Strong Evidence: Randomized Digitally Delivered Fall-Prevention Exercise Trial in Older Adults
Phase: NA
Conditions: Fall Prevention, Fall Prevention in Healthy Aging
Sponsor: University of California, San Diego

Strong Evidence: Randomized Digitally Delivered Fall-Prevention 
Exercise Trial in Older Adults 
 
NCT Number: Not yet assigned 
Document Date: 12/1/2025 upload to clinicaltrials.gov 
Document last updated 11/19/2025 
 
 

Office of IRB Administration (OIA) 
Biomedical Protocol for 
Interventional Research 
Version Date 12.08.21 
*= Required 
     Edited version of NIH-FDA Clinical Trial Template v1.07 
STRONG EVIDENCE 
Protocol Number: 812960 
National Clinical Trial (NCT) Identified Number:  N/A 
Principal Investigator: Ryan Moran, MD, MPH 
IND/IDE Number:  N/A 
IND/IDE Sponsor: N/A 
Funded by: Internally funded by anonymous gift 
Version Number:  1.1 
19 November 2025 
Summary of Changes from Previous Version: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 

 
 
  
 
ii 
Table of Contents 
1 
PROTOCOL SUMMARY ....................................................................................................................... 1 
1.1 
Synopsis ................................................................................................................................... 1 
1.2 
Schema..................................................................................................................................... 3 
1.3 
Schedule of Activities (SoA) ..................................................................................................... 3 
2 
INTRODUCTION ................................................................................................................................. 6 
2.1 
Study Rationale ........................................................................................................................ 6 
2.2 
Background .............................................................................................................................. 7 
2.3 
Risk/Benefit Assessment   ........................................................................................................ 9 
2.3.1 
Known Potential Risks ............................................................................................ 9 
2.3.2 
Known Potential Benefits .................................................................................... 10 
2.3.3 
Assessment of Potential Risks and Benefits ........................................................ 11 
3 
OBJECTIVES AND ENDPOINTS .......................................................................................................... 11 
4 
STUDY DESIGN ................................................................................................................................. 14 
4.1 
Overall Design ........................................................................................................................ 14 
4.2 
Scientific Rationale for Study Design ..................................................................................... 15 
4.3 
Justification for Dose ............................................................................................................. 17 
4.4 
End of Study Definition .......................................................................................................... 17 
5 
STUDY POPULATION ........................................................................................................................ 17 
5.1 
Inclusion Criteria .................................................................................................................... 17 
5.2 
Exclusion Criteria ................................................................................................................... 18 
5.3 
Lifestyle Considerations ......................................................................................................... 18 
5.4 
Screen Failures ....................................................................................................................... 18 
6 
STUDY INTERVENTION ..................................................................................................................... 19 
6.1 
Study Intervention(s) Administration .................................................................................... 19 
6.1.1 
Study Intervention Description ............................................................................ 19 
6.1.2 
Dosing and Administration .................................................................................. 19 
6.2 
Preparation/Handling/Storage/Accountability ..................................................................... 20 
6.2.1 
Acquisition and accountability ............................................................................. 20 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ............................................ 20 
6.2.3 
Product Storage and Stability .............................................................................. 20 
6.2.4 
Preparation .......................................................................................................... 20 
6.3 
Measures to Minimize Bias: Randomization and Blinding .................................................... 20 
6.4 
Study Intervention Compliance ............................................................................................. 20 
6.5 
Concomitant Therapy ............................................................................................................ 20 
6.5.1 
Rescue Medicine .................................................................................................. 21 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL
 
21 
7.1 
Discontinuation of Study Intervention .................................................................................. 21 
7.2 
Participant Discontinuation/Withdrawal from the Study ..................................................... 21 
7.3 
Lost to Follow-Up ................................................................................................................... 22 
8 
STUDY ASSESSMENTS AND PROCEDURES ....................................................................................... 22 
8.1 
Efficacy Assessments ............................................................................................................. 22 

 
 
  
 
iii 
8.2 
Safety and Other Assessments .............................................................................................. 26 
8.3 
Adverse Events and Serious Adverse Events ......................................................................... 26 
8.3.1 
Definition of Adverse Events (AE) ........................................................................ 26 
8.3.2 
Definition of Serious Adverse Events (SAE) ......................................................... 26 
8.3.3 
Classification of an Adverse Event ....................................................................... 27 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ..................... 29 
8.3.5 
Adverse Event Reporting ..................................................................................... 29 
8.3.6 
Serious Adverse Event Reporting......................................................................... 29 
8.3.7 
Reporting Events to Participants ......................................................................... 30 
8.3.8 
Events of Special Interest ..................................................................................... 30 
8.3.9 
Reporting of Pregnancy .......................................... Error! Bookmark not defined. 
8.4 
Unanticipated Problems ........................................................................................................ 30 
8.4.1 
Definition of Unanticipated Problems (UP) ......................................................... 30 
8.4.2 
Unanticipated Problem Reporting ....................................................................... 30 
8.4.3 
Reporting Unanticipated Problems to Participants ............................................. 31 
9 
STATISTICAL CONSIDERATIONS ....................................................................................................... 31 
9.1 
Statistical Hypotheses ............................................................................................................ 31 
9.2 
Sample Size Determination.................................................................................................... 32 
9.3 
Populations for Analyses ....................................................................................................... 33 
9.4 
Statistical Analyses................................................................................................................. 33 
9.4.1 
General Approach ................................................................................................ 33 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ....................................................... 33 
9.4.3 
Analysis of the Secondary Endpoint(s) ................................................................ 33 
9.4.4 
Safety Analyses .................................................................................................... 33 
9.4.5 
Baseline Descriptive Statistics ............................................................................. 33 
9.4.6 
Planned Interim Analyses .................................................................................... 33 
9.4.7 
Sub-Group Analyses ............................................................................................. 33 
9.4.8 
Tabulation of Individual participant Data ............................................................ 34 
9.4.9 
Exploratory Analyses ............................................................................................ 34 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ...................................... 34 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ..................................................... 34 
10.1.1 
Informed Consent Process ...................................... Error! Bookmark not defined. 
10.1.2 
Study Discontinuation and Closure ...................................................................... 34 
10.1.3 
Confidentiality and Privacy .................................................................................. 34 
10.1.4 
Future Use of Stored Specimens and Data .......................................................... 35 
10.1.5 
Key Roles and Study Governance ........................................................................ 35 
10.1.6 
Safety Oversight ................................................................................................... 35 
10.1.7 
Clinical Monitoring ............................................................................................... 35 
10.1.8 
Quality Assurance and Quality Control ................... Error! Bookmark not defined. 
10.1.9 
Data Handling and Record Keeping ..................................................................... 36 
10.1.10 
Protocol Deviations .............................................................................................. 36 
10.1.11 
Publication and Data Sharing Policy ....................... Error! Bookmark not defined. 

 
 
  
 
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10.1.12 
Conflict of Interest Policy ........................................ Error! Bookmark not defined. 
10.2 
Additional Considerations ..................................................................................................... 37 
10.3 
Abbreviations ......................................................................................................................... 38 
10.4 
Protocol Amendment History ................................................................................................ 40 
11 
REFERENCES..................................................................................................................................... 41 
 

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1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
Strong Evidence 
Study Description: 
We have successfully completed a pilot project focused on feasibility and 
user acceptability of a digitally delivered program for fall prevention in 
older adults.  It was well received among our population of lower and 
moderate risk individuals. We propose to extend this research by 
repeating the training program with the inclusion of a  wait list control 
group.  
 
Group A (immediate intervention) will start their initial 12 week exercise 
program (Intensive Exercise) within 4 weeks of baseline (BL) measurement 
(as a cohort).  This will be followed by an optional additional 12 week 
exercise program (Maintenance Exercise 2) that participants who 
complete at least 10 of the Exercise 1 classes will be invited to join.  This 
will be followed by a 12 week wash out period.  Measurements will occur 
each 12 weeks (BL, 12 wk post randomization, 24 wk post randomization, 
36 wk post randomization) 
 
Group B (waitlist control) will start with a 12 week life as normal period 
that is concurrent with Group A’s intensive Exercise.  They will start 
Intensive Exercise when Group A is doing Maintenance exercise.  They will 
be invited to Maintenance Exercise while Group A is doing washout.  They 
will not have a washout period.  Measurements will occur at the same 
period(s) as Group A (i.e. all participants measured during the same time 
period). 
  
The intervention will be identical to what was offered in the past, and 
measurements will be very similar (removing those that did not show 
change with intervention or were deemed too difficult for participants). 
 
 
Objectives: 
Primary Objectives:   
1) Reduce fall risk in both moderate and low risk populations using a 
digitally delivered exercise intervention. 
2) Compare intervention data with a wait list control to determine 
intervention effectiveness 
3) Measure peripheral blood mononuclear cells (PBMCs) based 
autophagy flux in older adults and relate these values to established 
measures of body composition and physical function, including 
fitness, balance, gait speed, posture, strength. 
Secondary Objectives:   
1) Determine the associations between changes in measures of body 
composition and physical function and changes in autophagy flux. 
functional maeasues  

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2) Determine the associations/reliability of zoom based measurements 
of common physiological field tests delivered via zoom to those 
delivered in person. 
3) To evaluate an ongoing, pooled cohort of the Strong Foundations 
digitally-delivered program extended beyond the initial 12 week 
onboarding, with reduced individualized coaching for an additional 
12 week, weekly program, and to assess programmatic feasibility, 
acceptability, and changes in measures of physical function. 
                                           
Endpoints: 
Primary Endpoint:  
1) Balance and fall risk:  This will be measured in-person using a 
variety of commonly deployed assessments of balance and physical 
function.   
2) Posture: This will be measured in-person using both prone and 
standing measures of posture 
3) Body composition utilizing Bioelectrical Impedience 
4) Strength: Measured by grip strength and 30 second chair stand for 
upper and lower body respectively.  
5) Cellular Autophagy measured in PBMC 
 
Secondary Endpoints:   
1)  Usability/Acceptability of exercise classes delivered via a digital 
format will be assessed using a questionnaire that uses the System 
Usability Scale (SUS).  
2) Attendance at exercise sessions. 
 
Study Population: 
Older adults with low to moderate risk of falling. 
We will extend our earlier research using a digitally delivered fall-
prevention exercise program (IRB 202026 and 806696) by engaging 1) two 
cohorts of up to 15 individuals each at low to moderate risk of falls and 2) 
two additional cohorts, of up to 15 individuals who will serve as a wait list 
control and will start their intervention 12 weeks after the initial groups. 
 
Phase: 
 
1/2 
 
Description of 
Sites/Facilities Enrolling 
Participants: 
 
The Exercise and Physical Activity Resource Center (EPARC) is a fully 
operating exercise physiology laboratory within the Herbert Wertheim 
School of Public Health.   
 
Description of Study 
Intervention: 
 
Our fall- risk reduction program, Strong Foundations, was designed to be 
delivered digitally, and while there are many such programs currently 
available on the Internet, especially in the time of COVID-19, the novel 
feature of this program is the delivery of semi-individualized instruction in 
real time within a small group setting.   
The program was designed with physician input and by exercise 
physiologists and a Doctor of Physical Therapy candidate, all with 
extensive training in both group and individualized exercise for geriatric 
populations.   

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Strong Foundations is a 12 week iterative curricular program with three 
core components: postural alignment and control, balance and mobility, 
and muscular strength and power.  All the exercises offered over the 
course of the intervention are appropriate for the target population and 
are standardized so all participants receive the same basic instruction, but 
level of difficulty is scaled to participant experience, capability, and 
musculoskeletal limitations. 
Study Duration: 
1 year 
Participant Duration: 
36-40 weeks deponding upon when basline measurement is completed 
 
 
1.2 
SCHEMA –FIGURE 1  
 
 
1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
NOTE:  All of these measures will be done at all (n=4) timepoints. 
 
The prescreening questionnaire (by phone or in person) and consent process are not documented here 
but will occur prior to the completion of assessment and/or intervention.   
 
Measurements are listed in more detail below. 
Measurements listed as “lab-based” will be completed in person at baseline, 12 weeks post 
randomization, 24 weeks post randomization, and 36 weeks post randomization. 
 
Lab based assessments will precede zoom based assessments by 1-3 days.  We will have a two week 
buffer period around the measurement times (16, 28, 40 weeks) shown below to accommodate 
participant scheduling needs.  
 
All baseline measures will be completed no more than 4 weeks before randomization.   
Table 1: Assessments/Measures Collected:  
Timepoints: Baseline, 12, 24 and 36 weeks post randomization.  

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Measures 
Domain and 
Participant 
Position 
Description 
Lab-
based 
Zoom-
based 
Short Physical 
Performance Battery 
(SPPB) 
Strength / 
Balance; 
Standing 
4-part validated scale 
for fall risk 
Yes 
No 
Timed Up and Go 
(TUG) 
Fall Risk; 
Standing 
Standardized 
assessment of 
functional mobility 
Yes 
Yes 
Better Balance Testing 
Balance; 
Standing 
Measure of 
proprioceptive and 
vestibular function 
utilizing computerized 
dynamic posturography Yes 
No 
25 foot walk 
Fall Risk; 
Standing 
Standardized 
assessment of gait 
speed and variability 
associated with fall risk 
Yes 
No 
2.5 minute walk test 
Endurance, 
strength 
Standardized 2.5 
minute timed distance 
walk with indirect 
calorimetry 
measurements 
Yes 
No 
  
  
  
  
  
Grip Strength 
Strength; 
Standing 
Standardized 
assessment of grip 
strength, which has 
good correlation with 
strength across all 
muscle groups  
Yes 
No 

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5 
30 Second Chair 
Stands 
Strength; 
Standing 
Common field measure 
of muscular strength 
and endurance of the 
legs 
Yes 
Yes 
  
  
  
  
  
Occipital to Wall 
Distance 
Posture; 
standing 
Measurement of 
kyphotic curvature of 
the spine. 
Yes 
No 
Block Measurement 
Posture; 
Supine 
Measurement of 
kyphotic curvature of 
the spine. 
Yes 
No 
Kyphometer and 
Flexiruler 
measurements 
Posture; 
standing 
Measurement of 
kyphotic curvature of 
the spine. 
Yes 
No 
Multiple measures of 
height 
Posture; 
standing 
Measurement of height 
while standing 
normally vs. standing 
‘as tall as possible’.  
Indicative of non-
specific postural 
deficiencies. 
Yes 
No 
 
 
 
 
 
Bio-Electrical 
Impedience Scale 
Body 
Composition 
Non-Invasive measure 
of body fat, muscle, 
and bone 
Yes 
No 
 
 
 
 
 
(Optional)  
Blood Draw 
Autophagy 
See description below.  
9 mL of fasting blood 
Yes 
No 

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drawn via 
venipuncture.   
Additional Activities after the intense and maintenance intervention periods 
Following the end of both the intense and maintenance  intervention periods, participants will be asked 
to complete the survey titled “Strong Evidence_SUS and follow up questions” via redcap. In the event 
that participants are unable or unwilling to complete the survey via email they will be mailed (and asked 
to return) a paper copy with a preaddressed stamped envelope. We envision that this survey will be sent 
within 3 days of completing the intervention. 
 
Additional Collection of Falls Information 
Finally, follow-up falls information will be gathered for up to 12 months after completion of the 
intervention. Participants will be contacted at the beginning of each calendar month to inquire if they 
have had any falls in the previous month, and if yes, were there any injuries. These communications will 
occur by email if participants are able, and if not, by pre-stamped postcard or phone calls.  
 
2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
Falls represent a significant cause of preventable injury, contributing to premature mortality and 
morbidity.  Fall related injuries are the major cause of accidental death and disability among older 
adults. Approximately one-quarter of community-residing men and women >65 years of age, and almost 
half of those over age 80, fall annually1.   Alarmingly, the rate of fall-related mortality has increased over 
30% just between 2007 and 2016.2  In San Diego County, falls remain the second most common cause of 
accidental deaths, with the age adjusted rate of mortality, emergency room discharge, and inpatient 
admission per 100,000 at 9.18, 1,939, and 336, respectively, in 2017. Moreover, these numbers have all 
increased or remained steady from the preceding 5 years3.  
 
COVID-19 has confounded social isolation in older adults, especially those in congregate settings.  
Appropriate technology/technologic driven approaches has promise (but limitations) to mitigate some 
aspects of loneliness/isolation in this population.16 Digitally delivered programs are an opportunity that 
help balance risks and benefits during times of social distancing, improve dissemination, and possibly 
improve objective measures of function.17  Therefore, approaches to improve access to fall-risk 
reduction exercise, including balance and strength training opportunities is imperatively important, and 
growing data suggests digitally formatted delivery may be feasible18.   
 
Additionally, aging is accompanied by progressive loss of physiological reserve, leading to frailty, 
functional decline, and increased risk of falls, the leading cause of injury and loss of independence in 
older adults. At the cellular level, aging is marked by accumulation of damaged proteins and organelles, 
reflecting a decline in homeostatic mechanisms such as autophagy, a conservation oriented recycling 
pathway.  Autophagy is essential for maintaining proteostasis and cellular quality control. Evidence from 
model organisms, such as mice, Drosophila and C. elegans, and post-mortem human tissues indicates 
that autophagy declines with age, and interventions that restore it improve healthspan and lifespan79. 
Despite its central role in aging biology, the relevance of autophagy to human health and resilience has 
been difficult to establish, largely because of the absence of reliable biomarkers. Recently, assays of 
autophagy flux in peripheral blood mononuclear cells (PBMCs) have been developed, enabling minimally 
invasive, reproducible measurement of this process in human cohorts. While these methods provide an 

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unprecedented window into peripheral autophagy dynamics, it remains unclear to what extent PBMC 
flux reflects organismal fitness, systemic resilience, or autophagy status in other tissues, particularly in 
humans. This interventional study provides an excellent opportunity to gather low-risk/high-yield data 
regarding links between PBMC-based assays of autophagy with functional outcomes in older adults.  
Establishing PBMC autophagy flux as a biomarker of resilience in this context would address a major 
translational gap, bridging basic mechanisms of aging biology with functional outcomes of intervention 
and help guide strategies to maintain health and independence in older adults. 
 
Data from Strong Foundations 2.0 (IRB # 806696) was very promising. However, it was determined that 
possible conclusions would be strengthened by inclusion of a control group.  Given the challenge of 
having individuals come for 4 measurment visits without a desirable intervention we felt that a wait list 
control was best. 
 
As such individuals will be randomized by cohort into either  
• 
Group A: who will start their 12 week exercise program with the intensive Intervention within 4 
weeks of baseline measurement. For those who qualify (see below) this will be followed by a 12 
week maintenance program.  This group will finish the program with 12 weeks life as usual.  
• 
Broup B: who willl have a 12 week lead in period of life as usual.  They will then begin their 12 
week intensive intervention.  Those who qualify, this will be followed by a 12 week maintenance 
program. 
 
 
2.2 
BACKGROUND  
 
While fall risk is multifactorial, identification of risk factors and referral to/participation in appropriate 
fall-risk reduction programs are established as an effective, evidenced-based approach to reduce fall-
risk4.  Specifically, targeted strength and balance exercise have consistently been shown to improve fall 
risk, and accordingly, the Centers for Disease Control and Prevention (CDC) has outlined an evidenced-
based clinical approach to identify those at risk for falls to help assess known risk factors and to refer for 
community-based fall-prevention programs5,6.  This toolkit, however, has been slow to penetrate in 
routine clinical practice, as barriers reported by physicians to implementing comprehensive falls-
prevention screening are time constraints, poor reimbursement for falls screening, and that existing 
toolkit utilization does not easily fit into a Medicare wellness visit7.  Because of this, only approximately 
one-third of older adults report being asked about fall-risk, and similarly only around a third of those 
who fall report discussing this with their healthcare provider.8,9  Compounding this, COVID-19 has 
created uncertainty in accessing community resources,  increased sedentary behavior, isolation and 
subsequent fall risk10.   This is especially disconcerting as a single fall predicts recurrent falls: between 
10% and 44% of elderly patients with a history of falls will sustain additional falls.11–15   
COVID-19 has confounded social isolation in older adults, especially those in congregate settings.  
Appropriate technology/technologic driven approaches has promise (but limitations) to mitigate some 
aspects of loneliness/isolation in this population.16 Digitally delivered programs are an opportunity that 
help balance risks and benefits during times of social distancing, improve dissemination, and possibly 
improve objective measures of function.17  Therefore, approaches to improve access to fall-risk 

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reduction exercise, including balance and strength training opportunities is imperatively important, and 
growing data suggests digitally formatted delivery may be feasible18.   
This project also offers the potential to expand our knowledge regarding successful aging using the basic 
sciences. Specifically, autophagy is the process by which the body packages and recycles damaged 
proteins and organelles making it essential for maintaining proteostasis and cellular quality control. 
Autophagy is a dynamic, multi-step process, and static measurements (e.g., LC3 protein levels) are 
insufficient to distinguish increased flux from impaired degradation. Recently, assays of autophagy flux 
in peripheral blood mononuclear cells (PBMCs) have been developed, enabling minimally invasive, 
reproducible measurement of this process in human cohorts, but there has currently been limited 
application to human models. Thus, this project creates a unique opportunity to begin linking autophagy 
biology with functional outcomes in older adults. Even more meaningfully, autophagy flux in PBMCs has 
not yet been assessed after any form of exercise, despite its known impact of functional outcomes and 
resilience. Establishing PBMC autophagy flux as a biomarker of resilience in this context would address a 
major translational gap, bridging basic mechanisms of aging biology with functional outcomes of 
intervention and help guide strategies to maintain health and independence in older adults. 
Fall Prevention Program:  Our fall- risk 
reduction program, Strong Foundations, 
was designed to be delivered digitally, and 
while there are many such programs 
currently available on the internet, 
especially in the time of COVID-19, the 
novel feature of this program is the delivery 
of semi-individualized instruction in real 
time within a small group setting. This is 
accomplished largely by use of the 
‘breakout room’ feature on the Zoom 
platform, where 2-3 trained intern 
instructors correct form while the lead instructor teaches the larger group.  The program was designed 
with physician input and by exercise physiologists and a Doctor of Physical Therapy candidate, all with 
extensive training in both group and individualized exercise for geriatric populations.  Strong 
Foundations is a 12 week iterative curricular program with three core components: postural alignment 
and control, balance and mobility, and muscular strength and power.  All the exercises offered over the 
course of the intervention are appropriate for the target population and are standardized so all 
participants receive the same basic instruction, but level of difficulty is scaled to participant experience, 
capability, and musculoskeletal limitations.   

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While many exercise interventions for 
fall prevention have been validated in 
different populations, our program is 
designed with the community in mind 
and with a novel platform to improve 
dissemination/availability across many 
populations. 
 
 
 
 
 
 
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
The potential risks associated with study participation are deemed by the research team to be no 
greater than minimal.  Risks will be mitigated as part of this study by only inviting participants not at 
elevated risk based on clinically available screening for falls. Because activities aim to address balance, 
strength, and posture, many of these activities potentially predispose individuals to injury or fall 
potential; therefore, we have included many mechanisms to safeguard against injury throughout this 
pilot as described below.  See below in section 8.3.3.2 for additional details regarding risk 
assessment/mitigation. 
Potential risks include: 
1. Adverse effect of an injury during objective, lab collected or digitally collected measures of fall 
risk.  We will have supervision throughout all lab measures, and EPARC has an excellent 
precedent of being able to conduct these measures in high(er) risk individuals without injury.  
For digitally collected measures, as described above, we have identified only measures which 
are relatively safe to do by video, and will be directly supervised throughout the collection 
process, including safeguarding for the individual to be able to necessary measures before 
starting (eg. if there is a perceived lack of space, the instructor will assure the area is cleared of 
clutter before starting). 
2. Adverse effect of a potential fall during a group exercise class.  Participants will be invited only if 
clinically assessed as not elevated risk.  Class sizes will be kept to 10-15, which is thought to be 
appropriately sized for monitoring both the in-person and by electronic interface. 
3. The participant may experience a musculoskeletal injury, or muscle fatigue and soreness due to 
the assessments of strength or from the exercises performed in the class.  
4. There is a small risk of cardiovascular event during in-lab testing, although the assessments are 
at an intensity of sufficiently low level that this is very unlikely. 
5. There is a small risk of cardiovascular event during at home training, although, because the 
focus of the training is not on cardiovascular development, the intensity will be kept very low, so 
the likelihood of cardiovascular injury is very low. 
80.6
0
20
40
60
80
100
1
3
5
7
9
11
13
15
17
19
21
23
25
27
29
31
33
35
38
Mean
Percentage Score (Acceptable = >60)
Participant Number and Mean value
Figure 3: Strong Foundations:
System Usability Scale (Brooke, 1996) Results

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6. Body composition measured by BIA passes a weak electrical current through the body which 
could interfere with and cause the malfunction of electrical medical implants. To ensure that we 
do not assess people who could be harmed we have included individuals with electrical medical 
implants in our exclusion criteria. 
7. The specific risk associated with the autophagy assays to be employed in this study is based on 
the drawing of blood. As with all blood draws, participants may experience temporary pain, 
bruising, bleeding and a small risk of infection or fainting or dizziness during the collection 
process. Only trained staff will be responsible for the collection of blood samples. 
8. Data compromise risk: clinical data without identifiers will be collected as part of this study.  We 
will be video recording the instructor during classes.  This will ensure that participant’s images 
are not included but if they speak during the exercise session their voices will be captured. 
A.  While personal information will not be shared, it will occasionally be possible for participants 
to view each other during the exercise sessions.  This risk is no larger than if participants were 
completing group exercise in person at an exercise training facility. 
B.  Exercise sessions will be recorded to provide in-home practice opportunities to participants 
between classes.  The “spotlight” feature will be used to ensure that only the demonstrating 
instructor is seen during the class period.  However, if participants speak during the recorded 
portion of the session their voice will be captured. 
Additional data protections are detailed in Section 10 of this protocol. 
2.3.2 KNOWN POTENTIAL BENEFITS  
For the individual participant, potential benefits include increased awareness of fall risk.  Further, 
individuals enrolled in exercise training may enhance their cardiovascular fitness, strengthen their 
muscles, improve balance and posture and/or reduce their fall risk. 
Benefits to the academic community include understanding the barriers and limitations, and benefits of 
digitally delivered exercise vs in person fall-prevention program, and the reception of these programs in 
a community setting.  Additionally, establishing the utility of PBMC autophagy flux as a biomarker of 
resilience and functional capability in an older adult population will address a major translational gap, 
bridging basic mechanisms of aging biology with functional outcomes of intervention and help guide 
strategies to maintain health and independence in older adults. 
While there are no known direct benefits to society, integrating Strong Foundations program and 
evaluating which modality is most effective and useful will be important to numerous stakeholders—
namely residence facilities and other similar community-based organizations.  As falls are increasing, 
and COVID-19 has presented increased uncertainty, there remains great importance to better 
understand mechanisms to provide scalable services to those with risk factors safely in a feasible, 
appropriate, participant-focused manner 
In addition, this program serves to potentially indirectly benefit society by introducing a larger 
awareness of falls prevention. 

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2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
The risks described above are inherent to an exercise program delivered via digital means.  The main 
risks (falling, musculoskeletal injury) have been minimized with the design of the program and will 
continue to be minimized by using appropriately trained and certified staff members. 
 
Risks will be managed as follows (in order of risks presented above): 
 
1) All electronic data and statistical analysis will be performed on a secured password protected 
computer with only study-identified potential users. 
2) Surveys will be kept either in electronic form as part of participants’ electronic medical record, or 
will be performed by phone or mail and stored/collected in a locked facility, recorded as above, and 
discarded/shredded as PHI is discarded in customary/usual practice. 
a. Participants will be allowed to skip any questions that they are uncomfortable answering. 
3) Assessments will be conducted by specially trained individuals and overseen by a licensed clinical 
exercise physiologist.  Our research unit has established standard operating procedures for these 
assessments and have successfully gathered data from thousands of participants without 
significant injury. 
4) Zoom based exercise classes will be monitored by certified and experienced personal trainers or 
senior research staff with extensive experience in exercise prescription and group-exercise 
instruction among geriatric populations.  These individuals are specifically trained to identify 
fatigue and instability likely to contribute to a fall.  Further, all classes will include cueing to utilize 
balance assistance (chair and/or wall) during exercise to minimize fall risk. 
5) Classes are designed to be progressive and participants will carefully monitored by licensed 
personal trainers to ensure that proper form and progressions are followed to minimize risk of 
musculoskeletal injury or soreness. 
6) Participants will be excluded if they have a non-removable implanted electrical device (pacemaker, 
cochlear implant, etc.) 
7) Only trained phlebotomists will draw blood. 
8) To prevent the loss of confidentiality, we will use our best efforts to keep participant information 
secure. Participants will be assigned an identification number, which will be used for data analysis 
purposes. The Project Manager will have a link between the subject number and the subject’s 
name. This information will be locked in a filing cabinet in the Project Manager’s office. All data 
that are securely downloaded during data collection procedures will be de-identified and stored on 
secure, password-protected servers. 
           A.  We will utilize the “spotlight” option in zoom to ensure that the participant’s view is of the 
demonstrating instructor. 
B.  We will preview all recording prior to sharing to ensure that no participant images are 
captured (videos will be edited to remove participants in the event that they are inadvertently 
recorded). 
We do not believe that the risks outweigh the potential benefit to individual participants in terms of 
reduced fall risk and do believe that the potential benefits of “in-person” digital design outweigh the 
(minimal) risks that this modality imposes. 
 
3 
OBJECTIVES AND ENDPOINTS 
 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
To measure and compare objective 
measures of physical function 
related to fall- and fracture-risk in 
older adults at low to moderate 
risk of falls between the 
intervention and wait list control. 
 
Balance/Fall Risk:  This will be 
measured in-person using a 
variety of commonly deployed 
assessments of balance and 
physical function.  These include 
the Short Physical Performance 
Battery (SPPB), Better Balance 
Test, the Timed up-and-Go (TUG), 
and measures of gait speed during 
a 25 foot walk completed both as 
fast as possible, and at normal 
walking speed. 
 
Muscular Strength:  Strength will 
be measured both in person and 
digitally using commonly deployed 
field measures (30 second chair 
stands).  We will also be 
completing additional in-lab only 
measures of strength via grip 
strength  
 
Spinal Posture:  Good posture is 
important to reducing the risk of 
vertebral fractures and has been 
identified as a potential locus of 
intervention for fracture 
prevention33.  We propose to 
measure posture using a variety of 
measures that can be easily 
integrated into clinical practice 
(occipital to wall distance and 
standing height), as well as those 
that require a higher level of 
expertise (standing measures of 
postural tilt, and standing and 
lying measures of kyphosis.) 
 
Body Composition:  This will be 
measured using a completely non-
invasive tool called BioElectrical 
Impedience Analsysis (BIA) which 
provides well validated data 
regarding the absolute amount of 
All of the 
balance/muscular 
strength/postural 
measures chosen are 
commonly used to assess 
fall risk, muscular 
strength, and postural 
control and were 
specifically chosen as 
being appropriate for this 
population. 
 
Measures of body 
composition will provide 
data regarding frailty and 
relative risk for negative 
health outcomes. 
 
Follow up questionnaires 
will allow us to determine 
if individuals who have 
participated in this 
program fall less and/or 
have less injurious falls 
than an age-matched 
epidemiologically drawn 
sample (i.e. prevalence 
rates reported for national 
samples). 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
an individual’s fat, muscle, and 
bone. 
 
Ongoing questionnaires about falls 
for up to 1 year following the 
intervention. 
Identify and quantify associations 
between cellular autophaghy and 
outcomes related to body 
composition and functional 
capabilities 
All of the above and (optional) 
blood draw 
Establishing PBMC 
autophagy flux as a 
biomarker of resilience in 
this context would 
address a major 
translational gap, bridging 
basic mechanisms of aging 
biology with functional 
outcomes. 
Secondary 
 
 
To compare objective measures of 
fall-risk, including balance, and 
muscular strength, assessed 
digitally vs. in-person. 
 
Test/retest from an in-lab to a 
digital (zoom ) environment for a 
limited number of the physical  
assessments to determine the 
validity and repeatability of these 
assessments in a zoom based 
environment. 
 
These were chosen based 
on being appropriate to 
being safely assessed in a 
zoom based testing 
environment/ 
To determine feasibility and 
participant acceptance of deploying 
this digitally-delivered program.  
System Usability Scale22 (SUS).  
The SUS is a nonpriority validated 
questionnaire designed to 
understand the ease of use of new 
systems or programs using a 5 
element Likert scale. This 
questionnaire includes the 10 
questions typically included in a 
SUS, 8 questions designed to 
assess the patient experience in 
the program and 2 questions 
assessing falls in the recent past.   
The SUS is a commonly 
used assessment tool to 
determine the ease of 
using new systems or 
programs and is 
commonly used to assess 
digital programs/tools. 
Tertiary/Exploratory  
 
 
To evaluate an ongoing, pooled 
cohort of the Strong Foundations 
digitally-delivered program 
extended beyond the initial 12 
week onboarding, with reduced 
individualized coaching for an 
additional 12 week, weekly 
program, and to assess 
Attendance  
This is, we believe, the 
best determination of the 
likelihood for ongoing 
engagement and exercise 
intervention compliance. 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
programmatic feasibility, 
acceptability, and changes in 
measures of physical function. 
 
4 
STUDY DESIGN  
4.1 
OVERALL DESIGN 
 
We hypothesize that using a novel exercise program that is delivered digitally with real time instruction 
and direct coaching we will be able to reduce objective measures of fall risk, will improve muscular 
strength, and will improve posture. 
 
This trial is between phase 1 and 2 and will be a randomized intervention with a wait list control group. 
We do not believe that there will be substantial bias as part of this trial, and will ensure that 
measurement staff are blinded to the randomization group of all participants. We will also ensure that 
all measurement staff are specifically trained in the assessments they are completing. 
 
This is a single site study conducted by the Exercise and Physical Activity Resource Center (EPARC) and is 
entitled Strong Evidence.  
We will be extending our earlier research using a digitally delivered fall-prevention exercise program 
(IRB 202026 and 806696).  Data from Strong Foundations 2.0 (IRB # 806696) was very promising. 
However, it was determined that possible conclusions would be strengthened by inclusion of a control 
group.  Given the challenge of having individuals come for 3 to 4 measurement visits without a desirable 
intervention we felt that a wait list control was best. 
With this in mind, we will be engaging 1) two cohorts of up to 15 individuals each at low to moderate 
risk of falls and 2) two additional cohorts, of up to 15 individuals each at low to moderate risk of falls 
who will serve as a wait list control and will start the intensive intervention 12 weeks after their 
matched/randomized group . 
 
As such individuals will be randomized by cohort into either  
• 
Group A: who will start their 12-week exercise program with the Intensive Intervention within 4 
weeks of baseline measurement. For those who qualify (see below) this will be followed by a 12-
week maintenance program.  This group will finish the program with 12 weeks life as usual.  
• 
Broup B: who willl have a 12 week lead in period of life as usual.  They will then begin their 12-
week intensive intervention.  Those who qualify, this will be followed by a 12-week maintenance 
program. 
   
For all cohorts enrolled, we aim to gather up to 4 lab-based measurement visits to assess physical 
function:  
(1) at baseline,  
(2) following the initial 12 weeks during which Group A will have received the intense intervention and 
Group B will have continued life as usual (e.g., 12 weeks post randomization),   
(3) after an additional 12 weeks (e.g. 24 weeks post randomization ) after the completion of the intense 
intervention for Group B and the end of the maintenance intervention for Group A, and  
(4) a final time 12 weeks later (e.g. 36 weeks post randomization) when Group A has had a 12 week life 
as usual “washout” period and Group B has completed the maintenance intervention. 

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This is summarized  in our schema section, and the specifics of what is performed via Zoom or in-lab are 
outlined in Table 1.   
 
Briefly, all participants will have some measures collected both in person (at EPARC) and by Zoom. 
Specifically, the TUG and 30-second chair rise will be gathered digially within three days of the in-person 
measurements. These assessments are believed to be appropriate and safe for participant’s to be able 
to complete at home. They are being gathered in support of answering the questions of the secondary 
aims (i.e. to test digital vs. in-person measurement for accuracy and precision).  With this in mind, lab-
based collection will also occur. 
 
In the lab, additional measures as outlined in Table 1 and below will be collected to perform deep 
phenotyping of balance, strength and posture, and (optionally) markers of autophagy gathered via 
traditional venipuncture blood draw.  These will include (in addition to the two measures listed above): 
block measurements of kyphosis, measurements of kyphosis (kyphomemeter and flexiruler), occipital to 
wall distance, multiple measures of height, grip strength, a 2.5 minute walk test, a 25 foot walk test, the 
SBBP, and Better Balance testing. 
 
Completion of all measures will be encouraged, however, participants may opt to not perform one or 
more based on their discretion.  In particularly, it will be made clear to participants during the initial 
gathering of informed consent that the blood draw is completely optional and not providing blood will 
not preclude participants from engaging in the rest of the study. In addition, the team may determine a 
participant unsafe or inappropriate for some measures. Please see Sections 6.4 and 7. for how this will 
be noted. 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
Falls represent a significant cause of preventable injury, contributing to premature mortality and 
morbidity.  Fall related injuries are the major cause of accidental death and disability among older 
adults. Approximately one-quarter of community-residing men and women >65 years of age, and almost 
half of those over age 80, fall annually1.   Alarmingly, the rate of fall-related mortality has increased over 
30% just between 2007 and 2016.2  In San Diego County, falls remain the second most common cause of 
accidental deaths, with the age adjusted rate of mortality, emergency room discharge, and inpatient 
admission per 100,000 at 9.18, 1,939, and 336, respectively, in 2017. Moreover, these numbers have all 
increased or remained steady from the preceding 5 years3. 
While fall risk is multifactorial, identification of risk factors and referral to/participation in appropriate 
fall-risk reduction programs are established as an effective, evidenced-based approach to reduce fall-
risk4.  Specifically, targeted strength and balance exercise have consistently been shown to improve fall 
risk, and accordingly, the Centers for Disease Control and Prevention (CDC) has outlined an evidenced-
based clinical approach to identify those at risk for falls to help assess known risk factors and to refer for 
community-based fall-prevention programs5,6.  This toolkit, however, has been slow to penetrate in 
routine clinical practice, as barriers reported by physicians to implementing comprehensive falls-
prevention screening are time constraints, poor reimbursement for falls screening, and that existing 
toolkit utilization does not easily fit into a Medicare wellness visit7.  Because of this, only approximately 
one-third of older adults report being asked about fall-risk, and similarly only around a third of those 
who fall report discussing this with their healthcare provider.8,9  Compounding this, COVID-19 has 

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created uncertainty in accessing community resources,  increased sedentary behavior, isolation and 
subsequent fall risk10.   This is especially disconcerting as a single fall predicts recurrent falls: between 
10% and 44% of elderly patients with a history of falls will sustain additional falls.11–15   
COVID-19 has confounded social isolation in older adults, especially those in congregate settings.  
Appropriate technology/technologic driven approaches has promise (but limitations) to mitigate some 
aspects of loneliness/isolation in this population.16 Digitally delivered programs are an opportunity that 
help balance risks and benefits during times of social distancing, improve dissemination, and possibly 
improve objective measures of function.17  Therefore, approaches to improve access to fall-risk 
reduction exercise, including balance and strength training opportunities is imperatively important, and 
growing data suggests digitally formatted delivery may be feasible18.  
 Autophagy is a conserved, multi-step pathway that maintains proteostasis and organelle integrity by 
degrading and recycling cytoplasmic components. It is dynamically regulated by stressors such as 
nutrient deprivation and exercise, and its dysregulation has been implicated in aging and numerous age-
related diseases (REF). Yet, its role in human aging remains unclear. Progress has been limited by 
methodological barriers: most approaches provide static snapshots that cannot distinguish between 
active flux and impaired degradation, leaving a fundamental gap in our ability to study autophagy 
dynamics in humans1.  
We recently optimized an ex vivo PBMC autophagy flux assay using chloroquine-mediated lysosomal 
inhibition2. Applying this assay to participants from the San Diego Nathan Shock Center Healthy Aging 
Cohort (SHOCK), we found that PBMC autophagy flux does not decline uniformly with age. Rather, flux 
becomes more heterogeneous across individuals, and may even trend upward with advancing age. In 
older adults, higher flux correlated with reduced VO₂max, suggesting that elevated peripheral 
autophagy flux may reflect physiological stress or diminished resilience rather than improved function. 
To extend these observations, we examined older adults enrolled in the Strong Foundations 2.0 and 2.5 
(STRONG) digital fall-prevention programs. At baseline, STRONG participants had higher PBMC 
autophagy flux than the SHOCK cohort; after 12 weeks of balance- and strength-focused training, flux 
decreased to SHOCK baseline levels and coincided with improvements in mobility and function. 
Although limited by small sample size and short follow-up, these preliminary data raise the novel 
possibility that PBMC autophagy flux is a modifiable biomarker of intervention response in humans. 
Fall Prevention Program:  As noted above (Background, see Figures 2 and 3), our fall- risk reduction 
program, Strong Foundations was designed to be delivered digitally, and while there are many such 
programs currently available on the internet, especially in the time of COVID-19, the novel feature of 
this program is the delivery of semi-individualized instruction in real time within a small group setting. 
This is accomplished largely by use of the ‘breakout room’ feature on the Zoom platform, where 2-3 
trained intern instructors correct form while the lead instructor teaches the larger group.  The program 
was designed with physician input and by exercise physiologists and a Doctor of Physical Therapy 
candidate, all with extensive training in both group and individualized exercise for geriatric populations.  
Strong Foundations is a 12 week iterative curricular program with three core components: postural 
alignment and control, balance and mobility, and muscular strength and power.  All the exercises 

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offered over the course of the intervention are appropriate for the target population and are 
standardized so all participants receive the same basic instruction, but level of difficulty is scaled to 
participant experience, capability, and musculoskeletal limitations.   
While many exercise interventions for fall prevention have been validated in different populations, our 
program is designed with the community in mind and with a novel platform to improve 
dissemination/availability across many populations. Our program content is drawn from several 
rigorously tested fall/fracture prevention exercise programs,4,19–21 which we have tested in a pilot trial 
described below: 
 
4.3 
JUSTIFICATION FOR DOSE 
 
This is a relatively standard dose for an exercise intervention in this population. 
 
4.4 
END OF STUDY DEFINITION 
 
A participant is considered to have completed the study if he or she has completed all phases of the 
study including responding to follow up queries regarding falls for up to 1 year following the final 
measurement visit.  
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
 
Screening and Enrollment: 
 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
1. Has the capacity to provide informed consent 
2. Stated willingness to comply with all study procedures and availability for the duration of the 
study  
3. Age 60 or older, ambulatory, including with the use of a cane or walker, and able to read and 
speak English.  
4. Completion of the STEADI Stay Independent Risk for Falling Questionnaire (uploaded as 
Supporting materials),   
a. A score of 7 or greater will make a participant ineligible for this study (see below). 
5. Access to internet/computer and Zoom-interface / broadband with a device with a minimum 
screen size of 7 inches (i.e. tablet or larger). 
 
Older adults will be recruited in blocks of up to 30 (minimum 24) to form cohorts of 12-15 that will be 
randomized to either Group A or Group B as described in the randomization section.  These individuals 
will be contacted via outreach to the UCSD Bone Health Interest Group, via communication with 
volunteers associated with the UCSD Bone Densitometry Training Program who have expressed an 
interest in being part of reseach studies, via the list of previous participants and patients who have 

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indicated that they are willing to be contacted regarding research opportunities maintained by EPARC, 
and via referral from the UCSD Osteoporosis Clinic and associated physicians, and from the Internal 
Medicine practice Fall Prevention Shared Medical Appointment.In all cases, individuals will be provided 
information via flyers.  This will be distributed via email for those on interest lists, and with physical 
flyers for those associated with programs that conduct in-person meetings (i.e. Bone Health Interest 
Group, physicians, etc.).  Only participants who initiate further contact by reaching out via phone or 
email will be screened/recruited.  
All participants who express interest will be contacted by study personnel to be screened for eligibility by 
phone or in person (if applicable); those who meet the eligibility requirements will be invited to 
participate.   
 
Potential participants will be scheduled to attend the first study visit and will be emailed a copy of the 
informed consent document to review. Informed consent will be conducted either in-person at Visit 1 or 
remotely face-to-face using a UC Health-encrypted Zoom appointment one to six days prior to Visit 1.  
Selection of digital vs in-person consent will be based on the logistics and participant preference (asked 
during initial phone discussion for eligibility).  If a participant does not feel comfortable consenting 
remotely/digitally, they will be met at the initial visit to review consent in person.  During the informed 
consent process, regardless of if it is completed remotely or in person, trained EPARC staff will review the 
study’s purpose and procedures, answer any questions, confirm the study inclusion and exclusion criteria. 
Regardless of the manner in which consent was presented, written consent will be gathered at the first 
visit.  In the event that participants received digital/zoom based familiarization with the consent 
document they will be asked if they have any questions and additional discussion, review, and answers 
will be available as needed.  
 
 
5.2 
EXCLUSION CRITERIA 
 
Additional screening criteria: 
An individual who meets any of the following criteria will be excluded from participation in this study: 
 
1. Individuals who are wheel-chair bound 
2. Score 7 or more on the STEADI Risk for Falling questionnaire. 
3. Individuals who have non removable (i.e. implanted) electrically driven medical implants 
(pacemakers, cochlear implants, etc) 
 
 
5.3 
LIFESTYLE CONSIDERATIONS 
Not applicable. 
 
5.4 
SCREEN FAILURES 
 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently randomly assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure participants, to 

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meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, and any serious adverse event (SAE). 
 
We do not expect to have a substantial number of screen failures, as the inclusion criteria are straight 
forward and do not require confirmatory testing. 
 
 
 
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
Fall Prevention Program:  Our fall- risk reduction program, Strong Foundations was designed to be 
delivered digitally, and while there are many such programs currently available on the internet, 
especially in the time of COVID-19, the novel feature of this program is the delivery of semi-
individualized instruction in real time within a small group setting. This is accomplished largely by use of 
the ‘breakout room’ feature on the Zoom platform, where 2-3 trained intern instructors correct form 
while the lead instructor teaches the larger group.  The program was designed with physician input and 
by exercise physiologists and a Doctor of Physical Therapy candidate, all with extensive training in both 
group and individualized exercise for geriatric populations.   
Strong Foundations is a 12 week iterative curricular program with three core components: postural 
alignment and control, balance and mobility, and muscular strength and power.  All the exercises 
offered over the course of the intervention are appropriate for the target population and are 
standardized so all participants receive the same basic instruction, but level of difficulty is scaled to 
participant experience, capability, and musculoskeletal limitations.   
For this project we will be delivering the well-received Strong Foundations program—denoted here as 
intensive intervention--and following with a maintenance intervention of an additional 12 classes for 
individuals who attend at least 10 classes during the intensive period.  Thus, all participants will be be 
able to attend 12 classes, and some will be able to attend a total of 24. 
All classes will be delivered remotely. The substantive difference between the intensive (initial 12 
weeks) and maintenance (following 12 weeks) interventions is that the maintenance intervention will 
have less personalized guidance and feedback.  
6.1.2 DOSING AND ADMINISTRATION 
There are a total of 12 classes in the intensive intervention that all participants will be eligible to receive. 
There are a total of 12 classes in the maintenance intervention that only participants who complete at 
least 10 classes in the intensive intervention will be invited to receive. 
Thus, a participant could receive a maximum of 24 classes. 

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Class times will be determined during the recruitment phase based upon the availability of instructors 
and preferred times of participants. 
 
 
 
 
 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
 
Not applicable 
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
Not applicable 
 
6.2.3 PRODUCT STORAGE AND STABILITY 
 
Not applicable 
 
6.2.4 PREPARATION 
 
Not applicable 
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
We will be using a random generator to provide a binary choice (1=Group A, 2=Group B) in blocks of 30. 
We will be recruiting and consenting up to 30 people within 4 weeks, and at the end of that period 
revealing the group allocation.  Participants will be provided the group allocation based on the order in 
which they are consented (i.e. first person consented receives first randomization slot).  In the event 
that less than 30 people are consented in the requisite four weeks, or some participants choose not to 
continue following consent, we will allow unequal class/group sizes. 
All measurement staff will be blinded to randomization group at all measurement timepoints. 
Not applicable 
 
6.4 
STUDY INTERVENTION COMPLIANCE 
 
Attendance will be taken at each class; additionally, those unable or unwilling to complete some 
measures (physical, internet-based, lab, or questionnaire) will be noted in data collection without 
identifiers. 
 
6.5 
CONCOMITANT THERAPY 

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Not applicable 
 
6.5.1 RESCUE MEDICINE 
 
Not applicable 
 
 
 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
 
• 
Rudeness or disruptive behavior during instruction 
• 
Inability or unwillingness to follow exercise recommendations regarding safety 
• 
Significant study intervention non-compliance  
• 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant 
• 
Disease progression which requires discontinuation of the study intervention 
• 
If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
• 
Participant unable to attend a minimum of 6 of the Strong Evidence classes 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
 
Discontinuation from The Strong Foundations 2.0 intervention does not mean discontinuation from the 
study, and remaining study assessment procedures should be completed as indicated by the study 
protocol.   
If a clinically significant finding is identified (including, but not limited to changes from baseline) after 
enrollment, the investigator or qualified designee will determine if any change in participant 
management is needed. Any new clinically relevant finding will be reported as an adverse event (AE). 
 
The data to be collected at the time of study intervention discontinuation will include all scheduled 
follow up measures.   
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants are free to withdraw from participation in the study at any time upon request. 
The reason for participant discontinuation or withdrawal from the study will be recorded. Research 
participants who sign the informed consent form but did not attend at least one class may be replaced.   

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Research participants who sign the informed consent form, and are randomized and receive the study 
intervention, and subsequently withdraw, or are withdrawn or discontinued from the study will not be 
replaced. 
 
7.3 
LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if he or she fails to return for more than one follow up 
(i.e. non baseline) scheduled visits, or is unable to be contacted by the study site staff.  
 
The following actions will be taken if a participant fails to attend a scheduled laboratory visit or misses 
an exercise class without making contact prior to the date of instruction. 
• 
The site will attempt to contact the participant and reschedule the missed visit for up to 3 weeks 
following the expected visit and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain if the participant wishes to and/or should continue in the 
study. 
• 
Effort to regain contact with the participant will be made using 3+ telephone calls and/or email 
communications. These contact attempts will be documented in the participant’s study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS  
UCSD research staff will be gathering and holding all data for this program.  All objective measures 
collected at EPARC will have the order of deployment randomly determined, (re)clustered by every 5 
participants to account for the possible contribution of fatigue during these assessments.  We anticipate 
the time-burden for participants in lab will last approximately 60 minutes to complete all measures (but 
are budgeting up to 90 minutes in the informed consent in case some individuals require additional rest 
time between measurements).  We anticipate the digital measures as outlined below to take no more 
than 15 minutes and anticipate both surveys to last approximately 20 minutes.  Measures below will be 
collected throughout the study as outlined above in our Schema.  
Primary Outcomes:  
1. Balance/Fall Risk:  This will be measured in-person using a variety of commonly deployed 
assessments of balance and physical function.  These include the Short Physical Performance 
Battery (SPPB), Better Balance Test, the Timed up-and-Go (TUG), and measures of gait speed 
during a 25 foot walk completed both as fast as possible, and at normal walking speed.  Balance 
tasks are expected to take a total of 20 to 25 minutes. 
a)  Short Physical Performance Battery (SPPB):  The SPPB measures gait speed, leg strength 
(via   chair stand time) and the three stage balance assessment recommended by the CDC 
for assessing fall risk.  This composite measure includes evaluating side-by-side, semi-
tandem, and tandem position, time to walk 4 meters , and time to rise from a chair and 
return seated five times23. 

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b) Better Balance Testing (Balance Tracking Systems, Inc).: Better Balance testing is a 
standardized approach to understanding balance based on measured sway via force 
transducer plates which participants stand upon with their feet hip distance apart and their 
eyes closed. 24,25.  Specifically trained research assistants will maintain “spotting position” to 
ensure safety.   
c) Timed Up-and-Go: The TUG is an easy to administer office-based assessment in which a 
person rises from a seated position without using their arms, walks three meters 
(approximately 10 feet), turns around, returns to the chair, and sits down while being timed.  
The TUG has been found to be reliable with good inter-rater and intra-rater reproducibility, 
and is a good predictor of frailty.26  While there is some disagreement regarding its role in 
falls-prediction,27–29 the CDC suggests a cutoff time of 12 seconds to discriminate fall risk.26  
This will be performed twice and the better of the two scores recorded. 
d) The 25 Foot Walk Test is a quantitative mobility and leg function performance test in which 
the participant is directed to one end of a clearly marked 25-foot course and is instructed to 
walk 25 feet.  We will ask the participant to complete the assessment 3 times.  Twice 
walking at a normal speed, and once walking as quickly as possible while still remaining safe. 
The time is calculated from the initiation of the instruction to start and ends when the 
patient has reached the 25-foot mark. Patients may use assistive devices when doing this 
task. 
e) 2.5 Minute Walk: The  2.5 minute walk test is an abbreviated test compared with the 6- 
minute walk, where a participant has indirect calorimetry measured as they walk 
comfortably around a prespecified track for 2.5 minutes; distance is measured along with 
measures of cardiorespiratory fitness30. 
2) Muscular Strength:  Strength will be measured both in person and digitally using commonly 
deployed field measures (30 second chair stands).  We will also be completing additional in-lab 
only measures of strength via grip strength.  Strength testing is expected to take 10 minutes or 
less. 
a) 30-Second Chair Stand: The 30-Second Chair Stand is intended to evaluate lower body and 
hip flexor strength and short endurance.  This assessment is easy and quick to administer, 
and has been shown to predict falls31 with cut-offs that are age and gender adjusted.32  
Individuals are instructed to sit in in an arm-less chair of approximately 17” seat-height, 
cross their arms across the chest, keep their feet flat on the floor and back straight, and 
sequentially rise and sit as many times as possible within a 30-second time frame. 
b) Grip Strength:  Hand grip strength will be measured in both hands using an adjustable grip 
strength dynamometer that quantifies force in kilograms (BL5001 Hydraulic Hand 
Dynamometer). The grip bar of the instrument will be adjusted so the second joint of the 
fingers first snugly under the handle and the hand position will be recorded (1-5). The 
dynamometer will be set to zero and the participant will be given a chance to familiarize 
themselves with the measurement by giving a submaximal effort on both hands to feel how 
the instrument will react. For the assessment, the participant will stand and hold the 
dynamometer in their hand with their arm down at their side. The participant will be 
instructed to take a deep breath in, and squeeze as hard as possible as they exhale. The 
measurement will be repeated twice on each hand, alternating between each side, and the 
highest score for each hand will be recorded to the nearest kilogram.  
3) Spinal Posture:  Good posture is important to reducing the risk of vertebral fractures and has 
been identified as a potential locus of intervention for fracture prevention33.  We propose to 
measure posture using a variety of measures that can be easily integrated into clinical practice 
(occipital to wall distance and standing height), as well as those that require a higher level of 

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expertise (standing measures of postural tilt, and standing and lying measures of kyphosis.)  
Postural measures are expected to take between 15 and 20 minutes. 
a) Height will be measured with participants instructed to stand normally, and then 
also to stand as tall as they can with a full breath of air to assess differences in 
height based upon postural changes reflective of activation of core muscles.   
b) Occipital to Wall Distance (OWD) will be measured with participants standing with 
their feet together and their heels and buttocks touching the wall while they look 
forward (or as close to the wall as possible.  The distance from the wall to their 
occiput (back of the head) will be measured to the nearest 0.1 cm.  Measurements 
will be taken twice, with a third measurement gathered in the event that there is 
greater than 0.3 cm difference between the first two measures.  An average of the 
closest two measurements will be used for analysis.  Pictures will be captured via 
Zoom to collect this measure. 
c) Kyphosis will be measured using three standard procedures:  1) Blocks method: 
Participant will have 1.7cm blocks placed in sequence beneath the head while in a 
supine position. 
a.  Blocks will continue to be added under the participants’ head until their 
neck is observed to be in a neutral position. The number of blocks needed 
to obtain a neutral position will be recorded.      
b. Debrunner kyphometer: Participants will be required to expose their back 
and have a device (similar to a protractor) placed against the C2 and T12 
vertebra and the angle will be recorded by a trained technician and  
c.  Flexiruler: A flexible ruler will be molded to the mid-line of the participants 
back, with one end on the spine at the C7 vertebra. The molded flexiruler 
will be traced onto a piece of paper and a straight line between the ends of 
the spinal curve. Distances will then be used to calculate the index of 
kyphosis measurement using a well validated formula34. 
d) Body Composition will be measured by bioelectrical impedance analysis (BIA) using 
a Tanita DC-430U Dual Frequency Total Body Composition Analyzer (device manual 
included as attachment). This machine looks like a doctor’s scale, but it also 
measures body composition using a weak constant current source with a high 
frequency current (6.25kHz, 50kHz, 90μA), which is not a significant amount of 
energy. The 4 electrodes are positioned so that electric current is supplied from the 
electrodes on the tips of the toes of both feet, and voltage is measured on the heel 
of both feet. 
e) Autophagy Flux will be measured in freshly isolated human peripheral blood 
mononuclear cells (PBMCs).  A trained phlebotomist will draw 9 mL ( of fasting 
blood into Vacuette lithium heparin tubes using standard venipuncture.  Freshly-
drawn whole blood will be treated with the late-stage autophagy inhibitor 
chloroquine, after which peripheral blood mononuclear cells (PBMCs) will be 
isolated, lysed, and analyzed by Western blot. PBMC isolation, lysing, and analysis 
will occur either at UCSD facilities located at the Stein Institute of Aging or the 
Sanford Burnham Prebys laboratory. 
Secondary Outcomes:  
1) Usability/Acceptability of exercise classes delivered via a digital format will be assessed using a 
questionnaire that uses the System Usability Scale22 (SUS).  The SUS is a nonpriority validated 

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questionnaire designed to understand the ease of use of new systems or programs using a 5 
element Likert scale. This questionnaire includes the 10 questions typically included in a SUS, 8 
questions designed to assess the patient experience in the program and 2 questions assessing 
falls in the recent past.  In general, scores >60 on the SUS are considered to have appropriate 
acceptability of a program/platform.  As noted in Figure 2 above, in our initial Strong 
Foundations pilot program, approximately 90% of the respondents found the program 
acceptable.   
2) Attendance: Attendance at exercise sessions will be recorded at each class and reported by 
cohort and by group.  For the extension/pooled cohort program as described above, attendance 
will be monitored/recorded and compared with paired attendance rates for the same 
participant as part of the initial 12 week program. 
For demographic purposes we will also assess the following: 
Participants will be asked to complete the following self-report questionnaires regarding their medical 
history, current mood/emotional state, and fall-history.  
a) Demographics and Medical History: This questionnaire provides an overview of an 
individual’s education and demographic background, personal medical history, family 
medical history, drug/alcohol use, current and recent medications, allergies, social 
history, diet, and mental health.  
b) Questionnaires - PROMIS-29 V.2.0 and an additional survey about experience: We will 
use the Health-related PROMIS scales to evaluate for social isolation, depression, 
emotional stress, and global perceived health,35 as well as created questionnaires to 
inquire about challenges accessing the program.   
c) Follow-up falls information – this will be conducted after completion of the intervention, 
by email if participants are able, and if not, by pre-stamped postcard or phone calls, 
monthly, for 12 months to follow-up and inquire a participant has had any falls.   
Questionnaires: All questionnaires will be made available for participants to fill out either electronically 
or by paper, and include Medical History form for all participants, the Staying Independent Brochure at 
enrollment, and if enrolled, the PROMIS-29, follow-up falls questions, and SUS at program completion 
and at the completion of the longitudinal program. An additional questionnaire will inquire about 
experiences/barriers for digital grouping/participant.  Thus, participants may have up to 4 surveys once 
enrolled, after the small cohort completion, and at the completion of this study if continued onto the 
pooled longitudinal cohort.   
Follow-up of Outcomes: Although the study duration and the sample size do not allow for adequate 
evaluation of falls, it is still important to assess falls to determine trends indicative of intervention 
effects.  Thus, falls will be collected by self-report as noted above, monthly for 12 months after 
participation in the class.  Methods of outreach may include, telephone interview, email, or pre-
stamped post-cards demarcating a fall. 
Specific information collected as part of this project will include: 
1. Data outlined above Cohort grouping  
2. Number in cohort 

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3. Baseline and Change scores in objectively collected functional measures 
4. Baseline and Change scores in objectively measured autophagy flux 
5. Score from the System Usability Scale Questionnaire  
6. Satisfaction/efficacy Questionnaire (PROMIS-29) 
7. Follow-up contact about falls and if behavioral change has been sustained 
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
While a computer/ Zoom interface is required to participate, demographics showcase at least 70% of the 
larger population have access to a smartphone; thus, we do not feel having this requirement impedes a 
significant number of potentially interested individuals.  We will track the number of individuals who are 
unable to enroll because of technological barriers/access to the requisite technology to determine if this 
affects their ability to participate.  
Lab based measures will be directly observed by staff trained both in the methods for data collection 
(respectively listed above) and on providing input for individuals to modify or stop should they be in a 
situation predisposing to injury.  Zoom based data collection will be directly observed by the research 
assistant, and in the unlikely event of an injury, we will collect a contact number and inform individuals if 
they’re unable to verify they are ok or respond that they are ok, we will call 9-1-1 on their behalf.  We will 
have and confirm their location addresses before all Zoom based sessions. Throughout the intervention, 
similar protocols will occur such that individual communication (if appropriate by Breakout room, or 
phone, or 9-1-1) be made to assure the safety of participants.   
Blood draws will be conducted by licensed phlebotomists with experience drawing blood from older 
adults. 
   
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
 The FDA definition of an Adverse event is any untoward medical occurrence associated with the use of 
an intervention in humans, whether or not considered intervention-related (21 CFR 312.32 (a)).  
 
All Adverse events (AE) based on the definition of 21 CFR 31232 (a) will be captured by study staff and 
reported to IRB and/or participant physician’s as needed. 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: death, a life-threatening adverse 
event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the participant and may require medical or surgical intervention to prevent one of 

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the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
SAE in the context of this intervention may include sudden death, cardiac death/cardiac event during 
exertion, and fall from intervention culminating with hospitalization, incapacity, or death. 
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
 
8.3.3.1 SEVERITY OF EVENT 
The following guidelines will be used to describe severity.  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”.] 
 
In the context of this intervention, either remotely or in the lab, musculoskeletal injury or a fall may 
occur which would be unexpected and an adverse event.  In the event of this culminating with injury 
requiring emergency room visit, but not inpatient hospitalization, or injury sufficient for withdrawal 
from the study, we will consider these AE and report accordingly. 
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
 
All AEs will be reviewed by the study PI and the following determination of their relationship to the 
study will be determined.  These will be reported to the IRB and other regulatory bodies following the 
timelines described below. 
 
• 
Related – The AE is known to occur with the study intervention, there is a reasonable possibility 
that the study intervention caused the AE, or there is a temporal relationship between the study 
intervention and event. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study intervention and the AE. 
• 
Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study intervention 
and event onset, or an alternate etiology has been established. 
The potential risks associated with study participation are deemed by the research team to be no 
greater than minimal.  Risks will be mitigated as part of this pilot by only inviting participants not at 
elevated risk based on clinically available screening for falls. Because activities aim to address balance, 
strength, and posture, many of these activities potentially predispose individuals to injury or fall 
potential; therefore, we have included many mechanisms to safeguard against injury throughout this 
pilot as described below. 

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Potential expected risks include: 
1. Adverse effect of potential injury or fall during objective balance measurement, which are 
performed as part of routine clinical procedures and directly supervised by clinical staff at the 
time of potential enrollment;  
2. Adverse effect of an injury during objective, lab collected or digitally collected measures of fall 
risk.  We will have supervision throughout all lab measures, and EPARC has an excellent 
precedent of being able to conduct these measures in high(er) risk individuals without injury.  
For digitally collected measures, as described above, we have identified only measures which 
are relatively safe to do by video, and will be directly supervised throughout the collection 
process, including safeguarding for the individual to be able to necessary measures before 
starting (e.g. if there is a perceived lack of space, the instructor will assure the area is cleared of 
clutter before starting). 
3. Adverse effect of a potential fall during a group exercise class, or any activity related to this 
study where there is synchronous digital connection (e.g. home-based measurement of 
balance/strength).  At intake, all information for contacting participants in the event of a 
disconnection, fall, or other observed event whereby the participant is unable to safely continue 
in the class without notifying the study team.   
a. Information collected will include: a preferred/available phone number; a point-of-
contact/next of kin preferred contact; their planned location of performing the Zoom-
based intervention, including barriers to entry if applicable (e.g. in a condominium with 
several doors, presence of pets, etc.).   
b. Participants will be instructed that while they are participating and have their camera 
on, should they need to leave/depart for any reason, they must notify the instructor(s) 
within 5 minutes of departure.  If this is not received and an injury is suspected, 9-1-1 
will be called if the study team is unable to contact the participant by active means 
including phone, collected at enrollment.   If injury is not suspected, the point of 
contact/next of kin will be contacted if the participant is unable to be contacted.  
Participants will be invited only if clinically assessed as not elevated risk.  Class sizes 
during the intensive intervention period of instruction will be kept to 10-15, which is 
thought to be appropriately sized for monitoring both the in-person and by electronic 
interface.   
c. Classes during the maintanance intervention will focus only on exercises that have been 
thoroughly taught during the initial 12 intensive intervention period.  While these 
classes will be less personalized, they will still have some direct instruction and exercises 
will be familiar and safe for participants. 
i. Only participants who attended at least 80% of the initial 12 week instruction 
period (i.e. 10+ classes) will be allowed to participate in the extended 
instruction. 
4. The participant may experience a musculoskeletal injury, or muscle fatigue and soreness due to 
the assessments of strength or from the exercises performed in the class.  
5. Data compromise risk: clinical data without identifiers will be collected as part of this study.  We 
will be video recording the instructor during classes.  This will ensure that participant’s images 
are not included but if they speak during the exercise session their voices will be captured. 
A.  While personal information will not be shared, it will occasionally be possible for participants 
to view each other during the exercise sessions.  This risk is no larger than if participants were 
completing group exercise in person at an exercise training facility. 

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B.  Exercise sessions will be recorded to provide in-home practice opportunities to participants 
between classes.  The “spotlight” feature will be used to ensure that only the demonstrating 
instructor is seen during the class period.  However, if participants speak during the recorded 
portion of the session their voice will be captured. 
There are no other known risks associated with this study. 
8.3.3.3 EXPECTEDNESS  
 
Ryan Moran, MD, MPH (PI) will be responsible for determining whether an adverse event (AE) is 
expected or unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of 
the event is not consistent with the risk information previously described for the study intervention and 
study procedures. 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
At the beginning of exercise classes, participants will be informally queried regarding how they are 
feeling (unsolicited query).  In the event that a participant shares a potential AE a staff member will take 
them to a “breakout room” to get further information including event description, self-reported severity 
and time of onset.  These data will be shared with the study PI who will make an additional assessment 
of severity, and likely relationship to study measures or intervention.  Follow up will continue until 
resolution/stabilization of the event has occurred with ongoing documentation. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
The study coordinator, Dr. David Wing, or the study PI, Dr. Ryan Moran will record all reportable events 
with start dates occurring any time after informed consent is obtained until 7 (for non-serious AEs) or 30 
days (for SAEs) after the last day of study participation.  At each study visit, the investigator will inquire 
about the occurrence of AE/SAEs since the last visit.  Events will be followed for outcome information 
until resolution or stabilization. 
 
SAE and AE will be reported to the PI, Ryan Moran by exercise instructors and/or clinical staff, 
immediately for considered SAE, and within 1 week for AE; these will be investigated within 1 week of 
occurrence. 
 
8.3.5 ADVERSE EVENT REPORTING  
 
We have no sponsors.  The PI, or study team under the direction of the PI will report all AE’s to the IRB 
and other UCSD regulatory bodies using timelines described above. 
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  

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There is no study sponsor.  All AE’s and other unexpected events will be reported to the IRB and UCSD 
regulatory bodies in a timely fashion in line with that described above. 
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
 
Not applicable.  We will not be informing participants of AE or SAE not related to themselves.  We do 
not anticipate there being any new risks beyond those described above and relayed to participants 
during the consent process. 
 
8.3.8 EVENTS OF SPECIAL INTEREST  
 
Not applicable given inclusion criteria. 
 
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
This definition could include an unanticipated adverse device effect, any serious adverse effect on 
health or safety or any life-threatening problem or death caused by, or associated with, a device, if that 
effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the 
investigational plan or application (including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects (21 CFR 812.3(s)).] 
 
We believe that this is not applicable because this is a digitally delivered intervention using exercises 
and instruction that are well established for in-person participation. 
In the event that there are unanticipated problems that meet the definition above we will notify all 
participants and the IRB, and get updated consent that includes awareness of the new problems. 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  

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The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB) in a timely fashion using the following timing guidelines. 
 
• 
UPs that are serious adverse events (SAEs) will be reported to the IRB three (3) days of the 
investigator becoming aware of the event.  
• 
Any other UP will be reported to the IRB and either at the time of continuing review in the event 
of very minor UP, or within 14 days for UPs which may have involve increased risk across the 
study population.  
• 
All UPs will be reported to the Office for Human Research Protections (OHRP) following the 
same timelines described above. 
The UP report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
Not applicable beyond informing the individual who has been affected.  We will maintain ongoing 
contact in this event until the problem is fully resolved. 
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
In this extension of our earlier work, we hypothesize that this digitally delivered program will result in 
improved performance in our primary (physical) outcomes, and high acceptability in our secondary 
outcomes. Further, we hypothesize that there will be significant differences following exercise between 
the intervention group and the wait list control group at the 12 weeks post randomization timepoint, 
but that there will not be significant differences between the two groups after both have gone through 
the exercise intervention.  For all analyses, the sample will be characterized using descriptive statistics 
determined for the entire sample and stratified fall risk, as well as attendance/participation in the 
exercise classes.  Analyses will be carried out according to the intention-to-treat rule (based on 
appropriate denominator) consistent with standard practice in most clinical trials.  Outcomes will 
include usability, and objective markers of physical function related to fall risk.   
 
• 
Primary Efficacy Endpoint(s): 1) Objective changes in markers of fall risk from Strong 
Foundations 
Descriptive statistics and paired Repeated Measures ANOVA’s will be used to compare changes for 
measures outlined above across groups over time.  Significant demographic, medical and social 
characteristics (via self-report) will be tested for additions to our model.  

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Logistic regression modeling will be used to characterize changes in objective markers of fall risk, 
controlling for socio-demographic, and comorbid conditions (via the self-report record).  Measurement 
of programmatic feasibility, per the SUS, will also be calculated and controlled for sociodemographic 
data, as collected, objective markers of risk (and risk-improvement based on intervention), attendance, 
and comorbid conditions.  Follow-up assessment (monthly, up to 12 additional months) will allow for 
determining if interventions changed behavioral aspects associated with falls and falls-based outcomes. 
• 
Primary Efficacy Endpoint(s): 2) Baseline associations between autophagy flux and objective 
markers of body composition and physical function 
Descriptive statistics and Pearson’s correlation coefficients will be calculated to identify significant 
associatinos beteen authophagy flux and metrics of body composition and functio.  
Logistic regression modeling will be used to identify predictors of autophoghy flux while controlling for 
socio-demographic, and comorbid conditions (via the self-report record).   
 
• 
Primary Efficacy Endpoint(s): 3) Changes in autophaghy flux from the Strong Foundations 
intervention and associations between change in autophagy flux and objective markers of body 
composition and physical function.  
 
Descriptive statistics and paired Repeated Measures ANOVA’s will be used to compare changes across 
groups over time.   
Logistic regression modeling will be used to characterize changes in autophagy flux and identify 
predictors of that change while controlling for socio-demographic, and comorbid conditions (via the self-
report record).  Secondary Efficacy Endpoint(s): Compare lab vs digital measures of fall-risk; to showcase 
the feasibility of longitudinal Strong Foundations. 
• 
Secondary Efficacy Endpoint(s): Compare lab vs digital measures of fall-risk; to showcase the 
feasibility of longitudinal Strong Foundations. 
Descriptive statistics and Repeated Measures ANOVA’s  will be used to compare digital / in person 
collected measures of fall risk across groups over time.  Additional analysis will explore the feasibility of 
attenuating programmatic improved fall risk in a larger group, with the hypothesis that there will be no 
change in objective markers at the completion of the 12 week program.   
• 
Exploratory Endpoint:  Further, a final survey will measure SUS scores as well as subjective 
markers of programmatic success.  We will also collect digital measures of balance/fall risk as 
outlined above and explore how measures of feasibility (attendance, SUS scores) correlate with 
changes in these measures through this study.   
 
9.2 
SAMPLE SIZE DETERMINATION 
 
This pilot is designed to showcase usability, feasibility and objective measures in outcomes, and 
compare measures collected digitally to best-practice lab based measures.  Given the pilot nature of 
these data, they will be used to fuel further research which will be appropriately powered based upon 
the magnitude of change observed here. 

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9.3 
POPULATIONS FOR ANALYSES 
 
We will utilize a modified intention to treat analysis including all individuals who consent and attend at 
least one of the visits, and follow up lab visits; we are unable to do otherwise given without the 
participant showing up, we are unable to calculate changes for our primary outcome.  However, these 
will be noted in our measures of feasibility including attendance. 
 
9.4 
STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
 
For primary and secondary outcomes, descriptive statistics will include: 
Percentages, means with standard deviations, median, ranges. Paired T tests and Chi squares will be 
utilized to showcase changes between individuals and groups, and to differentiate statistical differences 
(P<.05).  
 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
Repeated measures mixed analysis will be conducted to assess pre/post changes across the different 
cohorts (i.e. different level of risk and different SES status). 
Missing data will be excluded from all analysis. 
Outliers will be reviewed and if appropriate will be excluded from analysis. 
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
Paired sample t-tests will be used to determine if there is a difference in the assessment of interest 
based upon in-lab vs. digital data collection.  
 
9.4.4 SAFETY ANALYSES 
 
Not applicable.  We do not have any safety endpoints. 
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
 
Intervention groups will be compared on baseline characteristics, including demographics and 
laboratory measurements, using descriptive statistics.  
 
9.4.6 PLANNED INTERIM ANALYSES  
Data analysis will be done based upon all cohorts completing their initial 12 week intervention. 
A second set of data analysis will be done when all individuals have completed the follow up 
“maintenance” 12 week extended instruction period. 
 
9.4.7 SUB-GROUP ANALYSES 
 

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We will analyze sub-groups based on SES (CC Cohort vs. SD Cohort) and fall risk categories (low vs 
moderate risk) as well as total group. 
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
Individual data will be maintained based upon participant ID for each measure at each timepoint. 
 
9.4.9 EXPLORATORY ANALYSES 
 
Not applicable 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
10.1.1 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to study participants, and regulatory authorities by the 
Principal Investigator (PI). 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping    
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the PI and IRB.  
 
10.1.2 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover testing of the 
clinical information relating to participants. Therefore, the study protocol, documentation, data, and all 
other information generated will be held in strict confidence.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional 
Review Board (IRB), and other regulatory agencies for the University or State of California may inspect 

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all documents and records required to be maintained by the investigator, including but not limited to, 
medical and assessment.  The clinical study site will permit access to such records. 
 
The study participant’s identifiable information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure location for 
as long a period as dictated by the reviewing IRB, and institutional policies. Identifiable information will 
be destroyed after the required retention period 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at the Exercise and Physical Activity Resource Center. This will not include 
the participant’s contact or identifying information. Rather, individual participants and their research 
data will be identified by a unique study identification number.  
 
10.1.3 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Data collected for this study will be analyzed and stored at the Exercise and Physical Activity Resource 
Center.  
 
Blood Specimens: Blood Specimens will not be stored for future research and will only be tested for the 
Autophagy flux and destroyed after results are confirmed. 
 
10.1.4 KEY ROLES AND STUDY GOVERNANCE 
 
Ryan Moran, MD, MPH (PI): Dr. Moran is an early-career investigator and Associate Clinical Professor 
in the Department of Family Medicine and the Department of Medicine. Dr. Moran is a member of the 
Center for Wireless and Population Health Systems, and is the Medical Director for EPARC, and a core 
member of the DXA Training School, all based in the Qualcomm Institute. He sees primary care patients 
at La Jolla Internal Medicine at UCSD.  He serves as the PI for the ongoing pilot that has developed the 
Strong Foundations curricula. 
Address:  9500 Gilman Drive, La Jolla, 92093 Mail Code 0811 
Phone:  858-534-9315 
Email:  rjmoran@health.ucsd.edu 
 
 
10.1.5 SAFETY OVERSIGHT 
 
The PI will ensure that all study staff have appropriate certification and training to safely provide the 
measurement and intervention for this study. 
 
10.1.6 CLINICAL MONITORING 
 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of 
the trial is in compliance with the currently approved protocol/amendment(s), with International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), and with applicable regulatory 
requirement(s).  

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• 
Monitoring for this study will be performed periodically by the PI and the study coordinator and 
CO-I Dr. David Wing.  
• 
On site review of gathered data and intervention fidelity will occur at least 1x per month.   
• 
Independent audits will not be conducted by individuals outside the study unless there are 
concerns from the IRB or other regulatory bodies.   
 
10.1.7 DATA HANDLING AND RECORD KEEPING  
 
10.1.7.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
 
All source documents will be completed in a neat, legible manner to ensure accurate interpretation of 
data.  We expect the majority of our data to be entered directly into redcap at the time of 
measurement. Redcap captures data regarding who entered the data and any changes that occur after 
initial data entry. 
 
Hardcopies of the study visit worksheets will be provided for use as source document worksheets for 
recording data for each participant enrolled in the study.  Data recorded in the electronic case report 
form (eCRF) derived from source documents will be consistent with the data recorded on the source 
documents.  
 
Identifiable Information:  All identifiable information such as (name, contact information, MRN# will be 
protected in a HIPAA compliant manner as per UCSD policies.  Some identifiable information, notably 
name, phone number, and email will be stored in the HIPAA compliant secured REDCaP database. 
However, these data will be stripped for data analysis and coding. Further, only staff members with 
direct contact with participants (instructors and recruiters) will be given access to this portion of the 
database. 
 
Clinical data (including adverse events (AEs), and assessment data will be entered into redcap, a 21 CFR 
Part 11-compliant data capture system provided by the University of California San Diego. The data 
system includes password protection and internal quality checks, such as automatic range checks, to 
identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly 
from the source documents. 
 
10.1.7.2 STUDY RECORDS RETENTION  
Study documents should be retained for a minimum of 2 years after the last exercise session.  These 
documents will be retained for a longer period if required by local regulations.   After the retention 
period is met all identifiable information will be destroyed. 
 
 
10.1.8 PROTOCOL DEVIATIONS  
 

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A protocol deviation is any noncompliance with the clinical trial protocol, or International Conference on 
Harmonisation Good Clinical Practice (ICH GCP). The noncompliance may be either on the part of the 
participant, the investigator, or the study site staff. As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly.  
 
The study PI and coordinator to use continuous vigilance to identify and report deviations within seven 
(7) working days of identification of the protocol deviation, or within seven (7) working days of the 
scheduled protocol-required activity.  All deviations will be addressed in study source documents.  
Protocol deviations will be sent to the reviewing Institutional Review Board (IRB) per their policies. The 
site investigator will be responsible for knowing and adhering to the reviewing IRB requirements. 
  
10.2 ADDITIONAL CONSIDERATIONS 
Not applicable 
 
 

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10.3 ABBREVIATIONS 
 
AE 
Adverse Event 
ANOVA Analysis of variance 
BIA 
Bioelectrical Impedience Analyses 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
eCRF 
Electronic Case Report Forms 
EPARC 
Exercise and Physical Activity Resource Center 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act  
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
PBMC 
Peripheral Blood Mononuclear Cells 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
San Diego 
SF 
Strong Foundations 
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SPPB 
Short Physical Performance Battery 
SUS 
System Usability Scale 
TUG 
Timed Up and Go 
UCSD 
University of California San Diego 
UP 
Unanticipated Problem 
US 
United States 
 

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10.4 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale. A Summary of Changes table for the current amendment is 
located in the Protocol Title Page.  
 
Version 
Date 
Description of Change  
Brief Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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11 REFERENCES  
Include a list of relevant literature and citations for all publications referenced in the text of the protocol.  
Use a consistent, standard, modern format, which might be dependent upon the required format for the 
anticipated journal for publication (e.g., N Engl J Med, JAMA, etc.).  The preferred format is International 
Committee of Medical Journal Editors (ICMJE). Include citations to product information such as 
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