Health, Aging and Later-Life Outcomes Pilot Trial (HALLO-P): A 9-month Randomized Pilot Trial of 3 Nutritional Interventions in 120 Older Adults With an Indication for Weight Loss
Phase: NA
Conditions: Aging
Sponsor: Wake Forest University Health Sciences

 
 
HALLO-P Protocol 
 
Health, Aging and Later-Life Outcomes Pilot 
Trial (HALLO-P) 
A 9-month randomized pilot trial of 3 nutritional interventions in approximately 100 older adults 
with an indication for weight loss 
 
Principal Investigators: 
Stephen B Kritchevsky, PhD (Corresponding PI) 
Professor, Wake Forest School of Medicine 
Barbara J. Nicklas, PhD 
Professor, Wake Forest School of Medicine 
Michael E. Miller, PhD 
Professor, Wake Forest School of Medicine 
W. Jack Rejeski, PhD 
Professor, Wake Forest University 
 
Supported by: 
The National Institute on Aging 
The National Cancer Institute 
Cooperative Agreement U01AG073240 
  
 
Version 2.1 
November 30, 2023 

 
 
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TABLE OF CONTENTS 
Page 
PRÉCIS .......................................................................................................................................... v 
Study Title  .................................................................................................................................. v 
Objectives ................................................................................................................................... v 
Design and Outcomes ................................................................................................................. v 
Study Schematic......................................................................................................................... vi 
Interventions and Duration ....................................................................................................... vii 
Sample Size and Population...................................................................................................... vii 
STUDY TEAM ROSTER ............................................................................................................ 1 
PARTICIPATING STUDY SITES ............................................................................................. 3 
1 
Study objectives ..................................................................................................................... 4 
1.1 
Primary Objective ........................................................................................................... 4 
1.2 
Secondary Objectives ...................................................................................................... 4 
2 
BACKGROUND AND RATIONALE ................................................................................ 4 
2.1 
The Impact of Overweight and Obesity on Older Adults ............................................... 4 
2.1.1. Caloric Restriction (CR) as Strategy to Ameliorate the Impact of Overweight and    
Obesity in Older Adults …………………………………………………………………….. 4 
2.1.2  Caloric Restriction Affects Aging Biology…………………………………………... 5 
2.1.3  Potential Concerns Regarding Caloric Restriction in Older Adults ………………....  5 
2.1.4  Alternative Approaches to Energy Intake Manipulation to Mimic CR’s benefits …..  6 
 
2.2  Study Rationale …………………………………………………………………………6 
 
 2.2.1. Rationale for 20% CR ………………………………………………………………...7 
 
  2.2.2. Rationale for CR intervention delivered remotely ……………………………………7 
 
 2.2.3. Rationale for Time Restricted Eating ………………………………………………...7 
 
 2.2.4. Rationale for Including Physical Activity Promotion for all Participants ……………8 
3 
STUDY DESIGN ................................................................................................................... 8 
4 
SELECTION AND ENROLLMENT OF PARTICIPANTS .......................................... 10 

 
 
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4.1 
Inclusion Criteria .......................................................................................................... 10 
4.2 
Exclusion Criteria ......................................................................................................... 10 
4.3 
Study Enrollment Procedures ....................................................................................... 13 
5 
STUDY INTERVENTIONS .............................................................................................. 14 
5.1 
Interventions, Administration, and Duration ................................................................ 14 
 5.1.1   The Use of a mHealth Platform for Adaptive CR and TRE Interventions ………….15 
 5.1.2   The HALLO Interventions ………………………………………………………….15 
 5.1.3    Use of mHealth App and Tracking Appetite Metrics ………………………………16 
 5.1.4 Toolbox ……………………………………………………………………………….17 
5.2 
Handling of Study Interventions ................................................................................... 18 
 
5.2.1 Caloric Restriction Goals ……………………………………………………………..18 
5.3 
Concomitant Interventions ............................................................................................ 18 
5.4 
Adherence Assessment ................................................................................................. 18 
6 
STUDY PROCEDURES .................................................................................................... 19 
6.1 
Schedule of Evaluations ................................................................................................ 20 
6.2 
Description of Evaluations ............................................................................................ 22 
6.2.1.  Screening Visit 1 (SV1) ……………………………………………………………. 22 
 
6.2.2. Screening Visit 2 (SV2) / Run-in evaluation  ………………………………………  22 
 
6.2.3.  Baseline Visits 1 and 2 …………………………………………………………….. 23 
6.2.4 Randomization Procedure ............................................................................................. 26 
6.2.5 Six-month Interim Follow-up Visit 1 ........................................................................... 26 
6.2.6 Nine-month Follow-up Visits 2 and 3 .......................................................................... 27 
 
6.2.7 Assessments conducted during intervention ………………………………………….28 
7 
SAFETY ASSESSMENTS ................................................................................................. 29 
7.1 
Specification of Safety Parameters ............................................................................... 29 
7.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters .... 29 
7.3 
Adverse Events and Serious Adverse Events ............................................................... 30 
7.3.1  Adverse Event (AE) ..................................................................................................... 30 
7.3.2  Serious Adverse Event (SAE) ..................................................................................... 30 
 
7.3.3 Unanticipated Problem (UP) ………………………………………………………….31 
 
7.3.4 Severity of Event …………………………………………………………………......31 

 
 
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7.3.5 Expectedness…………………………………………………………………………. 31 
 
7.3.6 Relationship To Study Intervention …………………………………………………. 31 
7.4 
Reporting Procedures .................................................................................................... 33 
    7.5  
 Safety Monitoring…………...…………………………………………………………33 
8 
INTERVENTION DISCONTINUATION........................................................................ 33 
9 
STATISTICAL CONSIDERATIONS .............................................................................. 34 
9.1 
General Design Issues ................................................................................................... 34 
9.2 
Sample Size and Randomization .................................................................................. 34 
9.2.1 Treatment Assignment Procedures ............................................................................... 35 
9.3 
Interim analyses and Stopping Rules ............................................................................ 35 
9.4 
Outcomes ...................................................................................................................... 35 
9.4.1  Primary feasibility outcomes ....................................................................................... 35 
9.4.2  Secondary outcomes .................................................................................................... 36 
9.5 
Data Analyses ............................................................................................................... 36 
 
9.5.1 
Primary Feasibility Analyses ……………………………………………………..36 
 
9.5.2 
Analysis of Secondary Outcomes………………………………………………..  37 
 
9.5.3 
Safety Analyses..…………………………………………………………………..37 
9.5.4   
Other analyses helpful in planning future longer term studies…………………….37 
10  DATA COLLECTION AND QUALITY ASSURANCE ................................................ 38 
10.1 
Data Collection Forms .................................................................................................. 38 
10.2 
Data Management ......................................................................................................... 38 
 
10.2.1 
Clinical Site Responsibilities ……………………………………………………. 38 
 
10.2.2 
Biostatistics and Data Management Team Responsibilities …………………….. 39 
10.3 
Quality Assurance ......................................................................................................... 40 
10.3.1 Training ....................................................................................................................... 40 
10.3.2  Metrics ....................................................................................................................... 40 
10.3.3  Protocol Deviations ................................................................................................... 40 
10.3.4  Monitoring ................................................................................................................. 40 
11  PARTICIPANT RIGHTS AND CONFIDENTIALITY ................................................. 40 
11.1 
Institutional Review Board (IRB) Review .................................................................... 40 

 
 
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11.2 
Informed Consent Forms .............................................................................................. 41 
11.3 
Participant Confidentiality ............................................................................................ 41 
11.4 
Study Discontinuation ................................................................................................... 41 
12  ETHICAL CONSIDERATIONS ....................................................................................... 41 
13  COMMITTEES................................................................................................................... 42 
14  PUBLICATION OF RESEARCH FINDINGS ................................................................ 43 
15  REFERENCES .................................................................................................................... 43 
16  APPENDICES ..................................................................................................................... 52 
  
I. Abbreviations Used………………………………………………………………….…....52 
II. Protocol / Updates Revisions………………………………………………………….....56 

 
 
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PRÉCIS  
Study Title  
Health, Aging and Later-Life Outcomes Pilot Trial (HALLO-P)  
Objectives  
This pilot study is part of a larger planning process to design a full-scale randomized trial to 
evaluate the long-term effects of caloric restriction (CR) and time restricted eating (TRE) on 
the health of older adults.  The specific objective of the HALLO-P is to collect data to 
inform the design of the full-scale randomized trial to evaluate the long-term effects of 
caloric restriction and time restricted eating in older adults.   
 
The pilot is a 9-month clinical trial of: 1) 20% CR delivered in-person; 2) 20% CR delivered 
remotely via video conferencing; and 3) 8-hour TRE with ad libitum caloric intake. We will 
collect measures of adherence, safety, and biomarkers of aging in all three groups. The pilot 
data will be used to refine recruitment criteria, estimate recruitment yields, and refine 
intervention approaches. 
Design and Outcomes   
HALLO-P is a 9-month randomized trial to assess the feasibility and acceptability of three 
interventions: 1) 20% CR delivered in-person; 2) 20% CR delivered remotely via video 
conferencing; and 3) 8-hour TRE with ad libitum caloric intake.  All groups will be asked to 
increase physical activity by increasing their daily step count. It will enroll approximately 
100 adults 60 years and older with an indication for weight loss (i.e., BMI=30-<40 kg/m2 or 
Overweight (BMI=27-<30 kg/m2) with at least ONE obesity-related comorbidity). 
  
Primary feasibility outcomes   
a) Degree of sustained CR (Benchmark 1): CR > 10% at 9 months;  
b) TRE sustainability (Benchmark 2): At least 75% of participants eating within window 
on >80% of days; and  
c) Retention of study participants (Benchmark 3): Retention > 85% at 9 months. 
 
Secondary outcomes 
 Body weight change at baseline, 6 and 9 months 
 Changes in fat and lean body mass assessed by DXA at baseline and 9 months 
 Change in bone mineral density assessed by DXA at baseline and 9 months 
 Change in resting energy expenditure assessed by indirect calorimetry at baseline 
and 9 months 
 Change in physical activity energy expenditure assessed by ActivPAL at baseline 
and 9 months 
 Change in energy intake assessed at baseline and 9 months using doubly-labeled 
water 
 Change in total muscle mass at baseline and 9 months assessed by d3 creatine 

 
 
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(d3cr) 
 Change in self-reported energy intake assessed using the ASA24 at baseline and 9 
months 
 Change in physical and cognitive function assessed at baseline and 9 months 
 Change in age-related biomarkers at baseline and 9 months 
 
HALLO-P will also collect the following information to guide the design of a longer-
term study. 
 
HALLO-P Feasibility Benchmarks 
 Community Interest – Response rates to mailings and other outreach 
 Recruitment Yields – Ratio of initial contacts to randomizations 
 Participants with Inter-current Health Events – Health events that suspend 
intervention participation 
 Intervention Delivery Costs – fixed and variable costs associated with each 
intervention arm 
Study Schematic
 
 
Interventions and Duration  
In-Person Caloric Restriction: This group will undergo a 9-month behavioral diet 
intervention targeting a 20% reduction in caloric intake. During the first 6 months, 
participants will meet in-person one time each month individually and three times/month in 
a group setting with a dietitian and/or behavioral coach.  During the remaining three months 
of intervention, there will be one group and one individual meeting each month. Participants 
will keep diet records using the Fitbit app on a tablet and weight using a BodyTrace™ smart 
scale that transmits data through a study-specific Companion App. Participants will use 
wrist-worn Fitbit step monitors to track their physical activity and receive feedback via the 
app, with a goal to promote movement across the day, continuously increasing their daily 
step count. This arm was discontinued for the last wave (4) of the study to permit more 
participants to be randomized into the other two arms.  

 
 
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Remote Caloric Restriction: This group will have a similar 20% reduction in caloric intake 
and frequency of meeting schedule, and similar physical activity goal as the in-person arm. 
However, the remote arm intervention will be delivered via video conferencing.  
Time-restricted Eating: This group will undergo a 9-month dietary intervention targeting 
consumption of all daily caloric intake within an 8-hour window of time, with no restrictions 
on caloric intake. During the first 6 months, participants will meet in-person once per month 
individually and three times per month in a group setting with a dietitian and/or behavioral 
coach. During the remaining 3 months of intervention, there will be one group and one 
individual meeting each month. Participants in TRE will be asked to log into the study-
specific Companion App each day to document the beginning and end of their feeding 
cycles with timing of meals/snacks consumed. As in the CR arms, participants will use 
wrist-worn Fitbit step monitors to track their physical activity and receive feedback via the 
app, with a goal to promote movement across the day, increasing daily step count. 
Continuous glucose monitoring will be used at intervals to document glucose levels over a 
10-day period. 
Sample Size and Population 
The HALLO-P target population is older adults with an indication for weight loss for whom 
participation is feasible and safe. Approximately to one-hundred participants will be 
randomized to the three study arms in a 1:1:1 ratio for the first 66 participants. The 
remaining participants enrolled will be randomized with equal probability to the remote CR 
and TRE groups. Randomization is  stratified by sex.

 
 
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HALLO-P Protocol, Version 2.1 
STUDY TEAM ROSTER   
Principal Investigators:   
Stephen B. Kritchevsky, PhD   
  
 
 
Barbara J. Nicklas, PhD 
Wake Forest School of Medicine,  
 
 
 
Wake Forest School of Medicine, 
Department of Internal Medicine  
 
 
 
Department of Internal Medicine 
Medical Center Boulevard  
 
 
 
 
Medical Center Boulevard 
336-713-8548 
 
 
 
 
336-713-8558 
336-713-8588 
 
 
 
 
336-713-8588 
skritche@wakehealth.edu  
 
 
 
 
bnicklas@wakehealth.edu  
Corresponding PI, Overall Administration    
mPI, Clinical Research Activities   
Michael E. Miller, PhD  
 
 
 
 
W. Jack Rejeski, PhD 
Wake Forest School of Medicine,  
 
 
 
Wake Forest University, 
Division of Public Health Sciences                       Department of Health and Exercise Sciences 
525 Vine 
 
 
 
 
Worrell Professional Building 
336-716-6837 
 
 
 
 
336-830-1945 
336-716-6427 
 
 
 
 
336-758-4680 
mmiller@wakehealth.edu  
 
 
 
 
rejeski@wfu.edu  
mPI, Biostatistics and Data Management    
mPI, Intervention Design 
  
Co-Investigators: 
 
Jamy Ard, MD  
 
 
 
 
 
 
Jason Fanning, PhD 
Wake Forest School of Medicine,  
 
 
 
Wake Forest University, 
Division of Public Health Sciences                      Department of Health and Exercise Sciences 
Medical Center Boulevard 
 
 
 
 
Worrell Professional Building 
336-716-9837 
 
 
 
 
336-758-5042 
336-713-4300 
 
 
 
 
336-758-4680 
jard@wakehealth.edu  
 
 
 
 
fanninjt@wfu.edu  
Medical Safety Officer, Obesity    
 
 
 
mHealth Applications 
 
Fang-Chi Hsu, PhD 
 
 
 
 
Mark A. Espeland, PhD  
Wake Forest School of Medicine,  
 
 
 
Wake Forest School of Medicine, 
Department of Biostatistics and Data Science 
Department of Internal Medicine 
525 Vine 
 
 
 
 
Medical Center Boulevard 
 
336-716-8457 
 
 
 
 
336-713-8116  
 
 
 
 
 
 
336-716-6427 
 
 
 
 
336-713-8588  
 
 
 
 
 
 
fhsu@wakehealth.edu  
 
 
 
 
mespelan@wakehealth.edu  
Biostatistics   
 
 
 
 
Geroscience Outcomes 
 
 
 
 
  
 
Kristen Beavers, RD, PhD 
 
 
 
 
Denise K. Houston, RD, PhD  
 
 
Wake Forest University,  
 
 
 
 
Wake Forest School of Medicine, 
Department of Health and Exercise Science  
Department of Internal Medicine 

 
 
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HALLO-P Protocol, Version 2.1 
Worrell Professional Building 
 
 
 
 
Medical Center Boulevard 
336-758-5855 
 
 
 
 
336-713-8558 
336-758-4680 
 
 
 
 
 
 
     336-713-8588 
Beaverkm@wfu.edu 
 
 
 
 
dhouston@wakehealth.edu  
Body Composition Assessment, Nutrition  
 
Nutrition 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Consultants: 
Bret Goodpaster, PhD 
 
 
 
 
      James P. Delany, PhD 
Translational Research Institute  
 
 
 
Translational Research Institute  
 
Advent Health  
 
 
 
 
Advent Health 
Orlando, FL 
 
 
 
 
Orlando, FL 
412-901-9309 
 
 
 
 
412-716-2972 
407-303-1372 
 
 
 
 
407-303-1372 
bret.goodpaster@adventhealth.com   
 
 
James.Delany@adventhealth.com  
 
Energy Metabolism, Obesity 
 
 
 
 
Energy Metabolism, Doubly-Labeled Water 
 
Steven Cummings, MD 
 
 
 
 
 
University of California at San Francisco 
 
 
 
 
California Pacific Medical Center 
San Francisco, CA 
415-203-2864 
 
 
 
 
 
 
 
 
 
 
Steven.cummings@ucsf.edu 
 
 
 
 
 
 
Bone, Biomarkers 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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HALLO-P Protocol, Version 2.1 
PARTICIPATING STUDY SITES  
Wake Forest School of Medicine 
Departments of Internal Medicine1, Biostatistics and Data Science2, Epidemiology and 
Prevention3 & Division of Public Health Sciences4 
Wake Forest School of Medicine 
1 Medical Center Boulevard 
Winston-Salem, NC 
Ard, Hsu., Espeland, Houston, Justice, Kritchevsky, Miller, Nicklas 
 
Wake Forest University 
Department of Health and Exercise Science 
Worrell Professional Building  
Winston-Salem, NC 
Beavers K., Fanning, Rejeski. 
 
Translational Research Institute, Advent Health 
Orlando, FL 
Delany, Goodpaster 
 

 
 
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HALLO-P Protocol, Version 2.1 
1 
STUDY OBJECTIVES 
1.1 Primary Objective 
HALLO-P is a 9-month randomized trial to assess the feasibility of three interventions: 1) 20% 
CR delivered in-person; 2) 20% CR delivered remotely via video conferencing; and 3) 8-hour 
TRE with ad libitum caloric intake.  It will enroll approximately 100 adults 60 years and older 
with an indication for weight loss (i.e., BMI=30-<40 kg/m2 or Overweight (BMI=27-<30 kg/m2) 
with at least ONE obesity-related comorbidity). 
 
The Primary Objectives are to assess the ability to sustain an adequate degree of CR in groups 1 
and 2, to see differences in aging-related biomarkers at 9 months, and to see if an 8-hour TRE 
intervention can be sustained over 9 months. The pilot will also assess participant recruitment 
yields and retention at 9 months to gauge the potential to sustain a longer intervention period. 
 
1.2 Secondary Objectives 
As Secondary Objectives HALLO-P will assess: 
1) Changes in body weight, fat and lean mass, total muscle mass, and bone density. 
2) Changes in resting energy expenditure, physical activity energy expenditure, and energy 
intake. 
3) Changes in physical and cognitive function. 
4) Changes in aging-related biomarkers. 
 
2 
BACKGROUND AND RATIONALE  
2.1 The Impact of Overweight and Obesity on Older Adults 
 
Multi-morbidity (having > two health conditions) rises exponentially with age, and at age 70 
its incidence is about 10% per year (1). Obesity (BMI ≥ 30 kg/m2) is a major risk factor for 
common disabling conditions like osteoarthritis, cardiovascular disease, and diabetes, and the 
odds of multi-morbidity are sevenfold higher in persons with obesity than in those of normal 
weight (2). Even those in the overweight range (27≤ BMI <30 kg/m2) have increased risk of 
disease and functional impairment (3). Older adults with multi-morbidity use a highly 
disproportionate share of health care resources: the 40% of Medicare Beneficiaries with 4 or 
more conditions accounted for 78% of Medicare expenditures in 2018 (4). Thus, interventions 
that reduce age-related multi-morbidity either through the treatment of overweight/obesity or 
slowing the aging process are urgently needed.  
 
2.1.1. Caloric Restriction (CR) as Strategy to Ameliorate the Impact of Overweight and 
Obesity in Older Adults 
In the short-term, the metabolic and functional changes seen with moderate caloric restriction in 
older persons point towards better health (e.g., lower IL-6, blood pressure, fasting glucose, and 
increased gait speed) (5). In primary care, women with obesity who successfully maintain a loss 
of ≥5% have significantly lower risk of obesity-related cancer, osteoarthritis, and health care 
utilization (6). The Look AHEAD study randomized 5145 persons (age 45-76) with type 2 

 
 
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HALLO-P Protocol, Version 2.1 
diabetes to receive an intensive weight loss and exercise (ILI) or an education program (DSE). 
The ILI arm targeted 10% weight loss and increased exercise and was associated with reduced 
rates of advancing comorbidity, better mobility function and lower health care utilization (7-9).  
Whether these benefits pertain to older persons without diabetes is unclear. 
 
2.1.2. Caloric Restriction Affects Aging Biology   
These results jive with research findings from animal models evaluating caloric restriction. In 
many, but not all, animal models reducing caloric intake by 15-40% from ad libitum feeding 
prolongs lifespan and delays onset of numerous age-related health conditions (10, 11).  
Overlapping cellular and molecular mechanisms explain CR’s effects on lifespan and health-
span (12, 13). The most direct are those related to cellular energy homeostasis or ‘energy- and 
nutrient-sensing’ pathways, including AMP-activated protein kinase (AMPK), a master regulator 
of metabolism that activates catabolic pathways like glucose transport, glycolysis and fatty acid 
oxidation, and suppresses anabolic pathways such as fatty acid synthesis, cholesterol formation 
and protein synthesis (14, 15). The mammalian target of the Rapamycin (mTOR) pathway is 
inhibited by decreases in nutrient availability in order to conserve energy reserves by preventing 
protein synthesis and cellular growth, and strong experimental evidence links mTOR inhibition 
to extension of life and health-span (16, 17). Other nutrient sensing pathways such as 
insulin/insulin-like growth factor-1 signaling (IIS), and mammalian sirtuins, a family of 
nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases, also appear to respond 
directly to CR and are implicated in life and health-span extension (18, 19). The cellular energy- 
and nutrient-sensing pathways work synergistically and converge with other hallmarks of 
biological aging, including activation of autophagy, an internal cellular recycling system that 
mobilizes available energy stores to preserve critical cellular functions, and reducing oxidative 
damage, pro-inflammatory cytokine / chemokines, and other cellular and systemic stress 
response signaling (12, 20, 21). In older humans, weight loss interventions up to 18 months show 
reductions in inflammatory biomarkers, cystatin-c and mortality-linked physiologic and 
functional measures (22-24), and a meta-analysis of randomized trials of caloric restriction 
showed that randomization to caloric restriction was associated with a 15% reduction in all-cause 
mortality(25). Identifying which biomarkers may serve as intermediates between CR and its 
potential health benefits is important in understanding the potential benefits of interventions 
designed to mimic CRs effects. 
 
2.1.3. Potential Concerns Regarding Caloric Restriction in Older Adults 
While most data support the short-term benefits of CR in older adults, there is uncertainty with 
respect to its long-term consequences. CR causes the loss of skeletal muscle and bone, thus 
potentially exacerbating sarcopenia and osteopenia (26). In a number of studies, muscle function 
measured by strength has been unaffected by CR despite measurable losses of skeletal muscle 
mass or volume (27-29). However, these studies are mostly short-term leaving a gap in 
knowledge regarding long-term consequences. Bone density was measured in the CLIP II study 
which compared CR alone or combined with either aerobic or resistance exercise. Total hip 
BMD was reduced by 2% in all three groups (30). Based on data from fracture prevention trials, 
this change would be expected to increase vertebral fracture risk by ~ 30%. Whether this finding 
would apply to non-osteoporotic older persons is unknown. In the Look AHEAD study which 
was conducted over 8-10 years, there was no difference between the groups in total or hip 
fracture rates but a 39% increase in fragility fractures in the ILI arm. In subgroup analyses, the 

 
 
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HALLO-P Protocol, Version 2.1 
greatest risks were seen in those <56 yrs and those with baseline BMIs >37.7 kg/m² (31). The 
effect of CR on cognitive function in older adults is understudied. Unintentional weight loss in 
later life is associated with declining cognitive function and dementia risk (32). Short-term CR in 
non-elderly persons shows small improvements in cognitive scores (33). In a Look AHEAD 
ancillary study, the impact of ILI on long-term differences in cognitive function depended on 
baseline BMI: the ILI had worse cognitive function if baseline BMI >30 but better function if 
BMI < 30 kg/m² (34). In three short-term trials including older adults CR interventions were 
associated small cognitive improvements (35-37). Information relating to the long-term 
consequences of CR or related dietary interventions is needed to understand potential drawbacks 
and balance these against potential benefits. 
 
2.1.4. Alternative Approaches to Energy Intake Manipulation to Mimic CR’s benefits 
Researchers have used animal models to extend initial CR findings examining alternatives such 
as time restricted eating or alternate day fasting. In time restricted eating (TRE), animals receive 
all calories within a specified time interval but are allowed to consume as many calories as 
desired within that interval. Alternate day fasting provides unrestricted food access on most days 
but no calories or highly limited calories on other days. Diet manipulations involving alternate 
day fasting and/or TRE extend both lifespan and healthspan in yeast, worms, and rodents, and 
are effective in mice even when initiated late in life (38-40). TRE’s benefits appear to depend on 
feeding periods being aligned with the circadian cycle(41). In humans, some studies report short-
term metabolic benefits. Some weight loss typically occurs in these studies, but the magnitude is 
less than that observed with CR. The long-term effects of TRE on the health of older humans are 
unknown. However, it is an attractive alternative to CR because the potentially lower degree of 
weight loss would be expected to be associated with better retention of muscle and bone mass. 
 
A growing body of evidence suggests that time restrictive eating (TRE) targets biological 
pathways affecting aging in humans and may be an alternative to caloric restriction (CR) in 
adults with overweight and obesity, particularly in older adults where CR may exacerbate muscle 
and bone mass loss. Most TRE studies with ad libitum food and beverage intake have resulted in 
a 2-4% weight loss as well as fat loss in individuals with overweight or obesity (42-44). In those 
TRE studies that assessed energy intake, TRE with ad libitum food and beverage intake led to a 
decrease in total energy intake which may explain the weight loss. TRE interventions also have 
beneficial effects on systolic and/or diastolic blood pressure; however, effects of TRE on glucose 
homeostasis, insulin sensitivity, and plasma lipid and cholesterol metabolism are conflicting (42-
44). There are few studies of TRE in middle aged and older adults (45). However, TRE 
interventions in middle aged and older adults with overweight or obesity have shown similar 
results with significant weight and fat loss (46, 47) as well as improvements in systolic and 
diastolic blood pressure (48). A limitation of existing TRE intervention studies is the short 
duration, typically ≤12 weeks; thus, the long-term effects of TRE are unknown.  
  
2.2. Study Rationale 
The intent of HALLO-P is to demonstrate the feasibility of delivering 20% CR and 8 hours of 
TRE to older adults who are likely to represent participants in a long-term trial of these same 
interventions. One of the CR groups will receive their intervention remotely using approaches 
including internet-based conferencing in order to assess the adequacy of this approach for 

 
 
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HALLO-P Protocol, Version 2.1 
achieving the target level of CR.  In addition, all participants will receive instruction to promote 
light-intensity and weight-bearing movement throughout the day. 
2.2.1. Rationale for 20% CR 
Reducing caloric intake by 10–40% from ad libitum prolongs lifespan in some animal models. 
Within this range we sought a target that allows for adequate nutrition and is sustainable. In 
inactive older adults, aggressive CR targets are not feasible because baseline energy intakes are 
already low. For example, the INFINITE Study included 65–79 year-old sedentary adults with 
obesity (49). In the group randomized to a 600 kcal/day deficit (~26% CR), 42% of participants 
would have been prescribed a daily intake of <1100 kcals/d, which is too low to provide 
adequate overall nutrition. To minimize the loss of skeletal muscle, protein intake of 1.0-1.2 
g/kg/day of baseline body weight is recommended (50). In diets with low absolute energy intake, 
this level of protein consumption can be unpalatable unless protein supplements are provided. 
The pilot will provide data on baseline energy requirements, the feasibility of formulating 
palatable and nutritionally adequate meals, and the need to provide protein supplementation. We 
will use the gold-standard measure of energy expenditure, Doubly-Labeled Water (DLW), in 
conjunction with Dual X-ray Absorptiometry (DXA)-measured body composition in order to 
assess energy intake at baseline and 9 months, to document actual CR levels. We will also 
measure resting energy expenditure (REE) and physical activity energy expenditure (PAEE; via 
actigraphy) to estimate weight-maintenance energy needs for comparison to DLW values.  
 
2.2.2. Rationale for CR intervention delivered remotely 
A remote intervention strategy would increase HALLO’s resilience to disruptions similar to 
those experienced during the COVID-SARS2 pandemic. In addition, we anticipate that a remote 
intervention strategy would reduce the cost of intervention delivery and reduce participant 
burden. If this strategy produces adequate CR, it would allow for centralized intervention 
delivery in a multi-center study and allow for larger sample sizes at an equivalent cost compared 
to an in-person approach. 
2.2.3. Rationale for Time Restricted Eating 
The benefits of CR may not be due only to a reduction in total caloric intake but also to longer 
periods (and the timing) of fasting (51). Existing literature suggests that the cellular and 
molecular pathways implicated in TRE and alternate day fasting effects are nearly identical to 
those of CR, including AMPK activation, IIS signaling, mTOR inhibition, and inflammation (12, 
51). Studies in humans of dietary feeding modulation without daily CR have demonstrated 
considerable weight loss compared with ad libitum feeding, reduced biomarkers of aging and 
risk factors for age-related diseases, and yet these feeding patterns did not appear to affect lean 
mass. Few studies have attempted to uncouple weight loss effects of calorie manipulation from 
weight loss-independent effects of dietary feeding restriction (52, 53). The human studies of 
TRE have to date been short and often uncontrolled, and with one exception do not include older 
adults. There is some evidence that obesity sensitive biomarkers are beneficially affected and 
that fat loss predominates over lean mass loss which is attractive from the standpoint of older 
adults.  
Participants randomized to the TRE arm will be counselled to consume all caloric intake within a 
specified 8-hour eating window without a prescribed reduction in caloric intake. A zone of 
adherence is created by using a target of 8 hours ± 30 minutes. 

 
 
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HALLO-P Protocol, Version 2.1 
2.2.4. Rationale for Including Physical Activity Promotion for all Participants 
An adaptation to CR is decreasing energy expenditure, in part, by reducing non-exercise activity 
thermogenesis. This can increase sedentary behavior, which is associated with increased 
disability risk (54). TRE is also associated with reductions in weight and physical activity (55, 
56). Thus, we believe it is unwise to prescribe either CR or TRE for older adults without 
promotion of some amount of physical activity. The long-term loss of lean mass and bone 
amplify this concern (57). We found that CR coupled with an intervention that promotes 
movement across the day reduces weight regain compared to a traditional treadmill-based 
endurance exercise intervention (58, 59). Furthermore, both groups experienced improvement on 
a 400m walk test (60).  
Using a similar approach in HALLO-P, we will promote a day-long movement program in all 
three groups to: (a) reduce prolonged periods of sedentary behavior across the day, and (b) help 
preserve and possibly enhance mobility.  In addition, increase in stepping helps to address the 
reduction in voluntary energy expenditure observed in persons restricting energy intake.  To 
accomplish these goals, the intervention focuses on increasing daily steps in frequent bouts and 
weight-bearing activities such as step-ups and stair climbing. The focal process measure is steps 
per day, with an emphasis placed on distribution of steps throughout the waking period of the 
day. Based on our prior experience (59-61), our initial step goal will target an ~20% increase 
over average daily steps as assessed via ActivPAL at baseline. The interventionist then 
progresses weekly goals based on the ability and tolerance of each participant using Fitbits to 
track activity and provide feedback to participants via the Companion App. Using this approach, 
by the final assessment visit, most participants can be expected to increase their average weekly 
steps in the range of 50 to 100 percent over baseline. This increase in activity is modest given the 
sedentary status of HALLO-P participants at baseline. Also important is that the longer-term 
study will have a group that does not include dietary interventions and we would deliver the 
activity component to this group to allow isolating its effects from those of the dietary 
interventions.  This will offer value to those randomized to the non-dietary intervention arm 
which we believe is important to retention in a long-term study. 
 
3 
STUDY DESIGN 
Overview. HALLO-P is a 9-month randomized behavioral intervention trial to pilot three 
strategies to change the amount or timing of food intake in order to evaluate these strategies for 
use in a long-term trial. The three strategies include 20% CR delivered in-person, 20% CR 
delivered remotely, and TRE within an 8-hour window each day. All participants will also 
receive an intervention to reduce sedentary time and increase the number of daily steps.   

 
 
9 
HALLO-P Protocol, Version 2.1 
 
Inclusion / Exclusion. HALLO-P’s recruitment target is approximately 100 older (60+ years), 
community-dwelling men and women residing in Forsyth County, NC or surrounding counties 
who have obesity (BMI = 30 - < 40 kg/m2) or are overweight (BMI = 27 - <30 kg/m2) with an 
indication for weight loss (e.g., hypertension, hyperlipidemia, elevated waist girth, controlled 
diabetes). We will target up to 50% men but expect to be in the range of 35%-45% men, 50% > 
70 yrs, and > 23% minority participants which reflects racial demographics of our region.  
HALLO-P will exclude persons for whom the interventions are potentially unsafe, who have a 
history of eating or nutritional disorders, who are likely to drop out due to severe chronic illness 
or other reasons, or who show inability to perform self-monitoring activities required by the 
interventions. We will exclude those doing shift work because disturbances in circadian cycles 
may interfere with TRE. We will exclude persons with uncontrolled or previously undetected 
diabetes because disease management may interfere with the interventions and certain medical 
treatments may complicate outcome interpretation.  
Randomization / Study Duration. Recruitment is scheduled to last approximately 12-15 
months. Once eligibility is established and baseline testing is completed, participants will be 
randomized using blocked randomizations stratified by sex to one of the 3 intervention groups 
for the first 66 participants and blocked randomizations stratified by sex to either the remote CR 
or TRE groups for the remainder of the cohort. Randomized participants will be in the 
intervention for 9 months. 
Primary & Secondary Outcomes. 
HALLO-P is a pilot study to identify the feasibility of interventions designed to lead to either 
20% CR or the maintenance of TRE with sufficient retention to support the goals of a longer-
term study. The outcomes are:  
Primary feasibility outcomes   
a) Degree of sustained CR (Benchmark 1): CR > 10% at 9 months;  
b) TRE sustainability (Benchmark 2): At least 75% of participants eating within window 
on >80% of days; and  
c) Retention of study participants (Benchmark 3): Retention > 85% at 9 months. 
 
Secondary outcomes 
 Body weight change assessed using home scales at baseline, 6 and 9 months 

 
 
10 
HALLO-P Protocol, Version 2.1 
 Changes in fat and lean body mass assessed by DXA at baseline and 9 months 
 Change in bone mineral density assessed by DXA at baseline and 9 months 
 Change in resting energy expenditure assessed by indirect calorimetry at baseline 
and 9 months 
 Change in physical activity energy expenditure assessed by ActivPAL at baseline 
and 9 months 
 Change in energy intake assessed at baseline and 9 months using doubly-labeled 
water 
 Change in total muscle mass at baseline and 9 months assessed by d3 creatine 
(d3cr) 
 Change in self-reported energy intake assessed using the ASA24 at baseline and 9 
months 
 Change in physical and cognitive function assessed at baseline and 9 months 
 Change in age-related biomarkers at baseline and 9 months 
HALLO-P will also collect the following information to guide the design of a longer-
term study. 
 
HALLO-P Feasibility Benchmarks 
 Community Interest – Response rates to mailings and other outreach 
 Recruitment Yields – Ratio of initial contacts to randomizations 
 Participants with Inter-current Health Events – Health events that suspend 
intervention participation 
 Intervention Delivery Costs – fixed and variable costs associated with each 
intervention arm 
4 
SELECTION AND ENROLLMENT OF PARTICIPANTS  
4.1 Inclusion Criteria  
The inclusion criteria shown in the table below will be used.  
4.2 Exclusion Criteria 
The criteria listed below will exclude participants for whom study participation may not be safe 
or who may have conditions that may affect adherence to the study protocol. All candidates 
meeting any of the exclusion criteria at baseline will be excluded from study participation. 
          
Criteria 
Inclusion 
Exclusion 
Assessment 
Age 
60+ years (target - 
50% ≥70 yrs) 
<60 years 
Self-report (phone) 
Housing status 
Community-dwelling 
 
Resides in assisted living or skilled 
nursing home 
 
Resides with someone who is 
currently participating or previously 
participated in this study 
Self-report (phone) 
Obesity status 
Class I obesity  
(BMI=30-<40 kg/m2)  
OR 
Overweight (BMI=27-
<30 kg/m2) with at 
  
 
BMI <27 or >40 kg/m2 
  
 
BMI 27-<30 kg/m2 without an obesity-
related co-morbidity 
 
Self-report 
(phone), then 
confirmed with 
measured weight 
and height at 

 
 
11 
HALLO-P Protocol, Version 2.1 
least ONE obesity-
related comorbidity1 
  
screening visit with 
shoes off 
Physical function 
status 
  
 
Dependent on quad cane or walker 
 
Inability to walk independently  
 
Needing assistance with any Activity 
of Daily Living 
Self-report (phone) 
  
Cognitive function 
status 
  
 
History of mild cognitive impairment or 
dementia 
 
Cognitive impairment (score <22) on 
Montreal Cognitive Assessment 
(MoCA)2 (62) 
Self-report (phone) 
  
Conducted at 
screening visit 
 
Psychiatric status 
  
 
Depression (score >16) on the Center 
for Epidemiologic Studies Depression 
(CES-D)3 (63) scale 
Conducted at 
screening visit 
Smoking/ 
 alcohol use 
  
 
Use of >1 tobacco product per day or 
4 per week, or vaped more than once 
a week within past year 
 
Excessive alcohol use (>7 for women 
or >14 for men drinks/week) in the 
past month 
Self-report (phone) 
Nutritional status 
  
 
Weight loss or gain ≥5% in past 3 
months 
 
Vegan or other severe dietary 
restriction  
  
 
Any contraindications for caloric 
restriction or overnight fasting 
 
History of binge eating disorder 
assessed via the Binge Eating 
Disorder Screener-7 (BEDS-7)4 (64) 
  
 
Consume meals/snacks over a period 
of <11 hours per day 
Self-report (phone) 
  
  
  
Conducted at 
screening visit 
  
 
 
 
Recorded during 
the 7-day 
behavioral run-in 
Physical activity 
status 
  
 
Regular current participation in high 
intensity aerobic or resistance 
exercise training of >150 mins/week  
Self-report (phone) 
  
Sleep status 
  
 
Volunteer or paid work between 8pm-
8am 
Self-report (phone) 
Orthopedic status  
  
 
Severe arthritis, fracture, chronic 
injury, or other musculoskeletal 
disorder that prevents walking 
independently  
 
Joint replacement or other orthopedic 
surgery in past 6 months or planned 
in next 12 months 
Self-report  
Co-
morbidity/health 
history 
 
 
Osteoporosis (t-score ≤ -2.5 on total 
hip and/or femoral neck scan) 
  
 
Uncontrolled hypertension (systolic 
>160 OR diastolic >100 mmHg) upon 
repeated assessments (up to 3 
times)) 
 
 
Type 1 diabetes  
 
Uncontrolled type 2 diabetes (HbA1c 
>7.5%), diagnosed within last year, or 
newly identified (HbA1c >6.5%) 
Self-report or DXA 
scan at screening 
  
Screening BP 
 
 
 
 
Self-report and 
blood labs 
  
  

 
 
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HALLO-P Protocol, Version 2.1 
 
Dialysis or abnormal kidney function 
(eGFR <30 mL/min/1.73 m2) 
 
Liver disease or abnormal liver 
function (ALT levels 2 times above 
normal)  
 
Severe anemia (Hb <11/dL) 
 
Potassium or sodium above or below 
normal limit  
 
Uncontrolled thyroid disease 
(hypo/hyper) or requiring recent (past 
3 months) adjustments in thyroid 
hormone supplementation or thyroid-
stimulating hormone <0.45 or >4.5 
uIU/mL   
  
 
Stroke, heart attack, heart failure 
hospitalization, or revascularization 
procedure within the past year; New 
York heart failure Class >2; COPD 
requiring oxygen use; uncontrolled 
angina; PAD diagnosis within the last 
year; progressive neurologic disease 
(e.g., Parkinson’s, ALS, MS); other 
diseases suggesting a life-expectancy 
<3 years   
 
Cancer requiring treatment in past 
year, except non-melanoma skin 
cancers  
 
Cholelithiasis, severe irritable bowel 
syndrome or Crohn's disease  
 
Recent (within 4 weeks) acute 
respiratory illness, including confirmed 
Influenza or Coronavirus disease-19  
 
Major, uncorrectable vision or hearing 
loss 
  
  
  
  
  
  
  
  
 
 
 
 
Self-report  
 
 
 
 
 
 
 
  
  
 
Surgical/ 
hospitalization 
history 
  
 
Any history of stomach or small 
intestinal surgery (except 
appendectomy but including surgery 
for weight loss)  
 
Major abdominal, thoracic/spine or 
non-peripheral vascular surgery within 
past year 
 
Overnight hospitalization within past 6 
months for any reason 
Self-report 
  
  
  
  
 
 
Medication use 
  
 
Regular use of: growth hormones, 
medications prescribed for weight 
management, prescription 
osteoporosis medications, certain 
prescription medications for diabetes 
including insulin, sulfonylurea, 
meglitinides, GLP-1 agonists, SGLT2 
inhibitors 
 
Use of oral steroids for >1 month 
within prior 3 months  
 
Self-report  
Non-compliance 
  
 
Failure to complete behavioral and 
technology run-in  
 
Do not live within cellular signal 
coverage range 
  
Behavioral run-in 
  
Coverage map at 
screening 
  

 
 
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HALLO-P Protocol, Version 2.1 
Unable/unwilling to:  
 
Provide own transportation to study 
visits 
 
Commit to study protocol, including 
random assignment or use of 
technology  
 
Adhere to data collection visits 
Self-report 
Research 
participation 
  
 
Current participation in another 
intervention research study 
 
Planned out-of-town trip greater than 
3 weeks 
  
 
Unwilling to provide informed consent, 
including consent to access personal 
electronic health records 
 
Judged unsuitable for the trial for any 
reason by research team 
Self-report 
 
 
 
 
Principal  
Investigator / 
Medical Safety 
Officer 
1 Obesity-related comorbidities: 1) elevated waist circumference (>35” in women, >40” in men); 2) hypertension 
130-159 systolic or 80-99 diastolic (or on medication); 3) dyslipidemia (on medication or triglyceride >200 mg/dl or 
total cholesterol>240 mg/dl or LDL cholesterol>160 mg/dl); 4) controlled diabetes (Hba1c <7.5%); 5) other obesity-
related comorbidity: clinically manifest coronary artery disease [e.g., history of MI, angina pectoris, coronary artery 
surgery, coronary artery procedures (e.g., angioplasty) if not within the past year], other atherosclerotic disease 
[e.g., peripheral arterial disease, abdominal aortic aneurysm, symptomatic carotid artery disease if not within the 
past year], or sleep apnea. 
2 The Montreal Cognitive Assessment is a brief, standardized test of cognitive functioning. Higher scores indicate 
higher cognitive function, thus participants must score ≥22 to be eligible.  
3The Center for Epidemiologic Studies Depression scale is a 20-item self-report measure of depressive symptoms 
in adults. Scores of >15 indicate clinically significant depressive symptoms. 
4 The Binge Eating Disorder Screener-7 is a semi-structured interview and will be used to assess the presence of 
binge eating disorders. 
 
4.3 Study Enrollment Procedures  
Recruitment. Recruitment strategies will include a mix of community advertising via 
talks/seminars and IRB-approved flyers; advertising in the Wake Forest OAIC’s Volunteers in 
Touch with Active Living (VITAL) newsletter (distributed to 22,000+ older, community-
dwelling adults who provided informed consent to receive study recruitment newsletters), 
newspapers and other media outlets (e.g., tv, radio or social media); mass mailing of IRB-
approved study postcards; and mass mailing/emailing of IRB-approved letters of potentially 
eligible adults selected from WFBMC’s electronic medical record. 
Screening. Eligibility will be established based on an initial phone screen, a screening visit that 
includes a fasting blood draw for assessment of clinical blood chemistries and a bone 
densitometry test, and a short run-in period. Screening visit data will be entered into the study 
data management system. The system only permits a randomization assignment to be generated 
for participants who have complete eligibility assessment data and who meet all eligibility 
criteria. 
Consent and Enrollment. The first study contact will be a phone interview which is initiated 
based on a potential participant’s expressed interest in the study. On initial contact the 
interviewer will obtain and document verbal consent to collect basic demographic information 
(age, residence, sex, race/ethnicity). Then, the interviewer will describe the study and ask the 
participant if they are interested and whether they would be willing to do a phone administered 

 
 
14 
HALLO-P Protocol, Version 2.1 
questionnaire to establish eligibility. Eligibility questions that can be provided over the phone 
will be asked to establish eligibility for further screening. 
Participants who are eligible after the phone screen will be scheduled for an in-person screening 
visit. A trained study examiner will obtain full informed consent to participate in the study before 
any data collection. The informed consent form (ICF) obtains information describing both the 
screening and all other study procedures, including the intervention. The examiner will again 
describe the study and the requirements for participation, review the informed consent form in 
detail with the participant, and address any participant questions. Once the participant has had 
their questions addressed the participant will sign the informed consent and receive a copy for 
their records. The original signed consent will be placed in the participant’s study file. 
Participants are considered enrolled in the study after providing consent, but do not count 
towards the goal of ~100 until randomized. 
5 
STUDY INTERVENTIONS  
5.1 Interventions, Administration, and Duration  
The randomized study design for HALLO-P involves a target of approximately 100 participants 
randomized to one of three interventions: (1) in-person 20% caloric restriction (CR); (2) remote 
20% CR (see Calorie Restriction Goals below for more detail); (3) in-person 8-hour restricted 
eating (TRE). All 3 interventions last 9 months with both individual and group contacts delivered 
on an identical frequency in all intervention groups. For the first 6 months, participants meet 
weekly and then twice a month from months 6-9.  
 
The conceptual model that serves as the foundation for the caloric restriction (CR) and time 
restricted eating (TRE) interventions is depicted in the Figure below. Older adults’ ability to self-
regulate their eating behavior 
involves both conscious (65, 66) and 
nonconscious (67, 68) processes. 
Core conscious-based constructs 
include self-efficacy (69, 70), 
outcomes and outcome expectations 
(71, 72), and impediments to 
regulating eating behavior which 
often operate outside of conscious 
awareness. Nonconscious 
impediments include, among other 
factors detailed in the behavioral 
toolbox, physiological states that 
increase appetite and habitual 
patterns of eating conditioned to 
social (73) and environmental cues 
(74). People also engage in habitual patterns of eating to regulate the discomfort of negative 
emotions (71, 75).  
Key structural components of interventions for effective CR have evolved across time (76-82), 
and were progressively adopted by 4 major NIH funded multi-center clinical trials. These major 

 
 
15 
HALLO-P Protocol, Version 2.1 
advances have been integrated into our CR trials with older adults over this same period (58, 83-
85).  
 
 
5.1.1 The Use of a mHealth Platform for Adaptive CR and TRE Interventions 
 
Technological innovations (web-connected tablets, wearable monitors, and smart scales) now 
allow for behavior change strategies to extend into a person’s daily life and to be adaptive in near 
real time to participants’ progress. These tools offer improved approaches for self-monitoring 
key processes central to either CR or TRE and support other action plans important to successful 
treatment. Specific to the CR intervention, we will use an equation using in-home weights 
(captured with the smart scale) to model and monitor adherence to CR in real time, a strategy 
that was successful in CALERIE (82, 86) and will be adapted for HALLO-P. For the TRE 
intervention, we will track adherence to feeding schedules via the app using a Feedogram visual 
self-monitoring and feedback tool to quickly identify problems that arise. Importantly, 
interventionists also see the data from the app in real time and, when participants fall outside a 
“zone of adherence”, they can tailor strategies based on the conceptual model and toolbox 
discussed in greater depth in a separate document. A study-specific app named the Companion 
App will provide immediate reinforcement for achieving goals via mastery badges (87) and 
allows for interactive communication between participants and the intervention team. HALLO-P 
builds on experience garnered in several CR interventions with older adults for the past 4 years; 
(58, 87, 88) which has led to the development of methods to engage older adults in the design of 
the mHealth applications and provides hands-on training to optimize older adults’ comfort and 
confidence in use of the technology (58, 88).  
 
5.1.2 The HALLO-P Interventions  
Overall Design. For the first 6 months of intervention, participants in all three groups will meet 
as follows: (a) 1 time each month individually with a behavioral coach and/or a Registered 
Dietitian (RD) as needed; and (b) 3 times per month in a group setting. The groups will be 
formed in waves as participants join the study with the size of each group between 8-12 
participants. Participants in the CR group will keep diet records using a smartphone/tablet (study 
to provide) and record home weight using a BodyTrace™ electronic smart scale that transmits 
data to the center automatically and provides a vehicle for interventionists to adapt the 
intervention as needed for each participant. Those in TRE will log into the app each day to 
document the beginning and end of their feeding cycles with timing of meals/snacks consumed. 
These data also provide a vehicle for interventionists to adapt the intervention as needed as in the 
CR group. It is also important to note that all 3 intervention groups include a physical activity 
component that aims to have participants “move more and move more often across the day.” We 
will provide Fitbit step monitors as a means of tracking activity with the initial goal of increasing 
daily steps by 20% from baseline levels and spreading out movement across the day and 
incorporating additional weight-bearing physical activity such as step-ups and stair climbing. To 
ensure participants’ understanding of the requirements of their intervention assignment, each 
participant will receive a brief group-specific nutrition orientation following randomization but 
prior to the start of the intervention. Likewise, each participant will receive a brief group-specific 
technology orientation designed to build confidence in the use of technology following 
randomization and before the start of the intervention. The group sessions will be used to create a 
sense of community with others, educate and discuss with participants the health benefits of 

 
 
16 
HALLO-P Protocol, Version 2.1 
either CR or TRE, share experiences with the interventions, and facilitate group problem solving. 
During months 7-9 of the intervention, there will be one group and one individual meeting each 
month.  
 
The key difference between the remote and in-person CR arms is that the remote arm will be 
delivered via video conferencing, leveraging unique group formation activities (e.g., breakout 
rooms, ice breakers) developed in a recently completed pilot study (88). The TRE group does not 
monitor caloric intake or body weight. For similarities and differences between intervention arms 
see the table below. 
 
 
From a behavioral perspective, adherence to all 3 interventions is guided by a common 
framework for implementing this conceptual model using a toolbox to facilitate dietary goals. In 
addition, whereas the primary objective of the individual sessions is to tailor treatment, all 3 
intervention arms receive training in key areas related to the specific goals of the intervention; 
these are reinforced through both individual and group sessions whether these are in-person or 
remote.  
5.1.3 Use of mHealth App and Tracking Appetite Metrics  
Relying on our conceptual model, the interventions will combine specific nutritional and 
behavioral guidance for each participant to achieve adherence to treatment goals. Coaches and 
the RD have the ability to select specific nutritional and behavioral/environmental strategies 
Common Elements and Distinctions between HALLO-P Intervention Groups 
Component 
In Person CR (Waves 1-3 
only – 1st 66pp) 
Remote CR 
Time Restricted Eating 
(TRE) 
Individual Sessions 
(10-40 min by need) 
1 i per month (in-person, 
video or by phone)  
1 videoconference / call monthly  
1 per month (in-person, 
video or by phone) 
Group Sessions (30-45 
min each) 
3 in-person monthly for first 6 
months; 1 monthly thereafter 
3 videoconference calls monthly 
for first 6 months; 1 monthly 
thereafter 
3 in-person monthly for 
first 6 months; 1 monthly 
thereafter 
mHealth App 
Graphic feedback on zone of 
adherence & movement, 
group chat, within-day 
surveys 
Graphic feedback on zone of 
adherence & movement, group 
chat, within-day surveys 
Graphic feedback on 
feeding windows & 
movement, group chat, 
within-day surveys 
Physical Activity 
Increasing steps throughout 
the day with an initial 
increase of ~20% with 
progression based on the 
ability and tolerance of each 
participant 
Increasing steps throughout the 
day with an initial increase of 
~20% with progression based on 
the ability and tolerance of each 
participant 
Increasing steps 
throughout the day with an 
initial increase of ~20% 
with progression based on 
the ability and tolerance of 
each participant 
Dietary Goal 
20% caloric restriction (CR) 
20% CR 
8h Time Restricted Eating 
(TRE); no CR 
Use of toolbox 
Yes 
Yes 
Yes 
Computer Tracking 
Yes 
Yes 
Yes 
Mathematical Derived 
Weight Goals for CR 
Yes 
Yes 
No 
Objective Marker of 
Adherence: CR/TRE 
Doubly-labeled Water 
Doubly-labeled Water 
Continuous Glucose 
Monitoring 

 
 
17 
HALLO-P Protocol, Version 2.1 
from a “toolbox” based on individual needs (see the separate toolbox document in MOP). Using 
the HALLO-P mHealth app, participants in both CR groups will: (a) track the content of all food 
intake and body weight each day for the first two months and then at least every other week 
thereafter; (b) receive feedback in near real time that tracks participants’ daily weights, 
providing feedback and, when necessary, near real time adaptation to the intervention so that 
they remain in their personalized “zones of adherence” to the trajectory of weight across time 
using a predicted model developed by Hall et al. (89); (c) receive feedback on total calories, the 
average daily calories consumed each week, and the average calories consumed each month; (d) 
receive reinforcements in real time for meeting study goals in the form of both “mastery” badges 
(88) and app notifications; and (e) following an ecological momentary assessment (EMA) 
protocol (i.e., collection of responses in participants daily life with an app) report on several 
appetite related metrics across the day (this feature is turned-on during the first month of the 
study and for a week during every month thereafter)—these data will be utilized to provide 
feedback on patterns of appetite throughout the day.  
 
For the TRE group, participants will use the Feedogram as part of the app to track the beginning 
and end of their eating cycle each day along with meals/snacks consumed, for the first two 
months and then at least every other week thereafter for month 3-6, and at least one week in each 
month for months 7-9. The app also enables participants to: (a) receive prompts when outside the 
zone of adherence for TRE, (b) receive feedback each day on their success in meeting the TRE 
interval; receive weekly and monthly feedback on the %frequency of meeting the TRE interval; 
(c) receive reinforcements for meeting study goals in the form of both badges and app 
notifications; and (d) following an EMA protocol report on several appetite related metrics across 
the day. 
 
Daily physical activity level, body weight (CR groups only), macronutrient intake (CR groups 
only), timing of meals/snacks (TRE group only), and Companion App usage will be tracked 
using the Companion App suite during the 9-month pilot as these data will be integral to the 
provision of each intervention. Daily physical activity will be monitored using the Fitbit. 
Participants will synchronize the device throughout the day using an anonymized account on the 
study-provided tablet. These data will be retrieved in near-real time from Fitbit servers using the 
Fitbit Web application programming interface (API) and stored in secure internal servers. For 
those in the CR arms, we will use a BodyTrace smart scale to collect daily body weight from 
each participant. This device is equipped with an AT&T cellular data chip that wirelessly 
transmits weight data in real time. We will retrieve the weight data using the BodyTrace API. 
Participants in the CR arms will use the Fitbit app on the study-provided tablet to track dietary 
intake. Participants will receive the tablet with the app signed into an anonymized account. The 
intervention team will have access to daily macronutrient reports through the website to assist in 
providing feedback to participants, and these data will be exported from the web portal by the 
intervention team for each participant at the end of the pilot study. Participants in TRE arm will 
log into the Companion App each day to document the beginning and end of their feeding cycles 
with timing of meals/snacks consumed. 
 
5.1.4 Toolbox 
 
All 3 interventions are adaptive, meaning that strategies used to modify eating and movement 
behavior in CR and the timeframe for food consumption in TRE are implemented in near real 

 
 
18 
HALLO-P Protocol, Version 2.1 
time when participants’ weights in CR or timeframe for food consumption in TRE deviate from 
established zones of adherence. The behavioral toolbox to guide the selection of strategies is 
based on a conceptual model which is part of the toolbox and serves as the foundation for 
understanding eating behavior. The intervention guide document details the algorithms for 
implementing the toolbox which is activated by way of tracking daily data via the mHealth app 
on all participants.  
 
5.2 Handling of Study Interventions  
5.2.1 Caloric Restriction Goals: The calorie level assigned for each person assigned to one of 
the CR groups will provide him/her with a daily caloric deficit of approximately 20%.  The 
individual absolute calorie level is derived from subtracting 20% from each person’s estimated 
daily energy needs for weight maintenance.  The calorie level assigned for each person assigned 
to one of the CR groups will provide him/her with a daily energy intake (EI) approximately 20% 
lower than his/her baseline EI. Baseline EI will be determined by measuring Total Energy 
Expenditure obtained by DLW from Baseline Visit 1 and 2, or through estimating EI using body 
weight and composition, resting energy expenditure and physical activity level.   
No woman will be prescribed with less than 1100 kcals/d and no man less than 1300 kcals/d. 
 
5.3 Concomitant Interventions 
HALLO-P will deliver the step intervention to all 3 groups, using Fitbits to track and feedback 
activity data to participants via the companion app. The goal will be to promote daily movement; 
increasing daily steps from baseline. Also, participants will be advised to consume calcium (up 
to 1200 mg/d) and vitamin D (800 IU/d) supplements to mitigate the risk of BMD loss. The RD 
will also promote consuming 90 g of protein/day evenly distributed across daily meals in the CR 
groups; a target monitored via the tracking app for food intake. Finally, a high-quality diet 
focusing on eating patterns promoting satiety over the fasting period will be recommended to 
TRE participants.  
5.4 Adherence Assessment  
The primary measure of adherence to the CR regimen will be the change in energy intake from 
baseline to 9 months calculated using the DLW-measured change in TEE in conjunction with the 
DXA-measured fat and lean body mass changes over 9 months. 
Change in self-reported energy intake will be a secondary adherence measure. 
Change in scale-measured body weight in line with our model of expected body mass loss under 
the assumption of 20% CR is a secondary measure of adherence.  
Adherence to the TRE regimen will be assessed through data collected by the Companion App 
where participants will log occasions of caloric ingestion during waking hours. Participants will 
be considered compliant if they consumed calories within an 8-hour window on 80% of days. An 
objective secondary measure of adherence will be through the use of continuous glucose 
monitoring for 10-day intervals using spiking glucose blood levels as a biomarker of caloric 
intake.  
 

 
 
19 
HALLO-P Protocol, Version 2.1 
6 
STUDY PROCEDURES 
 

 
 
20 
HALLO-P Protocol, Version 2.1 
6.1 
Schedule of Evaluations 
HALLO Pilot Study Measurements 
Phone 
screen 
Screening 
visit 1 
Screening 
visit 2 
Baseline 
visit 1 
Baseline 
visit 2 
Inter- 
vention 
6-
month 
visit 
Inter- 
vention 
9 month 
visit 1 
9 month 
visit 2 
Visit Code 
TSI 
SV1 
SV2 
BV1 
BV2 
INT 
FV1 
INT 
FV2 
FV3 
Screening & safety assessments 
 
 
 
 
 
 
 
 
 
 
Phone screen/phone consent 
x 
 
 
 
 
 
 
 
 
 
Screening visit: Informed 
consent/HIPAA form, demographics, 
CES-D. Montreal Cognitive 
Assessment (MoCA), Binge Eating 
Disorder Screener-7, Readiness to 
change survey 
 
x 
 
 
 
 
 
 
CES-D, 
MoCA 
 
7-day behavioral and technology run-
in 
 
 
x 
 
 
 
 
 
 
 
Vital signs 
(height/weight/BP/pulse/waist 
circumference) 
 
x 
 
 
 
 
x 
 
x 
 
Medical history and medications 
 
x 
 
 
 
 
 
 
 
 
Blood lipids, HbA1c, CMP, CBC, TSH  
 
x 
 
 
 
 
 
 
x 
 
Extra tube of blood (SST) for 
instrument QC 
 
x 
 
 
 
 
 
 
 
 
DXA body composition (whole body) / 
bone density (hip, lumbar spine) 
 
x 
 
 
 
 
  
 
x 
 
Medication Updates/Health Status 
Updates  
 
 
x 
x 
x 
x# 
 x 
x# 
x  
x 
Siteman cancer online risk 
assessment & Cancer Screening 
Questionnaire  
 
 
 
 
 
 
x 
 
 
 
Intervention process and 
adherence measures & 
feasibility/acceptability 
 
 
 
 
 
 
 
 
 
 
Total energy expenditure (TEE; 
doubly-labeled water) 
 
 
 
 
dose / 
collect 
urine 
  
collect 
urine 
 
 
 
dose / 
collect 
urine 
collect 
urine 
Physical activity energy expenditure 
(PAEE; ActivPAL) 
 
 
 
dis-
pense 
return 
 
 
 
dispense 
return 
Continuous glucose monitoring 
(CGM)* 
 
 
 
 
 
x 
 
x 
 
 

 
 
21 
HALLO-P Protocol, Version 2.1 
HALLO Pilot Study Measurements 
Phone 
screen 
Screening 
visit 1 
Screening 
visit 2 
Baseline 
visit 1 
Baseline 
visit 2 
Inter- 
vention 
6-
month 
visit 
Inter- 
vention 
9 month 
visit 1 
9 month 
visit 2 
Questionnaires/Computerized Task: 
Power of Food Scale; Weight Efficacy 
Lifestyle Questionnaire; Food Craving 
Inventory; SF-36; Perceived Stress 
Scale; PROMIS 13a Fatigue Scale; 
Pittsburgh Fatiguability Scale; 
Pittsburgh Sleep Quality Index; 
PROMIS Interest in Sexual Activity; 
Emotional & Uncontrolled eating; 
Walking Self-Efficacy; Delayed 
Discounting, STOP & Epworth 
Sleepiness questionnaires 
 
 
 
x 
 
 
 
 
x 
 
 
Night Eating Assessment 
 
 
 
x 
 
 
 
 
 
 
Ecological momentary assessments 
(EMA) of hunger, desire to eat, and 
anxiety by study Companion App, 
Fitbit physical activity monitor, Body 
Trace smart scale^, App-based 
dietary tracking^ 
 
 
 
 
 
x 
 
x 
 
 
Interview: Positive/Negative 
Outcomes Associated with CR and 
TRE, Closeout Survey 
 
 
 
 
 
 
 
 
 
x 
 
Clinical/biological outcomes 
 
 
 
 
 
 
 
 
 
 
Resting energy expenditure (REE) 
 
 
 
x 
 
 
 
 
x 
 
Biomarker assays 
 
 
 
x 
 
 
x 
 
x 
 
Biological sample storage including 
blood and urine 
 
 
 
x 
 
 
x 
 
x 
 
D3 creatine dilution (d3cr) 
 
 
 
x 
 
 
 
 
x 
 
Physical performance/strength:  
Expanded Short Physical 
Performance Battery (eSPPB) / 
expanded SPPB, 400 meter walk 
(fast), grip strength 
 
 
 
 
x 
 
 
 
 
x 
24-hour dietary recalls (ASA24) 
 
 
 
x 
 
 
 
 
x 
 
 
*- TRE only – at ~3mo (weeks 8-12) and ~8 months (weeks 28-32) 
^- CR only 
# Commons signs and symptoms will also be assessed monthly during intervention at the individual sessions.  

 
 
22 
HALLO-P Protocol, Version 2.1 
6.2 Description of Evaluations  
Study evaluations include: 1) assessments of eligibility (Telephone screening interview, 
Screening Visit 1 and Run-In/Screening Visit 2) and safety (queried at each clinic visit and 
monthly during intervention), 2) outcome assessments (conducted during two baseline visits, a 6-
month follow-up visit, and two 9-month follow-up visits), and 3) assessments of adherence 
(collected during intervention) according to the schedule in Table 6.1. Details about each 
evaluation are below. We will follow the above table as best we can but may need to adjust the 
visit schedule depending on availability of staff, equipment, etc. 
6.2.1. Screening Visit 1 (SV1). Participants who remain eligible for the study following the 
phone screening will be scheduled for an in-person Screening Visit to continue assessing the 
study inclusion/exclusion criteria. Participants will be asked to fast for at least 10 hours the night 
before this visit and will first sign consent prior to any study measures consisting of the 
following: 
 Vitals (height, weight, BP, pulse, waist circumference) 
 Readiness to change survey indicating they are willing to change behavior and comply 
with intervention 
 Blood draw for lipids, comprehensive metabolic panel (CMP), complete blood count 
(CBC), thyroid stimulating hormone (TSH), HbA1c, and blood for biomarker instrument 
quality control (20ml or ~1 Tbsp) 
 Snack, then whole body, hip, and lumbar spine DXA for body composition and bone 
density measurements 
 Medical history and medications will be ascertained via self-report. 
 Questionnaires including the following: demographics, Center for Epidemiological 
Studies Depression (CES-D), Montreal Cognitive Assessment (MoCA), and the Binge 
Eating Disorder Screener-7 
If blood chemistries, bone densitometry, or any other items measured at the screening visit are 
exclusionary, the participant will be contacted by the study staff and excused from the study with 
referral to a health care provider if necessary. Testing may be repeated on a case-by-case basis 
for re-evaluation.  
6.2.2. Screening Visit 2 (SV2) / Run-in evaluation. All participants who remain eligible for the 
study following the SV1 will be scheduled to return for a visit to begin the process of a 
behavioral run-in. During this visit, participants will be provided with a BodyTrace cellular-
enabled scale and an iPad tablet computer. Participants will receive a self-efficacy-based 
orientation designed to develop confidence in the use of each tool, and will practice weighing 
using the scale and logging their foods and beverages onto a paper food record. They will be 
asked to place the scale on a hard and even surface and to weigh daily for 7 days. During this 
same 7-day period they will also be asked to record the type and amount of food and beverages 
consumed and document the start and stop time of all foods and beverages each day on a paper 
log. Participants are asked to take a picture of their paper log and email it to the study team after 
completing their 7th day to help the assessors determine eligibility prior to their next visit. 
Participants will receive a “frequently asked questions” handout containing key information for 
each tool and will receive a follow-up call on the first day of the assessment window (i.e., the 

 
 
23 
HALLO-P Protocol, Version 2.1 
day following SV2) to ensure the participant is able to use the technology and food record. 
Successfully completing the behavioral run-in will be marked by: 1) completing at least five 
daily weights, 2) completing five full days of food logging as determined by the study staff and 
3) eating at least an average of 11 hours each day.  
We will assess for any potential adverse events / change in medical history and medications at 
this visit as well. 
All eligibility will be verified before scheduling or conducting Baseline Visit 1.  
We will provide the participant with a tablet with 30mg of d3-creatine and instructions on when 
to take it 72-144 hours prior to their baseline visit 1. Urine is collected with the participant 
fasting at their baseline visit 1. Deidentified samples will be sent to Dr. Evans’s laboratory at 
University California, Berkeley where labeled creatinine will be assayed. 
6.2.3. Baseline Visits 1 and 2. Following confirmation of meeting all eligibility criteria and after 
approval to participate from the study clinician or his/her designee, there will be two baseline 
study visits. The two visits will be conducted after approximately 10-15 days, but ideally 
between 12-14 days apart to allow for the follow-up collection of urine for the TEE 
measurement.  
Baseline Visit 1 (BV1) evaluation procedures include the participant coming in fasting for the 
following:  
 Blood draw (completed after the REE) and urine collection for biomarker assays 
and biospecimen archive: 
 Venous blood samples will be collected in the morning following a fast of 
at least 10 hours. Total blood volume collected is estimated at 69.5 ml (~5 
Tbsp) at baseline, including: 
 Serum 
 plasma (EDTA and plasma citrate) 
 whole blood in ACD or CPT tubes for cell and DNA isolation 
 blood in RNA stabilizer tube 
 Urine will be collected per doubly-labeled water assessment of energy 
expenditure as well as for storage (pre-dose urine will be stored) and for 
the d3cr. 
 Biomarker assays. We will measure pre-specified blood-based biomarkers 
including but not limited to: fasting insulin, interleukin-6 (IL-6), tumor necrosis 
factor soluble receptor I (TNFRI), cystatin C, and CRP from serum. Additional 
biomarkers may be measured using serum, plasma, or urine. This panel will be 
expanded to include additional biomarkers supported by the NCI supplement and 
includes the Luminex Performance Human XL Cytokine Panel - NEW (25-Plex) 
FCSTM18B-25 
 DNA methylation biomarker. Cells and blood will be collected for DNA/RNA 
isolation and molecular measures such as DNA methylation. However, there is no 
plan to use DNA for genome sequencing; the anticipated use is to measure DNA 

 
 
24 
HALLO-P Protocol, Version 2.1 
CpG site methylation for a biomarker of “epigenetic age” and another candidate 
aging biomarker, telomere length. 
 Biospecimen archive. Serum, plasma, citrate plasma, urine, whole blood, and 
urine will be collected and stored for use in future ancillary studies. After 
processing, aliquots will be stored at -80ºC or liquid nitrogen until analyses. 
 Total Energy Expenditure (TEE) will be assessed using doubly labeled water. 
This method, which provides the most accurate assessment of free-living daily 
energy expenditure, is based upon the principle that oxygen atoms in body water 
and exhaled carbon dioxide are in equilibrium. Oxygen atoms are eliminated from 
the body as both water (H2O) and exhaled carbon dioxide (CO2), whereas 
hydrogen atoms are eliminated as water only. The difference between the 
elimination rates of oxygen and hydrogen from body water represents a measure 
of carbon dioxide flux, which is proportional to total energy expenditure.  
Participants will provide a baseline urine sample after which they will consume a 
DLW dose which will provide approximately 2.2 g 10% H2 18O per kilogram 
total body water and 0.14 g per kilogram total body water of 99% 2H2O. After 
consuming the DLW dose, participants will be instructed to lay quietly for 
approximately 20-30 minutes before initiating the resting energy expenditure test 
after which further urine samples will be collected approximately 4.5 and 5 hours 
after dosing, while any urine voids before 4.5 hours will be discarded. Two 
aliquots of each urine sample will be placed in pre-labeled tubes, stored in freezer 
boxes at -80°C and shipped in batches to Dr. DeLany’s lab at the Advent Health 
Orlando, Translational Research Institute in Florida for analysis.  
 Resting energy expenditure (REE) will be measured in the morning after at least a 
10-hour fast using indirect calorimetry (MCG Diagnostics, St. Paul, MN).  
 Physical activity energy expenditure (PAEE), including light and moderate to 
vigorous physical activity as well as sedentary behavior, will be objectively 
assessed over approximately a 10-15-day period using the  ActivPAL™ 
accelerometer (PAL Technologies, Glasgow, Scotland). 
 Dietary intake: 24-hour Dietary Recalls (ASA24) - Three 24-hour dietary recalls 
(two weekdays and one weekend day) will be collected on all participants. 
Participants will be asked to recall and report their dietary intake (foods and 
beverages) from the previous day’s 24-hour period. Participants will complete the 
first of their 24-hour dietary recalls during the visit and then be prompted to 
complete 2 additional 24-hour dietary recalls on their own using the study-
provided tablet prior to Baseline Visit 2. Data will be collected and nutrients and 
food groups analyzed using the publicly available National Cancer Institute’s 
Automated Self-Administered 24-Hour (ASA24) dietary assessment tool 
(https://epi.grants.cancer.gov/asa24). 
 We will assess for any potential adverse events / change in medical history and 
medications at this visit as well.  
 Questionnaires 

 
 
25 
HALLO-P Protocol, Version 2.1 
 Power of Food Scale assesses an individual’s drive to consume palatable 
food in an obesogenic food environment (90). 
 Weight Efficacy Lifestyle Questionnaire assesses participants’ confidence 
in their ability to self-regulate eating behavior in the face of common 
barriers (69). 
 Perceived Stress Scale assesses how uncontrollable and stressful life has 
been over the past week or month (91). 
 Walking Self-Efficacy assesses participants’ perceived ability to walk 
certain lengths of time at a moderate pace without stopping (92)  . 
 Quality of Life will be assessed using the Short Form-36 Health Survey 
(SF-36) (93). 
 Delayed Discounting assesses participants’ ability to delay seeking 
immediate rewards of less value for longer-term rewards of greater 
value—delay of gratification (94). 
 Food Craving Inventory & Emotional & Uncontrolled Eating(95) 
 An abbreviated emotional and uncontrolled eating questionnaire 
assesses participants’ degree of emotional eating and/or eating in 
which they feel as though they have lost control.  
 Three sleep/fatigue questionnaires will be administered: 1) PROMIS 13a 
(FACIT – Functional Assessment of Chronic Illness Therapy) Fatigue 
Scale (96); 2) Pittsburgh Fatigability Scale (97); and 3) Pittsburgh Sleep 
Quality Index (98) 
 Libido will be assessed using the PROMIS Interest in Sexual Activity 
questionnaire (99). 
 Participants who self-report ≥2 episodes of Night Eating during the 7-day 
run-in are identified for potential exclusion due to the night eating 
syndrome (NES). Participants who do self-report ≥2 episodes of night 
eating, are contacted for phone for additional follow-up. Specifically, 
participants are told that we would like to verify and expand upon 
information that was provided via the run-in food record data. Using an 
interview format, participants are queried about night eating using the 
Night Eating Questionnaire (NEQ) (116). 
 Sleep apnea risk will be assessed using the STOP Questionnaire (100). 
 Sleepiness will be assessed by using the Epworth Sleepiness Scale that 
assesses how likely someone is to doze off or fall asleep in different 
situations (101).   
 
Baseline Visit 2 (BV2). After approximately 10-15 days, the participant will come to the clinic 
and will return their ActivPal. Two urine samples will also be collected, at least 30 mins apart, to 
complete the DLW test for the TEE calculation. At this visit, the participant will be instructed 

 
 
26 
HALLO-P Protocol, Version 2.1 
not to change anything about their diet or exercise behavior prior to the intervention starting. We 
will also perform the following physical performance/strength tests:  
 The Short Physical Performance Battery (SPPB) is a widely used 
assessment of lower extremity physical function which includes 
progressively more challenging standing balance tasks held for 10 seconds 
each (side-by-side, tandem and semi-tandem), the faster of two 4-m walks 
to assess usual gait speed, and time to complete 5 repeated chair stands. 
Each of the three performance measures is assigned a score ranging from 0 
(inability to do the test) to 4 (the highest level of performance) and 
summed to create an SPPB summary score ranging from 0 (worst) to 12 
(best) (102). We will also administer the components of the expanded 
Short Physical Performance Battery (eSPPB) which was modified from 
the original SPPB to increase the holding time of the semi- and full-
tandem stands to 30 seconds and add a single leg stand and a narrow walk 
test of balance (walking at usual pace within lines of tape spaced 20 cm 
apart) (103).
 The fast 400 meter walk is a walking-based test of exercise tolerance and 
aerobic fitness. Participants are instructed to walk 400 m (10 laps of a 20-
m course) on a flat indoor surface as quickly as possible at a maintainable 
pace and the time to complete the walk is recorded in minutes and seconds 
(103).
 Grip strength will be measured twice in each hand using an isometric 
hydraulic hand dynamometer (Jamar, Bolingbrook, IL). Participants will 
be excluded from performing the test if they report hand-pain or recent 
hand or wrist surgery.  
We will assess for any potential adverse events / change in medical history and medications at 
this visit as well. 
6.2.4 Randomization Procedure 
Participants will be randomized after attending their Baseline Visit 2 according to the block (by 
sex) randomization scheme developed by the study statistician. An unblinded study staff member 
will call the participant and, after reconfirming their willingness to be randomized, will inform 
them of their group assignment and their planned intervention start date and time. Randomization 
date will be documented and will occur within approximately 12-16 weeks of the initial 
Screening Visit, but within approximately 4 weeks of their intervention start date. 
6.2.5 Six-month Follow-up Visit 1 (FV1) 
There will be one interim follow-up visit after approximately 22-26 weeks of intervention for 
each group. All assessments during this visit will be conducted by assessors blinded to the 
randomized group assignment of the participant. Participants will come in fasting and will have 
the following assessments: 
o Vital signs and waist circumference 
o Blood for archival storage and the expanded 25 panel biomarker assessment 
funded through the NCI supplement. Venous blood samples will be 

 
 
27 
HALLO-P Protocol, Version 2.1 
collected in the morning following a fast of at least 10 hours. Total blood 
volume collected is estimated at 36.5 ml (~2 Tbsp), including: 
 serum 
 plasma (EDTA and plasma citrate)  
o Urine Collection for storage 
o Siteman online cancer risk assessment (117) & Cancer Screening 
Questionnaire (Both may be done at a later visit or by phone for those who 
have completed all visits).  
6.2.6 Nine-month Follow-up Visits 2 and 3 
There will be two follow-up evaluation visits after approximately 34-40 weeks of 
intervention for each group. All assessments during these visits will be conducted by 
assessors blinded to the randomized group assignment of the participant. 
9-Month Follow- Visit 2 (FV2) - Fasting 
o Vital signs with waist measurement 
o Blood lipids, insulin, HbA1c, CBC, CMP, HbA1c, TSH 
o Fasting blood draw and urine collection for biomarker assays, DLW, d3cr 
and biospecimen archive: see Baseline Visit for detail, but with lower 
sample volume for archive. Total blood volume collected is estimated at 
85.5 ml (~6 Tbsp), including: 
 serum 
 plasma (EDTA and plasma citrate) 
 whole blood in ACD or CPT tubes for cell and DNA 
isolation  
 blood in RNA stabilizer tube 
o Resting Energy Expenditure  
o 24-hour Dietary Recalls (ASA24) 
o Doubly-labeled water (DLW Dosing) and urine collection for TEE 
o Physical activity energy expenditure using ActivPAL 
o DXA (Whole Body, Hip & Lumbar Spine) 
o CES-D 
o MoCA 
o Power of Food Scale 
o Weight Efficacy Lifestyle Questionnaire 
o Perceived Stress Scale 
o Delayed Discounting  
o Food Craving Inventory & Emotional & Uncontrolled Eating 
o Walking Self-Efficacy 
o SF-36  
o PROMIS 13a (FACIT) Fatigue Scale, Pittsburgh Fatigability Scale, and 
Pittsburgh Sleep Quality Index 
o PROMIS Interest in Sexual Activity questionnaire 
o Interim Medical Events / Adverse Events  
o STOP Questionnaire 

 
 
28 
HALLO-P Protocol, Version 2.1 
o Epworth Sleepiness Scale 
9-Month Follow-up Visit 3 (FV3): Final Evaluation 
o Final Medical Events / Medication Updates / Adverse Events 
o Doubly-Labelled Water (Final Urine Collections) 
o Physical Activity Energy Expenditure (Return of ActivPAL device) 
o Short Physical Performance Battery (and expanded SPPB)  
o Fast 400 meter walk 
o Grip strength 
o Participant evaluations of CR or TRE. We will ask participants to list any 
positive or negative outcomes that they associate with either the CR or TRE 
intervention. Participants are limited to identifying a maximum of 5 
outcomes in each category (they can report none). For each outcome listed, 
they are asked to rate how important each one was to either adhering or not 
adhering to the goals of the intervention.  
o Participant Satisfaction. Participants will be asked to rate a series of 
questions using a Likert scale and complete a series of open-ended 
questions assessing the acceptability of each key intervention component 
they received using questions modeled on our previous work and will assess 
their willingness to continue the intervention for longer durations (i.e., 
4yrs). 
We may contact some or all participants roughly one year after the end of their participation to 
ask about their weight and if it’s changed in the last year. This will be optional for participants 
and will not be considered outcome data.  
6.2.7 Assessments conducted during intervention: 
 Continuous Glucose Monitoring. Continuous glucose monitoring (CGM) will 
assess time in the fasting state in the TRE group using a continuous glucose 
monitor (G6 Pro, Dexcom) at approximately 3 months (weeks 8-12) and 8 months 
(weeks 28-32). The CGM records interstitial glucose concentrations every 5 
minutes for up to 10 days and will be in blinded mode so the participant cannot 
see their values. Although it measures glucose levels in the interstitial fluid – and 
not blood glucose levels – it has been demonstrated to be accurate in the 
comparison with capillary blood glucose results with the correlation between 
CGM and capillary blood glucose results of 0.95 (104, 105). The CGM is placed 
on the lower abdomen using a one-touch applicator by an unblinded study staff 
member.  
 Ecological Momentary Assessments of Hunger, Desire to eat and Anxiety (6 
assessments during 7 days of months 1, 4 and 7): Within the mHealth Companion 
App we will prompt participants to complete six brief (<60 seconds) ecological 
momentary assessments (EMAs) each day (waking, late morning, lunch, 
afternoon, dinner, bedtime) of hunger, desire to eat, and anxiety during 7 days of 
months 1, 4 and 7. Participants note their hunger in response to the question “to 

 
 
29 
HALLO-P Protocol, Version 2.1 
what extent are you hungry right now?”, with responses ranging from “no 
hunger” to “extreme hunger”. Participants note their desire to eat in response to 
the question “to what extent do you have a desire to eat right now?” with 
responses ranging from “no desire” to “extreme desire”. Anxiety will be rated in 
response to the question “how anxious do you feel right now?” with responses 
ranging from “no anxiety” to “extreme anxiety”. All responses are provided using 
a slider with values (which are hidden to the participant) ranging from 0-1000 to 
simulate a continuous slider. 
7 
SAFETY ASSESSMENTS  
The safety of HALLO-P’s participants is of paramount importance and will be monitored upon 
enrollment in the study. Enrollment starts after a participant gives verbal consent to be phone 
screened. The HALLO-P interventions are generally regarded as safe, as the entry criteria are 
based on the public health-based indications for weight loss.   
Nevertheless, the study’s entry criteria are designed to screen-out those for whom CR or TRE 
may have potentially adverse effects. These include: a history of eating disorders, moderate -
severe anemia, uncontrolled hypertension, uncontrolled thyroid disease, osteoporosis, a high risk 
of fracture, and uncontrolled diabetes. 
7.1 Specification of Safety Parameters 
Exclusion due to potential safety concerns:  
o Osteoporosis (self-report, osteoporosis medication, or DXA t-score ≤ -2.5 on total 
hip and/or femoral neck scan) 
o Self-Report of Type 1 diabetes, use of insulin 
o Self-Report of a new diagnosis of Type 2 diabetes (within one year) or newly 
discovered (elevated HbA1c > 6.5 at screening), use of some medications used to 
treat diabetes or HbA1c >7.5% 
Exclusions for Conditions associated with dietary management that might conflict with a study 
intervention. These can be rechecked two weeks later if needed to confirm exclusion.  
o Uncontrolled hypertension (>160 systolic OR >100 mmHg diastolic) 
o Dialysis or abnormal kidney function (eGRF <30 mL/min/1.73 m2) 
o Liver disease or abnormal liver function (ALT levels 2 times above normal)  
o Moderate-Severe anemia (Hb <11g/dL) 
o Potassium or sodium above or below normal limit  
o Uncontrolled thyroid disease (hypo/hyper) or requiring recent (past 3 months) 
adjustments in thyroid hormone supplementation or TSH <0.45 or >4.5 uIU/mL 
 
7.2 Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters 
All participants will be queried for safety events at each assessment visit after the screening visit, 
and on a monthly basis during intervention at the individual sessions. Both open-ended questions 
and pre-defined questions of symptoms relevant to common risks of the assessments and 

 
 
30 
HALLO-P Protocol, Version 2.1 
interventions will be asked. All AEs reported to study staff (including those not discovered 
during the monthly queries) will be recorded using the study’s Adverse Event Reporting Form.  
AEs and SAEs will be coded and summarized using MedDRA coding and intervention group, 
with the number of participants and percentage reporting the event.  The study investigators, 
except for Dr. Miller and Ard, will be blinded to review of AEs/SAEs by intervention group. 
Drs. Miller and Ard will review AEs on a quarterly basis and the study mPIs will review AEs 
blinded to intervention status.  
7.3 Adverse Events and Serious Adverse Events  
All participants will be queried at each assessment visit regarding any change in health or 
physical status using the Health Status Questionnaire and any AEs will be reported using the 
IRB-approved Adverse Event Reporting form and the running medication log will be updated, as 
needed. Expected events (signs and symptoms) will be assessed monthly by unblinded 
interventionist.  All AEs reported to study staff, including unsolicited AEs (not including those 
discovered during the monthly queries) will be recorded using the study’s Adverse Event 
Reporting Form. Study staff will try to match-up unsolicited AEs with events reported per 
scheduled assessment. Those that do match will be handled through the routine system will be 
followed and flagged, and reported separately when AEs are summarized. A summary of the 
expected AEs will be reported from the signs and symptoms questionnaire, but an AE form and 
evaluation is not required for these common events.  
The AE form includes a section for classifying the AEs: 1) Severity, 2) Expectedness 
(Expected—event is known to be associated with the intervention or assessment activity or 
Unexpected—not expected or consistent with known information regarding the activity), and 3) 
Relatedness to the study intervention (Definitely Related, Possibly Related, or Not Related).  
Double capture of AEs (e.g., a participant providing an unsolicited report and a second report of 
the same event at an ascertainment visit) is identified through assigning unique event numbers to 
AEs, which are then used to link repeated reports within the data capture system. Filtering out of 
repeated capture of the same event is done during report generation  
 
 
7.3.1 Adverse Event (AE): Any untoward or unfavorable medical occurrence in a clinical 
research study participant, including any abnormal sign (e.g., abnormal physical exam or 
laboratory finding), symptom, or disease, temporally associated with the participants’ 
involvement in the research, whether or not considered related to participation in the research. 
These will be assessed at each clinic visit and monthly during intervention 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the 
attention of study personnel during study visits and interviews of a study participant presenting 
for medical care, or upon review by a study monitor. 
All AEs not meeting the criteria for SAEs will be captured on the appropriate case report form 
(CRF). Information to be collected includes event description, time of onset, qualified medical 
professional’s assessment of severity, relationship to study product (assessed only by those with 
the training and authority to make a diagnosis), and time of resolution/stabilization of the event. 
All AEs occurring while on study must be documented appropriately regardless of relationship. 
All AEs will be followed to adequate resolution. 

 
 
31 
HALLO-P Protocol, Version 2.1 
7.3.2 Serious Adverse Event (SAE): Any adverse event that: 
 
Results in death 
 
Is life threatening, or places the participant at immediate risk of death from the event as it 
occurred 
 
Requires or prolongs hospitalization 
 
Causes persistent or significant disability or incapacity 
 
Is another condition which investigators judge to represent significant hazards 
 
7.3.3 Unanticipated Problem (UP): Any incident, experience, or outcome that meets all of the 
following criteria:  
 unexpected, in terms of nature, severity, or frequency, given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the study 
population;  
 related or possibly related to participation in the research (in this guidance document, 
possibly related means there is a reasonable possibility that the incident, experience, or 
outcome may have been caused by the procedures involved in the research);  
 suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized.  
7.3.4 Severity of Event 
All Adverse Events will be classified according to severity according to the following:  
• 
Mild: Awareness of signs or symptoms, but easily tolerated and are of minor irritant type 
causing no loss of time from normal activities. Symptoms do not require therapy or a medical 
evaluation; signs and symptoms are transient. 
• 
Moderate: Events that introduce a low level of inconvenience or concern to the participant 
and may interfere with daily activities but are usually improved by simple therapeutic measures; 
moderate experiences may cause some interference with functioning. 
• 
Severe: Events interrupt the participant’s normal daily activities and generally require 
systemic drug therapy or other treatment; they are usually incapacitating.  
7.3.5 Expectedness  
All AEs will be assessed as to whether they were expected to occur or unexpected, meaning not 
anticipated based on current knowledge found in the protocol and include:  
• Unexpected - nature or severity of the event is not consistent with information about the 
condition under study or intervention in the protocol, consent form, product brochure, or 
investigator brochure.  
• Expected - event is known to be associated with the intervention or condition under study.  
7.3.6 Relationship to Study Intervention 

 
 
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The study’s physician or medical officer will assess the relationship of all AEs to study 
intervention or study participation.  Based on clinical judgement and complete description of the 
event he will determine if the event is:  
• 
Definitely Related – The adverse event is clearly related to the investigational 
agent/procedure – i.e., an event that follows a reasonable temporal sequence from administration 
of the study intervention, follows a known or expected response pattern to the suspected 
intervention, that is confirmed by improvement on stopping and reappearance of the event on 
repeated exposure and that could not be reasonably explained by the known characteristics of the 
subject’s clinical state. 
• 
Possibly Related – An adverse event that follows a reasonable temporal sequence from 
administration of the study intervention follows a known or expected response pattern to the 
suspected intervention, but that could readily have been produced by a number of other factors. 
• 
Not Related – The adverse event is clearly not related to the investigational agent/procedure 
- i.e., another cause of the event is most plausible; and/or a clinically plausible temporal 
sequence is inconsistent with the onset of the event and the study intervention and/or a causal 
relationship is considered biologically implausible. 
7.4 Reporting Procedures 
Any major AE, i.e., any serious injury, including all SAEs, will be recorded and reported to the 
mPIs immediately after completing any and all actions that are necessary to protect the subject’s 
health and safety. Minor AEs will be recorded and reported to the PIs on at the regular PI 
meetings. A description of the event, and the date and location of the event will be recorded on 
the AE Reporting Form, which will be kept in the participant’s research file. The mPIs and the 
Study Physcian (Dr. Ard) will meet quarterly to review all reported events and these will be 
compiled and reported in aggregate to the DSMB. 
Within 48 hours of notification of any SAE that is unexpected and related (death within 24 
hours), the contact PI (Dr. Kritchevsky) will report the event to the WFSM Institutional Review 
Board (IRB), the NIH Program Officer and the Chair of the DSMB through channels specified 
by the NIH or its contractors.  
Any unanticipated problem involving risks to study participants or others will be reported within 
48 hours to the NIA and will be forwarded to OHRP within two weeks of the event. 
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE.  
Changes in the severity of an AE will be documented to allow an assessment of the duration of 
the event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
The study staff will record all reportable events with start dates occurring any time after 
informed consent is obtained until the last day of study participation, with follow-up of any 
active events.  At each study visit, the investigator will inquire about the occurrence of AE/SAEs 
since the last visit.  Events will be followed for outcome information until resolution or 
stabilization. 

 
 
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7.5 Safety Monitoring 
Safety will be monitored by an NIA appointed Data and Safety Monitoring Board (DSMB).  The 
DSMB will act in an advisory capacity to the NIA Director to monitor participant safety, data 
quality and progress of Nutritional Interventions Planning Project.  Meetings of the DSMB will 
be held regularly (e.g., every six to nine months) at the call of NIA or the DSMB Chair. The NIA 
staff will be present at every meeting. An emergency meeting of the DSMB may be called at any 
time by the Chair or the NIA, should participant safety questions or other unanticipated problems 
arise. 
DSMB meetings will consist of open, closed and optional executive sessions, all closed to the 
public because discussions may address confidential participant data. The study PI and key staff 
members, DSMB members and authorized NIA staff attend the open sessions. Discussions at 
these sessions focus on the review of the aggregate data, conduct and progress of the study, 
including participant accrual, protocol compliance, and problems encountered. Data by treatment 
group are not presented in the open session. 
 
The closed session will be attended by unmasked study staff, the DSMB members and the NIA 
PO or designee, but not by the NIA Project Scientist(s). The NIA PO attends the closed and open 
sessions as an observer, not as a DSMB member, to answer any policy or administrative 
questions the DSMB members may have. The primary objective of the closed sessions is to 
review data by study group. To ensure participants safety and well-being, DSMBs for NIA-
funded trials are usually required to review safety data by the actual treatment group. The timing 
of unmasking of the treatment groups is determined by the DSMB. In many instances, safety 
data could also be the outcome data. Therefore, the unmasked Boards no longer review and 
provide recommendations to NIA on any, but safety-related protocol changes. All other protocol 
modifications are subject to review by the masked working groups of the DSMBs. DSMBs’ 
working groups are appointed by NIA and provide their recommendations to NIA Director who 
makes decisions about whether to approve or decline proposed modifications.  
 
If necessary, an executive session may be requested by the DSMB and will be attended only by 
voting DSMB members. The NIA Program Officer or designee is not permitted to attend the 
executive sessions. 
8 
INTERVENTION DISCONTINUATION  
There are no specific events that would lead to intervention discontinuation.  
Participants may temporarily discontinue participation due to intercurrent illnesses.  In this case, 
participants will be asked to restart the intervention upon clearance from their primary care 
provider. 
Participants may withdraw voluntarily from participation in the study at any time and for any 
reason. Participants will continue to be followed, with their permission, even if the study 
intervention is discontinued. These participants will be invited to participate in the 6-month and 
9-month visits. 
Participant who drop from the study after randomization will not be replaced. 

 
 
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9 
STATISTICAL CONSIDERATIONS  
9.1 General Design Issues  
As suggested by multiple authors (106-108), the design and sample sizes for our HALLO pilot 
study have been chosen to focus on the feasibility of the design of the targeted full-scale study, 
rather than on power for hypothesis testing between groups. 
During the HALLO pilot, we target the enrollment of approximately 100 participants meeting the 
inclusion/exclusion criteria to one of three intervention arms 1) 20% CR delivered in-person; 2) 
20% CR delivered remotely via video conferencing; and 3) 8-hour TRE with ad libitum calorie 
intake for the first 3 waves (66pts) and the fourth wave will randomize ~24 pp to one of two 
intervention arms including 20% CR delivered remotely and 8-hour TRE groups. We anticipate 
randomizing 22:34:34 participants with fewer participants being in the in-person CR group since 
our group (and others) has more experience with that intervention. From those randomized, we 
anticipate approximately 20:30:30 participants to complete both pre-and post-measures at 9 
months.  Data from the enrollment process will be used to refine recruitment criteria, estimate 
recruitment yields, and test and refine intervention approaches. The pilot will inform three design 
benchmarks: a) The degree of sustained CR (Benchmark 1): CR > 10% at 9 months; b) TRE 
sustainability (Benchmark 2): At least 75% of participants eating within window on >80% of 
days; and c) Benchmark 3: Retention > 85% at 9 months.  
9.2 Sample Size and Randomization 
Sample sizes for each group in the pilot study were determined by focusing on the width of 90%, 
one-sided confidence intervals, as used previously for pilot projects (109). For Benchmark 1, 
the 20% CR interventions will be considered successful if the mean reduction in DLW-assessed 
weight-maintaining energy intake (EI) provides evidence that the %CR is >10% of the baseline 
mean (e.g., >200 kcal/day reduction from 2000 kcal/day). This level was chosen because it is 
approximately the lower end of the range of CR associated with benefits in animal models. Our 
primary outcome will be absolute rather than relative EI change to avoid the loss of efficiency 
and power from the direct modeling of ratio measures (110, 111). Analyses will be based on 
constrained, mixed linear models described in Section 9.5. The primary quantity of interest is 
whether each group’s least squares mean EI one-sided 90% lower confidence interval excludes 
the mean value for an average 10% reduction in caloric intake based on the mean baseline EI. 
Benchmark 1. Within the remote CR group with ~30 paired observation (i.e., 10% LTFU), and 
a conservative SD of 250 kcal/day for change in EI, as calculated from CALERIE, we project a 
90%, one-sided confidence intervals will have a lower bound excluding 200 kcal/day (a 10% 
reduction from a baseline mean of 2000 kcal/day) if we observe a 260 kcal/day or greater 
reduction (a 13% reduction).  In a case where the baseline mean intake is 2500 kcal/day, a 310 
kcal/day reduction (12.4%) would result in a confidence interval that excludes a 10% reduction 
in EI (112). With 20 evaluable participants in the in-person CR group, these percentages increase 
to 13.7% (for a baseline mean of 2000 kcal/day) and 13% (for a baseline mean of 2500 
kcal/day).  Note that these calculations assume the ICC capturing the dependence of change in EI 
resulting from group-based interventions is zero.  Should the ICC arising from group-based 
intervention delivery be large enough to inflate the variance of the within-group mean by as 
much as 10%, a slightly larger observed decrease in EI will be needed to rule out a 10% 

 
 
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reduction.  If the target is met for both CR groups, practical and economic considerations will be 
considered in developing the intervention for the larger trial.  
Benchmark 2.  We will estimate the proportion of individuals consuming calories within the 8-
hour window (+/- 30 min) on 80% of days (i.e., each participant will receive a yes/no 
categorization as to whether they consumed calories within the window on > 80% of days) based 
on participants’ self-report of first and last meal/snack times. If feasible, this calculation will also 
be performed using data from continuous glucose monitors. If ≥75% of individuals are compliant 
at this level, we consider it reasonable to consider that TRE within the window chosen could be 
sustained for a longer-term trial. With N=30 participants in this group, if the observed sample 
proportion is 87% or above, the lower bound on the Clopper-Pearson exact 90%, one-sided 
confidence interval will exclude retention values of 75% or below (112).  Here again, in the 
presence of a positive ICC for TRE 8-hour adherence, there will be an inflation in variance of the 
mean which will translate into needing observed sample proportions > 87% to exclude a value of 
75% or below. 
For Benchmark 3, we target ≥85% retention in each intervention group based on completion of 
the 9-month follow-up exam. If the observed sample proportion is 90% or higher (N=81/90), 
Clopper-Pearson exact 90%, one-sided confidence interval will exclude retention values of 85% 
or below.  In the presence of a large, positive ICC for dropout, there will be an inflation in 
variance of the mean which will translate into needing an observed proportion > 90% to exclude 
values of ~85% or below.  
9.2.1 Treatment Assignment Procedures 
The randomization protocol and the randomization process are prepared and executed by 
investigators from the Biostatistics and Design Team through the secure web-based data 
management system, so that eligibility is automatically confirmed, and records are current. The 
study statisticians have developed the randomization protocol to ensure that sufficient baseline 
and eligibility data are entered and validated before participants are randomized into the study.  
Randomization will be performed stratified on sex, and will use blocked randomizations.  
Recruitment will target equal numbers of men and women and 23% minority participation.  All 
study personnel, except for the Biostatistics Team will be blinded to the randomization table.  
We do not anticipate the need to break the randomization code with any urgency, but should it be 
necessary, it will be decided by the four PIs, with input from the NIH Project Officer. The Study 
Physician and/or Medical Safety Officer will review descriptions of safety events in an un-
blinded manner. 
9.3 Interim analyses and Stopping Rules 
No formal stopping rules are planned for this pilot study. Interim analyses on data quality and 
safety will be provided to the DSMB. Safety data will be provided by randomized group to the 
DSMB in a closed session. 
9.4 Outcomes  
9.4.1 Primary feasibility outcomes   
a) Degree of sustained CR (Benchmark 1): CR > 10% at 9 months;  

 
 
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HALLO-P Protocol, Version 2.1 
b) TRE sustainability (Benchmark 2): At least 75% of participants eating within window on 
>80% of days; and  
c) Retention of study participants (Benchmark 3): Retention > 85% at 9 months. 
9.4.2 Secondary outcomes   
Secondary  
 Body weight change assessed using home scales at baseline, 6 and 9 months 
 Changes in fat and lean body mass assessed by DXA at baseline and 9 months 
 Change in bone mineral density assessed by DXA at baseline and 9 months 
 Change in resting energy expenditure assessed by indirect calorimetry at baseline 
and 9 months 
 Change in physical activity energy expenditure assessed by ActivPAL at baseline 
and 9 months 
 Change in energy intake assessed at baseline and 9 months using doubly-labeled 
water 
 Change in total muscle mass at baseline and 9 months assessed by d3 creatine 
(d3cr) 
 Change in self-reported energy intake assessed using the ASA24 at baseline and 9 
months 
 Change in physical and cognitive function assessed at baseline and 9 months 
 Change in age-related biomarkers at baseline  and 9 months 
 
HALLO-P will also collect the following information to guide the design of a longer-
term study. 
 
HALLO-P Feasibility Benchmarks 
 Community Interest – Response rates to mailings and other outreach 
 Recruitment Yields – Ratio of initial contacts to randomizations 
 Participants with Inter-current Health Events – Health events that suspend 
intervention participation 
 Intervention Delivery Costs – fixed and variable costs associated with each 
intervention arm 
9.5 Data Analyses 
9.5.1 
Primary Feasibility Analyses. 
Our primary feasibility outcome (Benchmark 1) will be absolute rather than relative Energy 
Intake change to avoid the loss of efficiency and power that has been criticized relative to the 
direct modeling of ratio measures (110, 111). The primary analyses of DLW-based EI will use 
constrained mixed linear models (cLDA), with both baseline and follow-up values as model 
outcomes, to estimate within-group pre-post changes in EI, with group assignment as the primary 
variable of interest, adjusted for sex (113). We note that the constrained, linear mixed model is 
extremely flexible, constrains pre-randomization group means to be equal, allows for both intent-
to-treat analyses by including participants with incomplete data, and permits inclusion of random 
effects related to group-based interventions; the traditional ANCOVA can be shown to be one 
specific parameterization of this model.  Kenward et al. (114) note that with proper use of REML 

 
 
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HALLO-P Protocol, Version 2.1 
estimation, the constrained, mixed model and ANCOVA are equally efficient (115). Lu (2010) 
notes that for within group estimation, which is a focus of this pilot study analyses, the ability to 
include participants with partial data can have advantages relative to reducing bias due to 
missing data (113). 
From these models, the primary finding of interest is whether each group’s least squares mean EI 
one-sided 90% (80%) lower confidence interval excludes the mean value for an average 10% 
reduction in caloric intake at 9-months based on the mean baseline EI. In addition, using results 
from this model, we will estimate percent change in EI with a bootstrapped 90% (80%) one-
sided confidence interval to provide direct estimates of the relative reduction. Because 
participants are “grouped” for a component of each intervention, intra-class correlations will be 
estimated to characterize the dependence of response within intervention groups. Sensitivity 
analyses will be performed to determine how the width of confidence intervals may depend on 
the ICC and these analyses will be performed within all randomized groups. 
For Benchmark 2, we will use Clopper-Pearson 90% (80%), one-sided confidence intervals to 
provide a lower limit on the estimate of the proportion of individuals consuming calories within 
the 8-hour (+/- 30 min) window on 80% of days (i.e., each participant will receive a yes/no 
categorization as to whether they consumed calories within the window on > 80% of days) based 
on self-report. Marginal models for binary outcomes will also be used to explore the magnitude 
of the ICC for this outcome. This calculation will also be performed using proportion of days as 
a continuous outcome based on self-report or data from continuous glucose monitors (TRE 
group).  When considered a continuous outcome, methods identical to those outlined for 
Benchmark 1 can be used. 
For Benchmark 3, the primary outcome will be the proportion of participants that complete the 
9-month follow-up exam. As for Benchmark 2, Clopper-Pearson exact 90%, one-sided 
confidence intervals will be used to put lower limits on these estimates. Marginal models for 
binary outcomes will also be used to explore the magnitude of the ICC for this outcome. 
Supporting analyses will also be carried out within subgroups defined by sex and race/ethnicity.   
9.5.2 
Analysis of Secondary Outcomes 
The secondary outcomes listed in Section 9.4.2 have continuous distributions. Accordingly, we 
will use linear, mixed effects models to explore both between and within-group effects. 
Longitudinal trends will be investigated for measures such as: in-home body weights, patterns 
CGM, self-reported daily energy intake, and steps per day. Other important secondary analyses 
will focus on daily access to the intervention app and trajectories of adherence and engagement 
in the app as it relates to change in body weight and biomarker endpoints. Residuals will be 
examined for each outcome and should distributions be deemed not to be normal, appropriate 
transformations to normality will be sought.  
9.5.3 
Safety Analyses.  
In general, between-group differences in the proportion of participants with AEs will be 
compared between groups using either chi-square or Exact Tests (when expected cell counts are 
small). The proportion of participants with other adverse experiences are estimated within 
intervention groups and expressed as relative effects via risk ratios (95% CIs), or as absolute 
effects (95% CIs) for between-treatment differences in proportions. Continuous safety measures 

 
 
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HALLO-P Protocol, Version 2.1 
will be compared among groups using analysis of variance and 95% CIs. Withdrawals due to 
SAEs will be summarized by MedDRA code by intervention group. 
The exact presentation of analysis results for safety are developed in collaboration with the 
DSMB. No adjustment for multiplicity is planned for pre-specified safety endpoints. 
 
9.5.4.   Other analyses helpful in planning future longer term studies. 
Additional exploratory analyses will use a variety of analytical techniques to examine: (a) the 
distribution of changes over time in potential outcomes that may be used as part of a composite 
outcome in the larger study, (b) how adherence characteristics of TRE are associated with weight 
change, (c) agreement and potential biases between energy intake targets obtained by initially 
estimating energy intake necessary for a 20% CR through use of DLW versus based upon using 
REE and an activity level factor specific to sedentary older adults (or based on observed baseline 
ActivPAL data) (d) associations between actual weights and expected weights based on the  
trajectory-based model of the relationship of weight loss to energy intake restriction, and factors 
associated with discrepancies, and (e) measurement properties (e.g., test-retest reliability, 
variability in time-course within controls) of selected biomarkers (e.g., of IL6, CRP, TNFR1, 
Cystatin C, insulin levels). 
10 
DATA COLLECTION AND QUALITY ASSURANCE 
10.1 Data Collection Forms 
Data on eligibility, study outcomes and other clinical assessments will be collected by the 
clinical research staff of the Sticht Center for Health Aging and Alzheimer’s Prevention as 
overseen by the clinical research team. This staff will be blinded to group assignments. Data 
collection forms can be found in the study MOP. Participant contact information and other PHI 
will be stored in a secure location that is separate from study data. 
10.2 Data Management  
HALLO-P will use the World Wide Web to enter participant data.  
10.2.1 
Clinical Site Responsibilities. The single clinical site will maintain appropriate medical 
and research records for this study, in compliance with federal regulatory and institutional 
requirements for the protection of confidentiality of participants. The clinical site will also 
maintain documentation that all members of the research team have completed training 
requirements.  Data collection is the responsibility of the clinical site staff under the supervision 
of Dr. Nicklas, who will be responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
Data are collected in multiple ways at all participant contacts, including electronic CRFs (eCRF) 
or hard copy CRFs, mHealth app, and automatically generated device data. Clinical site staff are 
expected to review hard copy CRFs for accuracy and completeness and resolve any data issues 
prior to data entry. Clinical data (including AEs, concomitant medications) are entered into the 
website, a 21 CFR Part 11-compliant data capture system. Each clinical site staff member is 

 
 
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HALLO-P Protocol, Version 2.1 
authorized before being given a username, password, and staff ID to use the data system on the 
website. 
10.2.2 
Biostatistics and Design Team Responsibilities. During data entry, a variety of 
programmed error checks are performed for key variables, such as automatic range checks and 
logical consistency checks, to identify data that are inconsistent, incomplete, or inaccurate. When 
these edit checks fail, data may be flagged for further review or prevented from becoming part of 
the study database. At regular intervals, data queries are carried out on the computerized 
databases to perform consistency checks on key variables and other data. Metadata of the date, 
person, programmed edit check results, as well as the creation, modification, deletion, transfer, 
aggregation, and derivation of data are collected and documented. 
Clinical site-generated measurements utilizing instrumentation (e.g., wearable devices measuring 
activity or glucose levels) will be transmitted to the Data Management Team through 
Application Programmer Interfaces (APIs). Metadata from these devices is captured and each 
data type is evaluated for proper storage. Data are archived through the end of the study and/or as 
required by local and national regulations. 
Data security in the web-based data system uses 2048-bit encryption and SSL. Once data are 
received, recovery from disasters such as natural phenomenon (water, fire, or electrical) is 
possible through the ability to reconstruct both the database management system and the data up 
to the last back-up using nightly backups. This process ensures optimal recovery of data systems 
in the event of a disaster. 
Access to the website, privileges to various areas of the website, and to the data on the website is 
managed by the Biostatistics and Data Management Project Managers in consultation with the 
clinical site coordinator. 
Confidentiality of information is protected through a variety of procedures and facilities: 
1. The confidential nature of the data collected, processed, and stored is explained to all new 
personnel. 
2. All access to office space containing data is controlled through a single door, which is 
locked and only accessible by key or security badge. 
3. All participant data are encrypted as described above. 
4. All participant data stored on the WFBMC computers are likewise encrypted. In addition, 
all such databases are protected by passwords that must be supplied before the data can 
be accessed. Passwords are released only to Biostatistics and Data Management Team 
staff with a need to use the particular file and are changed on a regular schedule. 
5. All printouts, plots, and reports containing individually identifiable data are produced on 
printers and plotters within the Biostatistics and Data Management Team secure office 
space. 
PHI such as participant name, addresses, contact information and other identifiers of concern, if 
collected and data entered, are securely stored separately from the main clinical data on eCRFs. 
Access to these data is limited to a few primary people in the Biostatistics and Design Team and 
only the PID number connects these data, if required. 

 
 
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HALLO-P Protocol, Version 2.1 
Documents pertaining to the study will be maintained for at least until 5 years after the final visit 
of the last HALLO-P participant. 
10.3  Quality Assurance  
10.3.1. Training 
Study training will entail didactic and hands-on training. All study staff will be required to read 
the protocol, the informed consent form and the study manual of procedures. In a series of 
didactic sessions, the study investigators will explain the rationale of the study, provide an 
overview of study procedures and measurements, and discuss how to identify and report adverse 
events. The training will also include a discussion of the ethical conduct of research and the 
primacy of safety and privacy of study participants. Trainees take a test to make sure the most 
important training points are retained.    
Following this session senior Sticht Center for Health Aging and Alzheimer’s prevention staff 
will demonstrate specific study procedures, ask the staff to practice these procedures, and then 
observe and certify the examiner on the proper conduct of the measurement and procedure.  
Study staff will run through practice visits with non-study volunteers to gain experience with 
each assessment.    
The interventionist will be trained under the supervision of Dr. Jack Rejeski and Dr. Jason 
Fanning. 
10.3.2 Metrics 
Quality will be monitored by evaluating missing data on study forms and tracking the percent of 
visits that are within protocol-specified windows. 
10.3.3 Protocol Deviations 
Protocol deviations will be identified in several ways: staff report, missing data on study forms, 
and documentation of missed, or out-of-window visits.  The investigators will identify whether 
the deviation could have been prevented and discuss potential protocol or procedure changes 
with the Steering Committee. These deviations and pursuant protocol changes will be described 
in written communications with both the IRB and the DSMB. 
10.3.4 Monitoring 
Monitoring for data completeness will be tracked by the data management system. Senior staff 
will periodically review study binders to make sure informed consent has been appropriately 
obtained and documented.   
11 
PARTICIPANT RIGHTS AND CONFIDENTIALITY  
11.1 Institutional Review Board (IRB) Review 
This protocol and the informed consent document and any subsequent modifications will be 
reviewed and approved by the IRB and study DSMB.  

 
 
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HALLO-P Protocol, Version 2.1 
11.2 Informed Consent Forms    
Participants who are eligible after the phone screen will be scheduled for an in-person screening 
visit.  A trained study examiner will obtain full study consent as the first part of the visit. 
Consent forms will be Institutional Review Board (IRB)-approved and the participant will be 
asked to read and review the document.  The examiner will describe the study and the 
requirements for participation, review the informed consent form in detail with the participant, 
and address any participant questions.   A verbal explanation will be provided in terms suited to 
the participant’s comprehension of the purposes, procedures, and potential risks of the study and 
of their rights as research participants.  Participants will be informed that participation is 
voluntary and that they may withdraw from the study at any time, without prejudice, and that the 
quality of their medical care will not be adversely affected if they decline to participate in this 
study. Participants will have the opportunity to carefully review the written consent form and ask 
questions prior to signing. The participants will be given a copy of the ICF so that they may 
discuss the study with their family or surrogates or think about it prior to agreeing to participate. 
The informed consent process will be conducted and documented in the source document 
(including the date), and the form signed, before the participant undergoes any study-specific 
procedures. A copy of the signed informed consent document will be given to the participants for 
their records. 
11.3 Participant Confidentiality 
Any data, specimens, forms, reports, video recordings, and other records that leave the site will 
be identified only by a participant identification number (PID) to maintain confidentiality. All 
written records will be kept in locked file cabinets. All electronic data will be housed in 
password protected files with access limited to only study personnel. All computer entry and 
networking programs will be done using PIDs only. Identifiable information will not be released 
without written permission of the participant, except as necessary for monitoring by IRB, the 
NIA, and the OHRP. 
11.4 Study Discontinuation  
Given the short duration of the intervention and the low inherent risk of the intervention, there 
are no statistical rules that would lead to an early termination of the study. The study may be 
discontinued at any time by the IRB, the NIA, the OHRP, or other government agencies as part 
of their duties to ensure that research participants are protected.  
12 
ETHICAL CONSIDERATIONS 
The HALLO-P study will be conducted following the principles guiding human clinical research 
as laid out in the Belmont Report, the Declaration of Helsinki and aligned with the 7 specific 
tenets promulgated by NIH’s own Clinical Research Center 1) HALLO-P has social and clinical 
value providing important information to fully understand the implications of CR in older adults.  
2) It will be conducted with high rigor to yield scientifically valid results. 3) It will fairly select 
subjects in a way that aligns with the goals of the study.  4) The study has a favorable risk to 
benefit ratio. The risks of participation are low, and the participants will be coached in ways to 
eat more healthfully and be more active. 5) Study activities will be independently reviewed by an 
NIA appointed Data and Safety Monitoring Board. 6) We will provide a complete description of 

 
 
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HALLO-P Protocol, Version 2.1 
the study so that participant volunteers will be informed about what their participation would 
entail, and to make clear that their participation is entirely voluntary. 7) Potential and enrolled 
participants will be fully respected by keeping their information confidential, respecting their 
right to change their mind about participation without penalty, inform them of new information 
that might change their assessment of risks and benefits of participation, monitoring their welfare 
and adverse events to ensure appropriate medical responses, and to ensure that the safety of their 
continued participation, and providing a summary of results to participants after the study’s 
completion. 
13 
COMMITTEES 
 
The above diagram shows the HALLO-P study organization. The roles and responsibilities of the 
committees / teams are: 
 
Executive Committee:  This Committee is comprised of the four mPIs and the NIA 
representatives and is responsible for the coordination and overall progress of the Wake Project, 
budgetary issues and reallocations and sets the Agenda for the Steering Committee. 
 
Steering Committee: The Executive Committee and the members of all work teams comprise 
the Steering Committee which is responsible for coordinating all aspects of the HALLO-P 
project, and discusses and approves protocol changes, ancillary study proposals, publications and 
presentation activities, feedback from oversight and regulatory bodies. Each paid investigator 
and the NIA scientific officer each have one vote if a decision cannot be made by consensus. 
 
U01 Liaison Committee: This committee is a forum for the Wake and Pennington projects to 
compare progress, align measures and technologies.  
 

 
 
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HALLO-P Protocol, Version 2.1 
Scientific Advisory Board: This Board is made up of scientists external to the HALLO-P. It is 
advisory to the Executive Committee and gives advice on the scientific aspects of the study as 
well as serving to identify opportunities for improving the conduct and scientific impact of the 
study.   
 
Data and Safety Monitoring Board: The DSMB is advisory to the NIA which is responsible 
for its constitution.  It provides the NIA feedback on the conduct of the study, participant safety 
and burden.  
Administrative / Geroscience Team: This team is responsible for the administrative and 
regulatory aspects of HALLO-P including the preparation of budgets, correspondence with the 
NIA, arranging meetings, and interactions with the IRB and DSMB.  It is also responsible for the 
Geroscience aspects of the study including formulating a biobanking and specimen collection 
strategy, and selecting, measuring and interpreting biomarker results from the study. 
 
Intervention Development Team: This team is responsible for the development and 
implementation of HALLO-P's behavioral interventions. 
 
Biostatistics and Design Team: This team oversees the development of data collection / 
management systems for the study, and the analysis and interpretation of study data. 
 
Clinical Research Team: This team is responsible for the recruitment and management of study 
participants, and the collection of participant data related to eligibility, safety and study 
outcomes. 
 
14 
PUBLICATION OF RESEARCH FINDINGS 
Publication of the results of this trial will be governed by the policies and procedures developed 
by the Steering Committee.  All publications include an acknowledgement of the supporting 
grants including U01 AG073240 along with administrative supplements including one from the 
National Cancer Institute, UL TR001420 and P30 AG021332.  
15 
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16 
APPENDICES  
A. Abbreviations Used 
B. Protocol Updates / Revisions 
Appendix A. Abbreviations Used 
 
AE - Adverse Event 
ACD – Acid Citrate Dextrose 
ADL – Activity of Daily Living  
ALS – Amyotrophic Lateral Sclerosis / Lou Gehrig’s disease 
ALT – Alanine Transaminase 
AMPK - AMP-activated protein kinase 
ANCOVA - Analysis of Covariance 
API – Application Programming Interface 
App - Application  
ASA24 – Automated Self-Administered 24-hour Dietary Assessment Tool 
BEDS-7 – Binge Eating Disorder Screener – 7 
BMD – Body Mineral Density 
BMI – Body Mass Index 
BP – Blood Pressure 
BV1 – Baseline Visit 1 
BV2 – Baseline Visit 2 
CALERIE – Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy 
CBC – Complete Blood Count 
CES-D – Center for Epidemiologic Studies Depression Scale 

 
 
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CFR – Code of federal Regulations 
CGM – Continuous Glucose Monitoring 
CI – Confidence Interval 
CLIP- Cooperating Lifestyle Intervention Program 
cm – Centimeter 
CMP – Comprehensive Metabolic Panel 
CO2 – Carbon Dioxide 
COPD – Chronic Obstructive Pulmonary Disease 
CPT – Cell Preparation Tube 
CR – Caloric Restriction  
CRF – Case Report Form 
CRP – C-Reactive Protein 
CRU – Clinical Research Unit 
d – Day 
dL – Deciliter 
DLW – Doubly-Labeled Water 
DNA – Deoxyribonucleic Acid 
DSE- Education Program 
DSMB – Data and Safety Monitoring Board 
DXA- Dual-energy X-ray absorptiometry 
eCRF – Electronic Case Report Form 
EDTA – Ethylenediaminetetraacetic acid 
e.g. – Exempli Gratia (for example)  
eGFR – Estimated Glomerular Filtration Rate 
EI – Energy Intake  
EMA – Ecological Momentary Assessment 
eSPPB  - Expanded Short Physical Performance Battery 
FACIT – Functional Assessment of Chronic Illness Therapy 
FV1 – Follow-up visit 1 (~ 6 mos) 
FV2 – Follow-up visit 2 (~ 9 mos) 
FV3 – Follow-up visit 3 (~ 9 mos) 

 
 
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g – Gram 
h – Hour 
H – Hydrogen 
H2O – Water 
HALLO-P - Health, Aging and Later-Life Outcomes Pilot Trial  
Hb – Hemoglobin 
HbA1c – Hemoglobin A1c 
HIPAA – Health Insurance Portability and Accountability Act 
HMR – Health Management Resources Caloric System© 
ICC – Intraclass Correlation Coefficient 
ICF – Informed Consent Form 
IIS- Insulin-like growth factor-1 signaling 
Il6 – Interleukin 6 
ILI – Intensive weight loss and exercise 
INFINITE – Investigating Fitness Interventions in the Elderly  
IRB – Institutional Review Board 
IU – International Units 
kcal – Kilocalorie 
kg – Kilogram 
Look AHEAD – Look Action for Health in Diabetes Study 
LTFU – Lost to Follow-up 
m – Meter 
MedDRA – Medical Dictionary for Regulatory Activities 
ml – Milliliter 
mg – Milligram 
MI- Myocardial Infarction 
mins – Minutes 
mmHg – Millimeters of Mercury 
MoCA – Montreal Cognitive Assessment Tool  
MOP – Manual of Procedures 
mPI – Multiple Principal Investigator 

 
 
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MS – Multiple Sclerosis 
mTOR – Mammalian target of Rapamycin  
NAD+ - Nicotinamide adenine dinucleotide 
NC – North Carolina 
NCI - National Cancer Institute 
NIA – National Institute on Aging 
NIH – National Institutes of Health 
OHRP – Office for Human Research Protections 
PAD – Peripheral Arterial Disease 
PAEE – Physical Activity Energy Expenditure 
PHI – Protected Health Information 
PI – Principal Investigator 
PID – Participant Identification (Number) 
PO –Program Officer 
PROMIS – Patient-Reported Outcomes Measurement Information System 
RD – Registered Dietitian 
REE – Resting Energy Expenditure 
REML – Restricted Maximum Likelihood 
RNA – Ribonucleic Acid 
SAE –Serious Adverse Event 
SD - Standard Deviation 
SF-36 – Short Form 36-item Health Survey 
SPPB – Short Physical Performance Battery 
SSL – Secure Sockets Layer 
SV1 – Screening Visit 1 
SV2 – Screening Visit 2 
TBSP – Tablespoon 
TEE – Total Energy Expenditure 
TNFRI – Tumor Necrosis Factor Soluble Receptor I 
TRE- Time Restricted Eating 
TSH – Thyroid Stimulating Hormone 

 
 
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tv – Television 
uIU/mL – Micro-international Units per Milliliter 
UP – Unanticipated Problem 
VITAL – Volunteers in Touch With Aging and Life 
WF – Wake Forest 
WFBMC – Wake Forest Baptist Medical Center 
wks – Weeks 
yrs - Years 
Appendix B. Protocol Updates / Revisions 
 
Version Number: 2.1 
Version Date: 11/30/2023 
Summary of Revisions Made: 
 Removed Jamie Justice as a CoI as she is no longer at Wake Forest. 
 Added the National Cancer Institute as a sponsor from recent administrative supplement.  
 Added the online Siteman Cancer Center risk assessment, cancer screening questionnaire 
and expanded biomarker panel at baseline and 6mo as requested by the NCI. 
 
Version Number: 2.0 
Version Date: 7/17/2023 
Summary of Revisions Made: 
 Reduced sample size from 120 to approximately 100.  
 Discontinued the in-person CR group for the last wave and updated the statistical 
considerations as applicable.  
 
Version Number: 1.9 
Version Date: 5/3/2023 
Summary of Revisions Made: 
 Further expanded the BMI range from 27 - < 37 kg/m2 to 27 - <40 kg/m2. 
 Revised the 5% weight change to 3 months instead of 6 months.   
 Clarified how night eating is addressed and added in correct reference.  
 Revised one-on-one intervention sessions to be in person, by phone or by video to allow 
for flexibility.  
 
Version Number: 1.8 
Version Date: 2/2/2023 
Summary of Revisions Made: 
 Added CPT tubes as an option for whole blood collection.  
 
Version Number: 1.7 
Version Date: 1/3/2023 

 
 
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Summary of Revisions Made: 
 Updated the run-in to include a paper log instead of tracking using the fitbit app.  
 Revised the CGM collection to only 2 time points at ~3 and ~8 months. 
 Updated the visit window of the 9 month follow-ups to occur after 34-40 weeks of 
intervention instead of 36-40. 
 Updated the exclusion criteria for Osteoporosis to also include the femoral neck (t-score 
≤ -2.5 on total hip and/or femoral neck scan) 
 Revised the timing of the EMA assessments to occur 1 week out of months 1, 4 and 7 
instead of the first week of every month 
 
Version Number: 1.6 
Version Date: 11/29/2022 
Summary of Revisions Made: 
 Expanded the BMI range from 27 - < 35 kg/m2 to 27 - <37 kg/m2.  
 Revised that randomization can occur after the participant arrives for the BV2 visit and 
doesn’t need to complete the visit first.  
 
Version Number: 1.5 
Version Date: 9/22/2022 
Summary of Revisions Made: 
 Modified how randomizations will occur being blocked randomizations stratified by sex 
instead of a permuted block scheme with blocks of various sizes. 
 Changed the amount of time from 3 months to 4 weeks to wait before enrolling someone 
who had Covid, the flu or other acute respiratory illness. 
 
Version Number: 1.4 
Version Date: 8/19/2022 
Summary of Revisions Made: 
 Removed the use of home scales for weights at baseline, 6 and 9 month  
 Removed 6 month biomarkers from the secondary outcomes as blood will be banked but 
no planned biomarkers at that visit.  
 Modified how the ActivPal data will be reviewed at baseline averaging all days, not just 
5-7 days 
 Modified the inclusion/exclusion criteria to reduce the amount of time participants need 
to already be eating/drinking during the day from 12 to 11 to help aid in recruitment and 
other updates to further clarify the criteria.  
 Updated the participants receiving a paper log at SV2 to track their start and stop times of 
eating and drinking and that participants should email this log on day 7 to help study staff 
determine eligibility prior to the visit.  
 Added 2 new sleep questionnaires (STOP and Epworth) to BV1 and FV2. 
 Updated the EMA assessment from Hunger, Cravings, Affect, and Sleep to Hunger, 
Desire to eat and Anxiety 
 Minor editorial changes throughout.  
 
 

 
 
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HALLO-P Protocol, Version 2.1 
Version Number: 1.3 
Version Date: 7/13/2022 
Summary of Revisions Made: 
 Added TSH and tube for blood for biomarker QC to SV1 labs and TSH to FV2 
 Removed congenital birth defects as possible SAE 
 
Version Number: 1.2 
Version Date: 5/16/2022 
Summary of Revisions Made: 
 Provided clarification regarding the 20% increase in step count from baseline throughout 
the document 
 Removed Daniel Beavers as a Co-I and add Fang Chi Hsu as his replacement. 
 Removed DXA and ASA from the 6 month visit outcomes, assessment table and visit 
descriptions.  
 Revised the inclusion/exclusion criteria to be more inclusive; main changes include:  
o Use of regular cane is ok, quad cane or walker is not.  
o Revised that persons with type 2 diabetes can participate as long as they’ve been 
diagnosed at least one year and their HbA1c is <7.5% and not on insulin or any 
medication that could interfere with study. Anyone presenting with a HbA1c of 
>6.5% and not already diagnosed as a diabetic will be excluded.  
o Removed multiple psychiatric exclusions but will continue to screen for 
depression at screening.  
o Removed “Evidence of severely disturbed sleep/wake cycle”  
o Revised the anemia cutoff to <11 g/dL for both men and women.  
 Updated the assessment table to accurately reflect assessment of medication updates, 
health status changes and common signs and symptoms and described the collection and 
reporting of each in the applicable adverse event section.  
 Updating the timing of the DLW measurement from 9-12 days to 10-15 days to allow for 
more flexibility around scheduling visits 
 Updated the amount of blood being collected and stored as its less than originally 
planned.  
 Updated one of the questionnaires from the Barriers Self-Efficacy to Walking Self-
Efficacy. 
 Added a night eating assessment at baseline visit 1. 
 Provided an update on the Safety Monitoring now that we have a DSMB charter and 
removed the names of committee members at the request of the NIA. The study 
organization chart was revised and the DSMB listing was removed. 
 Minor editorial changes throughout.   
 
Version Number: 1.1 
Version Date: 4/4/2022 
Summary of Revisions Made:   
 Added d3 creatine dilution protocol at baseline and 9 months to assess change in total 
muscle mass. Added to secondary outcomes, assessment table, visit details and associated 
references.  

 
 
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 Removed the use of prepared meals for the first 3 weeks of intervention. There were a 
number of logistical concerns we couldn’t work out with the metabolic kitchen so instead 
during the first three weeks of the intervention, the RD will spend significant time 
reviewing and providing hands-on experience with both portion control and 
planning/preparation of meals. 
 Revised the target to aim to recruit up to 50% men, with the expectation we will likely 
enroll between 35%-45% based on our demographics.  
 Updated section 6.1 Schedule of Evaluations to note when the health status form (adverse 
event query) will be administered to avoid duplicate reporting between blinded and 
unblinded assessors.  
 Removed PAEE (ActivPAL) assessment at 6 month visit as it was only intended to be 
done at baseline and follow-up. 
 Moved the physical performance testing from BV1 and FV2 visits to BV2 and FV3 visits 
to avoid activity during the DLW initial collection and to fill time during the follow-up 
visits to allow enough time for 2 urine collections at BV2 and FV3.  
 Reordered the listing of some of the assessments to fall in line with the order of 
preference, especially for the fasting visits.  
 Added that we may contact participants roughly one year after the end of their 
participation to ask if their weight but will be optional and not considered outcome data. 
 Minor editorial changes throughout.