Enhanced Protein Intake During Obesity Reduction in Older Male Veterans: Differences in Physical Function and Muscle Quality Responses by Race
Phase: NA
Conditions: Prediabetes, Obesity
Sponsor: VA Office of Research and Development

 
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Enhanced Protein Intake During Obesity Reduction in Older Male Veterans:  
 
Differences in Physical Function and Muscle Quality Responses by Race 
 
 
 
Funding Agency: United States (U.S.) Department of Veterans Affairs Rehabilitation R&D (Rehab RD) Service 
 
Principal Investigator: Connie W. Bales, PhD, RD 
 
11/30/2023 
 
In addition to Dr. Bales, the study team includes two physicians (Kim M. Huffman, PhD, MD and Shelley 
McDonald, PhD, DO) who will review data for safety concerns, reviewing adverse events and new study 
findings, and making required decisions to protect the health of the subject. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Parent Research Protocol: Enhanced Protein Intake During Obesity Reduction in Older Male Veterans: 
Differences in Physical Function and Muscle Quality Responses by Race 
 
Principal Investigator: Connie W. Bales, Ph.D., R.D.  
Purpose 
The purpose of this research is to restore physiological function in obese black and white older Veterans using 
an innovative weight loss diet that is higher in protein and enhanced by cultural tailoring, safe, low impact 
exercise, and intensive adherence support. Recognizing the increasing prevalence of type 2 diabetes with age 
and its links with poor muscle quality, we will study men with pre-diabetes, assessing changes in insulin 
sensitivity, as well as physical function. Our objectives are (1) to determine the impact of a muscle-preserving 
obesity treatment on physical function and an array of critical secondary outcomes in obese older male 
Veterans with pre-diabetes, and (2) to examine racial (black versus white) differences in treatment responses. 
Equal numbers of obese, older white and black male Veterans with pre-diabetes are randomized to an 
enhanced protein group or control weight loss group consuming RDA-level protein. The intervention stands to 
benefit large numbers of Veterans by improving their functional status; it will also reduce the VHA burden of 
care for their diabetes. It will advance the RR&D mission by “improving musculoskeletal composition and 
maximizing physical function” in obese older Veterans with pre-diabetes, yielding novel results on the 
interactions of insulin sensitivity with muscle quality and exploring racial differences in treatment responses. 
 
Background and Significance: 
      The impact of late life obesity on physical limitations and reduced independence in older adults is under-
studied. Yet, most of the >40% of older Veterans who are obese have reduced physical function due to the 
combination of excess body fat and age-related decline in muscle mass/strength (sarcopenic obesity). Close to 
one in four Veterans receiving health care from the VA has diabetes and there is a high prevalence of obesity 
in this group; moreover, the majority of these Veterans are 65 years and older 1,2. Of special interest as we 
attempt to sort out the benefit/risk of obesity reduction is its impact on older African Americans, who have 
higher rates of obesity and are more likely to develop obesity-related functional decline and chronic health 
conditions like type 2 diabetes than their white counterparts. These Veterans are in critical need of 
interventions to restore their physiological function and ability to resume normal activities of living and 
achieve social autonomy. The primary focus of the proposed research is on the detrimental influences of 
obesity on physical function in older individuals who are at very high risk for frailty. Unless effective obesity 
interventions can be found, the functionally disabled, obese older adult may become the “most commonly 
encountered phenotype of frailty” in the near future 3. 
       Both obesity and the aging process lead to compromised muscle function. With age, lean muscle mass 
declines from about 50% of total body weight in young adults to about 25% at 75–80 yrs 4. The progressive 
deterioration of muscle quantity and quality leads to slower movement, a decline in strength and power, and 
increased risk for falls 5.  Obesity also causes deterioration of muscle quality and loss of physical function. 
Thus, the combination of sarcopenia and obesity markedly accelerates functional decline. Greater adiposity 
favors the accumulation of lipid between and within muscles (reduced muscle quality). Moreover, in most 
obese individuals, there is persistent low grade inflammation resulting from chronic activation of the innate 
immune system that leads to muscle depletion by enhancing protein breakdown and impairing myogenesis in 
parallel 6,7. Progressive muscle atrophy due to disuse contributes further to functional decline. Aging and 
obesity also precipitate impaired physical function through their association with increased insulin resistance 
and its progression to type 2 diabetes. Thus, insulin resistance is the third component of the “triple threat” to 
physical function in obese older adults. Increasingly, higher BMI, age, and comorbidity are being identified as 
significant co-risk factors for functional decline 8. 
 
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Obesity is the single most important risk factor for developing type 2 diabetes 9 and obesity reduction 
markedly slows the progression to prediabetes. However, weight reduction is difficult to achieve in adults of 
all ages 10,11 and it is especially challenging to treat in older adults, who have lower basal metabolic rates, 
calorie requirements, and rates of physical activity 12-14. Moreover, efforts to reduce body weight in obese 
older adults raise concerns about the concomitant loss of lean body mass 15. Lowering of muscle mass is a 
concern not only for future functional status but it is also linked with impaired glucose uptake and tolerance, 
even in those without diabetes 16.        
 
A higher protein intake during obesity reduction could help circumvent loss of muscle mass and strength. 
Protein intakes exceeding the RDA level (≥0.8 g/kg) are linked with better preservation of lean mass 17,18 and 
new findings from the Framingham study have confirmed the benefits of high quality (animal) protein for 
protection of appendicular lean mass 19, preservation of grip strength 20 and decreased risk of function decline 
in the long-term 21. While muscle becomes more resistant to anabolic stimulation with age, there is 
encouraging evidence that generous and balanced intakes of high quality (complete) protein can help off-set 
age-related anabolic resistance in the aging muscle 22-24. Short-term studies have shown that the essential 
amino acids, especially leucine, initiate the mTOR signaling pathway and stimulate muscle protein synthesis 25-
27. A generous and balanced intake of protein at each meal (~30 grams) may be essential for optimal protein 
synthesis in the aging muscle 28,29. Higher protein during obesity reduction may thus reduce the risk of physical 
frailty by increasing muscle anabolism; improvements in muscle quality may also result 17,29-32.  Our recent 
studies have confirmed the feasibility and efficacy of balanced higher protein weight loss diets for weight 
reduction and for improving physical function 33 and we seek to test this in vulnerable older Veterans with 
prediabetes. 
 
Our study is particularly unique because the impact of higher protein intake on glucose handling is not well 
understood. The results of a recent trial suggested that a higher protein intake might blunt insulin sensitivity 
benefits accrued from weight loss 34. However, at least two independent randomized controlled trials have 
demonstrated a beneficial effect of higher protein intakes on insulin sensitivity 35,36 and a recent systematic 
review found no detrimental effect of a higher protein diet in those with type 2 diabetes or those at risk of 
developing it 37. Given the potential benefit of higher protein intake for function, we seek to better 
understand its impact on the high-risk populations groups who stand to benefit most, including those who are 
at elevated risk for developing type 2 diabetes.  
 
Late-life obesity is one of the greatest health care challenges facing VHA as large numbers of Veterans 
approach old age. Obesity’s impact on physical function is under-studied in many of those at highest risk for 
frailty, including obese older men with prediabetes. Thus, the proposed research addresses an important gap 
in the evidence needed to guide obesity treatment and diabetes prevention in older Veterans.  It is based on 
evidence that balanced protein feeding benefits muscle function and the hypothesis that, in concert with 
moderate calorie restriction, it will provide an effective obesity treatment that preserves muscle while 
reducing body fat and improving glucose handling. The research also includes careful documentation of study 
participation and intervention adherence in order to analyze differential responses due to race, socio-
economic status, and other factors unique to older Veterans. This will be the first randomized controlled trial 
to examine balanced feeding of a higher protein diet during a period of metabolic challenge (caloric 
restriction) in those with prediabetes and the first study to look at racial differences in response of obese older 
men to this regimen.  There are very few studies of racial differences in response to obesity interventions. 
 
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Thus, the importance of our exploratory aim for understanding the unique challenges facing obese black men 
in later life and the potential benefit of new obesity treatments for them is underscored.  
    
Specific Aims 
Aim 1:  To compare a balanced, higher-protein weight loss diet to a control weight loss diet with regards to 
the primary outcome of physical function.            
 
 
Introduction. This proposal focuses on interventions to improve physical function in obese older white 
and black men who have prediabetes, a common condition strongly associated with obesity; 5 to 10 % of 
those with prediabetes progress to type 2 diabetes within one year 38. To date, the majority of weight loss 
study populations are predominantly female, despite substantial increases in rates of obesity in men 39-41. Our 
study focuses on obese older men because of the scarcity of well-controlled studies of effective obesity 
interventions for men and because older male Veterans have a higher prevalence of diabetes (33% for 65-74 
yr olds and 31.5% for 75 and older) than older female Veterans (26.9% for 65-74 yr olds and 25.7% for 75 and 
older) 42. Older Veterans who are obese are in critical need of interventions to restore their physiological 
function and ability to resume normal activities of living and achieve social autonomy. We know that obesity 
treatment can improve function and potentially restore muscle quality but it can also threaten loss of lean 
mass (25% or more of weight lost) 15 unless the intervention is designed to protect the muscle. 
The objective of this aim is to confirm the efficacy of a balanced higher protein weight loss diet for weight 
reduction and for improving physical function 33 in a population of vulnerable older male Veterans with 
prediabetes. The rationale for this aim is founded upon evidence that balanced protein feeding benefits 
muscle function and the hypothesis that, in concert with moderate calorie restriction, it will provide an 
effective obesity treatment that preserves muscle while reducing body fat. Upon completion of Aim 1, it is our 
expectation that the findings will show that a higher-protein weight reduction diet will result in improved 
functional performance (by Short Physical Performance Battery) relative to the control diet. 
 
Specific Aim 2:  To compare a balanced, higher-protein weight loss diet to a control weight loss diet with 
regards to impact on muscle quality, insulin sensitivity, lean body mass, rates of physical activity, recent 
falls/fear of falling, instrumental activities of daily living, and quality of life.  
Introduction. Obesity is the single most important risk factor for developing type 2 diabetes 9 and 
obesity reduction markedly slows the progression to prediabetes. However, weight reduction is difficult to 
achieve in adults of all ages 10,11 and it is especially challenging to treat in older adults, who have lower basal 
metabolic rates, calorie requirements, and rates of physical activity 12-14. Lowering of muscle mass is a concern 
not only for future functional status but it is also linked with impaired glucose uptake and tolerance, even in 
those without diabetes 16.  The objective of this aim is to assess the broad metabolic and physiological effects 
of a higher-protein weight loss regimen, including its impact on muscle quality, insulin sensitivity, lean body 
mass, rates of physical activity, recent falls/fear of falling, instrumental activities of daily living, and quality of 
life relative to a control weight loss treatment.   We will test the working hypothesis that an effective weight 
loss intervention will benefit insulin sensitivity and reduce the deleterious effects of obesity on muscle 
function, muscle quality, and the ability to be physically active and that these benefits will be greater in the 
higher-protein group than in the control weight loss group. We hypothesize that, compared to the control 
diet, the higher-protein regimen will lead to superior muscle quality and equal or superior improvements in 
insulin sensitivity, proportion of body lean and fat mass, physical activity by accelerometer, instrumental 
activities of daily living (IADLs), recent falls/fear of falling, and quality of life. 
 
 
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Aim 3 (Exploratory):  To assess racial differences in responses to the two diet treatments with regards to 
weight loss, function, muscle quality, insulin sensitivity, body composition, physical activity, recent falls/fear 
of falling, IADLs, and quality of life. 
     Introduction.  Racial differences in pre-diabetes and type 2 diabetes are well recognized; blacks have higher 
rates of obesity and are twice as likely to develop type 2 diabetes as non-Hispanic whites 43. Yet, there are very 
few studies of racial differences in response to obesity interventions. Even studies focusing on African 
Americans include low percentages (30% or less) of men 44 and there is evidence that traditional weight loss 
interventions are less effective for black individuals 45,46, under-scoring the need for further study. As captured 
in this exploratory aim, this trial was designed to assess the differential impact of race on responses of insulin 
resistance during a hypo-caloric diet providing higher, balanced amounts of protein.  We hypothesize that 
there will be a race differential in the responses of several outcomes to the diet treatments. It is our 
expectation that there will be less weight loss in blacks than whites and smaller improvements in function, 
muscle quality, and insulin sensitivity. This is based on literature findings on racial differences and our 
published findings in black women, as well as the tendency for more type 2 diabetes in the black population. 
Based on indirect evidence, we also speculate blacks will have lesser improvements in lean mass preservation, 
physical activity, recent falls/fear of falling, IADLs, and quality of life.  Additionally, we expect to identify 
determinants of study participation and intervention adherence that indicate racial differences and that these 
results can be used for cultural adaptation in future intervention trials.  
 
Design 
This is a randomized controlled study. The subject numbers and group allocations are based on the primary 
outcome of functional status, as well as our previous experience with protein enhanced nutrition 
interventions. Our experiment is a repeated measures design, with the purpose of assessing change over time 
for the WL-Protein arm relative to the WL-Control arm. With this design, we will be able to derive effects sizes 
(effectiveness), and to assess differences between the two arms. 
 
Setting: Screening, baseline, outcome testing and intervention meetings will be conducted at the Sarah W. 
Stedman Center for Nutritional Studies on the Center for Living Research and Wellness campus at Duke 
University. Diet and exercise classes will be offered virtually via WebEx or in person at the Center for Living 
campus. Anthropometrics, functions tests, and blood collection will take place in the Clinical Research Unit 
there or may be conducted virtually if needed. The Isokinetic knee extension peak torque testing and BodPod 
body composition measurements will be done in the Sports Sciences Institute, which is adjacent to the 
Stedman Building. The thigh CT scans will be conducted in Radiology at the Veterans Affairs Medical Center in 
Durham. 
 
We will enroll participants until we reach a total of 112 study completers.  We anticipate enrolling 
approximately 160, allowing for a 30% dropout rate.  
 
Study Arms: 
• Arm 1: WL-Control (n=56 completers)                                                                                                          
10%* WL diet with 0.8 g protein/kg body wt/day 
• Arm 2: WL-Pro (n=56 completers)                                                                                                                                  
10%* WL diet 1.4 g protein/kg body wt/day; >30g high quality protein per meal 
 
 
 
 
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*Participants enrolled after 10/1/2023 will participate in a shortened study period of 3 months, with only 0 and 
3 month assessments for most measures, as noted in the added footnotes below. Their weight loss prescription 
will be targeted to an expectation of at least 5-10% loss of body weight. 
 
Measurements: 
 After the participant has been consented and HIPAA Authorization forms have been signed, screening and 
baseline assessments will be conducted: 
 
Screening process:  
Screening Visit : Consent; confirm BMI >30 kg/m2, confirmed SPPB score of 4-11, confirmed  fasting 
plasma glucose ≥95 and <126 mg/Dl or A1c between 5.7-6.4 (will be confirmed with LapCorp results), 
and confirmed Mini-Cog score ≥3 (if less than 3, confirm participant can conduct all ADLs). 
 
Upon the completion of all baseline assessments (see below), the study biostatistician will then use permuted-
block randomization to assign participants to WL-Control or WL-Protein groups. The following variables will be 
blocked in this order: 1) Race (white versus non-white, 2) Couple/Single status. An equal number of 
participants will be randomized across the two arms to end up with N=84 (42 black and 42 white) in each arm. 
  
 
Measures and Data Collection Points 
Primary outcome: Physical function (SPPB) 
 
Secondary outcomes: muscle quality (the ratio of knee extensor peak torque to thigh muscle area (cm2) 
assessed by using compute tomography (CT) (in Nm/cm2); insulin sensitivity,Air Displacement Plethysmograph 
(BodPod) to measure body weight, lean mass, and body fat; waist circumference, function tests (handgrip, 8-ft 
up and go, 30-sec chair stand, 6-min walk); physical activity (Actigraph); recent falls and fear of falling, diet 
adherence and nutritional adequacy; activities of daily living and independent activities of daily living; and 
quality of life and mood indicators (SF-36 Health Status questionnaire, Profile of Mood States questionnaire, 
and Pittsburgh Sleep Quality Index). 
 
1 Participants who are consented after 10/1/2023 will participate in a shortened version of the study. Data will be collected at month 0 
and month 3 as outlined in this table. Body weights will still be collected weekly and the Nutrition and Exit questionnaires will be 
conducted at 3 months. 
 
Measurement/Procedure 
Time 
Points1 
Method 
Diet/Intervention 
Body weight 
Weekly 
Same scale, light clothing and no shoes, measured to 
nearest 0.1 kg 
3-day diet record;  
Daily food journal (Adherence) 
0, 3, 6 
months 
3-day diet record by multiple pass; analyzed Food 
Processor (Version 10.13, 2013; ESHA Research); Daily food 
journal assessed by RD 
Protein checklist 
Monthly 
RedCap analysis  
Actigraph, Axis accelerometer 
(activity counts, step counts, 
physical activity intensity) 
0, 3, 6 
months; 7 
Actigraph WGT3X-BT activity counts at 1-s epoch from 
three orthogonal axes at 30 Hz sampling frequency. We 
 
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days each 
time point 
have been using Actigraphs in previous studies and 
therefore have not included in the budget.  
Nutrition Questionnaires 
0 months 
Food Security Questionnaire 
Nutrition Questionnaires 
0, 6 months 
Nutrition Literacy Questionnaire 
Intervention Evaluation 
6 months  
Exit Questionnaire  
Tissue, metabolic analyses 
Routine chemistries, blood 
0, 3, 6 
months 
Metabolic Panel (LabCorp) 
Function, body composition 
SPPB (6, 64, 66) 
0, 3, 6 
months 
Balance (side-by-side, semi-tandem, tandem), gait speed 
(4-meter timed walk), strength (chair stands).  
6-minute walk test (aerobic 
endurance) 
0, 3, 6 
months 
As many walking laps as possible in six minutes between 
cones placed 40 meters apart 
8-ft Up and Go: (agility/dynamic 
balance) 
0, 3, 6 
months 
Begins seated. On word ‘go’ stands, walks around a cone 8 
feet away, returns to seated.  
30 second chair stands: (lower 
body strength) 
0, 3, 6 
months 
With arms across chest, stand up completely, returns to 
seated as many times as possible in 30 seconds. 
Isokinetic knee extension peak 
torque (muscle strength) 
0, 3, 6 
months 
Knee extensor at 60°/s with a dynamometer (HUMAC 
NORM Isokinetic Extremity System). Average peak torque 
for three trials will be recorded. 
Computerized axial tomography 
(CT) scan 
0, 3, 6 
months 
Cross sectional area of the thigh without contrast to 
determine muscle mass.  
Isometric hand grip 
(upper body strength) 
0, 3, 6 
months 
Jamar Hand Dynamometer (Sammons Preston Rolyan). 
Highest of two trials/hand. 
Minimal waist circumference 
0, 3, 6 
months 
At smallest horizontal circumference above umbilicus and 
below xiphoid process.  
Body Composition: BodPod 
0, 3, 6 
months 
Air displacement plethysmography method (Life 
Measurement, Inc., Concord, CA). The BodPod is has 
excellent sensitivity and test-to-test reliability, ease of use, 
and non-invasive nature, which is important for full 
participation from this population. 
Recent falls, fear of falling  
0, 3, 6 
months 
Fall Information Questionnaire 
Questionnaires 
Mini-Cog (64) 
Baseline 
Screens for cognitive impairment with minimal language 
content, reduces cultural and educational bias. A 3-item 
recall component plus a Clock Drawing Test. Score ≥3 for 
participant to be study eligibleif less than 3, confirm 
participant can conduct all ADLs). 
Quality of Life; Mood; 
Depression; Stress; Sleep; Life 
Satisfaction 
0, 3, 6  
months 
SF-36; POMS; CES-D; Perceived stress; Pittsburgh sleep; 
Frustration Discomfort; SWL 
Cognitive Testing 
Questionnaires 
0, 3, 6,  
months 
Symbol Digit Modalities; Grooved Pegboard; Hopkins 
Verbal Learning Test; Trail Making Test 
Cantab 
0, 3, 6 
months 
A battery of computerized tests, including: reaction time, 
paired associates learning, spatial working 
 
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Selection of Subjects 
Subjects will be obese (BMI ≥30 kg/m2) male Veterans aged 55 yrs and older, with mild to moderate functional 
impairment (Short Physical Performance Battery aggregate score of 4 to 11 units). Although the lower age 
limit is 55 years, there is no upper age limit and we expect the mean age of enrollees to be in the range of at 
least 65-70 years. We will enroll an equal number of black and white men in the study population. At the point 
of screening, race and ethnicity of potential participants will be ascertained using the categories specified in 
the OMB (Office of Management and Budget) Standards for the Classification of Federal Data on Race and 
Ethnicity. At screening, Veterans will be asked to self-identify as to ethnicity of Spanish/Hispanic/Latino (yes or 
no), and race of either Asian, American Indian/Alaska Native, Black or African American, White, or Native 
Hawaiian or Other Pacific Islander.   
memory, pattern recognition memory, delayed matching 
to sample, and rapid visual information processing will be 
administered using the CANTAB 
Inclusion Criteria  
• Male Veterans 
• African American or White 
• Obese (BMI ≥ 30 kg/m2) 
• Age > 55 years 
• Pre-diabetes (fasting plasma glucose ≥95 and <126 mg/dL or HbA1c 5.7-6.4%) 
o Will allow inclusion of HbA1c up to 6.9 if fasting plasma glucose is within pre-diabetes 
range  
o Will allow inclusion of fasting plasma glucose up to 140 if HbA1c is within pre-diabetes 
range  
• Age-normal renal function  
• English speaking 
• Able to record dietary intake or has a proxy who can record dietary intake   
• Willing and able to be randomized to either intervention group 
• Light smoking (Less than 10 cigarettes/day) 
Exclusion Criteria  
• Presence of unstable or symptomatic life-threatening illness. Glomerular filtration rates (GFR) less 
than 45 mL/min. A GFR of 45-59 requires bi-monthly testing per our established algorithm 50. Those 
with a GFR <45 mL/min are excluded. 
• Mini-Cog score of <3 and inability to conduct ADL’s. 
• Neurological conditions causing functional impairments, including Parkinson’s disease, multiple 
sclerosis, and permanent disability due to stroke. 
• Inability to complete physical function assessment.  
• History of significant weight instability or fluctuations.  
• Currently taking non-oral medications to control blood sugar and A1c (i.e. insulin). Oral glucose 
lowering medications will be allowed if stable dose and frequency over the last 3 months  
• Unwillingness to adhere to the diet structure of the study or following a diet that interferes with the 
diet structure of the study. Contraindicated medications, including narcotic mail-outs and active 
substance abuse. 
 
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To protect vulnerable populations or those subjects who may be susceptible to coercion or undue influence 
against, any Veteran who is approached by staff will be told that their participation is voluntary, and they may 
choose not to answer any questions that they find too sensitive. Also, Veterans will be told that their 
participation will not affect their care at the VA. The study staff member will explain the study in detail. No 
study procedures will begin until formal, written informed consent has been obtained.  
 
 
Study Interventions 
 
Caloric Prescription, Diet Monitoring and Exercise Intervention for Both Arms:  
All subjects will receive the same attention and support, meeting individually with an interventionist weekly 
for weeks 1-2. Individualized calorie prescriptions for a weight loss of ~1-2 pounds per week, calculated by a 
dietitian, are derived from estimated total energy expenditure (TEE) 51:                        
--TEE for OB men: 864 – (9.72 x Age [y]) + PA x (14.2 x Weight [kg] + 503 x Height [m]. 
The calorie level for a weight loss of ~1-2 pounds (average of 0.6 kg) per week will be calculated, generally a 
reduction of 500 to 1000 kcal/day. The intervention diet will be culturally tailored to meet the individual 
preferences of the target population and adapted to make sure low-income participants are able to afford the 
healthy foods in their diet plan. After 2 individual sessions, participants will continue to be submit their 
weights each week and attend weekly group sessions that provide a curriculum designed to enhance diet 
compliance 50; this includes group support, goal setting, self-monitoring, stress management, problem solving, 
and relapse prevention, daily diet journaling, email/phone reminders, and tutorials for on-line tools during the 
entire 6-month intervention.. (It should be noted that for participants enrolled after 10/1/2023, the study 
period will be 3 months instead of 6.) To insure a supportive weekly group size, we will wait to begin the 
intervention until the first cohort has at least 5 participants in each arm.  
Nutritional adequacy will not be compromised; protein intakes are adequate in both arms and the diet pattern 
will be rich in essential vitamins and minerals 52. Additionally, daily low dose multivitamin/mineral 
supplement, and calcium/vitamin D supplement will be provided, based on menu nutrient content and to 
achieve consistency (no other supplements permitted unless prescribed by physician). 
Physical activity and falls-prevention components of the intervention: Participants in both groups will attend a 
weekly session of safe, low intensity exercises to encourage safe progression to a more functional lifestyle, 
including individualized exercise prescriptions for those with military-acquired or other limitations. 
Instructions will be provided for safe repetition of the exercises at home on at least 2 more days per week. 
Additionally, weekly support group sessions will include training on falls reduction and safe ways to become 
more physically active. 
 
WL-Control Diet: 0.8 g protein per kg body weight. Participants will receive careful guidance for consuming 
only 15% of total calories from protein per day. Expressed another way, control participants will consume 
about ~0.8 g protein per kg body weight. Each week, participants will be provided 7 servings of whey protein 
• Any psychiatric condition that would prevent the subject from participating in a group intervention 
setting, including diagnosed personality disorders.  
• Primary care provider disapproves participation. 
 
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powder (15 g/serving) to support diet affordability and provided recipes for low calorie smoothies. The whey 
protein will be portioned by our research staff and delivered to the participants weekly on Duke’s campus. 
WL-Protein Diet: 1.4 g protein/kg body weight/day, >30 g of high-quality protein per meal. Subjects will 
receive careful guidance for evenly distributing >90 g high-quality protein between 3 meals plus snacks per 
day. Each meal includes >30 g high quality protein, provided directly to WL-Protein for two of three meals 
daily plus 1 snack, as lean red meats, whey protein, a high-protein milk-based, lactose-free beverage, and 
chicken. Twenty-one servings of high quality (30 g/serving) protein (lean red meats, whey protein, a high-
protein milk-based, lactose-free beverage, and chicken) will be provided to participants each week to increase 
compliance and enhance affordability. Weighed, individual servings will be chilled or frozen, and delivered to 
the participants at weekly group meetings in thermal bags. For those unable to transport the bags or using 
public transportation, delivery to the home will be arranged. The 30 g high quality protein for the third meal of 
the day will be per participant’s choice.  
Food record data analyses from previous studies indicates the WL-Control group will be consuming a typical 
American quantity/ distribution of protein (mean of 22 g per meal with range of 11-30 g), while the WL-
Protein group will be consuming the target intake of >30 g per meal.  
Supplemental Project Research Protocol: Feasibility and Acceptability of a Remote Obesity Intervention for 
Prediabetes: Improving Function on Older Veterans at high Risk During COVID-19 Isolation  
 
Background and Project Summary:  
Social isolation was recognized as a major threat to the health of older adults long before the Covid-19 
pandemic, with as many as one third reporting being isolated and feeling lonely.54,54 As the pandemic is 
predicted to persist throughout 2020, there is growing concern that long periods of COVID-19 related isolation 
will foster negative physical and mental health outcomes and speed the progression of physical frailty.55  
Building upon our preliminary findings (described below) and evidence from a large body of established 
literature on social isolation, we characterized (Table 1) some of the most important risks being faced by our 
older Veterans and explored opportunities to use remote interventions to reduce obesity and restore their 
physical function despite their need to isolate.56 The proposed research takes the next step by exploring the 
feasibility, acceptability, and effectiveness 
of our remote intervention in Veterans who 
are at especially high risk of further 
functional decline due to isolation. In our 
preliminary surveys, we identified “high risk 
characteristics” that may lead to greater 
social isolation. Using the same target 
population in the parent trial, we will 
specifically recruit and enroll Veterans 
meeting these age and COVID-19 related social isolation risk factors in addition to the parent trial inclusion 
criteria. As explained in the Aims section, the feasibility and acceptability of the intervention for this cohort 
will be determined, as will the successful attributes and time demands of the specialized attention they will 
require from interventionists. Pilot data on the effectiveness of the Protein treatment relative to the Control 
for restoring physical function in this population will also be acquired. 
Specific aims: 
 
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Aim 1: To evaluate the feasibility (recruitment and retention) and acceptability (participant satisfaction) of a 
virtual diet and exercise obesity intervention in Veterans at higher risk for negative physical and mental health 
outcomes during COVID-19 isolation.  
Aim 2: To determine the effect size for subsequent 
studies of virtual interventions for high risk obese older 
Veterans with physical function as the outcome of 
primary interest (virtual SPPB). Outcomes will also be 
collected for the secondary measures of weight loss, 
physical function, insulin resistance (Glycated 
Hemoglobin; Hb A1c), cognitive function, and quality of 
life.  
Exploratory Aim 3 (given restoration of full in-person 
clinical research testing visits):   
To determine the effect size for subsequent studies of virtual interventions for high risk obese older Veterans 
with regards to the primary outcome of (in-person) SPPB and the in-person secondary outcomes of insulin 
sensitivity and muscle quality (thigh CT scan, knee extensor peak torque).   
Achievement of this Aim would allow comparison of the high-risk participants to the participants that do not 
have 2 or more age and/or COVID-19 related social isolation risk factors (Table 2).   
 
Significance with regard to COVID-19 impact on Veterans: 
The COVID-19 pandemic and resulting social isolation is worsening health conditions in all older adults, 
including Veterans. Obesity is promoted by overeating due to increased stress and/or reduced access to 
healthy food options. In our recent recruitments for obesity trials, many of our participants are reporting 
experiencing a marked weight gain since the pandemic came to our community. Deterioration of physical 
fitness and function are also being documented.57 In addition to exacerbating chronic conditions like type 2 
diabetes and hypertension, obesity increases the risk of serious complications and death if a COVID-19 
infection occurs. There is a critical and time-dependent need to develop strategies to reverse the trend 
towards obesity-related physical frailty in our vulnerable older Veterans. The proposed research can be 
initiated quickly because effective remote interventions have already been developed in the parent trial and 
are ready for use in this study. Another significant point is that the trial also enrolls a substantial proportion of 
African American Veterans, an important advantage because minority older adults are known to be more 
vulnerable to COVID-19 complications.58 
 
 
Study Design: High risk, obese, male Veterans with prediabetes and 
SPPB score of 4-11 (out of 12), aged >55 yrs will be randomized to a 
higher protein, calorie-restricted diet OR a calorie-restricted diet with 
RDA level protein in a 6-month trial (Fig. 2).  
 
Selection of Subjects: 
From the parent study, 42 participants will have 2 or more age and/or 
COVID-19 related social isolation risk factors (Table 2). These 
individuals will be randomized into the Parent study’s WL-Protein arm 
(n=21) or the WL-Control arm (n=21) 
  
 
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Randomization: The following variables will be blocked in this order: 1) Race (white versus black, 2) chronic 
health conditions (≥3 versus <3), and 3) physical function, SPPB score (≥8 versus <8). An equal number of 
participants will be randomized across the two arms to end up with N=42. 
 
Arm 1: High Risk Weight Loss Protein (HR-WL-Protein; n = 21 completers) 10% WL diet with 1.4g protein/kg 
body wt/day; ≥30g high quality protein per meal 
Arm 2: High Risk Weight Loss Control (HR-WL-Control; n = 21 completers) 10% WL diet with 0.8g protein/kg 
body wt/day 
 
Screening (Two-step process):  
Screening Visit Level 1: Confirm 2 or more high risk criteria (see Table 2), confirm BMI ≥30 kg/m2, confirm 
SPPB score of 4-11, confirm fasting plasma glucose ≥95 and <126 mg/dL, confirm Mini-Cog ≥3 (or ability to 
complete all ADL’s). 
Screening Visit Level 2: Routine blood and urine chemistries and confirm age-normal renal status.  
 
 
Aim 1:   
Feasibility: Recruitment, retention, and intervention resources (defined in detail below)  
Acceptability (6 months): participant satisfaction of intervention (defined in detail below)  
Aim 2: 
Physical Performance (0, 3, 6 months): Short Physical Performance Battery (SPPB) including three domains 
Balance (side-by-side, semi-tandem, tandem), gait speed (4-meter timed walk), and lower extremity strength 
(chair stands) 
Anthropometrics: Body weights and body composition using Bod-pod.   
Insulin Resistance: Glycated Hemoglobin (HbA1c), assessed in whole blood.  
Cognition Testing: (all virtual) CANTAB battery of tests--reaction time, paired associates learning, spatial 
working memory, pattern recognition memory, delayed matching to sample, and rapid visual information. 
Other tests are the Symbol Digit Modalities Test of global cognitive ability, the Hopkins Verbal Learning Test of 
verbal learning, recall, and recognition and the Trail Making Test (TMT) of psychomotor speed and executive 
function in which participants connect dots according to either number (part A) or alternating number/letter 
(part B) will be administered virtually as a timed, 2-part, test. 
Aim 3: 
Muscle Quality (0,3,6 months): the ratio of knee extensor peak torque (Nm) assessed using isokinetic 
dynamometer to thigh muscle area (cm2) assessed by using computed tomography 
 
 
2 Participants enrolled after 10/1/2023 will complete a shortened study period of 3 months. Their data will be collected at month 0 and 
month 3, as outlined in this table. Body weights will still be collected weekly and the Nutrition and Exit questionnaires will be 
conducted at 3 months. 
  
Measurement/Procedure 
Time 
Points2 
Method 
Diet/Intervention 
Body weight 
Weekly 
Same scale, light clothing and no shoes, measured to 
nearest 0.1 kg 
 
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3-day diet record;  
Daily food journal (Adherence) 
0, 3, 6, 
months 
3-day diet record by multiple pass; analyzed Food 
Processor (Version 10.13, 2013; ESHA Research); Daily food 
journal assessed by RD 
Protein checklist 
Monthly 
RedCap analysis  
Actigraph, Axis accelerometer 
(activity counts, step counts, 
physical activity intensity) 
0, 3, 6 
months; 7 
days each 
time point 
Actigraph WGT3X-BT activity counts at 1-s epoch from 
three orthogonal axes at 30 Hz sampling frequency. We 
have been using Actigraphs in previous studies and 
therefore have not included in the budget.  
Nutrition Questionnaires 
0,  
Food Security Questionnaire 
Nutrition Questionnaires 
0, 6 months 
Nutrition Literacy Questionnaire 
Intervention Evaluation 
6 months  
Exit Questionnaire  
Tissue, metabolic analyses 
Routine chemistries, blood 
0, 3, 6 
months 
Metabolic Panel (LabCorp) 
Function, body composition 
SPPB (6, 64, 66) 
0, 3, 6 
months 
Balance (side-by-side, semi-tandem, tandem), gait speed 
(4-meter timed walk), strength (chair stands).  
Virtual SPPB  
0, 3, 6 
months 
Balance (side-by-side, semi-tandem, tandem), gait speed 
(4-meter timed walk), strength (chair stands). All 
assessments administered virtually. 
6-minute walk test (aerobic 
endurance) 
0, 3, 6 
months 
As many walking laps as possible in six minutes between 
cones placed 40 meters apart 
8-ft Up and Go: (agility/dynamic 
balance) 
0, 3, 6 
months 
Begins seated. On word ‘go’ stands, walks around a cone 8 
feet away, returns to seated.  
30 second chair stands: (lower 
body strength) 
0, 3, 6 
months 
With arms across chest, stand up completely, returns to 
seated as many times as possible in 30 seconds. 
Isokinetic knee extension peak 
torque (muscle strength) 
0, 3, 6 
months 
Knee extensor at 60°/s with a dynamometer (HUMAC 
NORM Isokinetic Extremity System). Average peak torque 
for three trials will be recorded. 
Computerized axial tomography 
(CT) scan 
0, 3, 6 
months 
Cross sectional area of the thigh without contrast to 
determine muscle mass.  
Isometric hand grip 
(upper body strength) 
0, 3, 6 
months 
Jamar Hand Dynamometer (Sammons Preston Rolyan). 
Highest of two trials/hand. 
Minimal waist circumference 
0, 3, 6 
months 
At smallest horizontal circumference above umbilicus and 
below xiphoid process.  
Body Composition: BodPod 
0, 3, 6 
months 
Air displacement plethysmography method (Life 
Measurement, Inc., Concord, CA). The BodPod is has 
excellent sensitivity and test-to-test reliability, ease of use, 
and non-invasive nature, which is important for full 
participation from this population. 
Recent falls, fear of falling  
0, 3, 6 
months 
Fall Information Questionnaire 
Questionnaires 
Mini-Cog (64) 
Baseline 
Screens for cognitive impairment with minimal language 
content, reduces cultural and educational bias. A 3-item 
recall component plus a Clock Drawing Test. Score ≥3 for 
 
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Intervention for High Risk Veterans: 
A weight loss of 10% 3is targeted for 
both groups; all will participate in 
nutrition and exercise group sessions 
delivered remotely by registered 
dietitian interventionists. To combat 
the impact of age and COVID-19 
isolation and the requirement of the 
intervention to be delivered remotely 
due to COVID-19, tools and strategies 
will be implemented to reduce 
barriers of participating in the obesity 
reduction intervention. Table 3 
outlines example interventions that 
will be incorporated and documented 
for usefulness and time demands. These components will complement intervention tools already in the parent 
study and will be utilized when needed to assist all participants (both high risk and non-high risk) in adherence 
to the weight loss intervention.    
 
Subject Recruitment 
This study will utilize a Request for HIPAA waiver of Authorization and waiver or alteration of informed 
consent process to identify potential participants for this research study. Each year of the study we will use 
the VA Informatics and Computing Infrastructure (VINCI) to conduct a query to identify Veterans seen at the 
Durham VAMC in the past year who were age > 55 yrs, were obese (BMI ≥30 kg/m2), and had prediabetes 
identified by either a HbA1c between 5.7 and 6.4 % or a fasting blood glucose of ≥95 to <126 mg/dl. We will 
also work with the MOVE program coordinator, Katherine Catolico, and the Diabetes Management Clinic at 
the VA, to recruit patients who fit the above description. Finally, we will conduct face to face recruitment at 
VA organizations within the community and local libraries. We will also provide flyers to various VA clinics for 
providers and clinic staff to share with veterans. Potential clinics include primary care and specialty clinics at 
the Durham VA, Hillandale, Raleigh and Wake County, and Clayton clinics.  
 
3 Participants enrolled after 10/1/2023 will have a goal of 5-10% reduction in body weight due to the shortened study period.  
participant to be study eligible (if less than 3, confirm 
participant can conduct all ADLs). 
Quality of Life; Mood; 
Depression; Stress; Sleep; Life 
Satisfaction 
0, 3, 6  
months 
SF-36; POMS; CES-D; Perceived stress; Pittsburgh sleep; 
Frustration Discomfort; SWL  
Cognitive Testing 
Questionnaires 
0, 3, 6  
months 
Symbol Digit Modalities; Grooved Pegboard; Hopkins 
Verbal Learning Test; Trail Making Test 
Cantab 
0, 3, 6 
months 
A battery of computerized tests, including: reaction time, 
paired associates learning, spatial working 
memory, pattern recognition memory, delayed matching 
to sample, and rapid visual information processing will be 
administered using the CANTAB 
 
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We will contact Veterans who meet inclusion criteria by mail via a recruitment letter signed by the PI that 
describes the study and emphasizes eligibility based on the fact that their prediabetes increases their risk for 
developing type 2 diabetes. In the letter, potential participants will call our office number and will be given an 
opportunity to “opt-out” and decline participation and/or further contact regarding participation. Five 
business days after the mailing, Veterans who have not called the study number to decline participation will 
be called by a study staff member to request their participation in the research study (see telephone screen 
script). Following a script, the recruiter will describe the study, query about potential exclusions and assess 
overall interest in participation. Interested and eligible subjects will then be scheduled for their first screening 
visit. 
 
Additional recruitment methods include the advertisement of the study via third parties, including Facebook 
or Instagram, Craigslist, DukeList and Google ads. Advertisements will direct interested participants to contact 
the study team for more information about the study.  
 
Consent Process  
On the day of the consent meeting, potential participants will be presented a full description of the study 
measurements, the interventions, and the randomization process. The participant will be told that their 
participation is voluntary, and they may choose not to answer any questions that they find too sensitive. Also, 
Veterans will be told that their participation will not affect their care at the VA. The study staff member will 
explain the study in detail. The participant will be given as long as they need to read through the consent form 
and HIPAA Authorization. Study staff will answer all questions and concerns. No study procedures will begin 
until formal, written informed consent has been obtained. This visit will determine if a participant is eligible to 
participate in the study. If a participant does not qualify, they will be given a letter indicating the reason of 
disqualification, and other resources/ programs for which they may qualify based on their condition. This visit 
will take place at the Duke Center for Living and will last approximately 90 minutes. 
 
Adverse Events 
All adverse events will be reported per Durham VAMC requirements. Given that the study population is older, 
somewhat functionally impaired and with metabolic risk factors, and based on our prior experience with a 
similar (non-Veteran) population, we anticipate that we will have adverse events, including one or more 
serious adverse events during the study period but that these adverse events will not be associated with the 
intervention, which is low risk. The most likely adverse event relating to the intervention would be a minor 
musculoskeletal injury during the exercise class. We will work to prevent this with close supervision by a 
trained exercise instructor and providing safety guidelines for when exercising at home. All Serious, 
Unanticipated and Related adverse events will be reported to the IRB within 5 business days of hearing of the 
event. All other adverse events will be reported at continuing review. 
 
Costs and/or Payments to Subjects 
Study participants in both arms may receive up to $325 for full participation in the study. Payment information 
is provided in the informed consent document. The study involves three time points; compensation will be 
$75 for completing Baseline Visits, $100 for Midpoint Visits and $125 for Endpoint Visits). Participants 
enrolling after 10/1/2023 may receive up to $200 for participation due to the shortened study period. 
Participants may receive compensation for travel, or food support if determined by the PI. Participants who do 
not qualify at screening will still receive $25 for participating. Payment will be issued to participants via a 
direct deposit or check. 
 
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Risk/Benefit Assessment 
The risk to human subjects for participation in this study is minimal compared to the potential health benefits 
they will receive from participating in the interventions and receiving detailed health, diet and body 
composition evaluations. The study is carefully designed for safety. Our study staff is carefully trained and has 
experience in implementing nutrition intervention in older, frail populations. They also have the expertise to 
safely conduct physical function measures. Furthermore, the study physician, Dr. Shelley McDonald, will 
always be “on page”; she and another physician co-investigator will be available as needed for consultation 
regarding medical concerns related to study participation. The low intensity chair exercises are carefully 
guided to improve strength, flexibility and balance, and the weight reduction diet is mildly restrictive, leading 
to a very safe, gradual rate of weight loss. Workbooks provided at the beginning of the study will include a 
listing of warning signs with instructions should injury or other health problems occur. Participants will be 
provided contact information for Dr. Bales and all study team members and encouraged to communicate with 
them about any concerns regarding the nutrition supplement or any other aspects of the study. All reported 
events will be recorded in the adverse event log (including the subject’s name, date, and event description) 
and the PI, mentor team, and data safety monitoring board will be notified. All health occurrences will be 
recorded and regularly reviewed by the study staff and reported to VA IRB according to IRB guidelines. The 
expected average weight loss will be 1-2 pounds per week.  In addition, weight loss will be carefully monitored 
in each subject by a licensed, board certified Registered Dietitian clinician. The increased protein in the protein 
supplementation arm will not exceed safe limits for total intake and has been studied extensively in older 
adults with no adverse effects.  Additionally, we will use screening blood testing to exclude from enrollment 
subjects with GFR <45. Phlebotomy carries minimal risk of infection and temporary pain. The CT-scan is the 
method of choice for the muscle quality measure because of the very low radiation dose (less than 10 mSv per 
scan) and the ease of undergoing the measurement.  
 
A number of potential health benefits that may accrue to participants and important scientific knowledge will 
likely result from this work. Subjects will receive a weight loss intervention that is very likely to produce a 
modest but metabolically beneficial amount of weight loss and an exercise intervention that will help them be 
more physically active. Furthermore, we expect that participants will achieve substantial life-style 
modifications that could be sustained as a part of their personal health regimen in the setting of their 
community environment.  Information collected from this study will benefit others through a greater 
understanding of how to best maintain muscle function and improve insulin sensitivity while reducing obesity 
in the older population. 
 
Data and Safety Monitoring 
The individuals responsible for data safety and monitoring will be the PI, the Registered Dietitian, the project 
coordinator, and the study Co-Investigators (Drs. Starr, McDonald, Huffman, and Pieper). Further data safety 
and monitoring will be provided by the PI. There will be several ongoing mechanisms for monitoring and 
reporting of adverse events: 1) ongoing participant contact via study personnel, 2) study telephone number 
provided to participants to report concerns related to study participation; and 3) weekly meetings between 
the PI and study personnel.   
 
In addition, an internal data safety advisory group will be established to monitor the study and assure that 
subject safety and confidentiality is being protected. This group will receive annual reports on subject 
enrollment and regular reports of any adverse events that occur. They will meet with Drs. Bales, Starr, 
McDonald, Huffman, and Pieper on an annual basis for review of study progress and results. The advisory 
 
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group will review clinical events to identify any excess event rate in the study population over that expected 
based upon historical experience. Based on our extensive previous experience, we have already established 
safety limits for an interim measure of renal function (GFR drops below 45) that could result in temporary or 
permanent discontinuation of individual subjects in the unlikely event that these limits are exceeded. 
 
The PI will meet at least weekly with study personnel to discuss participants’ reactions to outcome measures 
and assessments, weekly telephone calls, and any adverse events or unanticipated problems. Monthly 
meetings between the investigators and the project coordinator will allow for ongoing progress reports, 
including the number of participants currently involved in the study and scheduled data collection from 
participants, as well as notification and review of any AEs. Safety monitoring for adverse events (AEs) will be 
conducted in real time by the PI and/or project coordinator. The following information about adverse events 
will be collected: 1) the onset and resolution of the AE, 2) an assessment of the severity or intensity (use 
existing grading scales whenever possible), 3) an assessment of the relationship of the event to the study 
(definitely, probably, possibly or not related), and 4) action taken (e.g., none, referral to physician, start or 
increase concomitant medication). The PI will determine the severity of the event, will assign attribution to 
the event, and will monitor the event until its resolution. All adverse events will be reported per Durham 
VAMC requirements. All Serious, Unanticipated and Related adverse events will be reported to IRB within 5 
business days of hearing of the event. All other adverse events will be reported at continuing review.  
 
Withdrawal of Participants 
If a participant decides to withdraw from the study, they will be instructed to contact the PI and discuss the 
reason for withdrawal. This information will be documented to help better understand the reasons that the 
participant was unable to complete the study.  
 
Data Analysis and Statistical Considerations 
 
Data management and quality control:  We will employ REDCap (Research Electronic Data Capture) hosted 
within VIREC for data entry. Key components of this activity include data entry screen programming and 
database testing and validation. The database will include study default parameters and ranges for database, 
protocols, users, and access rights. Access and data entry to the database will be controlled by login 
permissions, and the database will be backed up daily, with full backups occurring weekly, and quarterly 
backups retained for perpetuity. The database will be routinely checked for data integrity and quality. In 
addition, since some data will require direct download from computerized databases (e.g. VA patient 
information, lab findings) a final relational database will be built to be used for analysis in SAS, combining data 
from all data sources. This process will include quality control, developing an appropriate query, validation, 
and justification procedures, auditing, developing a manual of procedures and documentation, interim 
reporting of data flow, and maintaining security and patient confidentiality of the data base. The analysis 
database derived from this source data will be de-identified. Identifying information will be viewed and 
managed only by the data manager and appropriately consented data collection staff.   
 
Quality control procedures will be established for each component of the study. At each level of data 
management, and for each subject contact, strict adherence to VHA policy will be observed regarding HIPAA, 
IRB and other VHA patient quality controls. These procedures include not identifying any patient or provider 
on any of the reports generated from this study. All computer files will be password protected. Files containing 
names and addresses will have a separate password, will be accessible only to personnel who need to contact 
the subjects, and will be stored separately. Ultimately, a de-identified file appropriate for analysis will be 
 
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produced for report generation and analysis. All analysis and data management personnel are current with all 
VA mandated security training.  
 
Analysis Plan for the parent protocol (Aims 1 and 2):  
This design is a two-armed clinical trial, with replicate measures at three time points: baseline, three, and six 
months. Since subjects are randomized to either WL-Control or WL-Protein arm, and the groups are presumed 
equal at baseline, the analysis is straightforward. Following the Good Clinical Practice Guidelines for the 
analysis of a clinical trial, we will employ mixed models, analyze under an Intent to Treat (ITT) criteria, and 
control for baseline and assess the impact of Time, Treatment Group and the interaction of these variables on 
the outcomes. Relative to the usual repeated measures designs, mixed models have several advantages: 1) 
missing values present no particular difficulties in estimation and the estimates are unbiased as long as the set 
of variables leading to MAR are estimated, 2) the usual assumption of conditional independence (compound 
symmetry) used in standard repeated measures need not be made, and 3) the actual times of measurement 
need not be equivalent across subjects. Controlling for the individual baseline values for the particular 
outcomes, the trajectories over time and differences in those trajectories will be assessed. Following the 
statistical principles section from the International Conference on Harmonization, we will select covariates 
(e.g., age, race, number of comorbidities) for the primary models a priori, but we also will conduct auxiliary 
sensitivity analyses that evaluate whether potential group imbalances bias the treatment effect estimate. 
These analyses will be performed using conventional testing for confounding. We note that we have listed 
numerous measures to be analyzed as outcomes, but have listed only 1 primary outcome (physical function, 
Aim 1).  
     For any particular outcome, the general form of the model will be: 
Yit = β0+ β 1(group) + β 2(timet) + β 3(group*timet) + β 4(covariates) + εit 
Where i is an indicator of person, and time is defined as t=1, 2 (measuring month 3, and 6), and the β’s are 
regression coefficients connecting the predictors to the outcome. For brevity, we list β4 as a vector of K 
regression coefficients linking the K covariates to the outcome. As defined, the overall test of the intervention 
effect will be the joint effect of group and group*time on 2 df (β1 and β2) assessing an overall effect of group, 
and if this group effect is constant over time. If significant, follow-up tests will assess where group differences 
lie. In particular, we note that if the time by group interaction is rejected, we will test if the groups differ at the 
end of 6 months (a test of effect at the completion of the intervention). We will carefully examine model 
assumptions, including the distribution of model residuals, additively, linearity, and influential observations, 
and will, if necessary, re-parameterize the models or transform the outcomes accordingly. 
     In addition to the impact of the intervention on the secondary outcomes, we will assess mediation of the 
group effect on the primary outcome by demographic, comorbid and adherence variables. Subjects may differ 
in their process of change depending on baseline demographic and functional status values. Second, we will 
assess the functional form of the change over time, by looking at non-linear functions of change. For example, 
change in function and performance is likely to be non-linear, initially changing quickly and leveling at points 
distal from baseline. It would be important to note if this change differed by group. Finally, we will assess 
whether the trajectories of change, irrespective of group assignment, are similar for individuals. In this 
application, we have listed several variables, which we expect to change as result of the intervention. We 
further hypothesize that all these variables will change in the same pattern. To test this hypothesis, across the 
range of outcome measures, we can look at overall change through the use of multivariate tests (Boc59 or 
Anderson60) for the singly measured functional items, and by assessment of correlated trajectories for those 
outcomes measured repeatedly. With appropriate weighting for number of observations per individuals, the 
correlation between individual trajectories can be assessed. A positive correlation between the trajectories for 
any two outcomes will indicate that the subjects changed similarly for the 2 outcomes, and will provide 
 
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additional support for the notion that the intervention had a generalized effect across the outcomes. 
Significant correlations would perhaps indicate mechanistic/causal linkage between variables over time, or, 
from a reliability standpoint, may indicate that the subsequent trial may want to employ summary measures 
aggregating across outcome measures, or, alternatively, employ multivariate tests across several outcomes to 
assess the group differences, reducing the chance of Type-I error inherent in the testing of multiple variables. 
We will not adjust for Type-I error rate for these secondary outcomes.  
 
Analysis Plan (Aim 3):  
Primary outcome data collected during the trial will be analyzed for differences due to race. Using the same 
analytic strategy listed in the analysis of Aims 1 and 2, race (B/W) will be included into the analytic structure 
for the physical function (SPPB) outcome, first as a main effect (mediating), and secondly, as an interaction 
(moderating) with group.  If the physical function change outcome is normally distributed, we will employ, 2-
way ANCOVA, with race and group serving as factors, and controlling for baseline physical function. While our 
working hypotheses are directional, our tests will be two-tailed. If physical function is not distributed 
approximately normal, we will attempt to assess the outcome using appropriate transformations, or 
bootstrapping simulations61. We are aware race and compliance may be partially confounded. As a final 
sensitivity analysis, we will assess if any observed relationships are mediated by compliance with the protocol.               
Next secondary outcomes data collected will be used to test the hypotheses about racial differences. 
Preliminarily, we will assess if the distributional assumptions of the outcomes of the ANCOVA model are met.  
If not, we will attempt to delimit an appropriate transformation, or employ bootstrapping.  To assess the racial 
effects, the change of these outcomes by intervention group and race will be assessed, controlling for the 
baseline levels.  Both the interactive (with group) and the main effects of race and group will be assessed. In 
addition, we will assess if the race effects are mediated by compliance. We will not control for the Type-I error 
rate inherent in multiple testing of multiple outcomes.  Rather, for any relationship declared statistically 
significant, the reader will be alerted to the preliminary nature of the findings, the multiple testing issues and 
the requirement for replication.  The results of these analyses will provide invaluable information regarding 
the process and functional forms and, potentially, the causal pathways of the intervention process. For 
example, one important analysis will enter 'level of compliance to the intervention' into the analysis, allowing 
for a 'per protocol' analysis of the results. 
 
Power Estimate: The sample size of n = 84 per group is based directly on our findings in the MEASUR-UP 
study, which used the same diet treatments, study population, and primary outcome as in the present Aim 1.  
In MEASUR-UP, the SPPB score for WL-Pro changed by +2.4 units over the course of the study, while the WL-
Control group experienced an increase of +0.9 units. The pooled standard deviation of these changes is 1.7. 
Thus, the MEASUR-UP study observed a standardized difference of 0.88 = (2.4 – 0.9)/1.7. Differences of this 
magnitude have been labeled as ‘large’ in the power analysis literature. Assuming equivalent effect sizes 
observed in the MEASUR-UP study, an overall sample size of 100 (evenly divided between groups), and a Type-
I error rate of 0.05 (two tailed), the power of our design is greater than 99% to declare significance for the 
effect size observed in the pilot. At 80% power, this design is powered to detect a difference in change scores 
in the SPPB of 0.96, or a standardized difference of 0.57. 
 
 
Analysis Plan for the supplemental protocol:  
Aim 1: Feasibility-Recruitment capability: Proportion of participants recruited will be calculated as the number 
of participants deemed potentially eligible and contacted for enrollment divided by the total number of 
 
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participants enrolled. Feasibility of recruitment hypothesis: ≥35% of participants approached for recruitment 
will agree to participate 
Feasibility-Retention: Retention proportion retention will be computed by dividing the number of retained 
subjects at the end of the intervention by the total number randomized into the study. 
Retention hypothesis: ≥80% of participants will remain in the study for the duration of the trial 
We will calculate the rate of retention and its respective confidence intervals overall and by group. While non-
powerful, we will assess if these rates differ by chi-square test of proportion and Poisson regression 
respectively. In a series of sensitivity tests, we will assess if retention overall was impacted by demographic 
and high risk variables. 
Feasibility-Intervention Tools: Records of intervention tools and time spent to administer them will be used 
for post-study analysis of intervention tool effectiveness.   
Acceptability-Satisfaction: participant satisfaction of intervention delivery, overall experience, and outcomes 
will be assessed using a Likert scale and open-ended questions.  
Aim 2 and 3: This design is a two-armed feasibility trial, with replicate measures at three time points: baseline, 
three, and six months. Since subjects are randomized to either HR-WL-Protein or HR-WL-Control, and the 
groups are presumed equal at baseline, we will employ mixed models, analyze under an Intent to Treat (ITT) 
criteria, and control for baseline and assess the impact of Time, Treatment Group and the interaction of these 
variables on the outcomes. Controlling for the individual baseline values for the particular outcomes, the 
trajectories over time and differences in those trajectories will be assessed. Following the statistical principles 
section from the International Conference on Harmonization, we will select covariates (e.g., age, race, number 
of comorbidities) for the primary models a priori, but we also will conduct auxiliary sensitivity analyses that 
evaluate whether potential group imbalances bias the treatment effect estimate. These analyses will be 
performed using conventional testing for confounding. As defined, the overall test of the intervention effect 
will be the joint effect of group and group*time on 2 df assessing an overall effect of group, and if this group 
effect is constant over time. If significant, follow-up tests will assess where group differences lie. In particular, 
we note that if the time by group interaction is rejected, we will test if the groups differ at the end of 6 
months (a test of effect at the completion of the intervention). We will carefully examine model assumptions, 
including the distribution of model residuals, additively, linearity, and influential observations, and will, if 
necessary, re-parameterize the models or transform the outcomes accordingly. 
 
 
Privacy, Confidentiality, and Information Security 
Lists of Data Reviewed and/or Collected for Screening/Recruitment and Conduction of Study:  
• Demographics: age, race, gender, weight, height, marital status, education, employment status, living 
arrangements, socioeconomic and smoking status 
• Diagnosis of pre-diabetes  
• Mini Cog 
• Hand-grip strength 
• Weight 
• Height  
• Physical Function – Short physical performance battery, 6-minute walk, 30 second chair stand, 8 foot 
up and go 
• Physical activity – Actigraph and wear log 
• CT-scan of the thigh  
 
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• Isokenetic knee extensor peak torque  
• Three-day food record 
• Protein checklist 
• Nutrition Literacy Questionnaire 
• Food Security Questionnaire 
• Intervention Evaluation Questionnaire 
• 24-hour dietary recall 
• Biological Markers – routing chemistries, HgA1C, GFR, and fasting glucose 
• Quality of life questionnaires –  SF-36, POMS, CES-D, Perceived Stress Scale, and the Pittsburgh Sleep 
Questionnaire, Trial Marking Test, Frustration Discomfort Scale, SWL, Hopkins Verbal Learning Test, 
Symbol Digital Modalities Form, Grooved Pegboard, and Cantab.   
• Body Composition – BodPod  
• Waist circumference measures 
• Medical History Questionnaire 
 
 
 
 
 
The Personal Health Information that will be obtained, used, and/or shared for this study includes:   
 
Identifier(s) 
Source(s) of Health Information 
 Names 
 Medical history & physical exam 
information 
 All geographic subdivisions smaller than a 
State, including street address, city, county, 
precinct, and zip code.  Describe: Address of 
participants will be collected 
 Photographs, videotapes, audiotapes, or 
digital or other images 
 All elements of dates (except year) for 
dates directly related to an individual, 
including birth date, admission date, discharge 
date, visit or treatment dates, etc.; and all ages 
over 89,  Describe:  Dates to be collected 
include date of birth and date of visits. 
 Biologic specimens (e.g., blood, tissue, 
urine, saliva). Describe: plasma will be 
collected at all times points for routine 
chemistries (HgA1C, GFR, and fasting 
glucose). 
 Telephone numbers 
 Progress notes 
 Fax numbers 
 Diagnostic / Laboratory test results 
 Electronic mail addresses 
Operative reports 
 Social Security Numbers 
 Imaging (x-ray, CT, MRI, etc.) 
 Medical record numbers 
 Discharge summaries 
 Health plan beneficiary numbers 
 Survey / Questionnaire responses 
 Account numbers 
 Billing records 
 Certificate and/or license numbers  
 HIV testing or infection records 
 
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Identifier(s) 
Source(s) of Health Information 
 Vehicle identifiers and serial numbers, 
including license plate numbers  
 Sickle cell anemia information 
 Device identifiers and serial numbers 
 Alcoholism or alcohol use information 
 Web Universal Resource Locators (URLs) 
 Drug abuse information 
 Internet Protocol (IP) address numbers 
 Mental health (not psychotherapy) 
notes 
 Biometric identifiers, including finger & 
voice prints 
 Psychological test results 
 Full-face photographic images and any 
comparable images 
 Genetic testing 
 Any other unique identifying number, 
linked study ID, characteristic, or code, 
describe:  a unique study ID will be assigned to 
each participant. 
 Other, describe:  Questionnaires 
include: Mini-Cog, SF-36, POMS, CES-D, 
Perceived Stress Scale, and the Pittsburgh 
Sleep Questionnaire, Frustration 
Discomfort, SWL. Three-day food records 
and protein checklists will be collected.  
Functional assessment, Short Physical 
Performance Battery, Isokenetic knee 
extensor peak torque, 6-minute walk, 30 
second chair stand, 8-foot up and go. 
Cognitive testing: Symbol Digit Modalities; 
Hopkins Verbal Learning Test; Trail Making 
Test; CANTAB.  
 
Several types of data will be collected over the course of the study. As described under the Request for Waiver 
or Alteration of Informed Consent and Waiver of HIPAA Authorization for Research, PHI to be collected during 
recruitment activities includes name, age, medical history, address, telephone number, social security 
number, date of birth, HbA1c, fasting blood glucose, and history of alcoholism or drug abuse. Other data to be 
collected over the course of the study (as described in the HIPAA authorization) include name; address; phone 
number; social security number; Physical Function; Physical activity; Three-day food record; Protein checklist; 
muscle quality (isokinetic knee extension peak torque and CT-scan of the thigh); hand-grip strength, body 
composition; quality of life and cognitive status; cognitive testing; Biological Markers including plasma for 
HgA1c, fasting blood glucose, and GFR, and account numbers (for Veterans who have bank accounts, payment 
will be issued via direct deposit, which requires a Vendorizing Coversheet that asks for account information 
and VA Form 10-7078 to be obtained). Additionally, a unique study ID will be assigned to each participant. 
Sources of health information include medical history and physical exam information, progress notes in CPRS, 
laboratory test results, survey responses, dietary intake including food and beverages and mental health 
notes. This information will be used for research purposes only.  
 
1. Data and/or Specimen Acquisition:   
Data for this study will be collected through (check all that apply): 
  Prospective data and/or specimen collection obtained from participants.  Provide description of 
processes: Potential participants identified will be sent an introductory letter signed by the PI that describes 
the study and informs them that they will be called regarding participation. In the letter, potential participants 
 
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will be given an “opt-out” number to call in order to decline participation and/or further contact regarding 
participation. Five business days after the mailing, Veterans who have not called the study number to decline 
participation will be called by a study staff member to request their participation in the research study (see 
telephone screen script). In the telephone contact, the study staff member will inform the Veteran that he/she 
was selected for recruitment because he/she is an older Veteran who is obese and has met the criteria for 
prediabetes on a recent screening.  
Any Veteran who contacts or is contacted by study staff will be told that their participation is voluntary, and 
they may choose not to answer any questions that they find too sensitive. Also, Veterans will be told that their 
participation will not affect their care at the VA. The study staff member will explain the study in detail, 
including compensation. No study procedures will begin until formal, written informed consent has been 
obtained. Participants will come to the Duke Center for Living and will be consented for study participation. 
Following consent, participants will be screened for pre-diabetes (fasting blood draw). Participants who qualify 
as being pre-diabetic and meet other eligibility criteria will return to the Center for Living to complete the 
remaining assessments (function, body composition, quality of life, dietary intake, isokinetic knee extensor 
peak torque (Cybex)). Finally, on a third visit they will report to Durham VAMC radiology for a CT-Scan.  These 
assessments will be completed again at the 3-month midpoint and 6-month endpoint.  
 
  Retrospective data collection and/or specimens obtained from medical chart review/data access.  
Describe how data will be obtained (e.g., fileman, CDW, etc.):  
 
  Retrospective data collection and/or specimens obtained from an IRB-approved data and/or specimen 
repository.  Indicate the repository source including name, VA location, and IRB number:       . 
Note:  for data and/or specimens obtained from a VA approved data repository, a Data Use Agreement (DUA) 
must be executed prior to obtaining data and/or specimens.  See VHA Handbook 1200.12 for further 
information. 
2. Level of Data:   
The following level(s) of data will be acquired/maintained for this study (check all that apply): 
  Identified (e.g., names, addresses or other identifiers included)  
  Coded (direct and/or all identifiers removed, but study code/ID included)  
  De-Identified (all HIPAA 18 and study ID/code removed): 
  Verified Statistically  
 
OR 
  Verified by Absence or Removal of HIPAA 18 and study ID  
  Limited Data Set 
  Other: Describe:        
 
3. Location of Data and/or Specimens, and Data Retention Plan:   
A.  
Data and/or Specimen Location:  All PHI data will be stored on the VA server at S:\GRECC\Grecc 
Research\Bales\Valor Up that is encrypted, password-protected, and only accessible to Dr. Bales and her study 
staff. All hard copy data, including, but not limited to, consent form, HIPAA authorization form, and survey 
responses will be stored in a locked file cabinet in a locked office suite at the Duke Aging Center Nutrition 
Laboratory, Room 00505. Data will be entered using VPN access by the VA Research team. 
 
The study team will employ REDCap (Research Electronic Data Capture) hosted within VIREC for data entry. 
Key components of this activity include data entry screen programming and database testing and validation. 
 
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The database will include study default parameters and ranges for database, protocols, users, and access 
rights. Access and data entry to the database will be controlled by login permissions, and the database will be 
backed up daily, with full backups occurring weekly, and quarterly backups retained for perpetuity. 
 
A second excel spreadsheet database will be created to electronically track participants through all 
components of the study including screening. This tracking will contain identifiable data, including the key that 
links participants to study identification numbers; other data collected in the course of the study will be kept 
separately from identifying information. This database will be stored on the VA server S:\GRECC\Grecc 
Research\Bales\Valor UP.  that is encrypted, password-protected, and only accessible to Dr. Bales and her 
study staff. 
 
 
Plasma specimens will be stored in the -80 degree freezer at the Duke Center for Living.  Specimens, as 
outlined above, will be coded when stored.  
 
  Data will be also be placed at the VA Informatics and Computing Interface (VINCI; 
http://vaww.vinci.med.va.gov/vincicentral/VINCIWorkspace.aspx). The VA Informatics and Computing 
Infrastructure is a partnership between the VA Office of Information Technology and the Veterans’ Health 
Administration Office of Research and Development. Researchers and operations staff can use VINCI to access 
data and statistical analysis tools in a virtual working environment through a certified VHA network computer 
using the VA Intranet or Virtual Private Network (VPN).  
B. Data Retention Plan 
 Research records will be maintained and destroyed according to the National Archives and Records 
Administration, Records Schedule Number:  DAA-0015-2015-0004.  Records destruction, when authorized, will 
be accomplished using the then current requirements for the secure disposal of paper and electronic records.  
Currently, destruction of research records (see DAA-0015-2015-0004, section 7.6 “Research Investigator Files” 
for materials included in research records) is scheduled for 6 years after the cut-off (the cut-off is the 
completion of the research project) and may be retained longer if required by other federal agencies.  Records 
will not be destroyed without pre-notification to the facility records manager.   
  Other data retention plan, describe:        
4. Data Access and Data Recipients: Only members of our DVAMC research team will have access to 
identifiers and coded data. Our statistician, Carl Pieper will have access to the de-identified data.  
All VA research personnel who have access to VHA records are instructed, in accordance with VA policy, on 
the requirements of Federal privacy and information laws and regulations, VA regulations and policies, and 
VHA policy. All study personnel who are VA employees working within the VA system have fulfilled all 
required HIPAA and other VA security and privacy policy training requirements and have agreed to follow 
guidelines pertaining to the protection of patient data. All research staff sign VA Rules of Behavior, and all 
study staff are up-to-date with VHA Privacy Policy Training and the VA Office of Cyber and Information 
Security Awareness Training Course. The data security and privacy procedures summarized in that course 
include logging off or locking the computer when walking away from it; no sharing of access codes, verify 
codes or passwords; not allowing anyone else to use the computer under one’s password; and disposing of 
sensitive information using VA-approved methods (e.g., shredder bins). 
Access to study data will be removed for all study personnel when they are no longer part of the research 
team.  
 
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5. Data and/or Specimen Transportation and/or Transmission for all data and/or specimens involved in the 
study:   
  
I. 
  Data and/or specimens will not be transported or transmitted outside of Durham VAMC 
environment. 
II. 
  Data and/or specimens will be transported BETWEEN sites that are under the auspices of the 
Durham VA Medical Center.   
III. 
   Data and/or specimens will be transmitted to other VA sites using the following method(s): 
A. Data 
  Data are de-identified and thus will be sent via unencrypted e-mail or unencrypted disk 
(encryption is optional). 
  Data are coded or contain identifiers and thus will be sent 
  Other, describe:        
B. Specimens 
  Specimens are de-identified and thus will be sent via standard carrier (tracking is optional). 
  Specimens are coded or contain identifiers and thus will be sent via VA-authorized carrier with 
tracking.   
  Other, describe:        
IV. 
  Data and/or specimens will be transported to non-VA/VHA sites (e.g., academic affiliates, 
laboratories, etc.) using the following method(s): 
A. Data 
  Data are de-identified and thus will be sent via unencrypted e-mail or unencrypted CD. 
   Data are coded or contain identifiers and thus will be sent via FIPS 140-2 encrypted hard 
drive/flash drive using VA—approved carrier with tracking.   
   
  Data are coded or identified and will be uploaded to sponsor website using electronic case 
report form (eCRF)  
 Other, describe: Data will be stored at the Duke Aging Center Nutrition Laboratory. Data will 
only be transferred to the VA if the Durham Office of Research and Development deem it 
necessary. In this event, data will be transferred using a FIPS 140-2 encrypted hard drive/flash drive 
and walked over to the VA by a member of the research team 
B. Specimens 
  Specimens are de-identified and thus will be sent via standard carrier (tracking is optional) or 
will be hand-delivered by research study personnel. Specify method of delivery:        
  Specimens are coded and thus will be sent via VA-approved carrier with tracking or will be 
hand-delivered by research study personnel. Specify method of delivery:  Specimens will be 
analyzed through the Duke Molecular Physiology Institute. Co-Investigator, Dr. Kim Huffman, will 
oversee the transfer of specimens from the Duke Center for Living to the Duke Molecular 
Physiology Institute. Specimens will be hand-delivered by members of the research team.  
 Other, describe: Specimens will be stored at the Duke Center for Living in a secured building 
that requires badge access to enter.  
 
 
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In accordance with the HIPAA and the Privacy Act, for any coded or identifiable data or specimens released 
from the Durham VAMC (with the exception of Limited Data Sets), an Accounting of Disclosure (AOD) will be 
maintained (e.g., in a database or spreadsheet) that includes the participant’s name, date of the disclosure, 
description of the nature of the Individually Identifiable Information (III) disclosed, purpose of each disclosure, 
and the name and address of the person/agency to whom the disclosure was made. 
C.      
 Local DVAMC memorandum “Authorization to Use, Process, Store, or Transmit VA Sensitive 
Information Outside VA Owned or Managed Facilities” has been pre-filled out for each study team 
member who may transport the data and/or specimens off-site.  This (these) forms are included with 
the IRB materials.   
 
D. 
  Containers (e.g., briefcase, bin) are labeled with the following notice (label placed on the 
outside of container) in accordance with VHA Directive 6609: 
NOTICE!!! 
Access to these records is limited to: AUTHORIZED PERSONS ONLY. 
Information may not be disclosed from this file unless permitted by all applicable legal authorities, 
which may include the Privacy Act; 38 U.S.C. §§ 5701, 5705, 7332; the Health Insurance Portability and 
Accountability Act; and regulations implementing those provisions, at 38 C.F.R. §§ 1.460 – 1.599 and 45 
C.F.R. Parts 160 and 164. Anyone who discloses information in violation of the above provisions may 
subject to civil and criminal penalties. 
 
V. 
  We will communicate with veterans enrolled as participants in this research study through 
Myhealthe.va.gov .    
 
6. Risk Mitigation Strategies:   
At each level of data management and for each subject contact, strict adherence to VHA policy will be 
observed regarding HIPAA, IRB, and other VHA patient quality controls. A unique code number will be assigned 
to each participant. The key to the code will be kept in a password-protected file on a secured network 
S:\GRECC\Grecc Research\Bales\Valor Up We will employ REDCap (Research Electronic Data Capture) hosted 
within VIRECfor data entry. Key components of this activity include data entry screen programming and 
database testing and validation. The database will include study default parameters and ranges for database, 
protocols, users, and access rights. Access and data entry to the database will be controlled by login 
permissions, and the database will be backed up daily, with full backups occurring weekly, and quarterly 
backups retained for perpetuity. 
 
As previously described, a second excel spreadsheet database will be created to electronically track 
participants through all components of the study including screening. This tracking will contain identifiable 
data, including the key that links participants to study identification numbers; other data collected in the 
course of the study will be kept separately from identifying information. This database will be stored on a 
Duke secured computer server S:\GRECC\Grecc Research\Bales\Valor Up that is encrypted, password-
protected, and only accessible to Dr. Bales and her study staff. 
 
These procedures will protect the identity of all patients and providers as pertains to any reports generated 
from this study. The individuals responsible for data safety and monitoring will be Drs. Bales, Starr, McDonald, 
Huffman, and Pieper.  
 
 
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  Data are fully de-identified (stripped of HIPAA 18 and study ID/code) before being shared outside of 
Durham VAMC. 
  Specimens are fully de-identified (stripped of HIPAA 18 and study ID/code before being shared outside of 
Durham VAMC. 
  Direct identifiers will be maintained separately from data and or specimens by using a code to “identify” 
subjects.  In a separate database (i.e., a “linking” or “cross-walk” database) this code will be linked to 
identifying subject information.   
  Other, specify:        
7. Suspected Loss of VA Information: 
Should any incident such as theft or loss of data, unauthorized access of sensitive data or non-compliance with 
security controls occur it will be immediately reported according to VA policy. All incidents regarding 
information security/privacy incidents will be reported to the ISO and PO within 1 hour of acknowledgement 
of issue and done so using the VHADUR Research Events Report e-mail group 
(VHADURResearchEventReport@va.gov). 
8. Reporting of Results:   
  Reporting of results, such as in scientific papers and presentations, will never identify individual subjects.  
Data will be presented in aggregate and individual-level data will not be published. 
  Other results reporting plan, describe:       
9. Future Use of Data: 
 
  Data will be retained for future use.  This is described elsewhere in the protocol and is noted in the HIPAA 
authorization. 
 
  Future Use of data is optional (i.e., not required by the research subject). 
  Future Use of data is required for participation in the study. 
  No future use of data is currently planned. 
10. Use of Mail Merge Technology 
  Mail merge programs will be used to generate letters and/or address labels for mailings to potential or 
already enrolled research subjects.  The study team is aware that to reduce risk of mail merge related privacy 
incidents, use of mail merge programs requires a 25% accuracy check to verify that (potential) research 
subject name and mailing address are properly “matched”.  If discrepancies are found, a 100% accuracy check 
is required before letters may be mailed.   
 
11. Use of Non-Standard Software 
 I do NOT intend to use any new specialized software (i.e. Software that’s not already approved OR 
installed) in this study. 
 
 I intend to use specialized software that has not already been installed and it has been approved for use by 
the VA Technical Reference Model (TRM) Group.  
(Note: All new software must be approved by TRM before it can be installed on VA systems.) 
 
 I intend to use previously installed software on my VA computer.  
 
 
12. Use of Cloud Computing Services 
 Cloud computing services will NOT be used in this study. 
 
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 Cloud computing services WILL be used in this study as described below and have been approved 
nationally by the VA Chief Information Officer (CIO).  (Note: ONLY cloud computing services that have been 
approved nationally may be used.) 
 
References 
 
1. 
Affairs USDoV. Close to 25 percent of VA patietns have diabetes. 
http://www.va.gov/health/NewsFeatures/20111115a.asp. Published 2015. Accessed June 1, 2017. 
2. 
Breland JY, Phibbs CS, Hoggatt KJ, et al. The Obesity Epidemic in the Veterans Health Administration: 
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2017;32(Suppl 1):11-17. 
3. 
Alley DE, Ferrucci L, Barbagallo M, Studenski SA, Harris TB. A research agenda: the changing 
relationship between body weight and health in aging. J Gerontol A Biol Sci Med Sci. 2008;63(11):1257-
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Short KR, Vittone JL, Bigelow ML, Proctor DN, Nair KS. Age and aerobic exercise training effects on 
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Melton LJ, 3rd, Khosla S, Crowson CS, O'Connor MK, O'Fallon WM, Riggs BL. Epidemiology of 
sarcopenia. J Am Geriatr Soc. 2000;48(6):625-630. 
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Costamagna D, Costelli P, Sampaolesi M, Penna F. Role of Inflammation in Muscle Homeostasis and 
Myogenesis. Mediators Inflamm. 2015;2015:805172. 
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Porter Starr KN, McDonald SR, Bales CW. Obesity and Physical Frailty in Older Adults: A Scoping Review 
of Lifestyle Intervention Trials. J Am Med Dir Assoc. 2014. 
8. 
Cheng FW, Gao X, Bao L, et al. Obesity as a risk factor for developing functional limitation among older 
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Menke A, Rust KF, Fradkin J, Cheng YJ, Cowie CC. Associations between trends in race/ethnicity, aging, 
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Cannon CP, Kumar A. Treatment of overweight and obesity: lifestyle, pharmacologic, and surgical 
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Ross R. The challenge of obesity treatment: avoiding weight regain. CMAJ. 2009;180(10):997-998. 
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Tzankoff SP, Norris AH. Effect of muscle mass decrease on age-related BMR changes. Journal of applied 
physiology: respiratory, environmental and exercise physiology. 1977;43(6):1001-1006. 
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Elia M, Ritz P, Stubbs RJ. Total energy expenditure in the elderly. Eur J Clin Nutr. 2000;54 Suppl 3:S92-
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Villareal DT, Apovian CM, Kushner RF, Klein S. Obesity in older adults: technical review and position 
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Weinheimer EM, Sands LP, Campbell WW. A Systematic Review of the Separate and Combined Effects 
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Kalyani RR, Metter EJ, Ramachandran R, Chia CW, Saudek CD, Ferrucci L. Glucose and insulin 
measurements from the oral glucose tolerance test and relationship to muscle mass. J Gerontol A Biol 
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17. 
Houston DK, Nicklas BJ, Ding J, et al. Dietary protein intake is associated with lean mass change in 
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Josse AR, Atkinson SA, Tarnopolsky MA, Phillips SM. Increased Consumption of Dairy Foods and Protein 
during Diet- and Exercise-Induced Weight Loss Promotes Fat Mass Loss and Lean Mass Gain in 
Overweight and Obese Premenopausal Women. J Nutr. 2011;141(9):1626-1634. Epub 2011 Jul 1620. 
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Sahni S, Mangano KM, Hannan MT, Kiel DP, McLean RR. Higher Protein Intake Is Associated with Higher 
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McLean RR, Mangano KM, Hannan MT, Kiel DP, Sahni S. Dietary Protein Intake Is Protective Against 
Loss of Grip Strength Among Older Adults in the Framingham Offspring Cohort. J Gerontol A Biol Sci 
Med Sci. 2016;71(3):356-361. 
21. 
Bradlee ML, Mustafa J, Singer MR, Moore LL. High-Protein Foods and Physical Activity Protect Against 
Age-Related Muscle Loss and Functional Decline. J Gerontol A Biol Sci Med Sci. 2017. 
22. 
Symons TB, Schutzler SE, Cocke TL, Chinkes DL, Wolfe RR, Paddon-Jones D. Aging does not impair the 
anabolic response to a protein-rich meal. Am J Clin Nutr. 2007;86(2):451-456. 
23. 
Pennings B, Groen B, de Lange A, et al. Amino acid absorption and subsequent muscle protein 
accretion following graded intakes of whey protein in elderly men. Am J Physiol Endocrinol Metab. 
2012;302(8):E992-999. 
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Symons TB, Sheffield-Moore M, Wolfe RR, Paddon-Jones D. A moderate serving of high-quality protein 
maximally stimulates skeletal muscle protein synthesis in young and elderly subjects. J Am Diet Assoc. 
2009;109(9):1582-1586. 
25. 
Casperson SL, Sheffield-Moore M, Hewlings SJ, Paddon-Jones D. Leucine supplementation chronically 
improves muscle protein synthesis in older adults consuming the RDA for protein. Clinical Nutrition. 
2012;31(4):512-519. 
26. 
Koopman R, Verdijk L, Manders RJF, et al. Co-ingestion of protein and leucine stimulates muscle 
protein synthesis rates to the same extent in young and elderly lean men. American Journal of Clinical 
Nutrition. 2006;84(3):623-632. 
27. 
Volpi E, Kobayashi H, Sheffield-Moore M, Mittendorfer B, Wolfe RR. Essential amino acids are primarily 
responsible for the amino acid stimulation of muscle protein anabolism in healthy elderly adults. Am J 
Clin Nutr. 2003;78(2):250-258. 
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