Time Course Adaptations Using Deuterated Creatine (D3Cr) Method: A Pilot Study
Phase: NA
Conditions: Sarcopenia
Sponsor: University of Florida

Cover Page 
 
Title: Time Course Adaptations Using Deuterated Creatine (D3Cr) Method 
NCT number: NCT03573583 
Document Date: 04/1/2021. 
 

 
Study Protocol 
 
Funding agency: 
Pepper Older Americans Independence 
Center (National Institute on Aging) 
Study Name: 
Time Course Adaptations using Deuterated 
Creatine (D3Cr) Method 
Study acronym 
D3-Cr Study 
Study type 
Single blind, RCT 
Protocol Number: 
IRB 201801249 
Date of Issue: 
Principal Investigator: 
• 
Todd Manini, Ph.D 
Sub investigators 
• 
Anoop Balachandran, Ph.D. 
• 
Stephen Anton, Ph.D. 
• 
Duane Corbett Ph.D 
• 
Peihua Qiu, Ph.D 
Consultants 
• 
Peggy Cawthon, Ph.D 
• 
William Evans, Ph.D 

Table of Contents 
 
 
1. Abstract………………………………………………………………………………………….. 
2. Background…………………………………………………………………………………… 
3. Study Aims…………………………………………………………………………………… 
• 
Primary Objective 
• 
Secondary Objectives 
4. Research Plan……………………………………………………………………………………. 
• 
Design 
• 
Time and Schedule of events 
• 
Participants 
• 
Interventions 
• 
Outcomes Measures & Questionnaires 
• 
Recruitment 
• 
Screening 
• 
Interventions 
• 
Adherence 
• 
Retention 
• 
Statistical Plan 
• 
Data Safety and Monitoring Board 
• 
Confidentiality 
5. Possible Discomforts and Risks……………………………………………………………. 
6. Possible Benefits……………………………………………………………………………… 
7. Conflict of Interest………………………………………………………………………………. 

1. ABSTRACT 
 
Muscle loss with age is considered to be an important cause of disability in older adults1, 2. However, current 
tools frequently used and recommended to measure muscle mass in trials have limitations: For example, 
DEXA (Dual-energy X-ray absorptiometry) and BIA (Bioelectrical impedance analysis)- both widely used in 
clinical trials cannot distinguish muscle tissue from non-muscle elements such as subcutaneous and 
intramuscular fat, skin, water and connective tissue3-5 
 
 
Deuterated creatine (D3Cr) dilution is a novel promising method that provides an accurate measure of the 
functional contractile tissue, without including the non-contractile elements, by measuring total body creatine. 
Our preliminary cross-sectional results in men aged >65 years show functional muscle mass (FMM) assessed 
by D3-Cr to be significantly associated with performance outcomes (SPPB, 400m walk, and chair stands) and 
long-term outcomes (incident mobility problems, serious injurious falls), while DEXA showed no associations. 
However, these are observational data and cannot determine a causative role of muscle per se on functional 
outcomes. 
 
 
Hence, the objective of the pilot study is to assess the feasibility of our proposed future study to evaluate the 
role of muscle mass on functional outcomes. Specifically, the pilot study will randomize moderate to low- 
functioning older adults to a resistance training program or successful aging program to assess recruitment 
yields, participant adherence, retention, training program design aspects, sample size, and the cost of the main 
trial. Further, the impact of these changes in FMM on short-term performance outcomes, such as strength, 
walking speed, SPPB, self-reported measures, and balance will be examined. 

2. BACKGROUND 
It has now been well established that there is a progressive loss of muscle mass with aging. Prospective 
studies have shown this decline to be around 1% per year for both men and women6-8. This dramatic change in 
anatomy with age has prompted the coining of the term sarcopenia (sarx: flesh; penia: loss)9 Although not the 
sole cause of strength loss in older adults, the loss of muscle mass is thought to be a major cause of the 
decline in strength observed with age. Consequently, the loss of muscle and strength has direct adverse 
consequences on physical function leading to disability and mobility impairments1, 2. The recent establishment 
of ICD-10 code by CDC recognizing sarcopenia as an “independent reportable condition” further emphasize 
the role of muscle and muscle loss as major medical concern that needs immediate attention10. 
But, current tools frequently used and recommended to measure muscle mass in trials have limitations11-13. 
 
• 
DEXA and BIA- both widely used in clinical trials and recommended to diagnose sarcopenia, cannot 
distinguish muscle tissue from non-muscle elements such as subcutaneous and intramuscular fat, 
skin, water and connective tissue3, 14. 
• 
Magnetic resonance imaging (MRI) and computed tomography (CT) can detect non-muscle tissue 
in body segments but are extremely expensive and cumbersome when the analysis involves total 
body skeletal muscle15. 
Deuterated creatine (D3Cr) dilution is a novel promising method that provides an accurate measure of the 
functional contractile tissue, without including the non-contractile elements, by measuring total body creatine. 
Briefly, the method involves ingestion of deuterated non-radioactive, labeled-creatine in a capsule and 
subsequently measuring total creatine from a single urine sample, without any special diet restrictions; thus 
making the method quite safe and feasible. Considering there is no gold standard in vivo measurement of total 
body skeletal muscle mass, construct validation studies have shown a strong correlation with MRI in both men 
and women16 (young and old) (r = 0.87) and in animal studies17 (r = 0.95). More importantly, our preliminary 
cross-sectional results in community-dwelling men aged >65 years show functional muscle mass (FMM) 
assessed by D3-Cr to be significantly associated with physical performance (SPPB, 400m walk, and chair 
stands) and long-term outcomes (incident mobility problems, serious injurious falls), while DEXA showed no 
associations. 
However, these observational data cannot determine a causative role of muscle per se on functional 
outcomes. Additionally, there are no longitudinal or experimental studies that establish D3-Cr as a standard 
measure of functional muscle mass (FMM). Our future study will use an experimental approach to evaluate 
the causative role and time course of FMM changes with D3-Cr on functional outcomes. The accomplishment 
of this future longitudinal study will also validate this promising method for characterizing FMM in response to 
muscle-targeted interventions for low functioning older adults (e.g., selective androgen receptor modulators). A 
pilot study will fill necessary gaps that include feasibility and within-person variability of the D3-Cr method that 
is currently unknown. Hence, the objective of the pilot study is to assess the feasibility of our proposed future 
trial. 
Achieving the above aims will help in gathering feasibility information for our future study, but also provide 
novel insights into the time course of early FMM to resistance training and its relation to short-term outcomes. 
In addition, future studies can use D3-Cr to evaluate the effectiveness of interventions to increase functional 
muscle mass. 

3. SPECIFIC AIMS / OBJECTIVES 
Primary objective 
• 
To evaluate the feasibility of implementing the D3Cr method in a resistance training trial as it 
relates to participant adherence, retention, training program design aspects (intensity, 
volume, frequency & safety) sample size, and cost of the main study. 
 
Secondary objectives 
The secondary objectives are to: 
• 
Evaluate and compare the time-course adaptations in skeletal muscle mass measured by 
D3-Cr and DEXA 
• 
Correlate the changes in functional muscle mass with the change in walking speed, SPPB, 
strength, and balance. 
4. RESEARCH PLAN 
Trial Design 
• 
The pilot study will be single-blind, parallel group, randomized controlled trial of 24 
moderate to low functioning participants randomized in a 1:1 allocation ratio to a high- 
intensity Resistance Training group (RT) or a Health Education comparator group (HE) for 
14 weeks. We chose the specified population since they are at a greater risk of disability 
and is often excluded from trials18. 
 
Scehdule of Events 
 
 
Table 1. Study visit and schedule 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Schedule of Events 
Training Intervention 
Preparatory 
Phase 
Training 
Phase 
Phone scr. 
Scr. Visit 
Baseline 
Week 1 
Week 2 
Week 8 
Week 11 
Week 14 
Post-Test 
Screening 
Basic eligibility phone screening 
X 
Short consent 
X 
Informed consent 
X 
Physical exam, Medical History, Height 
X 
Weight & Vitals 
X 
X 
X 
Interventions 
Resistance Training 
Successful Aging 
Assessments 
DEXA 
X 
X 
X 
D3Cr Dosing & Collection 
X 
X 
X 
SPPB 
X 
X 
X 
Physical Functional Tests 
X 
X 
X 
Questionnaires 
X 
X 
X 

Participants 
24 low functioning, both males and females, with 12 participants in each of the treatment arm. 
Inclusion criteria 
A participant must meet the following criteria to be eligible for inclusion in the study: 
• 
men and women aged 70 or greater 
• 
at high risk for mobility disability based on lower extremity functional limitations 
measured by Short Physical Performance battery (SPPB) with a score ≤ 8 out of 12 
• 
could safely participate in the resistance training intervention as determined by medical 
history and physical examination. 
• 
willing to give informed consent to be randomized to either the resistance training group or 
successful aging (Heath Education) comparison group and willing to follow the study 
protocol 
Exclusion criteria 
 
• 
Severe cardiac disease, including NYHA Class III or IV congestive heart failure, clinically 
significant aortic stenosis, history of cardiac arrest, use of a cardiac defibrillator, or uncontrolled 
angina 
• 
Myocardial infarction, major heart surgery, stroke, deep vein thrombosis, or pulmonary embolus 
in the past 6 months 
• 
Lung disease requiring either oral or injected steroids, or the use of supplemental oxygen 
• 
Short, portable mental status questionnaire with 3 or more errors 
• 
Severe arthritis (either osteoarthritis or rheumatoid arthritis) that severely limits mobility 
• 
Severe lower back or shoulder pain that can worsen with weight lifting exercises. 
• 
Cancer requiring treatment in the past 1 year (Melanomas excluded) 
• 
Any present or recent history of severe psychiatric illness including depression that might 
preclude providing informed consent, safe participation, or compliance (self‐report and 
investigator judgement 
• 
Development of chest pain or severe shortness of breath on the 400 m self-paced walk test 
• 
Parkinson’s disease or other serious neurological disorders; renal disease requiring dialysis; 
other illness of such severity that life expectancy is considered to be less than 12 months 
• 
Current diagnosis of schizophrenia, other psychotic disorders, or bipolar disorder 
• 
Current consumption of more than 14 alcoholic drinks per week 
• 
Uncontrolled hypertension (systolic blood pressure > 200 mm Hg and/or diastolic blood 
pressure >110 mm Hg) 
• 
Currently on testosterone, Dehydroepiandrosterone (DHEA), or anabolic steroids. 
• 
Undergoing physical therapy involving the lower extremities 
• 
Currently enrolled in another randomized trial involving a pharmaceutical or lifestyle 
intervention. Observational studies are permitted 
• 
Participation in progressive resistance exercise regimen ( ≥1 day/week) within the previous 6 
months prior to screening. 
• 
Weight change (intentional or not) over the last 6 months of > 5% of body or plan to lose or gain 
weight during the study 
• 
Any other cardiovascular, pulmonary, orthopedic, neurologic, or other conditions that in the 
opinion of the local clinician would preclude participation and successful completion of the 
protocol 
Temporary Exclusion Criteria 

A person meeting any of the following temporary exclusion criteria at the time of screening will not 
be enrolled but may be re-screened later. 
 
• 
Recent bacterial/viral infection (e.g. pneumonia) (< 2 weeks); 
• 
Acute febrile illness in past 2 months; 
• 
Severe hypertension, e.g., SBP > 200 mm Hg, DBP > 110 mm Hg 
• 
Major surgery or fracture or hip/knee replacement (< 6 months); 
• 
Hospitalization within the last 6 months ( Not ER visits) 
 
Premature Withdrawal from the Study: A participant has the right to withdraw from the study at 
any time, for any reason, and without repercussion. The investigators have the right to withdraw a 
participant from the study in the event of an intercurrent illness, AE, treatment failure, protocol 
deviation, and for administrative, or other reasons. An excessive rate of withdrawals would render 
the study uninterpretable; therefore, unnecessary withdrawal of participants should be avoided. 
Sample Size: Our goal is to enroll a total of 24 participants. Since studies looking at changes in 
functional muscle mass in response to resistance training are not available, the sample size was 
arrived based on budgetary constraints and minimum number of participants required to meet 
feasibility goals. Assuming a conservative 20% loss to follow up, we estimate 12 participants per 
group (10 evaluable participants after the 20% loss due to attrition) would inform variance of the 
outcomes and feasibility for powering a future large-scale RCT. 
Randomization: Randomization will be executed via a computer algorithm using random block 
lengths and stratified by gender. To ensure concealment of the allocation, the randomization 
procedures will be performed by an investigator who are not involved in the assessments 
Recruitment 
 
Participant recruitment will be coordinated in conjunction with the OAIC Clinical Research Core. Potential 
participants will be recruited from the general population in the North/Central Florida region through: 
• 
IRB-approved advertisements (postcards, brochures, social media, newspaper ads) providing 
basic information about the study and inviting potential participants to call for additional 
information; 
• 
Contact of potential participants who are enrolled in the Claude D. Pepper Recruitment 
Registry (IRB#417-2007) by Registry staff; 
• 
We will also use existing entities of UF Health that include the Consent2Share program. 
Individuals who screen out of other studies may also be approached and asked about their 
interest in this study; 
 
Screening process 
We will employ a staged screening process where we will verify eligible participants over a series of 
contacts. 
• 
Interested participants are first screened by phone. The phone interview is designed to exclude 
individuals who are ineligible due to safety concerns or not interested after learning about the 
study. 
• 
After the phone screening, at the first in-person screening visit, we will consent participants with 
a short form and perform the SPPB test. Participant with SPPB score of ≤ 8 will be invited for 
the baseline visit. 
Interventions 

Resistance Training Intervention: The 14-week supervised resistance training intervention will 
include a full body, resistance training performed three days per week. The intensity, volume, tempo, 
and progression will be based on the Federal Physical Activity guidelines19 as shown in Table 2. 
Exercises: The resistance training exercises will include mainly multi-joint exercises using selectorized 
machines to minimize training duration and maximize the benefit. Each session will include upper body 
exercises (Chest Press, Shoulder Press, Seated Rows) and lower body exercises (Leg Press, Leg 
Extension and Leg Curls, and Calf raise) that will be tailored to the particpant needs. Inerventionists will 
suprvise all exercise sessions. 
 
Warm up & cool down: Each training session will begin with 1 set of warm-up at a lighter load for 8–10 
repetitions on 1 multi-joint upper body and 1 lower body machine. Each session will end with a 5 min 
cool-down involving stretching exercises and light calisthenics 
Preparatory phase: Considering the participants are low functioning; we will use a 2-week preparatory 
phase, which will ensure sufficient time for connective tissue adaptations and for the participants to 
learn proper lifting form and breathing technique. 
 
Training Phase: The training phase will last for 12 weeks and will be divided into 2 phases as shown in 
Table 2. 
Intensity: The intensity will be maintained at 6-8 (moderate to vigorous RPE) as recommended by 
ACSM for older adults20 and the sets will be done until volitional fatigue. The CR-10 BORG’s scale 
ranges from 1-10 will be used to document perceived exertion during resistance training21. 
 
Progression: The load will increased when participants can perform all repetitions in all sets . 
 
Table 2. Resistance training parameters 
Preparatory Phase 
Training Phase 
Week 1-2 
Week 3-5 
Week 5-14 
Days/wk 
3 
3 
3 
Sets * Reps 
1-2* 12-15 
3 *12-15 
3* 8-10 
RPE 
6 - 8 
6 - 8 
6 - 8 
Rest (min) 
1 
1 
1 
Progression 
Can do 3 sets of 15 
Can do 3 sets of 10 
Note: All values are subject to change based on participant availability and ability of the 
participant to conduct the number of sets and reps prescribed. 
 
 
Successful Aging: The comparator group will meet every 2 weeks. Weekly workshops will include 
flexibility exercises and presentation topics related to older adults, such as preventive services and 
screenings, finding credible health information, and so forth. We instruct all control participants not to 
change their PA levels and the importance of remaining weight stable throughout the study period. The 
rationale for the health education group in place of a sedentary control is to minimize the social 
interaction effects and to minimize participant drop-outs22. 
 
Outcomes & Questionnaires 
All outcomes and questionnaires will be conducted at the Institute on Aging by trained and 
certified clinical site staff. 
Medical history: A questionnaire that asks about health conditions will be administered prior to 
performing activities. Medical staff will evaluate participants with any health conditions 
(cardiovascular disease, falls, metabolic diseases, etc.) that are exacerbated with physical 
exertion. 

Medication inventory: Many adults use both prescription and non-prescription pharmaceutical 
products. The use of these products is of interest for several reasons. All participants are asked 
to bring all prescription and non-prescription medications taken in the past two weeks to their 
first visit. 
 
Short, portable mental status questionnaire: The questionnaire will be administered to 
identify potential participants with cognitive dysfunction who would pose a potential safety risk 
 
PROMIS: The NIH developed Patient-Reported Outcomes Measurement Information System 
(PROMIS) physical function questionnaire uses item response theory (IRT) and computer 
adaptive tests (CAT) to improve precision and minimize respondent burden. The test has been 
shown to be reliable and valid across a range of population, including high-functioning and low 
functioning individuals 23 The following PROMIS tests will be used: physical Function, upper 
extremity, and mobility. All measures are administered via computer. Time to complete each 
measure ranges from 1‐3 minute 
Photograph Series of Daily Activities Scale - Short Electronic Version (PHODA-SeV) – The 
PHODA-SeV is an assessment of pain-related fear in the context of chronic back pain. The 
PHODA-SeV includes 40 photographs depicting common activities ranging from household 
chores to physical exercise. Using a 0–100 scale, respondents indicate their concern of harming 
their back when engaging in each depicted movement25. 
 
Five Facet Mindfulness Questionnaire (FFMQ) – The FFMQ is a reliable and valid 
comprehensive instrument for assessing different aspects of mindfulness. The FFMQ is based 
on a factor analytic study of five independently developed mindfulness questionnaires26. 
 
Tampa Scale for Kinesiophobia (TSK) – The TSK is a reliable and valid self-report checklist 
that uses a 4-point scale to measure of fear of movement or (re)injury. The scale is based on 
the model of fear avoidance, fear of work related activities, fear of movement and fear of re- 
injury. The TSK is considered as one of the most suited questionnaires to evaluate pain beliefs 
and fear of movement/(re) injury in chronic low back pain27. 
 
Borg Category Ratio (CR) 10 pain/RPE scale – The Borg CR10 pain/RPE scale is a reliable, 
valid, and frequently used quantitative measure of perceived exertion and pain during each 
exercise session and after the physical function tests. The Borg CR10 uses a category ratio 
scale that ranges from 0 (no pain/exertion) to 10 (maximal pain/exertion)28. 
 
Gait Analysis: We will ask participants to walk at their usual pace and a rapid pace two times 
across a carpet that contains sensors arranged in a grid pattern (48 X 288) (GAITRite Inc.). The 
system collects temporal (step time, gait cycle, single support time, double support time, stance 
time and swing time) and spatial (step length and stride length) parameters. 
Vital signs: During screening, resting blood pressure and heart rate, height, weight will be 
measured. Blood pressure and heart rate are measured to assess eligibility criteria and for 
safety purposes and others are collected for descriptive purposes. 
Oxygen Consumption: Oxygen consumption will be measured using a portable metabolic unit 
(Cosmed K4b2) for three daily tasks for 6 minutes each. Oxygen consumption will be measured 
breath-by-breath through a mask that is fitted to the participants face. 

Mopping: Mop a 200 sqft room using mop and water 
Lifting: Lift chairs and transfer across a 200 sq ft room 
 
Muscle mass measurements: 
• 
D3-Cr method: The participant will ingest a 60-mg dose of deuterated creatine (D3-Cr), a non- 
radioactive isotope, at the baseline assessment. They will return morning to provide a urine 
sample 3-5 days later. The sample will be frozen and deidentified for D3-creatinine analysis. 
urine samples (-200) will be shipped to University of California, Berkeley where unlabeled 
creatinine and creatine will be measured using high-performance liquid chromatography(HPLC) 
and mass spectrometry (MS). The details of methods have been published previously.16 
• 
DEXA: Total and regional body composition will be measured using at UF site Dual-energy X- 
ray absorptiometry (DEXA, QDR-4500w; Hologic, Waltham, MA, USA). DEXA is widely used in 
trials, is safe and is currently recommended to diagnose sarcopenia11, 12. 
Walk Tests: The 400m walk test is a feasible, objective, reliable, well-validated and used in large 
clinical trial. Participants will be asked to walk 400 m at their usual pace, without overexerting, on a 20- 
m course for 10 laps (40 m/lap)29, 30. The 6 min walk test will include walking at a rapid pace around 2 
cones 20 m apart wearing the portable metabolic unit. 
Physical performance will be measured using the Short Physical Performance Battery (SPPB), which 
is based on a timed 4-m walk, balance, and chair stand tests. This scale is reliable and valid for 
predicting institutionalization, mortality and disability31, 32, 2933, 34 The score ranges from 0 (worst 
performers) to 12 (best performers). 
Muscle strength will be measured using tests of isometric grip strength and isokinetic leg extension 
test. Grip strength is frequently used of upper body skeletal muscle function and has been widely used 
as a general indicator of functional status35. Grip strength will be measured using the Jammar 
dynamometer. Leg strength will be assessed using Isokinetic dynamometry (System 3 pro; Biodex 
Medical Systems, Shirley, NY, USA) at velocities of 60º and 120º per second36.2429 
Participants will perform 2 sets of 5 maximal isokinetic leg extensions at each velocity with one-minute 
of rest between each set for the dominant leg. 
Dynamic balance will be measured using the Timed Up and Go test which is widely used to examine 
mobility and dynamic balance. Also, the test is recommended as a screening test for falls by the 
American Geriatric Society and the British Geriatric Society37, 38. Standing or static balance (narrow, 
tandem and semi-tandem) will also be assessed as part of the SPPPB test. 
Adherence 
Adherence involves both attendance to scheduled sessions as well as the quality of the training that 
occurs during each session. Adherence to the exercise protocols are affected by personal, social and 
environmental factors. At a personal level, it is important to ensure that the goals of each participant are 
realistic. We recognize that social interactions between staff and participant as well as the broader 
social environment surrounding the study influence adherence. All staff will be instructed to engage with 
and be supportive toward all participants. We will also adopt a number of other strategies to improve 
attendance and quality of training sessions. Some strategies include, having trained interventionists to 
supervise training, including a preparatory phase to educate the participants about proper lifting 
technique, tailoring the training program based on the physical needs of the participant, maintaining a 
workout log to help motivation, monitoring missed visits so that the study coordinator can take prompt 
action and so forth 
 
The physical environment and accessibility influence adherence. This includes such factors as ease of 
parking, transportation, and accommodations made for friends or significant others who may come to 

training facilities to support participants via transportation, etc. At the time of baseline assessments, 
staff discuss these topics with each participant to be certain there are no significant barriers in this 
domain and/or to problem solve potential challenges that exist. 
The comparator group will not participate in a resistance raining intervention and hence pose a greater 
risk of dropping out. We expect, based on our previous experiences, that the flexibility exercises and 
health education classes offered every 2 weeks will serves an effective “active control” that will help to 
promote retention in the study. We will also provide an exercise prescription and education materials at 
the end of the study duration so that they can start a resistance training program outside the site. 
Retention 
The following guidelines promote compliance to the protocol and retention 
 
• 
Participant-staff relationship. A key element contributing to participants’ continued commitment 
to the study involves fostering positive, respectful relationships between study participants and 
individual members of the staff. 
• 
Continuity of care. In general, participants appointments should be scheduled so that they can 
be seen by the same clinic staff members during each visit. 
• 
Clinic environment. A clinic environment that is warm and pleasant, and oriented to the comfort 
of the participant. 
• 
Participant-staff communications. Good and consistent communication is essential. Instructions 
are clear and interactions are friendly and individualized. The participant is reminded of the 
benefits of study participation. Written reminders about appointments further enhance 
communication efforts. 
• 
Convenience and accessibility. An easily accessible clinic location, availability of transportation, 
and convenient clinic hours all serve to facilitate study adherence. We will make study visits as 
easy as possible for participants, a critical factor to the success of the study. All sites take steps 
to ensure that clinic attendance is not compromised by a lack of transportation, unsuitable hours 
of clinic operation, or any similar circumstance. If necessary, participants are reimbursed for or 
are provided transportation to the clinic assessment visits. 
• 
Time in clinic. Total clinic visit time is kept to a minimum, consistent with maintaining quality. If 
waiting is necessary, the situation is explained to the participant and, if possible, an offer is 
made for the participant to see another staff member, or to reschedule the visit. On the other 
hand, participants are not rushed or made to feel unwelcome. Study personnel trained to take 
time to visit with participants. 
• 
Appointment reminders. Appointment reminders are used to prompt participants to come for 
clinic visits. These written reminders are mailed to participants so that they receive them before 
their scheduled visit date. 
• 
Compensation: Participant will be compensated $100.00 for being in the study. The 
remuneration is given for attendance at clinic assessments, regardless of the level of 
participation in intervention activities 
 
Statistical plan 
Data analysis will be conducted at the Biostatistics and Data Management Core under the direction of 
Peihua Qiu, Ph.D. Our primary analysis will use an intention to treat approach in which participants are 
grouped according to randomization assignment without consideration of their adherence to the 
exercise or successful aging health education programs. We will also perform “per protocol” analyses to 
examine muscle adaptations in those individuals with adherence rates > 80%. 
 
Although pilot studies are not powered for hypothesis testing, we will use a mixed effects model to 
assess changes in the outcomes with baseline measure serving as covariate. Associations between 
muscle mass and other outcomes will be explored using a correlational analysis 

Data Safety and Monitoring Board 
 
This project is funded as a Pilot Study through the UF Claude D. Pepper Older Americans 
Independence Center (OAIC) grant (NIH P30 AG028740 ) and thus uses the OAIC Data Safety 
Monitoring Board (DSMB). 
The OAIC DSMB consists of an established board which has reviewed all studies conducted within the 
UF OAIC during for the past seven years. This board meets annually. DSMB Reports will be provided 
to the UF IRB-01 with annual Continuing Review submissions. 
 
 
Confidentiality 
Confidentiality of data is maintained by using research identification numbers or alphanumerics that 
uniquely identify each individual. Phone pre-screeners will be de-identified by replacing identifiable 
information with numbers or alphanumerics. Collected data will be used only for research purposes, 
and publications will not contain any individual identifiers Safeguards are established to ensure the 
security and privacy of participants’ study records. The research records are kept in a locked room in 
locked computer files and file cabinets. Storage Areas for all records containing PHI or other restricted 
information is physically secure and environmentally controlled, to protect the records from 
unauthorized access and damage or loss from temperature fluctuations, fire, water damage, pests, and 
other hazards. Only study personnel have access to these files. After the study is completed, local data 
are stored with other completed research studies in a secured storage vault. According to the HIPAA 
rules, consent forms signed by the study participants, the study’s research records containing 
identifiable data will be stored for a minimum of 6 (six) years after the study is completed and closed 
with IRB. 
In compliance with the Health Insurance Portability and Accountability Act (HIPAA) and the Standards 
for Privacy of Individually Identifiable Health Information of the Department of Health and Human 
Services, study staff accesses personal health information and medical records only after receiving 
informed consent (verbal for phone screener and signed for short form and main consent). 
 
 
4. POSSIBLE DISCOMFORTS AND RISKS 
400-m walk: The 400-meter test may be associated with the risk of falling or development of chest 
discomfort due to coronary ischemia or dyspnea due to heart failure or lung disease. Rarely, falling 
during the 400-meter walk test may result in a fracture. Similar to the six-minute walk test, completion of 
the SPPB may be associated with the risk of falling or development of chest discomfort due to coronary 
ischemia or dyspnea due to heart failure or lung disease. Rarely, falling during the SPPB test may 
result in a fracture. In our experience conducting thousands of 400 m walk tests on individuals within 
various studies, the risk of falling is less than 1/500 and the risk of a fracture-associated fall is less than 
1/5000. In the LIFE study we have performed approximately 10,000 400 m walk tests with no safety 
concerns raised by the DSMB. 
Questionnaires: There are some risks associated with questionnaire administration. Sensitive 
information collected for this study includes lifestyle factors (e.g., alcohol use) and personal health 
information (PHI) and are used predominantly in screening for eligibility and safety. Participation 
includes a risk of loss of confidentiality of this information. 
To minimize risk, questionnaire data are collected in secure spaces where the interview cannot be 
overheard. Participants are reminded that they can decline to answer questions that are uncomfortable 
or concerning. All research staff members complete annual HIPPA for Researchers training as 
required by UF. 

DXA: DXA scans to determine body composition involve small amounts of radiation 
exposure. The amount of radiation exposure from each whole body DXA scan is <2.5 mRem per scan. 
Although the potential long‐term risk from these radiation doses is uncertain, such doses are 
exceedingly low and have never been associated with any definite adverse effects. 
 
Resistance Training: Potential risks associated with RT will be explained to each participant by 
appropriately trained clinical site staff during the initial informed consent, screening, and study 
orientation. 
• 
Difficulty breathing and/or shortness of breath 
• 
Muscle, joint strains and soreness 
• 
Soft tissue injury, falls and fractures 
• 
Increasing intraocular and systemic pressures associated with use of the Valsalva 
maneuver to levels that may cause injury (detached retina, hernia, conjunctival 
hemorrhage), which is greatly reduced by instruction in proper exercise technique. 
• 
Hernia 
• 
Exacerbation of arthritis or other joint conditions 
• 
Lumbar disk hernia 
• 
A small increase in the risk of sudden death, stroke, and acute MI occurring during a bout of 
• 
vigorous exercise has been reported, especially in previously sedentary individuals. 
• 
Orthostatic hypotension 
• 
Triggering of an asthma episode 
These risks are minimized in all exercise sessions by having supervised and trained exercise 
interventionists who instruct participants in the proper exercise techniques, including instructions to breathe 
normally during the exercise. Procedures to minimize injury include warm‐up and cool‐down activities that 
include large muscle movements and stretching. The preparatory phase is designed so that participants 
can learn proper exercise technique and gradually increase training volume and intensity. 
The entire exercise intervention is conducted on‐site and all sessions are supervised by trained 
interventionists, who will monitor potential adverse experiences and symptoms. During the exercise 
sessions, a defibrillator and on‐site trained staff are available to deal with medical emergencies. 
To minimize these risks, research staff are trained in the conduct of all physical performance tests and 
certified by before they work with study participants. Study staff are instructed not to perform these 
tests if they feel that testing is unsafe for an individual participant or if the participant is concerned about 
safety. If safety concerns are identified by either the study staff or the participant during the testing 
procedures, testing is halted and the participant is not allowed to complete the test. In either case, the 
participant is assessed to determine the need for medical intervention and the cause for concern is 
evaluated. All study staff are trained in activating the emergency response system at The University of 
Florida’s Institute on Aging facility. 
All sessions are conducted by research staff trained to monitor potential adverse experiences and 
symptoms during the testing sessions. All personnel associated with the study have completed Basic 
Life Support (BLS) training and education on management of acute events including syncope, chest 
pain, acute dyspnea, focal neurological symptoms and abnormal vital signs. Additionally, a study 
physician is available on call and contact numbers for emergency services are posted. Institutional and 
community EMS services will be activated if needed. 
Participants will be instructed to talk with the investigators about any discomforts that occur during the 
study. If a participant reports an injury, chest pain, leg swelling, excessive shortness of breath, 
palpitations, or dizziness, he/she will be referred to medical attention (his/her doctor, or Emergency 
Department). 
All research staff complete human participants training required by The University of Florida 
institutional review board (IRB) and National Institutes of Health (NIH). 

Adverse events (AE) and serious adverse events (SAE) 
The study will collects and reports only Serious Adverse Events (SAEs) and (nonserious) 
AEs associated with the intervention or study procedures. Pre‐existing conditions and preplanned 
procedures (surgeries or therapies) scheduled prior to signing the Informed Consent are not considered 
AEs/SAEs. 
Adverse events (AE): For this study’s purposes, an AE or experience is defined as any health‐related 
unfavorable or unintended medical occurrence that happens after randomization. Examples of AEs include, 
but are not limited to, the following: 
• 
A clinically significant laboratory or clinical test result at follow up assessments 
• 
An event that requires a visit to a physician because it alters the participant’s ability to exercise 
• 
An event that occurs as a result of a study procedure which is not listed in the Risks section of 
the consent 
 
Serious adverse events (SAE): SAEs are defined as events that may be harmful to the participant and/or 
may be serious enough to warrant either temporary or permanent discontinuation of the study intervention 
or study procedures, 
either because they are intolerable or because they are judged to be potentially harmful. Consistent 
with NIH guidelines, SAEs are AEs that meet any of the following criteria: 
• 
results in death 
• 
is life‐threatening 
• 
requires inpatient hospitalization 
• 
prolongs an existing hospitalization 
• 
results in a persistent or significant disability/incapacity 
• 
important medical events that investigators judge to represent significant hazards or harm to 
• 
participants, and may require medical or surgical intervention to prevent one of the other 
SAEs 
• 
listed in this definition (e.g., hospitalization, death, persistent disability) 
Relationship to study intervention: The classification of potential relationship to the intervention is as 
follows. 
• 
Not Related – AE is clearly not related to the intervention or procedure (e.g., temporal sequence 
of events is not consistent with administration of intervention or procedures, other causes are 
more plausible or causal relationship is implausible. 
• 
Possibly Related – AE that follows reasonable sequence from administration of intervention or 
procedure but that could readily have been produced by several other factors. 
• 
Definitely Related – AE is clearly related to the intervention or procedure (e.g., follows 
reasonable temporal sequence from administration of the study intervention or procedure, 
confirmed by improvement after stopping intervention or procedure, and reappearance on repeated 
exposure to intervention or procedure, and cannot be explained by participants clinical or health 
status). 
 
Expected AE’s: Expected AEs are defined as anticipated events based on the prior experience 
with the intervention and listed in the participant consent and protocol; these can be attributed to an 
underlying condition or the patient population being studied. These conditions that may be 
unpleasant and bothersome to the participant, such as sore muscles, muscle or joint pain, or 
breathing problems, do not require discontinuing the study intervention or components of the 
intervention. 
 
Unexpected Adverse Events: Unexpected adverse events (UAEs) are defined as events that 
occur during participation in the study but do not commonly occur in the study population and are 

not listed in the informed consent. An AE is not defined as a UAE unless it meets all three defining 
criteria: 
 
unexpected given the research procedures described in the informed consent and 
characteristics of the study population; 
 
definitely related or possibly related to participation in the study intervention or 
procedures; 
 
suggests that the research intervention or procedures place participants or others at 
greater risk of harm than was previously realized. 
5. POSSIBLE BENEFITS 
 
 
• Participant will receive health and medical screening examinations at baseline. 
• Participant will have the opportunity to participate in a strength training program or health 
education program with professional supervision. Participation in these activities has the 
potential to improve participant’s health, body composition, and quality of life. 
• Also, all participants will receive an individualized report of your strength, muscle 
mass, fat percentage, bone density and physical function in comparison with other 
older adults in your age group and gender at the end of the intervention. 
• The results of the study will help validate a new tool to measure muscle mass that will 
have a number of potential uses, ranging from detecting muscle loss in both health 
and disease (cachexia) to evaluating the efficacy of behavioral and pharmacological 
interventions to increase muscle mass. 
 
6. CONFLICT OF INTEREST 
None 
 
 
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