 
 
 
15 
exclusion criteria; monitor for safety (e.g. adverse events) and assure that all essential 
documentation required by GCP guidelines are appropriately filed.   
 
Retention of Study Documents 
Study documents will be retained for a period of two years on-site following the completion of 
the study.  Study documents will then be transferred to a storage facility and secured.  If the 
investigator relocates, retires, or withdraws from the clinical study for any reason, all records 
required to be maintained for the study will be transferred to an agreed-upon designee, such 
as another investigator at the institution where the study was conducted. Medical records 
used for treatment purposes will be retained separately as required by state data retention 
laws, HIPAA and other applicable laws. 
 
8. PROCEDURES FOR HANDLING ADVERSE EVENTS (AEs) AND SERIOUS ADVERSE EVENTS 
(SAEs) 
 
Due to the nature of this study, we do not expect adverse events of the same nature as might 
be expected if an investigational pharmaceutical were being investigated. The exercise 
intervention in this study includes moderate intensity aerobic physical activity that is approved 
by a physician, which is likely to not  include a physiological adverse event . However, adverse 
events could still occur to participants, including adverse events not related to the study. 
Suicide or attempted suicide would be an example of an adverse event. SAEs will be reported 
to the Institutional Review Board, Data and Safety Monitoring Board and NIA representatives 
within 48 hours of the PI learning of the events. A report of all AEs will be sent to the Chair of 
the DSMB on a monthly basis. 
 
 
Internal Data and Safety Monitoring Board (DSMB) 
   This plan describes the monitoring activities of our internal DSMB. In addition to the 
activities of the DSMB, clinical monitoring is an ongoing process. These responsibilities  are 
assumed by co-I and the Director of the Pacific Brain Health Center (Dr. Merrill) and the 
clinical infrastructure of the Pacific Brain Health Center. 
            The DSMB will be comprised of Chair, Dr. Kirk Erikson, and Dr. Prabha Siddarth and Dr. 
Sean Mullen. The DSMB will meet initially prior to patient enrollment in the first year of the 
trial and then twice in subsequent years (2020, 2021) via conference call to monitor/audit the 
following, for a total of up to 3 calls during the course of this study: 
 
1.    Review all adverse event reports since the study initiation or since the last review will be 
reviewed at the DSMB meetings; 
 
2.    Review the medical record of all patients who have had a protocol-related serious adverse 
event since the last review; 
 

Sponsor: National Institute of Health (NIH) 
Protocol #: mSIM (NIH 1R21AG061494-01) 
Version #/Date: Ver. 04/26-Oct-2021 
 
 
16 
3.    Perform random audits of informed consent documents to verify that the informed 
consent procedures have been carried out and that necessary informed consent documents 
have been signed by study participants and staff; 
 
4.    Review data quality, completeness, and timeliness; 
 
5.    Review adequacy of compliance with goals for recruitment and retention, including those 
related to the participation of women and minorities; 
 
6.    Review adherence to the protocol; 
 
7.    Discuss factors that might affect the study outcome or compromise the confidentiality of 
the trial data (such as protocol violations); 
 
8.    Discuss factors external to the study such as scientific or therapeutic developments that 
may impact participant safety or the ethics of the study; 
 
9.    Follow up on problems previously identified 
            At the end of the meeting, the Principal Investigator, will summarize the findings of the 
DSMB and will subsequently implement recommendations for improvement in a timely 
manner. Special meetings of the DSMB may be convened when necessary, for urgent concerns 
regarding patient safety or data integrity. We don’t anticipate that there will be many urgent 
patient concerns given the low risks associated with this trial. 
 
Definition of an AE 
The following definition of an adverse event (AE) will be used for this study: 
 
• Any untoward medical occurrence in an enrolled subject who underwent procedures 
required by the study. 
 
An AE can be any unfavorable and unintended sign, symptom, or disease (new or 
exacerbated) occurring after starting the procedures required by the study, even if the event is 
considered not related to the study procedures. 
 
As far as possible, each adverse event will also be described by its duration (start and 
end dates), the intensity, its expectedness related to the known risks associated with the study 
procedures, and the action(s) taken.   
 
It is the responsibility of the investigator to perform periodic and special assessments 
for AEs. The investigator and clinical staff will note all AEs reported by the subjects. All clinical 
complaints volunteered by, or elicited from, the subject during the study will be recorded 
separately on the appropriate page of the CRF.  If any AE occurs, the subject will receive 
appropriate treatment and medical supervision if warranted.  

Sponsor: National Institute of Health (NIH) 
Protocol #: mSIM (NIH 1R21AG061494-01) 
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All AEs judged to be clinically significant will be followed until resolution. 
 
 
Definition of an SAE 
The definition of a serious adverse event (SAE) in this study is an AE that meets any of the 
following criteria: 
• Results in death 
• Is life-threatening 
 
NOTE: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the 
subject was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death if it were more severe. 
 
• Requires hospitalization or a prolongation of an existing hospitalization 
 
NOTE: In general, hospitalization signifies that the subject has been detained at the hospital or 
emergency ward for observation or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during hospitalization are AEs 
but not necessarily SAEs. An occurrence or complication that prolongs hospitalization is an 
SAE. When in doubt as to whether hospitalization occurred or was necessary, the AE should be 
considered an SAE. Hospitalization for elective treatments of a pre-existing condition that did 
not worsen from its original baseline is not considered an SAE. 
 
• A persistent or significant disability or incapacity 
 
NOTE: The term disability means a substantial disruption of a person’s ability to conduct 
his/her regular life functions. This definition is not intended to include AEs of relatively minor 
medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza 
and accidental trauma (e.g., sprained ankle) which may interfere or prevent everyday life 
functions but do not constitute a substantial disruption. 
 
• Other important medical event 
 
NOTE: Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate for other important medical events that may not result in death, be life-
threatening, or require hospitalization but still may jeopardize the subject or may require 
medical intervention to prevent one of the outcomes listed in this definition. These events 
should also be considered serious.  
 
Recording AEs and SAEs 
If an AE or SAE occurs, and it is deemed related and unanticipated to this study, it is the 
responsibility of the PI to review all documentation (e.g., hospital progress notes, laboratory, 

Sponsor: National Institute of Health (NIH) 
Protocol #: mSIM (NIH 1R21AG061494-01) 
Version #/Date: Ver. 04/26-Oct-2021 
 
 
18 
and diagnostic reports) relative to the event(s). The PI is to record all relevant information 
regarding any AE (including SAEs) on the AE page of the CRF. The PI will also attempt to 
establish a diagnosis of the event based on the signs, symptoms, or other clinical information. 
In such cases, the diagnosis, not the individual signs and symptoms, should be documented on 
the appropriate CRF as the AE or SAE.   
 
Assessment of Intensity 
The PI will make an assessment of intensity for each AE and SAE reported during the study. 
The assessment will be based on the investigator’s clinical judgment. The intensity of each AE 
recorded in the CRF should be assigned to one of the categories shown in Table 1. 
 
Table 1: Classification of AEs by Intensity 
 
Intensity 
Definition 
Mild AE 
An event that is easily tolerated by the 
subject, causing minimal discomfort and not 
interfering with everyday activities. 
Moderate AE 
An event that is sufficiently discomforting, 
causing interference with normal everyday 
activities. 
Severe AE 
An event that prevents the subject from 
performing their everyday normal activities. 
 
Any AE that changes in intensity or grade during its course will be recorded on the CRF at the 
highest-level experienced by the subject. 
 
NOTE: An AE that is assessed as severe should not be confused with an SAE. Severity is a 
category utilized for rating the intensity of an event (such as mild, moderate, or severe 
myocardial infarction). However, the event itself may be of relatively minor medical 
significance (such as a severe headache), and both AE(s) and SAE(s) can be assessed as severe.  
 
Expectedness of AEs 
An expected AE is one that is consistent with the known risk information associated with the 
study procedures. 
 
An unexpected AE is defined, as any AE, the specificity or severity of which is not 
consistent with the known risk information. “Unexpected,” as used in this definition, refers to 
an AE that has not been previously observed rather than from the perspective of such an AE 
not being anticipated based on the known effects of procedures required by the study. 
 
Follow-Up of AEs and SAEs 
After the AE or SAE report, the PI will proactively follow each subject. 
All AE(s) and SAE(s) will be followed until: 
• Resolution 

Sponsor: National Institute of Health (NIH) 
Protocol #: mSIM (NIH 1R21AG061494-01) 
Version #/Date: Ver. 04/26-Oct-2021 
 
 
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• The condition stabilizes 
• The event is otherwise explained 
• The subject is lost to follow-up 
Once the event is resolved, the appropriate SAE report page will be updated. The PI will also 
ensure that the follow-up includes any supplemental information that may explain the 
causality of the event(s). 
 
All SAEs will be reported to DSMB and NIH representatives within 48 hours of the PI learning 
about the SAE. 
 
9. CONFIDENTIALITY 
 
Data 
All information regarding the nature of the study provided by the sponsor or study monitor to 
the investigator (with the exception of information required by law or regulations to be 
disclosed to the IRB or the subject) must be kept in confidence by the investigator. 
 
Subject Anonymity 
The anonymity of participating subjects must be maintained. Subjects will be identified by 
their initials and an assigned subject number on CRFs and other documents retrieved from the 
site or sent to the study monitor, sponsor, regulatory agencies or central 
laboratories/reviewers. Documents that identify the subject (e.g., the signed informed 
consent document) must be maintained in strict confidence by the investigator, except to the 
extent necessary to allow auditing by the appropriate authorities, the study monitor, or 
sponsor representatives. 
 
Table 1: Classification of AEs by Intensity 
 
Intensity 
Definition 
Mild AE 
An event that is easily tolerated by the 
subject, causing minimal discomfort and not 
interfering with everyday activities. 
Moderate AE 
An event that is sufficiently discomforting, 
causing interference with normal everyday 
activities. 
Severe AE 
An event that prevents the subject from 
performing their everyday normal activities. 
 
Any AE that changes in intensity or grade during its course will be recorded on the CRF at the 
highest-level experienced by the subject. 
 
NOTE: An AE that is assessed as severe should not be confused with an SAE. Severity is a 
category utilized for rating the intensity of an event (such as mild, moderate, or severe 

Sponsor: National Institute of Health (NIH) 
Protocol #: mSIM (NIH 1R21AG061494-01) 
Version #/Date: Ver. 04/26-Oct-2021 
 
 
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myocardial infarction. However, the event itself may be of relatively minor medical 
significance, such as a severe headache), and both AE(s) and SAE(s) can be assessed as severe.  
Although subjects will be encouraged to complete the study, they may voluntarily 
withdraw at any time. The investigator will document the reasons for discontinuation. 
 
10. SUBJECT DISCONTINUATION AND TERMINATION OF STUDY 
Although subjects will be encouraged to complete the study, they may voluntarily withdraw at 
any time. The investigator will document the reasons for discontinuation. 
Also the investigator may withdraw the subject from the study. The subject will be removed 
from the study without their consent for various health, safety or administrative reasons, 
including but not limited to the following:  
 
• 
The investigator decides that continuing in the study would be harmful to 
subject. 
• 
The sponsor cancels the study. 
• 
Other administrative reasons. 
 
The investigator will make the decision and let the subject know if it is not possible for 
him/her to participate.  
 
11. COVID-19 PRECAUTIONS  
If needed, depending on the status of the coronavirus pandemic, precautions may be taken to 
limit the risk of transmitting COVID-19 via study procedures per our institutional policies 
(Providence Health). Study visits including intake, neuropsychological evaluation at the 
discretion of the clinician, and physical status assessments may be done using remote 
procedures. In order to collect physical status assessments, study equipment such as a blood 
pressure cuff and a calibrated scale may be sent to the participant’s home. The participant will 
be responsible for returning any additional study equipment.   Although all COVID-19 related 
healthy and safety precautions will be addressed throughout this study, some participants 
may still not be willing to come on-site to PBHC to undergo the mSIM on-boarding session.  In 
this instance then there will be an option for the study staff to perform this in-person visit at 
their home. Remote visits may continue after the COVID-19 crisis if deemed necessary by the 
PI or DSMB to preserve the integrity of the research study data. Some study participants may 
want to further minimize on-site activity. During COVID, participants may request to skip the 
MRI or QEEG assessments. The following precautions for any in-person study visits may be 
employed based on the discretion of the PI and institutional policies: screening of participants 
with questions regarding COVID-19 symptoms/exposure, temperature checks prior to in-
person visits, physical distancing as much as possible during the visit, use of personal 
protective 
equipment (e.g. masks) during in-person visits, or pre-visit COVID-19 testing. 
If a study participant tests positive for COVID-19 and cannot exercise, they may pause 
participation in the study. They can re-initiate in the study where they left off and the timeline 
will be paused for up to four weeks and depending on the severity of the case. Participants 

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will be asked to provide medical clearance to re-initiate into the study. The participant may be 
asked to ramp up exercise for up to 2 weeks at the discretion of the PI and DSMB. If the 
participant requires more than 4 weeks to re-initiate into the protocol, they will be terminated 
from the study at that time. 
 
 
 
 
 

Sponsor: National Institute of Health (NIH) 
Protocol #: mSIM (NIH 1R21AG061494-01) 
Version #/Date: Ver. 04/26-Oct-2021 
 
 
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APPENDIX I. STUDY TIMELINE (IN MONTHS) THE MSIM TRIAL RCT 
Each participant (N=30) will be enrolled for up to 26 weeks (6 months). Participants in the active arm 
(N=15, Group 2) arm will have the “mSIM Intervention” sessions outlined below, and patients in the 
control arm will only have activity monitoring via FitBit device. Group 1 will be granted access to the mSIM 
web-application after completing the intervention.    
 Screen 
Randmz. 
Baseline 
1 Mo 
2 Mo 3 Mo 4 Mo 5 Mo 6 Mo  Post-Trial  
Visit Window 
-30 to -1 
days 
+/- 7 days +/- 7 days 
 
+/- 7 days 
 
+/- 7 
days 
+/- 7 
days 
+/- 7 
days 
+/- 7 
days 
+/- 7 
days 
 
*Consent & screening 
1x 
  
  
  
  
  
  
  
  
  
*Intake questionnaires and 
assessments  
1x 
 
 
 
 
 
 
 
 
 
Medical Clearance to Exercise 
1x 
 
 
 
 
 
 
 
 
 
Randomization 
  
1x 
 
 
 
 
 
 
 
 
Credit card authorization 
 
 
1x 
 
 
 
 
 
 
Physical status assessment 
 
 
1x 
 
 
 
 
1x 
 
Lifestyle and/or satisfaction 
data 
 
  
1x 
 
 
1x 
1x 
 
mSIM Intervention (Group 2 (SIM)) 
Equipment instruction 
 
 
1x 
 
 
 
 
 
 
Equipment drop-off  
 
 
 1x 
 
 
 
 
 
 
 
Equipment pick-up 
 
 
 
 
 
 
1x 
 
Exercise ramp-up session  
 
 
  
4-12x  
(2-6 weeks duration) 
 
 
 
 
 
Gain access to mSIM web-app 
 
 
 
 
  
Virtual Support Sessions 
 
 
 
 
 
mSIM exercise session 
  
  
  
24 x (12-14 weeks duration) 
 
mSIM homework  
 
 
  
24x (12-14 weeks duration) 
 
mSIM Intervention (Group 1 (CON)) 
Access to mSIM web-app 
 
 
 
 
 
 
 
 
 
1x 
On-going Data Collection 
Fitbit 
 
 
 
 
 
Imaging Data Collection 
 QEEG 
  
  
1x  
 
 
 
 
1x 
 
MRI* 
 
 
*1x 
 
 
 
 
*1x 
 
Biological Sample Collection 
Blood sample 
 
 
1x 
 
 
 
 
1x 
 
Neuropsychological/Cognitive Assessments 
Virtual neuropsychological 
assessment 
1x 
 
 
 
 
 
1x 
1x 
 
Notes:  #x indicates the number of times a test or an intervention will occur in protocol window (e.g. 2x = 
two times). *In participants that are eligible for an MRI. 
   indicates ongoing data collection.  
 
 

Sponsor: National Institute of Health (NIH) 
Protocol #: mSIM (NIH 1R21AG061494-01) 
Version #/Date: Ver. 04/26-Oct-2021 
 
 
23 
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Version #/Date: Ver. 04/26-Oct-2021 
 
 
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